Rule: Food For Human Consumption: Current Good Manufacturing Practice&#8212 Dietary Supplements Manufacturing, Packaging, Labeling, or Holding Operations

Monday,
June 25, 2007
Part II
Department of
Health and Human
Services
Food and Drug Administration
21 CFR Part 111

Current Good Manufacturing Practice in
Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary
Supplements; Final Rule
Petition To Request an Exemption From
100 Percent Identity Testing of Dietary
Ingredients; Interim Final Rule
sroberts on PROD1PC70 with RULES
VerDate Aug<31>2005 20:59 Jun 22, 2007 Jkt 211001 PO 00000 Frm 00001 Fmt 4717 Sfmt 4717 E:\FR\FM\25JNR2.SGM 25JNR2
34752 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations
DEPARTMENT OF HEALTH AND 1. Overview (Proposed § 111.2)

HUMAN SERVICES 2. Written Procedures That Are 2. ‘‘Exclusions’’ (Proposed § 111.6)
Required by This Final Rule VII. Comments on Personnel (Final
Food and Drug Administration 3. Written Procedures That Are Not Subpart B)
Required by This Final Rule A. Organization of Final Subpart B
21 CFR Part 111 D. Other Comments on Written B. Highlights of Changes to the
[Docket No. 1996N–0417] (formerly Docket
Procedures Proposed Requirements for
No. 96N–0417) E. What Other General Comments Did Personnel
We Receive? 1. Revisions
RIN 0910–AB88 V. What Legal Authority Comments Did 2. Changes After Considering
We Receive? Comments
Current Good Manufacturing Practice A. Modeled After CGMP for Food C. General Comments on Proposed
in Manufacturing, Packaging, Labeling, B. Records Authority Subpart B
or Holding Operations for Dietary C. Public Health Service Act D. What Are the Requirements Under
Supplements Authority This Subpart for Written
AGENCY: Food and Drug Administration, 1. The Communicable Disease Risk Procedures? (Final § 111.8)
HHS. Posed by Dietary Supplements E. What Requirements Apply for
ACTION: Final rule. 2. Activities For Which We Are Preventing Microbial
Asserting Legal Authority Under Contamination From Sick or
SUMMARY: The Food and Drug the PHS Act Infected Personnel and for Hygienic
Administration (FDA) is issuing a final D. The Interstate Commerce Nexus for Practices? (Final § 111.10)
rule regarding current good the Final Rule 1. Final § 111.10(a)
manufacturing practice (CGMP) for 1. The PHS Act 2. Final § 111.10(b)
dietary supplements. The final rule 2. The Act F. What Personnel Qualification
establishes the minimum CGMPs 3. Commerce Clause Requirements Apply? (Final
necessary for activities related to E. Fifth Amendment § 111.12)
manufacturing, packaging, labeling, or F. Miscellaneous G. What Supervisor Requirements
holding dietary supplements to ensure VI. What Comments Did We Receive on Apply? (Final § 111.13)
the quality of the dietary supplement. the General Provisions? (Subpart A) H. Under This Subpart, What Records
The final rule is one of many actions A. Organization of Final Subpart A Must You Make and Keep? (Final
related to dietary supplements that we B. Who Is Subject to This Part? (Final § 111.14)
are taking to promote and protect the § 111.1) VIII. Comments on Physical Plant and
public health. C. What Definitions Apply to This Grounds (Final Subpart C)
Part? (Final § 111.3) A. Organization of Final Subpart C
DATES: This rule is effective August 24,
1. Actual Yield B. Highlights of Changes to the
2007. 2. Batch
Compliance Dates: The compliance Proposed Requirements for Physical
3. Batch Number, Lot Number, or Plant and Grounds
date is June 25, 2008; except that for Control Number 1. Revisions
businesses employing fewer than 500, 4. Component 2. Changes After Considering
but 20 or more full-time equivalent 5. Contact Surface Comments
employees, the compliance date is June 6. Ingredient C. General Comments on Proposed
25, 2009; and except that for businesses 7. In-Process Material Subpart C
that employ fewer than 20 full-time 8. Lot D. What Sanitation Requirements
equivalent employees, the compliance 9. Microorganisms Apply to Your Physical Plant and
date is June 25, 2010. 10. Must Grounds? (Final § 111.15)
FOR FURTHER INFORMATION CONTACT: 11. Pest 1. Final § 111.15(a)
Vasilios H. Frankos, Center for Food 12. Physical Plant 2. Final § 111.15(b)(1)
Safety and Applied Nutrition (HFS– 13. Product Complaint 3. Final § 111.15(c)
810), Food and Drug Administration, 14. Quality 4. Final § 111.15(d)
5100 Paint Branch Pkwy., College Park, 15. Quality Control 5. Final § 111.15(e)
MD 20740, 301–436–1696. 16. Quality Control Personnel 6. Final § 111.15(f)
SUPPLEMENTARY INFORMATION: 17. Representative Sample 7. Final § 111.15(g)
18. Reprocessing 8. Final § 111.15(h)
Table of Contents 19. Reserve Sample 9. Final § 111.15(i)
I. Background and Related Information 20. Sanitize 10. Final § 111.15(j)
II. How is the Final Rule Organized? 21. Theoretical Yield 11. Final § 111.15(k)
III. What Does the Final Rule Do? 22. Water Activity E. What Are the Requirements Under
A. Overview of CGMP 23. We This Subpart for Written
B. Highlights of the Final Rule 24. You Procedures? (Final § 111.16)
IV. What General Comments Did We 25. What Other Terms Did the F. What Design and Construction
Receive? Comments Want Defined? Requirements Apply to Your
A. What Comments Did We Receive 26. What Definitions Did the Physical Plant? (Final § 111.20)
on the Structure and Organization Comments Want Us to Delete? 1. Final § 111.20(a) and (b)
of the Rule? D. Do Other Statutory Provisions and 2. Final § 111.20(c)
B. What Comments Did We Receive Regulations Apply? (Final § 111.5) 3. Final § 111.20(d)
on the Need for Dietary Supplement E. What Sections Did We Remove 4. Final § 111.20(e)
CGMP Requirements? From the Rule, and Why? 5. Final § 111.20(f)
C. What Comments Did We Receive 1. ‘‘What Are These Regulations 6. Final § 111.20(g)
on Written Procedures? Intended to Accomplish?’’ 7. Final § 111.20(h)
Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34753
G. Under This Subpart, What Records 1. Final § 111.70(a) Control Operations

Must You Make and Keep? (Final 2. Final § 111.70(b) 1. Revisions
§ 111.23) 3. Final § 111.70(c) 2. Changes Associated With the
IX. Comments on Requirements Related 4. Final § 111.70(d) Reorganization
to Equipment and Utensils (Subpart D) 5. Final § 111.70(e) 3. Changes After Considering
A. Organization of Final Subpart D 6. Final § 111.70(f) Comments
B. Highlights of Changes to the 7. Final § 111.70(g) C. General Comments on Proposed
Proposed Requirements for H. What is Your Responsibility for § 111.37 (Final Subpart F)
Equipment and Utensils Determining Whether Established D. What Are the Requirements Under
1. Revisions Specifications Are Met? (Final This Subpart for Written
2. Revisions Associated With the § 111.73) Procedures? (Final § 111.103)
Reorganization I. What Must You Do to Determine E. What Must Quality Control
3. Changes After Considering Whether Specifications Are Met? Personnel Do? (Final § 111.105)
Comments (Final § 111.75) 1. Final § 111.105(a)
C. General Comments on Proposed 1. Final § 111.75(a) 2. Final § 111.105(b), (c), (d), and (e)
Subpart D 2. Final § 111.75(b) 3. Final § 111.105(f)
D. What Are the Requirements Under 3. Final § 111.75(c) and (d) 4. Final § 111.105(g)
This Subpart for Written 4. Final § 111.75(e) 5. Final § 111.105(h)
Procedures? (Final § 111.25) 5. Final § 111.75(f) 6. Final § 111.105(i)
E. What Requirements Apply to the 6. Final § 111.75(g) F. What Quality Control Operations
Equipment and Utensils That You 7. Final § 111.75(h) Are Required for Laboratory
Use? (Final § 111.27) 8. Final § 111.75(i) Operations Associated With the
1. Final 111.27(a) J. What Must You Do if Established Production and Process Control
2. Final § 111.27(b) Specifications Are Not Met? (Final System? (Final § 111.110)
3. Final § 111.27(c) § 111.77) 1. Final § 111.110(a)
4. Final § 111.27(d) 1. Final § 111.77 2. Final § 111.110(b)
F. Reorganization of Certain 2. Final § 111.77(a) 3. Final § 111.110(c)
Paragraphs in Proposed § 111.25 3. Final § 111.77(b) G. What Quality Control Operations
G. What Requirements Apply to 4. Final § 111.77(c) Are Required for a Material Review
Automated, Mechanical, or K. Comments on Shelf Life and Disposition Decision? (Final
Electronic Equipment? (Final L. What Representative Samples Must § 111.113)
§ 111.30) You Collect? (Final § 111.80) 1. Final § 111.113(a)
1. Comments on the Organization and 1. Final § 111.80(a) 2. Final § 111.113(b)
Framework of Proposed § 111.30 2. Final § 111.80(b) 3. Final § 111.113(c)
2. Comments Specific to Proposed 3. Final § 111.80(c) H. What Quality Control Operations
§ 111.30 4. Final § 111.80(d) Are Required for Equipment,
3. Reorganization of Certain 5. Final § 111.80(e) Instruments, and Controls? (Final
Paragraphs in Proposed § 111.30 M. What Are the Requirements for § 111.117)
H. Under This Subpart, What Records Reserve Samples? (Final § 111.83) 1. Final § 111.117(a) through (c)
Must You Make and Keep? (Final 1. Final § 111.83(a) 2. Final § 111.117(d)
§ 111.35) 2. Final § 111.83(b)(1) I. What Quality Control Operations
1. Final § 111.35(a) 3. Final § 111.83(b)(2) Are Required for Components,
2. Final § 111.35(b)(1) and (b)(2) 4. Final § 111.83(b)(3) Packaging, and Labels Before Use in
3. Final § 111.35(b)(3) 5. Final § 111.83(b)(4) the Manufacture of a Dietary
4. Final § 111.35(b)(4) N. Who Conducts a Material Review Supplement? (Final § 111.120)
5. Final § 111.35(b)(5) and Makes a Disposition Decision? 1. Final § 111.120(a)
6. Final § 111.35(b)(6) (Final § 111.87) 2. Final § 111.120(b)
X. Comments on Requirement to O. What Requirements Apply to 3. Final § 111.120(c)
Establish a Production and Process Treatments, In-Process 4. Final § 111.120(d)
Control System (Final Subpart E) Adjustments, and Reprocessing 5. Final § 111.120(e)
A. Reorganization of Proposed When There is a Deviation or J. What Quality Control Operations
§ 111.35 Into Final Subpart E Unanticipated Occurrence or When Are Required for the Master
B. General Comments on Proposed a Specification Established in Manufacturing Record, the Batch
§ 111.35 Accordance With § 111.70 Is Not Production Record, and
C. Final Subpart E and Highlights of Met? (Final § 111.90) Manufacturing Operations? (Final
Changes to the Proposed 1. Final § 111.90 § 111.123)
Regulations 2. Final § 111.90(a) 1. Final § 111.123(a)(1)
D. What Are the Requirements to 3. Final § 111.90(b) 2. Final § 111.123(a)(2)
Implement a Production and 4. Final § 111.90(c) 3. Final § 111.123(a)(3)
Process Control System? (Final P. Under This Subpart, What Records 4. Final § 111.123(a)(4)
§ 111.55) Must You Make and Keep? (Final 5. Final § 111.123(a)(5)
E. What Are the Design Requirements § 111.95) 6. Final § 111.123(a)(6)
for the Production and Process 1. Final § 111.95(a) 7. Final § 111.123(a)(7)
Control System? (Final § 111.60) 2. Final § 111.95(b) 8. Final § 111.123(a)(8)
F. What Are the Requirements for XI. Comments on Requirements for 9. Final § 111.123(b)
Quality Control Operations? (Final Quality Control (Final Subpart F) K. What Quality Control Operations
§ 111.65) A. Organization of Final Subpart F Are Required for Packaging and
G. What Specifications Must You B. Highlights of Changes to the Labeling Operations? (Final
Establish? (Final § 111.70) Proposed Requirements for Quality § 111.127)
1. Final § 111.127(a) and (b) 3. Final § 111.165(c) 3. Changes After Considering

2. Final § 111.127(c) 4. Final § 111.165(d) Comments
3. Final § 111.127(d) 5. Final § 111.165(e) C. What Is the Requirement to
4. Final § 111.127(e) H. What Requirements Apply to Establish a Batch Production
5. Final § 111.127(f) and (g) Rejected Components, Packaging, Record? (Final § 111.255)
6. Final § 111.127(h) and Labels, and to Rejected D. What Must the Batch Record
L. What Quality Control Operations Products That Are Received for Include? (Final § 111.260)
Are Required for Returned Dietary Packaging or Labeling as a Dietary 1. Final § 111.260(a)
Supplements? (Final § 111.130) Supplement? (Final § 111.170) 2. Final § 111.260(b)
1. Final § 111.130(a) I. Under This Subpart, What Records 3. Final § 111.260(c)
2. Final § 111.130(a)(1) and (a)(2) Must You Make and Keep? (Final 4. Final § 111.260(d)
3. Final § 111.130(b) § 111.180) 5. Final § 111.260(e) and (f)
4. Final § 111.130(c) 1. Final § 111.180(a) 6. Final § 111.260(g)
5. Final § 111.130(d) 2. Final § 111.180(b)(1) 7. Final § 111.260(h)
M. What Quality Control Operations 3. Final § 111.180(b)(2) 8. Final § 111.260(i)
Are Required for Product 4. Final § 111.180(b)(3) 9. Final § 111.260(j)
Complaints? (Final § 111.135) XIII. Comments on the Production and 10. Final § 111.260(k)
N. What Records Must You Make and Process Control System: Requirements 11. Final § 111.260(l)
Keep? (Final § 111.140) for the Master Manufacturing Record 12. Final § 111.260(m)
1. Final § 111.140(a) (Final Subpart H) 13. Final § 111.260(n)
2. Final § 111.140(b)(1) A. Organization of Final Subpart H E. Review of Batch Production Record
3. Final § 111.140(b)(2) B. Highlights of Changes to the Deviations (Proposed § 111.50(d)(1),
4. Final § 111.140(b)(3) Proposed Requirements for the (e)(2), (e)(3), and (e)(4))
XII. Comments on the Production and Master Manufacturing Record XV. Comments on Production and
Process Control System: Requirements 1. Revisions Process Control System: Requirements
for Components, Packaging, and Labels, 2. Changes Associated With the for Laboratory Operations (Final
and for Product That You Receive for Reorganization Subpart J)
Packaging or Labeling as a Dietary 3. Changes After Considering A. Organization of Final Subpart J
Supplement (Final Subpart G) Comments B. Highlights of the Changes to the
A. Organization of Final Subpart G C. General Comments on Proposed Proposed Requirements for
B. Highlights of Changes to the § 111.45 (Final Subpart H) Laboratory Operations
Proposed Requirements for 1. Comments on Written Procedures 1. Revisions
Components, Packaging, and 2. Comments That Support Proposed 2. Changes Associated With the
Labels, and Product That You § 111.45 Reorganization
Receive for Packaging or Labeling as D. What Is the Requirement to 3. Changes After Considering
a Dietary Supplement Establish a Master Manufacturing Comments
1. Revisions Record? (Final § 111.205) C. What Are the Requirements Under
2. Changes After Considering 1. Final § 111.205(a) This Subpart for Written
Comments 2. Final § 111.205(b)(1) Procedures? (Final § 111.303)
C. General Comments on Proposed 3. Final § 111.205(b)(2) D. What Are the Requirements for the
§ 111.40 (Final Subpart G) 4. Final § 111.205(c) Laboratory Facilities That You Use?
D. What Are the Requirements Under E. What Must the Master (Final § 111.310)
This Subpart for Written Manufacturing Record Include? E. What Are the Requirements for
Procedures? (Final § 111.153) (Final § 111.210) Laboratory Control Processes?
E. What Requirements Apply to 1. Final § 111.210(a) (Final § 111.315)
Components of Dietary 2. Final § 111.210(b) 1. Final § 111.315(a)
Supplements? (Final § 111.155) 3. Final § 111.210(c) 2. Final § 111.315(b)
1. Proposed § 111.35(d) 4. Final § 111.210(d) 3. Final § 111.315(c)
2. Final § 111.155(a) 5. Final § 111.210(e) 4. Final § 111.315(d)
3. Final § 111.155(b) 6. Final § 111.210(f) 5. Final § 111.315(e)
4. Final § 111.155(c) 7. Final § 111.210(g) F. What Requirements Apply to
5. Final § 111.155(d) 8. Final § 111.210(h)(1) Laboratory Methods for Testing and
6. Final § 111.155(e) 9. Final § 111.210(h)(2) Examination? (Final § 111.320)
F. What Requirements Apply to 10. Final § 111.210(h)(3) 1. Final § 111.320(a)
Packaging and Labels Received? 11. Final § 111.210(h)(4) 2. Final § 111.320(b)
(Final § 111.160) 12. Final § 111.210(h)(5) G. Appropriate Test Method
1. Final § 111.160(a) F. Quality Control Responsibility Validation (Proposed
2. Final § 111.160(b) (Proposed § 111.45(c)) § 111.60(b)(1)(v))
3. Final § 111.160(c) XIV. Comments on the Production and H. Under This Subpart, What Records
4. Final § 111.160(d) Process Control System: Requirements Must You Make and Keep? (Final
5. Final § 111.160(e) for the Batch Production Record (Final § 111.325)
G. What Requirements Apply to a Subpart I) 1. Final § 111.325(a)
Product Received for Packaging or A. Organization of Final Subpart I 2. Final § 111.325(b)(1)
Labeling as a Dietary Supplement B. Highlights of Changes to the 3. Final § 111.325(b)(2)
(and for distribution rather than for Proposed Requirements for the XVI. Comments on the Production and
return to the supplier)? (Final Batch Production Record Process Control System: Requirements
§ 111.165) 1. Revisions for Manufacturing Operations (Final
1. Final § 111.165(a) 2. Changes Associated With the Subpart K)
2. Final § 111.165(b) Reorganization A. Organization of Final Subpart K
B. Highlights of Changes to the Filling, Assembling, Packaging, C. General Comments on Proposed

Proposed Requirements for Labeling, and Related Operations? § 111.85
Manufacturing Operations (Final § 111.415) D. What Are the Requirements Under
1. Revisions H. What Requirements Apply to This Subpart for Written
2. Changes Made After Considering Repackaging and Relabeling? (Final Procedures? (Final § 111.503)
Comments § 111.420) E. What Requirements Apply When a
3. Revisions Associated With the 1. Final § 111.420(a) Returned Dietary Supplement is
Reorganization 2. Final § 111.420(b) and (c) Received? (Final § 111.510)
C. General Comments on I. What Requirements Apply to a F. When Must a Returned Dietary
Manufacturing Operations Packaged and Labeled Dietary Supplement be Destroyed, or
D. What Are the Requirements Under Supplement That Is Rejected for Otherwise Suitably Disposed Of?
This Subpart for Written Distribution? (Final § 111.425) (Final § 111.515)
Procedures? (Final § 111.353) J. Under this Subpart, What Records G. When May a Returned Dietary
E. What Are the Design Requirements Must You Make and Keep? (Final Supplement Be Salvaged? (Final
for Manufacturing Operations? § 111.430) § 111.520)
(Final § 111.355) 1. Final § 111.430(a) H. What Requirements Apply to a
F. What Are the Requirements for 2. Final § 111.430(b) Returned Dietary Supplement That
Sanitation? (Final § 111.360) XVIII. Comments on Holding and Quality Control Personnel Approve
G. What Precautions Must You Take Distributing (Final Subpart M) for Reprocessing? (Final § 111.525)
to Prevent Contamination? (Final A. Organization of Final Subpart M I. When Must an Investigation Be
§ 111.365) B. Highlights of Changes to the Conducted of Your Manufacturing
1. Final § 111.365(a) Proposed Requirements for Holding Processes and Other Batches? (Final
2. Final § 111.365(b) and Distributing § 111.530)
3. Final § 111.365(c) 1. Revisions J. Under This Subpart, What Records
4. Final § 111.365(d) 2. Changes Associated With the Must You Make and Keep? (Final
5. Final § 111.365(e) Reorganization § 111.535)
6. Final § 111.365(f) 3. Changes After Considering 1. Final § 111.535(a)
7. Final § 111.365(g) Comments 2. Final § 111.535(b)(1)
8. Final § 111.365(h) C. General Comments on Proposed 3. Final § 111.535(b)(2)
9. Final § 111.365(i) §§ 111.80, 111.82, 111.83, and 4. Final § 111.535(b)(3)
10. Final § 111.365(j) 111.85 5. Final § 111.535(b)(4)
11. Final § 111.365(k) D. What Are the Requirements Under XX. Comments on Product Complaints
H. What Requirements Apply to This Subpart for Written (Final Subpart O)
Rejected Dietary Supplements? Procedures? (Final § 111.453) A. Organization of Final Subpart O
(Final § 111.370) E. What Requirements Apply to B. Highlights of Changes to the
I. Under This Subpart, What Records Holding Components, Dietary Proposed Requirements for Product
Must You Make and Keep? (Final Supplements, Packaging, and Complaints
§ 111.375) Labels? (Final § 111.455) 1. Revisions
XVII. Comments on the Production and 1. Final § 111.455(a) 2. Changes After Considering
Process Control System: Requirements 2. Final § 111.455(b) Comments
for Packaging and Labeling Operations 3. Final § 111.455(c) C. General Comments on Proposed
(Final Subpart L) F. What Requirements Apply to § 111.95 (Final Subpart O)
A. Organization of Final Subpart L Holding In-Process Material? (Final D. What Are the Requirements Under
B. Highlights of Changes to the § 111.460) This Subpart for Written
Proposed Requirements for 1. Final § 111.460(a) Procedures? (Final § 111.553)
Packaging and Labeling Operations 2. Final § 111.460(b) E. What Requirements Apply to the
1. Revisions G. Proposed Requirement for Holding Review and Investigation of a
2. Changes Associated With the Reserve Samples of Components Product Complaint? (Final
Reorganization (Proposed § 111.83(a)) § 111.560)
3. Changes After Considering H. What Requirements Apply to 1. Final § 111.560(a)(1)
Comments Holding Reserve Samples of Dietary 2. Final § 111.560(a)(2), (b), and (c)
C. General Comments on Proposed Supplements? (Final § 111.465) F. Under This Subpart, What Records
Requirements for Packaging and 1. Final § 111.465(a) Must You Make and Keep? (Final
Labeling Operations 2. Final § 111.465(b) § 111.570)
D. General Comments on I. What Requirements Apply to 1. Final § 111.570(a)
Requirements for What Must Be on Distributing Dietary Supplements? 2. Final § 111.570(b)(1)
the Product Label Rather Than for (Final § 111.470) 3. Final § 111.570(b)(2)
Labeling Operations J. Under This Subpart, What Records 4. Final § 111.570(b)(2)(i)
E. What Are the Requirements Under Must You Make and Keep? (Final 5. Final § 111.570(b)(2)(ii)
This Subpart for Written § 111.475) XXI. Comments on Records and
Procedures? (Final § 111.403) XIX. Comments on Returned Dietary Recordkeeping (Final Subpart P)
F. What Requirements Apply to Supplements (Final Subpart N) A. Organization of Final Subpart P
Packaging and Labels? (Final A. Organization of Final Subpart N B. Highlights of Changes to the
§ 111.410) B. Highlights of Changes to the Proposed Requirements for Records
1. Final § 111.410(a) Proposed Requirements for and Recordkeeping

2. Final § 111.410(b) Returned Dietary Supplements 1. Revisions
3. Final § 111.410(c) 1. Revisions 2. Changes After Considering
4. Final § 111.410(d) 2. Changes After Considering Comments
G. What Requirements Apply to Comments C. General Comments on Proposed
§ 111.125 also stipulates that such regulations requirements for dietary ingredients and
D. What Requirements Apply to the shall be modeled after CGMP dietary supplements (the 2003 CGMP
Records That You Make and Keep? regulations for food and may not impose Proposal). The preamble to the 2003
(Final § 111.605) standards for which there are no current CGMP Proposal addressed the
1. Final § 111.605(a) and generally available analytical comments we had received regarding
2. Final § 111.605(b) methodology. The final rule establishes, the nine questions in the 1997 ANPRM,
3. Final § 111.605(c) in part 111 (21 CFR part 111), the discussed our legal authority to issue a
E. What Records Must Be Made minimum CGMPs necessary for CGMP rule, and described the basis for
Available to FDA? (Final § 111.610) activities related to manufacturing, each proposed requirement.
1. Final § 111.610(a) packaging, labeling, or holding dietary
2. Final § 111.610(b) supplements to ensure the quality of the The 2003 CGMP Proposal specifically
XXII. Other Comments and dietary supplement. The final rule is requested comment on a variety of
Miscellaneous one of many actions related to dietary areas, including the need for written
A. Comments on Guidance supplements that we are taking to procedures and recordkeeping
Documents To Be Used With the promote and protect the public health. requirements. Although the proposed
Final Rule In response to DSHEA, we issued an rule’s comment period was scheduled to
B. Comments on Consideration for Advance Notice of Proposed end on June 11, 2003, in the Federal
Other CGMP Programs Rulemaking (the 1997 ANPRM) in the Register of May 19, 2003 (68 FR 27008),
C. Comments on Public Involvement Federal Register of February 6, 1997 (62 we extended the comment period to
D. Comments on Implementation and FR 5700). The 1997 ANPRM contained August 11, 2003.
Enforcement a CGMP outline submitted to us on After we published the proposed rule,
E. Removal of References to Part 112 November 20, 1995, by representatives we conducted and/or participated in
XXIII. Paperwork Reduction Act of 1995 of the dietary supplement industry. The outreach activities related to dietary
XXIV. Analysis of Impacts 1997 ANPRM also asked nine questions supplements and dietary ingredients.
A. Introduction that addressed issues that the industry We held public stakeholder meetings on
1. Summary of the Economic Analysis outline did not. For example, we asked April 29, 2003, in College Park, MD, and
2. Summary of Comments on the if there is a need to develop specific on May 6, 2003, in Oakland, CA. We
Economic Analysis defect action levels (DALs) for dietary
also held a public meeting, via satellite
B. Final Regulatory Impact Analysis ingredients. We also asked whether a
downlink, on May 9, 2003, with viewing
1. The Need for the Final Current CGMP rule should require
Good Manufacturing Practice Rule sites at our district and regional offices
manufacturers to establish procedures to
2. Regulatory Options document, on a continuing or daily throughout the country. These public
3. Coverage of the Final Rule basis, that they followed pre-established meetings gave an overview of the
4. Baseline Practices procedures for making dietary proposed rule, and clarified specific
5. Baseline Risk supplements. points in the proposed rule. Since the
6. Benefits We received more than 100 comments public stakeholder meetings held as part
7. Costs in response to the 1997 ANPRM. We of our outreach efforts, we also have
8. Summary of Benefits and Costs evaluated these comments before we participated in several meetings with
9. Benefits and Costs of Regulatory drafted and ultimately issued a industry and other interested parties
Options proposed rule on CGMPs for dietary which are reflected in the public docket.
10. Cost Effectiveness Analysis ingredients and dietary supplements We received approximately 400
11. Uncertainties in the Analysis (which we discuss later in this section comments in response to the proposal.
C. Final Regulatory Flexibility of this document). The comments came from trade
Analysis Additionally, during 1999, we associations, government organizations
1. Introduction conducted a number of outreach and officials, manufacturers of dietary
2. Economic Effects on Small Entities activities related to dietary supplements and dietary ingredients,
3. Regulatory Options supplements. We held several public health care practitioners, consumer
4. Description of Recordkeeping and meetings to develop our overall strategy groups, and individuals. In general, the
Reporting for achieving effective regulation of comments supported the idea of
5. Summary dietary supplements, which could CGMPs, although many comments
D. Unfunded Mandates include establishing CGMP regulations. disagreed with specific aspects of the
XXV. Analysis of Environmental Impact We also held public meetings focused proposal.
XXVI. Federalism specifically on CGMPs and the
XXVII. References economic impact that any CGMP rule Published elsewhere in this issue of
for dietary ingredients and dietary the Federal Register we are also issuing
I. Background and Related Information an interim final rule that sets forth a
supplements might have on small
On October 25, 1994, the Dietary businesses. Further, we toured several procedure for requesting an exception to
Supplement Health and Education Act dietary supplement manufacturing a CGMP requirement in this final rule.
(DSHEA) (Public Law 103–417) was facilities to better understand the The interim final rule allows for
signed into law. DSHEA, among other manufacturing processes and practices submission to, and review by, FDA of an
things, amended the Federal Food, that potentially would be subject to alternative to the required 100-percent
Drug, and Cosmetic Act (the act) by CGMP requirements for dietary identity testing of components that are
adding section 402(g) of the act (21 ingredients and dietary supplements dietary ingredients (as discussed in
U.S.C. 342(g)). Section 402(g)(2) of the (Refs. 1 through 6). These activities section X of this document (subpart E)),
act provides, in part, that the Secretary contributed to our knowledge about the provided certain conditions are met.
of Health and Human Services (the industry. The interim final rule also includes a
Secretary) may, by regulation, prescribe In the Federal Register of March 13, requirement for retention of records
good manufacturing practices for dietary 2003 (68 FR 12157), we published a related to the FDA grant of an exception
supplements. Section 402(g) of the act proposed rule to establish CGMP request.
II. How is the Final Rule Organized? requirements, and supervisor process control requirements for
The 2003 CGMP Proposal was divided requirements. manufacturing, packaging, labeling, and
into eight subparts, with each subpart In response to comments seeking a laboratory operations in a single subpart
devoted to a particular topic. For simpler, more ‘‘user-friendly’’ final rule (proposed subpart E). The final rule
example, proposed subpart A was titled or seeking clarification of the rule’s creates separate subparts for the specific
‘‘General Provisions’’ and contained applicability to certain persons, items, operations to make it easier to find the
sections describing the rule’s scope, or activities, and to reduce redundant relevant production and process control
purpose, definitions, applicability of provisions or combine similar requirements for a particular activity.
other statutory and regulatory provisions, we have reorganized the Table 1 of this document summarizes
provisions, and exclusions. As another final rule into 16 subparts, with new how we reorganized the rule. We are
example, proposed subpart B was titled subparts focusing on specific aspects of providing this information to help
‘‘Personnel’’ and described microbial the manufacturing process or addressing readers understand the structural
contamination and hygiene specific issues. For example, the changes we made between the proposed
requirements, personnel qualification proposed rule placed all production and and final rules.
TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE
Proposed Sections Final Subpart Final Sections
Proposed Subpart and Title in the Subpart and Title in the Subpart
A—General Provisions 111.1 A—General Provisions 111.1

111.2 111.3
111.3 111.5
111.5
111.6
B—Personnel 111.10 B—Personnel 111.8 (new)

111.12 111.10
111.13 111.12
111.13
111.14 (new)
C—Physical Plant 111.15 C—Physical Plant and 111.15

111.20 Grounds 111.16 (new)
111.20
111.23 (formerly proposed
§ 111.15(d)(3) and (e)(2))
D—Equipment and Utensils 111.25 D—Equipment and Utensils 111.25 (formerly proposed
111.30 § 111.25(c)(1) and (e)(1))
§ 111.25 (a), (b), (d)1, and (e))
111.30
§§ 111.25 (c)(1), (c)(2), (d), (f),
111.30(b)(2), (b)(5), and (c),
111.50(c)(4))
TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued
E—Production and Process Controls 111.35 E—Requirement to Establish 111.55 (formerly proposed
111.37 a Production and Process § 111.35(a))
111.40 Control System 111.60 (formerly proposed
111.45 § 111.35(b))
111.50 111.65 (formerly proposed
111.60 § 111.35(c))
111.70 § 111.35(e), (f), (g), and (k))
§ 111.35(f), (g), and (h)
§ 111.35(e) through (i), (k), and
(l)), § 111.37(b)(11(iv), and
§ 111.40(a)(2)
111.77 (new)
§ 111.37(b)(11))
§§ 111.37(b)(12), 111.50(h), and
111.83(b)(2))
§§ 111.35(i) and (n), 111.37(b)(5)
and (b)(14), 111.40(a)(3),
111.50(d)(1), and 111.85(a) and
(c))
§§ 111.35(i)(4), 111.50(d)(1), (f),
and (g), and 111.65(d))
§ 111.35(o))
F—Production and Process 111.103 (new)

Control System: Require- 111.105 (formerly proposed
ments for Quality Control § 111.37(a), (b)(1), (b)(11), and
(b)(12))
§ 111.37(b)(9) and (b)(13))
§§ 111.35(i)(2), (i)(3), (i)(4)(i),
(i)(4)(ii), (j), and (n), 111.37(b)(3)
and (c), 111.40(a)(3) and (b)(2),
111.50(d)(1), 111.65(d), and
111.70(c))
§§ 111.30(b)(4) and 111.37(b)(6)
through (b)(8))
§§ 111.35(i)(4)(i) and (i)(4)(ii),
111.37(b)(2) and (b)(10),
111.40(a)(3) and (b)(2), and
111.50(e)(1))
§§ 111.35(e)(2), (f), (i)(2), and
(o)(2) 111.37(a), (b)(2), (b)(4),
(b)(5), and (b)(11), 111.45(c),
and 111.50(d)(1), (d)(2), and (g))
§§ 111.37(b)(2), (b)(10), and
(b)(11), 111.40(a)(2) and (a)(3),
and 111.70(c), (d) and (e))
§§ 111.37(b)(2) and (b)(15), and
111.85(a))
111.135 (new)
§§ 111.35(j) and 111.37(c) and
(d)
G—Production and Process 111.153 (new)

ments for Components, §§ 111.35(d)(1) through (d)(5)
Packaging, and Labels and and 111.40(a)(1) through (a)(5))
for Product That You Re- 111.160 (formerly proposed
ceive for Packaging or La- §§ 111.35(e)(4), and 111.40(a)(2)
beling a Dietary Supplement and (b)(1) through (b)(4))
§ 111.40(a)(1) through (a)(5))
§ 111.74)
§§ 111.35(d)(4), and
111.40(c)(1)(i) through (c)(1)(iv)
and (c)(2))
H—Production and Process 111.205 (formerly proposed

Control System: Require- § 111.45(a)(1), (a)(2), and (d))
ments for the Master Manu- 111.210 (formerly proposed
facturing Record § 111.45(b))
I—Production and Process 111.255 (formerly proposed

Control System: Require- § 111.50(a), (b), and (i))
ments for the Batch Produc- 111.260 (formerly proposed
tion Record §§ 111.35(i)(2), (j), (m), and
(o)(2), 111.37(b)(3), (b)(5), (b)(9)
and 111.50(c)(1) through (c)(11),
(c)(13), (c)(14), (d)(2), (e), and
(g), and 111.70(b)(6) and (g))
J—Production and Process 111.303 (new)

ments for Laboratory Oper- § 111.60(a))
ations 111.315 (formerly proposed
§ 111.60(b)(1))
§ 111.60(c) and (d))
§ 111.60(b)(2) and (b)(3))
K—Production and Process 111.353 (new)

ments for Manufacturing Op- § 111.65(a))
erations 111.360 (formerly proposed
§ 111.65(b))
§ 111.65(c))
§ 111.74)
111.375 (new)
L—Production and Process 111.403 (new)

ments for Packaging and § 111.70(a), (b)(6), and (f))
Labeling Operations 111.415 (formerly proposed
§ 111.70(b))
§ 111.70(d) and (e))
§ 111.74)
§ 111.70(g) and (h))
F—Holding and Distributing 111.80 M—Holding and Distributing 111.453 (new)

111.83 § 111.80)
111.90 § 111.82)
§ 111.83(b)(1) and (b)(2))
§ 111.90)
111.475 (new)
N—Returned Dietary Sup- 111.503 (new)

plements 111.510 (formerly proposed
§ 111.85(a))
§ 111.85(b) and (c))
§ 111.37(b)(15))
§ 111.50(g))
§ 111.85(d))
§§ 111.50(g) and 111.85(e) and
(f))
G—Consumer Complaints 111.95 O—Product Complaints 111.553 (new)

§ 111.95(a) through (d))
§ 111.95(e) and (f))
H—Records and Recordkeeping 111.125 P—Records and Record- 111.605 (formerly proposed
keeping § 111.125((a) and (b))
§ 111.125(b) and (c))
1The reference to (d) is the second (d) in the proposed rule in this section due to a misnumbering in the proposed rule.
We discuss all subparts and sections, implemented separate, and more manufactured, processed, packed, and
and our reasons for amending or specific, CGMPs for various types of held under sanitary conditions. Process
creating subparts and sections, in our food products to provide for process controls for dietary supplement
discussion of the comments to the controls in manufacturing that are not manufacture include establishing and
proposal. captured by the more general part 110 meeting specifications to ensure the
food CGMPs. (See discussion in section finished dietary supplement contains
III. What Does the Final Rule Do?
V of this document (‘‘Legal Authority’’) the correct ingredient, purity, strength,
A. Overview of CGMP on product specific CGMP and composition intended.
In considering the specific requirements). At the time DSHEA was Vitamins can present a concentrated
requirements necessary for dietary enacted, there were four such source of biologically active
supplement CGMPs, we considered additional, specific food CGMP components. A vitamin, for example,
information from a variety of sources. regulations: Those for infant formula that contains too high a concentration,
We considered information from our (part 106 (21 CFR part 106)), thermally such as vitamin D at levels that are
outreach activities, as described in processed low-acid canned food (part many times greater than intended, can
section I of this document; comments to 113 (21 CFR part 113)), acidified food lead to illness and hospitalization (Refs.
the 2003 CGMP Proposal; our own (part 114 (21 CFR part 114)), and bottled 7 and 8). A manufacturer must establish
knowledge and expertise about CGMP water (part 129 (21 CFR part 129)). a process for manufacturing a dietary
for foods, including dietary Dietary supplements are a type of supplement product in order to produce
supplements; and characteristics of food product for which specific food the product consistently and reliably
CGMP that apply to manufacturing, CGMPs also are needed. Manufacturing each time. In order to achieve
labeling, packaging, and holding process controls are needed to ensure consistency and reliability, there must
operations. that a dietary supplement contains what be process controls in place to ensure,
The general food CGMPs in part 110 the manufacturer intends. Unlike most for example, that appropriate tests and
(21 CFR part 110) largely address foods, the majority of dietary examinations are conducted, a master
practices designed to ensure that food is supplements are packaged into tablets, manufacturing record is prepared, each
manufactured, processed, packed, and gelcaps, and capsules. Some dietary batch production follows the master
held under sanitary conditions and that supplements may contain bioactive manufacturing record, and the finished
the food is safe, clean, and wholesome. ingredients for which certain, controlled tablet or capsule is placed in the
Although the general food CGMPs in amounts are intended to be in each intended package with the intended
part 110 apply to a variety of food tablet or capsule. The process controls label.
products, including dietary that must be in place to ensure the tablet These same types of controls are
supplements, they do not address the or capsule contains what it purports to needed for herbal and botanical dietary
unique characteristics of certain specific contain are different than those that supplements. Botanicals are often
types of food products. The agency has must be in place to ensure a food is complex mixtures that can vary in
composition depending on factors such desired outcome of the dietary manufacturing controls to prevent the
as the part of the plant used, the supplement manufacturing process.1 In dietary supplement from being
location of harvesting and growing fact, several comments asked us to adulterated under section 402(a)(1) of
conditions that can vary from year to define ‘‘quality’’ and suggested various the act due to the presence of
year even in the same location. It can be definitions, each of which related to a contaminants, under section 402(a)(2) of
difficult to distinguish between closely dietary supplement having the identity, the act, for example, if it bears or
related species of botanicals, and the purity, strength, and composition contains any unintentionally added
biological activity of components of an intended (see comment 49 in section VI poisonous or deleterious substance,
incorrectly identified species can lead to of this document). Some comments under section 402(a)(3) of the act if the
adverse consequences. In addition, distinguished the concept of quality dietary supplement consists in whole or
different species may be present in from that of preventing adulteration. in part of any filthy, putrid, or
different ratios or blends in a particular These comments objected to our decomposed substance, or if it is
product. Various products might statement that dietary supplement otherwise unfit for food, or under
contain different parts of the plant— CGMP requirements are needed to section 402(a)(4) of the act if the dietary
flower, leaf, root, stem, extract—and the prevent adulteration and stated that supplement has been prepared, packed,
test methods for each can vary in the CGMP is focused on assuring that or held under insanitary conditions
nature, sensitivity, and specificity of the finished products are manufactured whereby it may have become
test. using quality procedures, but are not contaminated with filth, or whereby it
Well-established principles of CGMP related to preventing adulteration. Other may have been rendered injurious to
require process controls at each step of comments asked us to define health. The definition of quality limits
the manufacturing process as early in ‘‘adulteration.’’ to section 402(a)(1), (a)(2), (a)(3), and
the production process as possible. We agree that a critical aspect of (a)(4) of the act the types of adulteration
Quality cannot be tested into the CGMP is achieving control over that you must control for in this CGMP
product only at the end (Ref. 9). Instead, manufacturing processes. Controls are final rule. The definition applies to the
the quality of the dietary supplement necessary to ensure that you controls that are designed to prevent
must be built into the product manufacture what you intend so that the contamination of the product that you
throughout the manufacturing process; characteristics and/or attributes desired intend to manufacture.
quality begins with the starting material in a final product will be consistently In the 2003 CGMP Proposal, we said
and continues with the product being and reliably achieved. We disagree with that our purpose was to present a broad
manufactured in a reproducible manner the comments to the extent that they enough scope to the proposed rule so
according to established specifications. were suggesting that quality is not that we could receive the depth and
It is not sufficient, nor effective, to rely related to preventing contamination in breadth of comment needed to develop
solely on end product testing to assure the manufacturing process that may a final rule that would provide the
the quality of the individual dietary adulterate the finished product. proper balance of regulation (68 FR
supplement product sold to the However, we have reconsidered, as 12157 at 12161). We asked for comment
consumer. discussed in this section, what types of on whether each of the provisions
CGMPs are intended to establish a adulteration and misbranding are proposed was necessary to ensure the
comprehensive system of process necessary to control for in this dietary safety and quality of the dietary
controls, including documentation of supplement CGMP rule. supplement and was adequate to protect
each stage of the manufacturing process, To clarify what dietary supplement the public health (id.). We stated that
that can minimize the likelihood of, or CGMP requirements are intended to the proposed rule ‘‘would establish the
detect, problems and variances in achieve, we have added a definition of minimum CGMPs necessary to ensure
manufacturing as they occur and before quality in the final rule. As defined, that, if you engage in activities related
the product is in its finished form. quality means ‘‘that the dietary to manufacturing, packaging, or holding
These process controls that are a part of supplement consistently meets the dietary ingredients or dietary
CGMPs are essential to ensure that the established specifications for identity, supplements, you do so in a manner
dietary supplement is manufactured, purity, strength, and composition and that will not adulterate and misbrand
packaged, held, and labeled in a such dietary ingredients or dietary
has been manufactured, packaged,
consistent and reproducible manner. supplements’’ (68 FR 12157 at 12158).
labeled, and held under conditions to
Manufacturing according to CGMP For example, we stated that the
means that the manufacturing process prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the proposed rule would require the
incorporates a set of controls in the manufacturer to test for toxic
design and production processes to Federal Food, Drug, and Cosmetic Act.’’
Ensuring the quality of the dietary compounds in botanicals that may
assure a quality finished product. likely be present to ensure that no such
CGMPs specific to dietary supplements supplement means that you consistently
compounds are present that may
are necessary to help ensure that these and reliably manufacture what you
adulterate the dietary supplement (68
products have the identity, purity, intend and that you establish
12157 FR at 12162). Further, we
strength, and composition that meet 1 Throughout this final rule, we refer to the
included a requirement that the
specifications established in the master ‘‘manufacture’’ or ‘‘manufacturing process’’ of ingredients, other than dietary
manufacturing record and that they are dietary supplements. We use these terms in the ingredients under section 201(ff) of the
not adulterated. broad sense, i.e., the terms refer to those activities act, be lawful under the applicable food
Many comments stressed that the that may be done from receipt of raw ingredients additive regulations or be generally
through the distribution of a finished dietary
most critical aspect of a successful supplement, including labeling, packaging, and recognized as safe (GRAS) (proposed
CGMP system is effective process holding activities. We discuss the various roles and § 111.35(d).
control. Comments asserted that, with responsibilities of those who ‘‘manufacture’’ dietary The approach that we set forth in the
effective process control, quality is built supplements in the context of final § 111.1 ‘‘Who 2003 CGMP Proposal was designed to
is subject to this part?’’ We also sometimes use the
into a product throughout the entire terms to apply to only part of the process, i.e., those
prevent a manufacturer, under CGMP
production process. The term ‘‘quality’’ operations other than labeling, packaging, and regulations, from using an ingredient,
came up repeatedly in comments as the holding. whether a dietary ingredient or another
component, in the manufacture of a (21 U.S.C. 343) (proposed batch of dietary supplement. Nothing in
dietary supplement that would § 111.45(b)(4)). the dietary supplement CGMPs relieves
adulterate the product under relevant Several comments seemed to question manufacturers from complying with any
provisions of the act, such as section why the dietary supplement CGMP rule other substantive provisions of the act
402(a)(1) or (a)(2)(C). The manufacturer would require that a manufacturer use relating to the safety of ingredients and
would have been required to establish lawful ingredients when other other components.
specifications at any point, step, or stage provisions of the act would require such Quality not only means that you
in the manufacturing process where use. In fact, some comments objected to produce what you intend, but that you
control is necessary to prevent the proposed requirement in the rule prevent contamination in your
adulteration (proposed § 111.35(e)). that required that a component, other manufacturing process that could
Thus, the manufacturer would not have than a dietary ingredient, be approved adulterate your product. Food CGMP
been able to establish a specification, for use as a food additive or be GRAS. regulations, after which the dietary
consistent with proposed § 111.35(e), for The comments stressed that such a supplement CGMP rule is modeled,
the use of an unlawful ingredient provision was not necessary because the require that the manufacturer take
because such use would not prevent statute already requires that such an precautions to ensure that the
adulteration. In addition, the ingredient be approved as a food manufacturer does not adulterate the
manufacturer would have to establish additive or be GRAS. In light of these product under section 402(a)(1), (a)(2),
specifications for contaminants that may comments, we reconsidered our (a)(3), and (a)(4) of the act. For example,
adulterate or that could lead to interpretation of the scope of ‘‘prevent under § 110.5 (food CGMP), the criteria
adulteration of the dietary supplement. adulteration’’ in the proposed rule and and definitions apply in determining
The manufacturer would have to take whether that interpretation should be whether a food is adulterated under
necessary precautions to prevent the narrowed. We also considered whether section 402(a)(3) and (a)(4) of the act.
presence or level of contaminants, that to require, as part of a CGMP Specifically, § 110.80(a)(2) states that
would otherwise adulterate the dietary requirement, that the label that raw materials shall not contain levels of
supplement under another provision of accurately reflects the ingredients in the microorganisms that may produce food
the act, from being present in the dietary product be applied or whether such a poisoning or other disease in humans,
supplement. The specifications were requirement was not necessary, given unless otherwise treated during
intended to ensure that adulterated and our existing authority in section 403 of manufacturing operations so that they
misbranded dietary supplements would the act. no longer contain levels that would
not reach the marketplace (68 FR 12157 We determined that ensuring quality adulterate the product within the
at 12197). in dietary supplement CGMP, in part, meaning of the act. In addition,
means that you produce what you § 110.80(a)(3) states that raw materials
In addition to the general intend to produce. As stated in section and other ingredients susceptible to
specifications established under V of this document, manufacturers must contamination with natural toxins must
proposed § 111.35(e), the proposed rule plan what they intend to produce, comply with current FDA regulations
would have required the manufacturer institute adequate controls to achieve and action levels for poisonous or
to establish specifications for the the desired outcome, and ensure that deleterious substances before such
identity, purity, quality, strength, and the controls work so that the desired materials are incorporated into finished
composition of the components received outcome is consistently achieved. Thus, food. Under dietary supplement CGMP,
(proposed § 111.35(e)(1)) and for the for example, the manufacturer decides we believe it is appropriate to require
finished batch of dietary supplement on the identity, purity, strength, and you to establish specifications that are
(proposed § 111.35(e)(3)). Although we composition of the dietary supplement designed to prevent adulteration under
stated that the proposed rule did not it manufactures. The focus of CGMP is section 402(a)(1), (a)(2), (a)(3), and (a)(4)
address questions related to the safety of on process controls to ensure that the of the act from contamination during the
dietary ingredients used (68 FR 12157 at desired outcome is consistently manufacturing, packaging, labeling, and
12172), if a dietary ingredient was achieved, and not on the inherent safety holding operations. For example, if you
deemed to be unsafe under the act— of the ingredients used (which is are manufacturing a dietary supplement
under section 402(a)(1) or another addressed by other statutory that you know is likely to contain a
provision—a specification could not prohibitions). contaminant, you would need to
have been established for that dietary We agree with the comments that the establish limits on the contaminant in
ingredient, consistent with proposed safety of a particular ingredient is your supplement, and you must design
§ 111.35(e). Thus, a manufacturer would governed by other provisions of the act. these limits to prevent the dietary
not be able to use, under dietary If you manufacture a dietary supplement from being adulterated
supplement CGMP, a dietary ingredient, supplement, you have a responsibility under section 402(a)(1), (a)(2), (a)(3),
or other component, that would as a manufacturer to evaluate the safety and (a)(4) of the act.
otherwise adulterate the product under of the ingredients under, for example, Quality, as the term is used for the
another provision of the act. section 402(f) of the act.2 Dietary purposes of this final rule, relates both
Further, the proposed rule was supplement CGMP would require you to to producing what is intended (i.e.,
designed to ensure that the correct label establish the identity, purity, strength, establishing and ensuring that
was applied during manufacture so that and composition specifications for the specifications for the identity, purity,
the dietary supplement label would product and ensure that such strength, and composition are met) and
accurately identify the dietary specifications are met in the finished to ensuring that the dietary supplement
supplement (proposed §§ 111.45(b)(7), that you intend to produce has been
111.50(c)(12), and 111.70(b)(7)). The 2Under section 402(f) of the act, a dietary manufactured, packaged, labeled, and
proposed rule also would have required supplement is deemed to be adulterated if it is or held under conditions to prevent
the master manufacturing record to contains a dietary ingredient that presents a adulteration within the meaning of
significant or unreasonable risk of illness or injury
contain the identity of each ingredient under conditions of use recommended or suggested
section 402(a)(1), (a)(2), (a)(3), and (a)(4)
that is required to be declared on the in labeling or, if no such conditions, under ordinary of the act. Thus, this final rule is not
ingredient list in section 403 of the act conditions of use. designed to specifically prevent all
types of adulteration that may occur supplement is packaged and labeled as process control system that will ensure
under the act. Rather, this final rule is specified in the master manufacturing dietary supplements meet the identity,
designed to prevent adulteration from record.’’ Such change is intended to purity, strength, and composition
those types of contamination that are clarify that the use of the packaging and established in specifications and are
commonly controlled in other food labeling that is stated in the master properly packaged and labeled as
CGMP regulations. We do expect, manufacturing record is what is specified in the master manufacturing
however, that compliance with CGMP required in this final rule. record;
requirements in the final rule will help A failure to follow the requirements • Provides for the option to use a
to avoid other types of adulteration. in this final rule, including a failure to certificate of analysis (for specifications
Also, nothing in this rule exempts a establish required specifications, could other than the identity of a dietary
manufacturer from compliance with result in an enforcement action by the ingredient) from a component supplier
other relevant adulteration provisions of agency under section 402(g) of the act instead of having manufacturers
the act. because the dietary supplement is conduct tests or examinations on the
We are replacing the phrase ‘‘prevent adulterated in that it was prepared, components they receive;
adulteration’’ in the codified with words packed, labeled, or held under • Requires testing of a subset of
that relate to ensuring the quality of the conditions that do not meet CGMPs for finished batches of dietary supplements
dietary supplement. Thus, for example, dietary supplements. The act establishes based on a sound statistical sampling or,
we have modified proposed § 111.35(e) certain prohibited acts and enforcement alternatively, testing all finished
(now final § 111.70(a)) to read, ‘‘You mechanisms to remove adulterated batches;
must establish a specification for any product from the market and prevent • Requires implementation of quality
point, step, or stage in the manufacturers from continuing to control operations to ensure the quality
manufacturing process where control is manufacture adulterated product. of a dietary supplement;
necessary to ensure the quality of the Enforcement mechanisms currently • Requires the preparation and use of
finished dietary supplement and that available to us under the act are not a written master manufacturing record
the dietary supplement is packaged and affected by this final rule. for each unique formulation of
labeled as specified in the master Finally, we have included in this final manufactured dietary supplement, and
manufacturing record’’ instead of rule the existing requirements in part for each batch size, to ensure your
‘‘* * * necessary to prevent 110 that we believe are common to manufacturing process is performed
adulteration.’’ This phrase is replaced in dietary supplement manufacturing. For consistently and to ensure uniformity in
several codified provisions and an example, the requirements in subpart C, the finished batch from batch to batch;
explanation of this change is not Physical Plant and Grounds, are similar • Requires the preparation of a batch
provided in the preamble of this to those in § 110.20. We recognize that production record every time a dietary
document each time it is made. there may be operations related to the supplement batch is made. The batch
Moreover, you have a responsibility manufacturing of dietary supplements production record must accurately
under CGMP to ensure that the label for which certain provisions in part 110 follow the appropriate master
you specify in the master manufacturing apply, but that we did not determine to manufacturing record;
record is applied to the product. Under be common to most dietary supplement • Requires the establishment and use
section 403 of the act, you are required manufacturing operations. For example, of laboratory control processes related to
to ensure that your label accurately there may be some dietary supplements establishing specifications and to the
reflects the ingredients in the product. that are dehydrated and rely on the selection and use of testing and
Because section 403 of the act provides control of moisture consistent with examination methods;
that food, including dietary § 110.80(b)(14). A manufacturer would • Requires reserve samples of dietary
supplements, is misbranded if a label be expected to comply with the supplements to be held in a manner that
that does not contain accurate regulations in part 110 in addition to the protects against contamination and
statements is applied, we do not need to regulations in part 111, unless the deterioration;
impose the same requirement in this regulations conflict. To the extent that • Requires identification and
final rule. Thus, if the representative the regulations conflict, the dietary quarantine of returned dietary
label in the master manufacturing supplement manufacturer must comply supplements until quality control
record for the product does not identify with the regulation in part 111. personnel conduct a material review
the correct dietary ingredients and the and make a disposition decision;
label that lists inaccurate information is B. Highlights of the Final Rule • Requires quality control personnel
applied, that dietary supplement would The final rule: to conduct a material review and make
be misbranded under section 403 of the • Applies to persons who a disposition decision under certain
act. Such labeling would not be a manufacture, package, label, or hold circumstances;
violation of dietary supplement CGMP dietary supplements unless subject to an • Requires a qualified person to
unless there is a mixup in your process exclusion in § 111.1; investigate any ‘‘product complaint’’
control and you do not put the • Establishes minimum requirements that involves a possible failure of a
representative label specified in the for personnel, physical plant and dietary supplement to meet any CGMP
master manufacturing record on the grounds, and equipment and utensils; requirement, with oversight by quality
product. Such a mixup would be a • Requires the establishment and use control personnel; and
violation of dietary supplement CGMP of written procedures for certain • Requires records associated with
requirements (see e.g., final operations, including those related to the manufacture, packaging, labeling, or
§§ 111.127(d), 111.160(e), 111.410(c), equipment, physical plant sanitation, holding of a dietary supplement to be
111.415). certain manufacturing operations, kept for 1 year beyond the shelf life
Thus, in addition to stating ‘‘ensure quality control, laboratory testing, dating (when such dating is used, such
the quality of the dietary supplement,’’ packaging and labeling, and product as expiration dating, shelf life dating, or
in the codified instead of ‘‘prevent complaints; ‘‘best if used by’’ dating), or if shelf life
adulteration,’’ we are adding the • Requires the establishment of dating is not used, for 2 years beyond
language ‘‘and that the dietary specifications in the production and the date of distribution of the last batch
of dietary supplements associated with firms, and we should rewrite the rule to requirement of making and keeping
those records. be more user friendly. records.
IV. What General Comments Did We Yet another comment says that any B. What Comments Did We Receive on
Receive? final rule we issue must clearly set forth the Need for Dietary Supplement CGMP
CGMP requirements. This comment Requirements?
We received approximately 400 seems to suggest the requirements need
comments on the proposed rule. to be more detailed in describing what (Comment 2) Some comments state
Although most comments support is required. The comment asserts that that dietary supplement CGMP
CGMP requirements for dietary ambiguities in interpretation could requirements will protect consumers
supplements and dietary ingredients, result in economic disadvantage for from supplements that contain
others question the need for a regulation small businesses because they typically inherently unsafe dietary ingredients.
and many sought changes to the rule. do not have in-house legal counsel and, Other comments request that we take
We describe, in this section, comments thus, must be more conservative in additional action to ensure the safety of
on general aspects of the final rule. We interpreting ambiguous regulatory dietary ingredients.
include comments related to the provisions. (Response) This final rule focuses on
structure and organization of the final the manufacturing practices of dietary
(Response) In response to these
rule, comments we received on why supplements and not on whether certain
comments, as well as comments on
CGMP requirements are needed, and dietary ingredients are or are not safe.
specific subparts and provisions, we
comments on written procedures. In Therefore, comments related to whether
have reorganized the final rule and have
addition, we describe some general certain dietary ingredients are
re-phrased or introduced concepts in a
comments we received on multiple inherently unsafe and any request to
‘‘user-friendly’’ or plain language
sections of the proposed rule that we take actions related to the inherent
format. We also have eliminated certain
believe are better addressed in one safety of dietary ingredients are outside
redundant regulatory requirements and the scope of this rule.
response.
To make it easier to identify combined similar requirements. For (Comment 3) Some comments support
comments and our responses, the word example, rather than put all production the rule, explaining that it will address
‘‘comment,’’ in parentheses, will appear and process control system current problems with superpotent and
before each comment, and the word requirements in a single subpart, we subpotent dietary supplements,
‘‘response’’ will appear before each have reorganized the final rule to create undeclared ingredients, and varying
response. We also have numbered the a series of subparts that first describe levels of ingredients. Others indicate the
comments to make it easier to the requirements for the overall design rule will better protect consumers and
distinguish between comments; the and implementation of the production increase consumer confidence. One
numbers are for organizational purposes and process control system and then comment states that CGMP
only and do not reflect the order in describe the requirements of the requirements for dietary supplements
which we received the comments or any individual operations associated with are not needed for responsible
value associated with the comment. that system. We also present each manufacturers because they already
requirement as a question rather than as manufacture safe dietary supplements.
A. What Comments Did We Receive on a paragraph within a section. This Some comments state that dietary
the Structure and Organization of the question format will help readers focus supplement CGMP requirements are not
Rule? on the subparts or sections that apply to needed because the dietary supplements
(Comment 1) Several comments seek specific operations. have a track record of safety. Other
to restructure or reorganize the rule. For As another example, we reduced the comments say there were more adverse
example, one comment states we should redundancy associated with the events reported from drug use than from
simplify the entire section on interrelated nature of the proposed rule dietary supplement use and that a large
production and process controls. The by combining most similar number of Americans take dietary
comment asserts it would be more requirements. Both proposed supplements, and on that basis
logical to list contaminants that may §§ 111.35(m) and 111.60(b)(2) would suggested that dietary supplements are
adulterate a dietary supplement or lead require you to keep testing and safer than foods or drugs.
to adulteration as part of the examination results. The final rule (Response) We agree the final rule
requirements for specifications places this requirement in a single will better protect consumers and help
(proposed § 111.35(e)) than to list such section (§ 111.325(b)(2)(ii)). address the types of manufacturing
contaminants as part of the testing The final rule also shortens the problems identified in the preamble to
requirements (proposed § 111.35(k)). construction ‘‘includes, but is not the 2003 CGMP Proposal (see 68 FR
Other comments say it would be more limited to’’ to ‘‘includes.’’ We did this 12157 at 12162 through 12163) through
logical to list the tests that are because the use of the word ‘‘includes’’ consistent use of established production
considered appropriate as part of indicates that the specified list that processes and controls.
proposed § 111.35(h) (concerning follows is not exclusive. The phrase However, we disagree with the
appropriate tests or examinations to ‘‘but is not limited to’’ is unnecessary. comments asserting dietary
determine whether specifications are Finally, some changes we have made supplements have a track record of
met) than to have a separate to one specific section have an impact safety such that dietary supplement
requirement for appropriate tests in on other sections. For example, after CGMP requirements are unnecessary.
proposed § 111.35(l) (which listed the considering the comments, we revised Section 402(g) of the act does not
types of analyses that should be part of subpart B to require you to establish and require us to establish a ‘‘bad’’ track
a test). follow written procedures to fulfill the record of safety in the manufacture of
Another comment claims the rule is requirements of subpart B. Those dietary supplements before we may
too complex, asserting it would create written procedures are records you must issue a dietary supplement CGMP rule.
chaos. Other comments say that the make and keep in accordance with the Furthermore, we disagree with the
proposal’s degree of detail required is recordkeeping requirements of subpart comments comparing dietary
unrealistic for small dietary supplement P, thus we made changes to include that supplement safety to drug safety; there
are different statutory requirements, additional requirements are necessary. Another example involved recalls of
different regulatory requirements, and The comments do not explain why the super- and subpotent dietary
different safety evaluations for dietary specific requirements set forth in the supplements (id.).
supplements and drugs. proposed rule that are not also in part Comments objecting to the Prevention
We also disagree that the final rule 110 are unnecessary. As discussed in survey said it provided no rationale for
should apply only to manufacturers greater detail in response to comments why CGMP requirements are needed.
who cannot manufacture dietary on our legal authority in section V of Other comments said the nine examples
supplements responsibly. Establishing this document, the particular we provided represent a failure to
who is or is not a responsible characteristics and hazards of dietary conform to an existing regulation and do
manufacturer is not a threshold supplements call for CGMP not demonstrate a need for a new CGMP
requirement in section 402(g) of the act, requirements tailored to dietary regulation for dietary supplements. One
and it would be impractical to regulate supplements. Congress specifically comment disagrees that the CGMP
dietary supplement CGMP in such a provided independent authority under requirements would prevent adverse
manner, because parties may differ as to section 402(g) of the act for us to reactions, as one example suggested in
whether a particular manufacturer acted promulgate CGMP requirements for the preamble to the 2003 CGMP
‘‘responsibly’’ in a particular situation. dietary supplements. That authority Proposal (see 68 FR 12157 at 12162)
All dietary supplement manufacturers would have been unnecessary if because, the comment claims, most
are subject to this final rule, just as all Congress had concluded that part 110 adverse reactions are not the result of
dietary supplement manufacturers are was adequate. manufacturing problems. Another
subject to section 402(g) of the act. We We also disagree that enforcement of comment states the example involving
therefore are not persuaded that dietary part 110 would eliminate a need for plantain (68 FR 12157 at 12162), where
supplement CGMP requirements are not dietary supplement CGMP a raw material was labeled as ‘‘plantain’’
needed, or should only be applied to requirements. The dietary supplement when it was, in fact, Digitalis lanata (a
manufacturers who have not acted CGMP requirements include practices plant that can cause life-threatening
‘‘responsibly.’’ specifically tailored to the heart reactions), shows that, had there
(Comment 4) Some comments state characteristics and hazards of dietary been a system in place to test finished
that our authority under the current supplements and their manufacturers. product for purity and identity or to
food CGMP regulation in part 110 and The comments asserting that current perform identity testing upon receipt,
our authority to take actions against food CGMP requirements in part 110 are the manufacturer could have prevented
adulterated and misbranded products sufficient provided no persuasive or that adulterated product from entering
generally are sufficient. Other comments compelling reasons for that assertion, or the market place. The comment states
state that DSHEA gives us the necessary for why we should not implement identity testing is necessary in the final
legal authority to protect the public dietary supplement CGMP requirements rule.
health and that additional regulatory under section 402(g) of the act. For these Another comment objects to the
requirements are unnecessary. Several reasons, we are not persuaded by the example of ‘‘non-food grade chemicals’’
comments object to our statement that comments that these dietary supplement (id.) because the reference supporting
dietary supplement CGMP requirements CGMP requirements are not needed. the example involved Gamma-
are needed to prevent adulteration. (Comment 5) Some comments object Butyrolactone, a substance we have
These comments suggest dietary to the examples of manufacturing stated is an unapproved new drug and
supplement CGMP is focused on problems that we used to support the not a dietary supplement. Some
ensuring finished products are need for CGMP requirements. comments say the risks cited in the
manufactured using quality procedures, Specifically, some comments object to justification for these regulations are
but are not related to preventing the Prevention magazine citation and hypothetical or theoretical and current
adulteration. Other comments state we also object to the nine examples we statutory or regulatory authority is
should enforce current food CGMP presented in the preamble to the 2003 adequate.
regulations rather than adopt new CGMP Proposal (see 68 FR 12157 at (Response) We disagree, in most part,
regulations. 12161 through 12163). We cited the with the comments. We cited the
(Response) We disagree that dietary Prevention magazine survey on Prevention survey to illustrate consumer
supplement CGMP requirements are not consumer use of dietary supplements to perception and support for increased
related to preventing adulteration. In show that only 41 percent of surveyed government involvement in dietary
fact, under the statutory scheme a consumers who use vitamins and supplement regulation. We did not
dietary supplement is deemed to be minerals think those products are very describe the survey as illustrating CGMP
adulterated under section 402(g)(1) of safe, and only 50 percent think the problems associated with dietary
the act if it fails to meet CGMP products are somewhat safe; among supplements.
requirements we promulgate by those using herbal products, only 24 We also disagree that the risks cited
regulation. As we discussed in section percent thought the products were very in the preamble to the 2003 CGMP
III of this document, dietary supplement safe, and only 53 percent thought the Proposal are merely hypothetical or
CGMP requirements are necessary to products were somewhat safe. We noted theoretical. We provided actual
ensure the quality of the dietary that 74 percent supported increased examples of failures in the
supplement; ensuring quality includes government regulation of dietary manufacturing of products marketed as
ensuring that the dietary supplement supplements (see, id.). As one example dietary supplements. The comments
has been manufactured, packaged, of adulterated dietary supplements may have misunderstood what the
labeled, and held under conditions to caused by manufacturing practices, the CGMP requirements for dietary
prevent adulteration under section preamble to the 2003 CGMP Proposal supplements are intended to
402(a)(1), (a)(2), (a)(3), and (a)(4) of the mentioned an instance where a young accomplish. A principal goal of the
act. woman suffered a life-threatening CGMP requirements is to have those
We also disagree with those abnormal heart function that was traced who manufacture, package, label, or
comments stating that the requirements to a mislabeled or contaminated dietary hold dietary supplements do so in a
in part 110 are adequate and that no ingredient (68 FR 12157 at 12162). manner that ensures the quality of the
dietary supplement and that the dietary into the marketplace. The dietary describes the forms that dietary
supplement is packaged and labeled as supplement CGMP requirements ensure supplements intended to be ingested
specified in the master manufacturing adequate controls are in place to may take, i.e., tablet, capsule, powder,
record. It is the manufacturer who needs identify many of these types of softgel, gelcap, or liquid form, and if not
to establish procedures for its manufacturing errors before the product in such a form, limitations on how
manufacturing operations to ensure, for is in the marketplace and not through dietary supplements can be represented,
example, the final product is produced postmarketing adverse event reports or i.e., not as conventional food or as a sole
according to its specifications in the consumers’ illnesses.3 item of a meal or the diet.
master manufacturing record, meets The dietary supplement industry is Congress included separate additional
limits on contaminants, and is a quality diverse, as are the number and types of provisions under section 402 of the act
dietary supplement. If a product does products marketed as dietary (see section 402(f) and (g) of the act) for
not meet its specifications, a supplements. As we stated in the when a dietary supplement may be
manufacturer who observes the CGMP preamble to the 2003 CGMP Proposal adulterated. Congress considered that
requirements should know that and be (68 FR 12157 at 12163), given the wide dietary supplements may warrant CGMP
able to take corrective action before the range of public health concerns requirements that are different than
dietary supplement enters the presented by the manufacturing those for conventional food. Although
marketplace. The onus is on the practices for dietary supplements, a dietary supplements may include
manufacturer, and not simply on us, to comprehensive system of controls is substances that are used as ingredients
take action to prevent the adulterated necessary. This final rule will set the in conventional foods, the amounts
product from entering the market or, if standards for CGMP for dietary consumed as a dietary supplement and
the product has already been released, supplements that, if followed, will help as a conventional food product may not
to remove the product from the market. ensure the quality of the dietary be the same and, in fact, may be more
The umbrella food CGMP requirements supplement and that the dietary concentrated, and in higher amounts,
in part 110 do not contain specific supplement is packaged and labeled as when taken as a dietary supplement.
provisions establishing specifications, specified in the master manufacturing The forms in which dietary
requiring identity testing, or requiring record. The establishment of production supplements are consumed differ (e.g.,
in-process and/or finished product and process controls and adherence to capsule, tablet), as may the frequency,
testing. Through this final rule, we are these and other CGMP requirements of when compared to conventional foods.
establishing a new CFR part regarding this final rule will help to prevent the The uses of dietary supplements also
CGMP requirements specifically for types of events (and others) we differ from use as conventional food.
dietary supplements. described in the nine examples Consequently certain manufacturing
presented in the preamble to the 2003 practices considered to be a part of
The examples we used in the CGMP Proposal.
preamble to the 2003 CGMP Proposal CGMP for dietary supplement
(Comment 6) Several comments manufacturing may not be necessary for
included adverse event reports suggest that dietary supplements are no
associated with contamination with all types of food.
different in safety or physiologic effect
Digitalis lanata, the possible and require no different requirements C. What Comments Did We Receive on
contamination of botanical ingredients than conventional food with respect to Written Procedures?
with toxic compounds, the use of non- CGMP. One comment disagrees with us
food grade chemicals, the manufacture 1. Overview
that dietary supplements require
of super- and subpotent dietary different requirements than In the 2003 CGMP Proposal (68 FR
supplements, the presence of conventional food because dietary 12157 at 12165), we stated that written
undeclared ingredients, and the supplements are ground up or in procedures were included in the dietary
variability of ingredients from what is powder form and may not be easily supplement CGMP outline submitted to
declared on the label (Refs. 7, 8, and 10; recognized or differentiated; the us by industry, namely, the National
see, also, 68 FR 12157 at 12162 through comment says the same is true of many Nutritional Foods Association standards
12163). These were all examples where food ingredients as well. (NNFA), the NSF International draft
products were manufactured, labeled, (Response) We disagree with the standards, and the United States
and sold to the consumer as dietary suggestions by these comments that Pharmacopoeia (USP) draft
supplements. We disagree with the dietary supplement CGMP requirements manufacturing practices. We also stated
comments’ assertions that all these need not differ from those for that, to limit the burden to
problems can be adequately dealt with conventional foods. By definition, a manufacturers, we were not proposing
by the food CGMP requirements in part dietary supplement is in a category of to require written procedures for all the
110, but agree with the comment that, food separate and distinct from the requirements. We invited comment on
had there been a system in place ‘‘to category of conventional food. The whether we should require written
perform identity testing upon receipt, definition of dietary supplement in procedures for a variety of operations;
the manufacturer could have prevented section 201(ff) of the act, in part, specifically, for complying with the
that adulterated product from entering essentially describes a dietary CGMP requirements, under proposed
the market place.’’ Most of these supplement as a type of food that differs § 111.10 for personnel hygiene and for
examples present situations in which from conventional food. The definition preventing microbial contamination due
the manufacturer could have identified refers to section 411(c)(1)(B)(i) and to personnel (68 FR 12157 at 12182);
these problems through the dietary (c)(1)(B)(ii) of the act (21 U.S.C. maintenance, cleaning, and sanitation
supplement CGMP requirements for 350(c)(1)(B)(i) and (c)(1)(B)(ii)), which for the physical plant under proposed
specifications and testing or § 111.15 (68 FR 12157 at 12187);
examination, such as identity 3Mandatory reporting to FDA of serious adverse calibrating instruments and controls
verification, and could have prevented events is now required as a result of the enactment under proposed § 111.25(b), (c), and (d)
of the ‘‘Dietary Supplement and Non-Prescription
such products from entering the market Drug Consumer Protection Act’’ (Public Law 109–
(68 FR 12157 at 12191); maintaining,
or at least provided a greater assurance 462) signed into law on December 22, 2006 (see cleaning, and sanitizing equipment and
that such products would not make it discussion in section XX of this document). utensils under proposed § 111.25(e) (68
FR 12157 at 12192); calibrating, One comment points out that all well- testing, and approval or rejection of
inspecting, and checking automatic recognized quality systems require components, packaging, and labels;
equipment under proposed § 111.30 (68 establishment of written procedures to • Laboratory operations, including
FR 12157 at 12193); the duties of the ensure consistent process control, and the establishment of specifications and
quality control unit under proposed cites examples such as the International descriptions of laboratory test methods
§ 111.37 (68 FR 12157 at 12201); Organization for Standardization, the used to ensure that components, in-
implementing the proposed American National Standards Institute process materials, and finished product
requirements for receipt of components, (ANSI), and the Malcolm Baldridge meet established specifications;
dietary supplements, packaging, and National Quality Award criteria. Other • Packaging and labeling operations,
labels under proposed § 111.40(a) and comments state that written procedures including issuance and use of
(b) (68 12157 at FR 12203); preparing are necessary for the definition, appropriate labels, labeling, and
the master manufacturing record under operation, and documentation of a packaging materials;
proposed § 111.45 (68 FR 12157 at process control system, and that without • Holding and distribution
12205); laboratory operations under such procedures it would be virtually procedures, including procedures for
proposed § 111.60 (68 FR 12157 at impossible for any company, regardless quarantine and parameters for storage;
12209); manufacturing operations under of size, to consistently manufacture • Return and salvage operations;
proposed § 111.65 (68 FR 12157 at products that meet established • Handling of consumer complaints;
12211); packaging and labeling requirements for identity, purity, and
operations under proposed § 111.70 (68 • Procedures for product recall.
quality, strength, and composition. The Many comments assert an effective
FR 12157 at 12213); holding comments note that written procedures
components, dietary supplements, process control system that includes
contain the necessary instructions for all extensive written procedures would
packaging, labels, and in-process employees to successfully execute their
materials under proposed §§ 111.80 and justify a decreased testing burden with
respective functions. Another comment respect to the finished product. One
111.82 (68 FR 12157 at 12214); supports a requirement for conducting
identifying, quarantining, and salvaging comment suggests we exempt
key operations using written procedures manufacturers from the requirement to
returned dietary supplements under and states that records document that
proposed § 111.85 (68 FR 12157 at test each finished batch of product if
operations were performed, but that they have a qualified manufacturing
12216); and receiving, reviewing, and written procedures show how the task is
investigating consumer complaints process that meets certain basic criteria,
to be performed and at what frequency including a requirement for written
under proposed § 111.95 (68 FR 12157 it should be performed. One comment
at 12217). procedures for each stage of the process.
states effective communication is One comment notes it would be clearer
We stated that if comments assert that essential to build quality into a process,
written procedures are necessary, to all parties if specific written
and written procedures provide that procedures were listed as required and
comments should include an throughout all levels of an organization.
explanation of why the requirement is stresses the importance of having all
Another comment states it is difficult to companies know exactly what is
necessary to prevent adulteration imagine how the quality control unit
including how such a requirement procedurally expected of them.
could carry out its obligations under In addition to these general reasons
would ensure the identity, purity, proposed § 111.37(b)(1) to ‘‘approve or
quality, strength, and composition of the for requiring that key operations be
reject all processes, specifications, conducted using written procedures,
dietary supplement. Conversely, if controls, tests, and examinations, and
comments assert that written procedures several comments provide specific
deviations from or modifications to reasons for requiring that specific
are not necessary, we asked for an them * * *’’ if these are not subject to
explanation of why and how, in the operations be conducted using written
written procedures. procedures. In response to our request
absence of the requirement, one can Many comments which present one or
prevent adulteration and ensure the for comment on whether written
more of these general reasons for procedures should be required for
identity, purity, quality, strength, and requiring written procedures also list
composition of the dietary supplement. complying with proposed § 111.10
operations that they believe should be (personnel hygiene and for preventing
(Comment 7) Many comments stress conducted using written procedures.
the most critical aspect of a successful microbial contamination due to
The operations that one or more personnel), one comment states that
CGMP system is effective process
comments list as key operations are: written procedures help to ensure
control, which requires conducting key • Employee training;
operations using written procedures. • Cleaning the physical plant, compliance with the proposed hygiene
Several comments assert that written including pest control; requirements by clearly listing the
procedures are an important part of • Maintenance, cleaning, and requirements and requiring the
manufacturing operations to ensure sanitizing of equipment and utensils; employees to follow them on a
uniform practices in production • Calibration of equipment used in consistent basis.
operations, from receiving through final manufacturing or testing; In response to our request for
operations. Several comments assert • All aspects of the production comment on whether written
written procedures provide a sound process, including a general procedure procedures should be required for
basis for employee training and to document the minimum complying with the proposed
supervision. Several comments state investigation, review, and approval requirements for maintenance, cleaning,
that without a written training program, requirements for failures in and sanitation for the physical plant
it is very likely that some employees manufacturing or packaging operations; under proposed § 111.15, one comment
may not receive sufficient training, or in • All quality control operations; states that having written procedures in
some cases, any CGMP training at all. • Reprocessing of batches or start-up place to clean the physical plant will
One comment specifically suggests that materials that do not conform to ensure that there is no cross-
companies develop written procedures specifications; contamination. Another comment states
for the minimum CGMP training • Receipt, identification, utility areas such as effluent treatment,
common to all departments. examination, handling, sampling, boilers, cooling towers, and water
treatment plants also should have preparing the master manufacturing locations, manner of storage, and
documented procedures for cleaning in record; and one comment suggests such container and storage location
order to create a general awareness of a written procedure is not necessary identification codes.
cleanliness throughout the plant. Other because the proposed regulations for In response to our request for
comments state that such written preparing the master manufacturing comment on whether written
procedures should not be required record already delineate the procedures should be required for
because they would not directly prevent requirements for what information must complying with the proposed
contamination or ensure the identity, be included in the master requirements for returned dietary
purity, quality, strength, and manufacturing record. supplements, one comment states
composition of the dietary supplement In response to our request for written procedures should govern all
if, as the ‘‘bottom line,’’ a manufacturer comment on whether written return and salvage operations to create
maintains the physical plant in a clean procedures should be required for a standard for quarantine and salvage
and sanitary condition. complying with the proposed and to establish parameters for proper
Responding to our request for requirements for laboratory operations salvage conditions.
comment on whether written under proposed § 111.60, some Responding to our request for
procedures should be required for comments specifically note the need for comment on whether written
complying with the proposed written procedures for the laboratory procedures should be required for
requirements for calibrating instruments test methods used to ensure that complying with the proposed
and controls under proposed components, in-process materials, and requirements for handling consumer
§ 111.25(b), (c), and (d), several finished product meet established complaints, some comments state
comments assert we should require specifications. Some comments written procedures will encourage
manufacturers to establish and follow emphasize written procedures would companies to handle consumer
written procedures for calibrating create a standard for testing of products complaints in a uniform manner. One
equipment and controls. According to or groups of products and establishing comment asserts written procedures
these comments, such procedures parameters for passing or failing should be required for handling
would provide us with a written record products. consumer complaints because some
that is sufficient to evaluate the In response to our request for complaints could relate to serious
adequacy of the company’s calibration comment on whether written illness or injury. The comment states
procedures and would provide the procedures should be required for that written procedures would set out
necessary controls to meet the complying with the proposed exactly what steps need to be taken
underlying intent of the rule. These requirements for manufacturing when complaints are reviewed, and are
comments assert that written procedures operations under proposed § 111.65, one the best way to ensure the essential
will lessen the risk that adulterated comment asserts this is an effective way information is captured.
products will be produced. to train personnel and a means to hold (Response) We agree with the
In response to our request for operators accountable to a quality comments that effective process control,
comment on whether written standard. Another comment states using written procedures, is an
procedures should be required for written procedures can improve quality important aspect of a successful CGMP
complying with the proposed and consistency in a manufacturing program. We also agree requiring
requirements for maintaining, cleaning, operation. written procedures will help to ensure
and sanitizing equipment and utensils In response to our request for consistent practices in operations i.e.,
under proposed § 111.25(e), several comment on whether written help to ensure the operation is
comments assert such written procedures should be required for conducted in the same manner
procedures are crucial. These comments complying with the proposed regardless of who conducts the
claim that written procedures promote requirements for packaging and labeling operation or when the operation is
consistency, clearly lay out expectations operations under proposed § 111.70, one conducted. We also agree that written
for employees, facilitate training, and comment asserts this is an effective way procedures provide a sound basis for
provide a reference for individuals in to train personnel and a means to hold employee training and supervision, are
performing their job functions. One operators accountable to a quality an effective communication tool, and
comment states that written procedures standard. enable quality control personnel to carry
for maintaining, cleaning, and sanitizing Responding to our request for out the responsibility to approve or
equipment are an industry standard. comment on whether written reject all processes, specifications,
In response to our request for procedures should be required for controls, tests, and examinations, and
comment on whether written complying with the proposed deviations from or modifications to
procedures should be required for requirements for holding components, them. In addition, written procedures
complying with the proposed dietary supplements, packaging, labels, establish expectations for each covered
requirements for preparing the master and in-process materials under operation so the operation does not
manufacturing record under proposed proposed §§ 111.80 and 111.82, one proceed in an ad-hoc manner. Written
§ 111.45, one comment states that comment asserts this is an effective way procedures provide specific guidance if
written procedures for in-process to train personnel and a means to hold there is an unanticipated occurrence
control and quality checks should operators accountable to a quality and, thus, can play a key role in
ensure the addition of the proper standard. Another comment states a ensuring a quality product, because
ingredients in the proper amount, and company cannot be considered to be a actions to correct the unanticipated
proper blending and control of other CGMP operation without having written occurrence can take place swiftly and
critical points. Another comment states procedures for every product with confidence in the outcome.
written procedures are a critical element manufacturing activity, including This final rule establishes the
for ensuring consistent implementation holding and distributing. This comment minimum CGMPs necessary for
of proper corrective action. Other states mixups and adulterations will be activities related to manufacturing,
comments state they do not support a more likely to occur if there are no packaging, labeling, and holding dietary
requirement for written procedures for written procedures for control of storage supplements to ensure a quality
product. The operations required by this For example, volunteer food workers at We note that the manufacturers of
final rule must be conducted in a an outdoor music festival were found to equipment often provide written
consistent manner, regardless of who is be the source of contamination for an procedures for calibrating equipment.
conducting an operation or when the outbreak of Shigellosis (Ref. 11). Depending on your circumstances and
operation is conducted. As discussed in We include in final subpart B a applications, you may be able to rely on
the following paragraphs, with a few requirement (final § 111.8) that you written procedures provided by the
exceptions, we are requiring that you establish and follow written procedures manufacturer of the equipment with
establish and follow written procedures for fulfilling the requirements of subpart little or no modification.
to fulfill the requirements for the B. Final § 111.25(a), pertaining to
operations covered by this final rule. b. Written procedures for cleaning the establishing and following written
The exceptions include final subpart A, physical plant, including pest control procedures for calibrating instruments
which addresses the scope of the rule, (final subpart C). We agree with the and controls used in manufacturing or
rather than operations covered by the comments that written procedures for testing components or dietary
rule; final subparts E, H, and I, in which cleaning the physical plant would supplements, is similar to proposed
we conclude that a requirement for reduce the potential for cross- § 111.25(c)(1) which would provide an
written procedures would be redundant contamination and that such written option, in relevant part, that you
to other requirements; and final subpart procedures must include written establish written procedures for
P, which establishes requirements for procedures for pest control. Cleaning calibrating such instruments and
making and keeping records, rather than operations and pest control must be controls in addition to requiring you to
for conducting operations. conducted in a consistent manner, document that the procedure was
We believe requiring you to establish regardless of who conducts the followed each time a calibration is
and follow written procedures to fulfill operation or when it is conducted. performed.
the requirements of subparts B through Failure to conduct cleaning operations d. Written procedures for
D, F, G, and J through O, when and pest control in a consistent manner maintaining, cleaning, and sanitizing
combined with other requirements of could lead to failure in ensuring product equipment and utensils (final subpart
this final rule, justifies reduced quality. For example, application of a D). Maintaining, cleaning, and
requirements for testing finished chemical such as a fumigating agent or sanitizing equipment and utensils must
batches of product compared to the rodenticide in a production area must be conducted in a consistent and
proposed requirements for such testing be performed correctly to avoid appropriate manner, regardless of who
as found in proposed § 111.35. By contaminating dietary supplements. conducts the operation or when it is
establishing and following written Therefore, we disagree that written conducted. Failure to clean and sanitize
procedures, you will focus your procedures would not directly prevent equipment and utensils in a consistent
production and process control system contamination or ensure the identity, and appropriate manner could lead to a
on ensuring the quality of the finished purity, strength, and composition of the product that is adulterated because, for
product at each stage in the production dietary supplement even if a example, equipment and utensils that
process, rather than relying entirely on manufacturer maintains the physical are not properly cleaned and sanitized
testing at the end of the process. plant in a clean and sanitary condition. could be a source of microorganisms, or
We include in final subpart C a could lead to cross-contamination of
2. Written Procedures That Are requirement that you establish and products. In addition, failure to
Required by This Final Rule follow written procedures for cleaning maintain equipment in a consistent
a. Written procedures for personnel the physical plant and for pest control manner could lead to the failure to
(final subpart B). We believe that (final § 111.16). ensure product quality. For example,
successful programs for process control c. Written procedures for calibrating equipment that is properly maintained
are directly connected to appropriate instruments and controls and for is less likely to malfunction than
training programs. Employee training calibrating, inspecting, and checking equipment that is not maintained, and
must be conducted in a consistent automated, mechanical, or electronic using equipment that malfunctions
manner, regardless of who conducts the equipment (final subpart D). Calibrating could lead to errors in production, such
training or when it is conducted. Failure instruments and controls, and as dispensing an incorrect amount of
to conduct employee training in a calibrating, inspecting, and checking each ingredient.
consistent manner could lead to a automated, mechanical, or electronic We include in final subpart D a
failure in ensuring product quality. For equipment must be conducted in a requirement that you establish and
example, an employee who has not consistent manner, regardless of who follow written procedures for
received appropriate training on how to conducts the operation or when it is maintaining, cleaning, and sanitizing
conduct a specific physical examination conducted. Without a consistent equipment and utensils (final
to verify the identity of a dietary approach, the performance of these § 111.25(c)). Final § 111.25(c) applies to
ingredient may erroneously report that operations could lead to equipment that equipment, utensils, and any other
the correct ingredient was received produces inaccurate results. For contact surfaces used in labeling
when, in fact, the received dietary example, if a scale is out of calibration, operations as well as in manufacturing,
ingredient is related to, but different the wrong amounts of components packaging, and holding operations.
from, the ingredient that is specified in could be added to a mixer. We include Although the factors you must consider
the master manufacturing record. in final subpart D a requirement that for maintaining, cleaning, and sanitizing
We also believe the requirements that you establish and follow written equipment used for labeling operations
apply to preventing microbial procedures for calibrating instruments likely are different from those for
contamination due to sick or infected and controls that you use in equipment used in manufacturing or
personnel and that apply to proper manufacturing or testing a component packaging operations, you nevertheless
hygienic practices must be conducted in or dietary supplement (final § 111.25(a)) must determine the appropriate steps to
a consistent manner. For example, it is and for calibrating, inspecting, and take to ensure that labeling equipment
well known that foodborne illness can checking automated, mechanical, and is appropriately maintained and does
be transmitted by workers who are sick. electronic equipment (final § 111.25(b)). not become a source of contamination
for dietary supplements. For example, the equipment and it is not properly follow written procedures for
equipment used for labeling operations cleaned and/or sanitized. reprocessing from two perspectives: (1)
has a greater potential to contaminate a e. Written procedures for quality Determining whether reprocessing
dietary supplement when labeling control operations, including written should be approved or rejected and (2)
operations are carried out in concert procedures for conducting a material performing the reprocessing. In general,
with packaging operations, because the review and making a disposition reprocessing is performed when there is
dietary supplement could be exposed to decision and written procedures for a problem with the manufacturing
one or more contact surfaces during the approving or rejecting reprocessing process, such as when a specification is
packaging operations. (final subpart F). Quality control not met or any step in the master
Final § 111.25(c) requires you to operations must be conducted in a manufacturing record is omitted.
establish and follow written procedures consistent manner. Failure to carry out Depending on the nature of the dietary
for maintaining, cleaning, and quality control operations in a supplement, the manufacturing process,
sanitizing, as necessary, all equipment, consistent and appropriate way could and the problem, reprocessing may or
utensils, and any other contact surfaces lead to failure to ensure product quality may not be able to correct the problem.
used to manufacture, package, label, or and to ensure the dietary supplement is From the perspective of determining
hold components or dietary packaged and labeled as specified in the whether reprocessing should be
supplements. Final § 111.25(c) relates to master manufacturing record. For approved or rejected, under the final
proposed § 111.25(e)(1) which would, in example, you could use a component rule it is quality control personnel who
relevant part, require you to maintain, that should not have been released for must approve or reject any reprocessing
clean, and sanitize as necessary, all use in manufacturing, or you could (see final §§ 111.90, 111.113, 111.120,
equipment, utensils, and contact distribute a packaged and labeled 111.123, and 111.130). The decision to
surfaces used to manufacture, package, dietary supplement that should not have approve reprocessing must be made in
label, or hold components, dietary been released for distribution. a consistent manner, regardless of who
ingredients, or dietary supplements. We include in final subpart F a conducts the operation or when it is
requirement that you establish and conducted. For example, if it is not
(Comment 8) Some comments suggest
follow written procedures for quality possible to test the product at the
that written procedures for maintaining,
control operations (final § 111.103). We finished batch stage to determine
cleaning, and sanitizing equipment
agree with the comments that there whether the reprocessing corrected the
require visual inspection of equipment
should be written procedures for problem (because, for example, there is
when more than one product is
investigating failures in manufacturing no scientifically valid method available
manufactured using the same
operations. In the 2003 CGMP Proposal, to test for a specification that is directly
equipment, and that the presence of we referred to the process of
residual components from one product related to the reason for reprocessing),
investigating such failures as a ‘‘material you must have a clear basis to decide
in a different product could be harmful. review’’ and proposed a series of
The comments also suggest the written that reprocessing will actually correct
requirements related to a material the problem or you will not know if all
procedures include residual limits of review and the disposition decision that required specifications can be met.
components from different product lines follows a material review. The review Without written procedures for
to guarantee the safety of the dietary must be conducted in a consistent approving reprocessing, different
supplement. manner, and the criteria for making a individuals who approve or reject any
(Response) The final rule gives you disposition decision must be consistent, reprocessing could make very different
flexibility to develop written procedures regardless of who is conducting the decisions on when reprocessing can
appropriate to your products and material review or when it is conducted, correct a problem and when it cannot.
equipment. Consequently, final and regardless of who makes the Therefore, we are specifically requiring
§ 111.25(c) neither requires nor disposition decision and when the that the written procedures for quality
prohibits any specific procedure, such decision is made. For example, if you do control operations include written
as the visual inspection suggested by the not have written criteria for determining procedures for approving or rejecting
comment. whether a deviation from specifications any reprocessing.
As for the residual limits, the has resulted in, or could lead to, From the perspective of performing
comment provides no data or other adulteration, different individuals who the reprocessing, we agree that any
information that would provide a basis conduct a material review could reach procedure for reprocessing must be
for setting residual limits for any different decisions regarding the written because, for example, quality
particular components. However, as we appropriate disposition of the affected control personnel may need to rely on
discuss more fully in the discussion of dietary supplement, including decisions the procedure that you followed to
final § 111.70(e) in section X of this that incorrectly result in the release of determine whether all specifications are
document, the final rule requires you to an adulterated product. As discussed met for the reprocessed material.
establish and meet specifications for the more fully in sections X and XI of this However, the final rule requires you to
identity, purity, strength, and document, the final rule requires that document any reprocessing in the batch
composition of dietary supplements and quality control personnel conduct all record (final § 111.260(n)) rather than
for limits on contamination for dietary required material reviews and make all establishing and following written
supplements that you manufacture. required disposition decisions. procedures to conduct reprocessing,
When considering the specifications Therefore, we are requiring that the because the actual procedure you follow
you must establish to ensure the quality written procedures for quality control to reprocess a dietary supplement likely
of the dietary supplements, you must operations include written procedures will be different depending on the
take into account the need to ensure that for conducting a material review and circumstances.
components or dietary supplements are making a disposition decision (final f. Written procedures for components,
not contaminated as a result of using the § 111.103). packaging, labels, and product that is
same equipment. Such equipment could We considered the comments that received for packaging and labeling as
be a source of contamination if more suggest that there should be a a dietary supplement (final subpart G).
than one product is manufactured using requirement for you to establish and We agree with the comments that the
receipt, examination, quarantine, and operations would be an effective way to specified in the master manufacturing
release from quarantine of components, train personnel, provide a means to hold record. For example, if you do not have
packaging, labels, and product that are operators accountable to a quality procedures for identifying filled, but
received for packaging and labeling as standard, and improve quality and unlabeled, containers of dietary
dietary supplements must be conducted consistency in a manufacturing supplements, mixups could occur
in a consistent manner, regardless of operation. The final provisions for before the labels are applied. The final
who conducts the operation or when it manufacturing operations require you to product could contain ingredients other
is conducted. Failure to carry out these design or select manufacturing than those identified on the label
operations in a consistent way could processes to ensure that dietary specified in the master manufacturing
lead to failure to ensure product quality supplement specifications are record. Therefore, we include in final
if, for example, you use a component consistently achieved, conduct all subpart L a requirement that you
that should not have been released for manufacturing operations in accordance establish and follow written procedures
use in manufacturing. with adequate sanitation principles, and for packaging and labeling operations
We include in final subpart G a take all necessary precautions to prevent (final § 111.403).
requirement that you establish and contamination of components and j. Written procedures for holding and
follow written procedures for fulfilling dietary supplements. These distributing operations (final subpart
the requirements of subpart G (final manufacturing operations must be M). We agree with the comments that
§ 111.153). conducted in a consistent manner, written procedures for holding and
g. Written procedures for laboratory regardless of who conducts the distributing operations are an effective
operations (final subpart J). Testing and operation or when it is conducted. means to hold operators accountable to
examination of components, packaging, Failure to perform these operations in a CGMP standards, and that mixups and
labels, and product that are received for consistent way could lead to failure to other problems that affect the final
packaging or labeling as a dietary ensure the quality of the dietary product will be more likely to occur if
supplement, or packaged and labeled supplement. For example, surfaces that there are no written procedures for
dietary supplements, must be conducted come in contact with a dietary operations such as control of storage
in a consistent manner, regardless of supplement are potential sources of locations, manner of storage, and
who conducts the operation or when it microbial contamination if consistent container and storage location
is conducted. The reason a firm procedures are not in place to ensure identification codes. The final
conducts these tests and examinations is good sanitary practices. We are provisions for holding and distributing
to ensure that a dietary supplement including in final subpart K a operations require, among other things,
meets established specifications. Failure requirement that you establish and that you hold components and dietary
to conduct tests and examinations in a follow written procedures for
consistent manner could lead to failure supplements under appropriate
manufacturing operations (final conditions of temperature, humidity,
in ensuring the quality of the dietary
§ 111.353). and light so that the identity, purity,
supplement. For example, a test
designed to determine the concentration i. Written procedures for packaging strength, and composition of the
of a product before it is diluted to the and labeling operations (final subpart components and dietary supplements
appropriate concentration could provide L). We agree with the comments that are not affected; that you hold
different results if it is conducted in a written procedures for packaging and components, dietary supplements, and
different manner by different labeling operations are an effective in-process materials under conditions
individuals. means to hold operators accountable to that do not lead to the mixup,
In addition, laboratory operations ensure the quality of the dietary contamination, or deterioration of
such as use of criteria for establishing supplement and that the dietary components or dietary supplements;
appropriate specifications and use of supplement is packaged and labeled as and that you distribute dietary
sampling plans for obtaining specified in the master manufacturing supplements under conditions that will
representative samples must be record. The final provisions for protect them against contamination and
conducted in a consistent manner, packaging and labeling operations deterioration.
regardless of who conducts the require that you fill, assemble, package, These holding and distributing
operation or when it is conducted. For label, and perform other related operations must be conducted in a
example, failure to consider that operations in a way that ensures the consistent manner, regardless of who
specifications are needed to ensure that quality of the finished product, conducts the operation or when it is
a dietary supplement derived from a including practices such as cleaning and conducted. Failure to follow these
botanical source does not contain sanitizing all filling and packaging requirements for holding and
contaminants, such as an unlawful equipment, utensils, and containers; distributing in a consistent manner
pesticide, could result in a dietary protecting manufactured dietary could lead to a failure to ensure the
supplement that contains unsafe levels supplements against airborne quality of the dietary supplement
of a contaminant. contamination, using sanitary handling product. For example, if employees do
We include in final subpart J a procedures; taking actions to prevent not know how to store an in-process
requirement that you establish and mixups; and suitably disposing of batch of a botanical dietary supplement
follow written procedures for laboratory obsolete packaging and labels. These to control humidity, the growth of mold
operations, including written packaging and labeling operations must could be promoted. Furthermore, if a
procedures for the tests and be conducted in a consistent manner, distributor does not refrigerate a dietary
examinations that you conduct to regardless of who conducts the supplement that requires refrigeration to
determine whether specifications are operation or when it is conducted. ensure its strength, the dietary
met (final § 111.303). Failure to perform these operations in a supplement may not meet its
h. Written procedures for consistent way could lead to a failure to specification for strength. Therefore, we
manufacturing operations (final subpart ensure the quality of the dietary include in final subpart M a
K). We agree with the comments that supplement and that the dietary requirement that you establish and
written procedures for manufacturing supplement is labeled and packaged as follow written procedures for holding
and distributing operations (final regardless of who conducts the met (final §§ 111.73 and 111.75); collect
§ 111.453). operation or when it is conducted. representative samples (final § 111.80);
k. Written procedures for returned Failure to comply with these hold reserve samples of packaged and
dietary supplements (final subpart N). requirements for review and labeled dietary supplements (final
We agree with the comments that investigation of a product complaint in § 111.83); have quality control
written procedures for returned dietary a consistent way could lead to a failure personnel conduct all required material
supplements would help to ensure to ensure the quality of the dietary reviews and make all required
appropriate handling of such supplement. For example, if you do not disposition decisions (final § 111.87);
supplements prior to a disposition have a procedure in place to determine and adhere to certain requirements for
decision. The final rule requires you, whether the product complaint involves treatment, in-process adjustments, and
among other things, to identify and a possible failure of a dietary for reprocessing (final § 111.90).
quarantine returned dietary supplement to meet any of its In considering whether we should
supplements until quality control specifications, you may not recognize require that you establish and follow
personnel conduct a material review that a particular product complaint is written procedures to fulfill the
and make a disposition decision. You indicative that a problem has occurred requirements of final subpart E, we
must destroy, or otherwise suitably with one of your manufacturing evaluated whether requirements in
dispose of, any returned dietary processes. That undiscovered problem other subparts that address specific
supplement that quality control may lead to continued distribution of operations for the production and
personnel do not approve for salvage or product that is contaminated or process control system substitute for the
reprocessing. These operations for otherwise not consistent with your requirement of written procedures in
returned dietary supplements must be specifications in the master final subpart E.
conducted in a consistent manner, manufacturing record. Therefore, we Final subparts F through M establish
regardless of who conducts the include in final subpart O a requirement specific requirements for
operation or when it is conducted. that you establish and follow written manufacturing, packaging, labeling, and
Failure to comply with these procedures to fulfill the requirements of holding dietary supplements, including
requirements for quarantine, salvage, subpart O (final § 111.553). requirements for quality control
and disposition in a consistent way operations (final subpart F);
could lead to a failure to ensure the 3. Written Procedures That Are Not components, packaging, labels, and
quality of the dietary supplement. For Required by This Final Rule product that is received for packaging
example, if an investigation leads to a a. Written procedures for final subpart and labeling as a dietary supplement
conclusion that a dietary supplement E (‘‘Requirement to Establish a (final subpart G); establishing a written
requiring refrigeration to ensure its Production and Process Control master manufacturing record and batch
strength was not refrigerated while held System’’). In the CGMP proposal, we did record (final subparts H and I);
at a customer’s warehouse, and this not specifically request comments on laboratory operations (final subpart J);
dietary supplement was not quarantined whether we should require that you manufacturing operations (final subpart
while quality control personnel establish and follow written procedures K); packaging and labeling operations
conducted a material review, the dietary to fulfill the requirements of proposed (final subpart L); and holding operations
supplement could be inadvertently co- § 111.35 (‘‘What Production and Process (final subpart M). We require you to
mixed with other containers of that Controls Must You Use?’’), and we establish and follow written procedures
same lot of product and then received no specific comments to fulfill the requirements of final
inadvertently redistributed. Therefore, regarding whether we should establish subparts F, G, J, K, L, and M. Given
we are including in final subpart N a and follow such written procedures. these requirements, we conclude it
requirement that you establish and Given the strong support in the would be redundant to require you to
follow written procedures to fulfill the comments for the use of written establish and follow written procedures
requirements of subpart N (final procedures in a production and process to fulfill the requirements of final
§ 111.503). control system, we nonetheless §§ 111.55, 111.60, and 111.65 in subpart
l. Written procedures for product considered whether the requirements E.
complaints (final subpart O). We agree that we establish in final subpart E, Final subpart J requires you to
with the comments that written Requirement to Establish a Production establish and follow laboratory control
procedures for handling consumer and Process Control System, would processes that include the use of criteria
complaints (now called product require written procedures. for establishing appropriate
complaints) will encourage companies Final subpart E requires that you specifications (final § 111.315(a)); use of
to handle product complaints in a implement a system of production and sampling plans for obtaining
consistent manner and help ensure the process controls that covers all stages of representative samples (final
essential information is captured during manufacturing, packaging, labeling, and § 111.315(b)); use of criteria for selecting
investigation of a product complaint. holding of the dietary supplements and appropriate examination and testing
The final rule requires you, among other that your system be designed to ensure methods (final § 111.315(c)); use of
things, to review all product complaints the quality of the dietary supplement criteria for selecting standard reference
to determine whether the product and that the dietary supplement is materials used in performing tests and
complaint involves a possible failure of packaged and labeled as specified in examinations (final § 111.315(d)); and
a dietary supplement to meet any of its your master manufacturing record (final use of test methods and examinations in
specifications; investigate any product §§ 111.55 and 111.60); implement accordance with established criteria
complaint that involves a possible quality control operations to ensure the (final § 111.315(e)). In addition, under
failure of a dietary supplement to meet quality of dietary supplements and that final § 111.303 you must establish and
any of its specifications; and extend the the dietary supplement is packaged and follow written procedures for laboratory
review and investigation of the product labeled as specified in your master operations. Given the requirements of
complaint to all relevant batches and manufacturing record (final § 111.65); final subpart J, we conclude it would be
records. These operations must be establish specifications (final § 111.70); redundant to require you to establish
conducted in a consistent manner, determine whether specifications are and follow written procedures to fulfill
the requirements of final §§ 111.70, procedures for preparing the master written procedures for product recalls.
111.75, and 111.80 in subpart E. manufacturing record. Under final However, we encourage you to refer to
Final subpart M establishes subpart H, the master manufacturing our ‘‘Guidance for Industry: Product
requirements for holding reserve record must include written Recalls, Industry Removals and
samples. Under final § 111.453, you instructions, including specifications for Corrections’’ (Ref. 12) (available at
must establish and follow written each point, step, or stage in the http://www.fda.gov/opacom/
procedures for holding operations. manufacturing process where control is 7alerts.html).
Given the requirements of final subpart necessary to ensure the quality of the
M, we conclude that it would be D. Other Comments on Written
dietary supplement and that the dietary
redundant to require you to establish Procedures
supplement is packaged and labeled as
and follow written procedures to fulfill specified in the master manufacturing (Comment 9) One comment stresses
the requirements of final § 111.83 in record; procedures for sampling, testing, the need for flexibility in requiring
subpart E for reserve samples. and examinations; specific actions written procedures, based on differences
Final subpart F establishes necessary to perform and verify points, between individual activities and
requirements for quality control steps, or stages in the manufacturing companies. The comment suggests
personnel to conduct a material review process where control is necessary to companies should be required to review
and make a disposition decision (final ensure the quality of the dietary and determine the need for written
§ 111.113); approve any reprocessing supplement and that the dietary procedures at each critical step of their
(final § 111.123(a)(5)); and document supplement is packaged and labeled as operations and be prepared to defend
any material review and disposition specified in the master manufacturing those determinations as necessary.
(final § 111.140(b)(3)). In addition, as record; special notations and (Response) To the extent the comment
discussed, under final § 111.103 you precautions to be followed; and suggests we do not require any written
must establish and follow written corrective action plans for use when a procedures specific to a particular
procedures for quality control specification is not met. With all of this function or requirement, and allow
operations. Given the requirements of detail specified for the written firms to decide when and when not to
final subpart F, we conclude that it instructions the master manufacturing include them, we disagree. We believe
would be redundant to require that you record must include, we believe a that written procedures for the specific
establish and follow written procedures written procedure for developing a operations we have identified should
to fulfill the requirements of final master manufacturing record can be not be optional. We have no objection
§§ 111.87 and 111.90 in subpart E. optional. Therefore, we do not require if firms decide to establish and follow
We conclude that it would be you to establish and follow written additional written procedures, beyond
redundant to require you to establish procedures for preparing the master those we require in this final rule.
and follow written procedures for each manufacturing record. Although we require written procedures
of the requirements established in final A batch is prepared by following the for entire subparts, or specific
subpart E. We, therefore, do not require written instructions provided in the requirements within certain subparts,
you to establish and follow written master manufacturing record. The we provide flexibility for firms to
procedures to fulfill the requirements master manufacturing record functions establish those written procedures that
established in subpart E. as a written procedure for the will ensure the requirements are met.
b. Written procedures for preparing production of the batch. Therefore, we (Comment 10) Some comments stress
the master manufacturing record (final do not require you to establish and the importance of written procedures in
subpart H) and for preparing the batch follow written procedures for the batch enabling FDA to ensure compliance
record (final subpart I). As discussed in production record because such with the dietary supplement CGMP
the 2003 CGMP Proposal (68 FR 12157 practices would be redundant to the requirements.
at 12203), a master manufacturing requirements for the master (Response) We believe written
record is analogous to a recipe that sets manufacturing record in final subpart H. procedures will help us to ensure
forth the ingredients to use, the amounts c. Written procedures for records and compliance with these CGMP
of ingredients to use, the tests to recordkeeping (final subpart P). Final requirements because they will clearly
perform, and the instructions for subpart P establishes general communicate the steps the firm must
preparing the quantity the recipe calls requirements for making and keeping take to satisfy the requirements. During
for. This master manufacturing record records required in other subparts. We an inspection, we observe the practices
helps ensure that you manufacture each did not request comments on written that employees follow. However, to
ingredient or dietary supplement in a procedures, nor did we receive any ensure that a firm is consistently
consistent and uniform manner. If you comments that supported such a complying with CGMP requirements,
neglect to follow the master requirement. Because we believe that our investigators need access to records
manufacturing record, you might not requiring written procedures to fulfill that both describe a firm’s processes and
add all of the necessary components in subpart P requirements would be procedures and demonstrate whether
the appropriate strength or amount, and redundant or unnecessary, we do not the firm has been following them. Under
this could result in a final product not require such written procedures. the final rule, we require you to make
consistent with the master d. Written procedures for product and keep records of the written
manufacturing record. Thus, you must recalls. We acknowledge that a product procedures in each applicable subpart.
follow a written master manufacturing recall by persons who manufacture, Such records would be available to us
record in a consistent manner, package, label, or hold dietary under the requirements of final subpart
regardless of who conducts the supplements must be conducted in a P, Records and Recordkeeping.
operation or when it is conducted. consistent manner, regardless of who (Comment 11) Many comments object
However, we agree with the conducts the operation or when it is to FDA’s stated reasons for not requiring
comments that the specific requirements conducted. However, the final rule does written procedures for most activities,
for what must be in the master not establish any requirements for including concerns about cost control
manufacturing record make it product recalls. Therefore, we do not and burden reduction. The comments
unnecessary to require written require you to establish and follow contend that written procedures
actually save time and other resources The general parameters include the rule should stay focused on end
because they greatly facilitate employee identification of the company; title that results and not process.
training and ensure that activities are reflects the activities to be performed; (Response) We disagree. The essence
performed consistently and correctly. identification or control number with a of good manufacturing practice that is
Some comments assert most companies revision level code; effective date; the established by this final rule is a
already have written procedures in number of pages in the procedure (e.g., production and process control system
place, so start-up costs associated with by a procedure such as listing page that is designed to ensure the quality of
such requirements would be minimal. numbers using a convention such as the dietary supplement.
One comment notes written procedures ‘‘page 1 of 4’’); approval date and
would be among the least costly of all E. What Other General Comments Did
signature(s); references to linked or
the procedural requirements proposed We Receive?
related procedures or forms; definitions
by FDA. of technical terms and acronyms; list of (Comment 16) Some comments say
(Response) We agree that requiring equipment, materials, and supplies any final rule should not require written
that operations be conducted using needed in performing the task; who has procedures, should not propose a
written procedures can save time and the responsibility for performing each definition of appropriate tests, and
other resources by facilitating employee task; when and where a task is to be generally should not include
training and ensuring operations are performed; concise step-by-step requirements for procedures better left
performed consistently and correctly. instructions for performing the task; the to ‘‘normal business practices.’’ The
Because following written procedures expected results from performing the comments cited Executive Order 12866
can help ensure uniformity in the task; what data to collect; and how to and the Small Business Regulatory
process and ensure the quality of the analyze, file, or report the collected Enforcement Flexibility Act (SBREFA).
dietary supplement at every step, data. In the specific case of written The comment added that there is no
periodic end product testing can be procedures for cleaning equipment and such requirement in the food CGMPs or
sufficient to determine whether your utensils, some comments suggest the in the 1997 ANPRM.
manufacturing process is controlled. written procedures include descriptions (Response) We disagree the final rule
CGMP is premised upon quality of appropriate cleaning agents, methods violates either Executive Order 12866 or
assurance at every step of the process. of cleaning, and the intervals and SBREFA and discuss this in section
It is less costly to establish and follow schedules for cleaning equipment. XXIV of this document. We address
written procedures than it would be to (Response) We agree the suggestions SBREFA’s regulatory flexibility issues
test each finished batch for conformance provided by these comments are useful by staggering compliance dates so that
with specifications. As suggested by to include in any written procedures. certain businesses would have 24 and
these comments, our analysis (section However, to provide the flexibility 36 months, respectively, to comply with
XXIV of this document) shows that the necessary to address diverse dietary the final rule. As for the assertion that
overall costs are reduced, in part, supplement manufacturing processes, food CGMPs do not require written
because requiring that certain procedures, we discuss the
we are leaving details such as these to
operations be conducted using written requirements of food CGMPS in relation
the judgment of the company rather
procedures enables us to reduce to the requirements of these dietary
than prescribing them within the final
requirements for testing at the finished
rule. supplement CGMPs in section V of this
batch stage.
(Comment 14) Some comments document. The comment’s assertion that
(Comment 12) One comment states
training employees on the required request the final rule include the 1997 ANPRM did not contain
hygienic practices prior to their first day requirements for managing changes to written procedures is incorrect. The
of handling product is critical to written procedures. One comment states industry draft that we published in the
ensuring product safety. changes to written procedures should be 1997 ANPRM had multiple written
(Response) The requirement to reviewed, justified, documented, procedures, including written
establish and follow written procedures approved, and implemented in a procedures for:
to fulfill the requirements of subpart B defined manner. The comments explain • Cleaning and maintaining
does not establish any fixed requirement that ‘‘Change control procedures’’ define equipment and utensils used in the
for when an employee must receive what is and what is not covered by the manufacture of products;
such training relative to when the written procedure and how proposed • The receipt, identification,
employee handles product. However, changes will be identified or examination, handling, sampling,
final § 111.12(c) requires that any recommended, processed, reviewed, testing, and approval or rejection of raw
person engaged in manufacturing, and approved. materials;
packaging, labeling, or holding, or in (Response) As discussed in final • Appropriate tests and/or
performing any quality control subpart F, the final rule requires that examinations to be conducted to assure
operations, must have the education, quality control personnel approve all the purity, composition, and quality of
training, or experience to perform the written procedures. ‘‘All’’ written the finished product;
person’s assigned functions. We procedures includes revisions to written • The method for reprocessing
therefore assume that employees will procedures. As discussed in this batches or operational start-up materials
have the necessary education, training, section, the final rule requires you to that do not conform to finished goods
or experience for each operation that establish and follow written procedures standards or specifications;
they perform before they perform it. for quality control operations. We • The control procedures employed
(Comment 13) Some comments make believe that procedures for managing for the receipt, storage, handling,
recommendations for what written changes to written procedures can be sampling, examination, and/or testing
procedures should contain, including addressed within the written procedures that may be necessary to assure the
general parameters that should be for quality control operations. identity of labeling and the appropriate
included in all written procedures and (Comment 15) Some comments assert identity, cleanliness, and quality
specific parameters that should be the final rule should not require written characteristics of packaging materials
included in specific written procedures. procedures for key operations because for dietary products;
• Ensuring correct labels, labeling, V. What Legal Authority Comments Did entail overly burdensome methods for
and packaging materials are issued and We Receive? production and process controls. Some
used for dietary products; and Many comments were submitted from comments contend that some of the
• Describing the handling of all individuals, companies, and trade proposed rule requirements exceed the
written and oral complaints regarding a groups concerning our legal authority drug CGMP requirements.
Most of the comments assert that the
product. for this rule. Most of the comments
proposed dietary supplement CGMP
(62 FR 5700 at 5704 through 5706). question the scope of the rule based on
requirements are not modeled after the
the language in section 402(g) of the act
(Comment 17) In the analysis of CGMP regulations for food. The reasons
(21 U.S.C. 342(g)) stating that
impacts in the 2003 CGMP Proposal (68 for this assertion vary. Some assert that
‘‘regulations shall be modeled after
FR 12157 at 12222), we stated that we certain provisions in the proposed rule
current good manufacturing practice
had considered imposing fewer CGMP were not found in, or differ from, the
regulations for food.’’ Other comments provisions in part 110. Examples of
requirements for the manufacture of question our authority for records
vitamins and minerals. Although this proposed requirements that comments
access. Some comments assert that indicate exceeded food CGMP included
issue arose as a discussion of regulatory certain provisions of the proposed rule
options that we had considered and batch testing, packaging and labeling,
are unconstitutionally vague, and recordkeeping, consumer complaints,
rejected, we received several comments therefore violate the Fifth Amendment. and the use of validated methods. Other
on this subject. Some comments state A few comments disagree with our comments state that the proposed
we should not create different CGMP rationale for why dietary supplements requirements exceeded those for food
standards based upon the type of dietary are different than conventional food and because the proposed rule provided for
ingredient. These comments state that need separate CGMP requirements. We finished testing of certain substances
one set of appropriately flexible address these comments immediately when used as dietary supplements, such
standards would be more efficient and below in this section. as garlic and ginger, whereas no such
less confusing to industry than separate testing is required under existing food
A. Modeled After CGMP for Food
standards for each portion of the CGMP regulations when those same
industry. Some comments say that (Comment 18) Some comments substances are used as conventional
different requirements for vitamins and support our approach of proposing food. One comment says the rule was
minerals would cause problems because requirements that are more modeled after juice hazard analysis and
most people who use these products comprehensive than the CGMP critical control point (HACCP) and
take a multivitamin/mineral preparation requirements for food. One comment therefore goes beyond existing food
as their primary and sole dietary states that the current requirements for CGMP regulations.
supplement, so the risk of adverse food CGMP are less comprehensive than Some comments assert that the
events arising from adulteration, the CGMP requirements in current use proposed requirements exceed the
misidentification, or misformulation of by both the food and dietary existing food CGMP regulations because
products would be much higher if supplement industries and the current certain proposed provisions contained a
vitamins and minerals were subject to ‘‘best practices’’ should be incorporated level of detail that is not in the food or
fewer requirements compared to other into the dietary supplement CGMP rule. the drug CGMP regulations, or because
dietary supplements. Other comments Several comments state that the elements of a provision in the proposed
supported the concept of differing requirements for dietary supplement rule were similar to a provision in part
standards. Some comments assert, in CGMP do not need to be identical to the 210 (21 CFR part 210) (drug CGMP
order for the CGMP regulations to set requirements in existing food CGMP regulation). Other comments disagree
minimum quality standards for all regulations, that appropriate with our rationale that the proposed
dietary supplements, we would have to manufacturing controls are needed for rule was designed on the same
regulate each facet of the manufacture, dietary ingredients contained in dietary principles as the existing food CGMP
packaging, and storage of a dietary supplements to protect the public regulations to address the characteristics
health, that some borrowing of drug and hazards specific to dietary
supplement independently of product
CGMP concepts may be necessary, and supplements, or to prevent adulteration
type. These comments state reducing
that we should balance effective control in preparing, packaging, or holding
the requirements for vitamin and
with necessary flexibility in the dietary dietary supplements. The comments
mineral manufacturers would not allow
supplement CGMP rule. In addition, one also disagree that we may include
the development of minimum quality
comment states that the USP provisions in the dietary supplement
standards across the entire dietary
manufacturing guidelines, which CGMP final rule that were not found in
supplement industry.
contain wording from the drug CGMP the food CGMP regulations at the time
(Response) The concept of fewer requirements, are a model for dietary DSHEA was enacted.
requirements for vitamins and minerals supplement CGMP for many in Several comments state that we
was simply one regulatory option we industry. exceed our legal authority for the
considered as part of the 2003 CGMP Several comments express concern proposed rule because it used too broad
Proposal’s analysis of impacts (see 68 about not deviating too drastically from a definition of ‘‘modeled after.’’ Some
FR 12157 at 12220 through 12223). We the requirements in existing food CGMP comments offer their own definitions of
rejected it (id.). We disagree with the regulations. Although several comments ‘‘model;’’ others object to the use of the
comments that there should be fewer recognize that additional CGMP noun form ‘‘model’’ and provide
CGMP requirements for vitamins and provisions for dietary supplements, dictionary definitions of the verb form
minerals. Neither the 2003 CGMP such as those related to identity, purity, ‘‘modeled.’’ A few comments assert that
Proposal, nor this final rule, imposes strength, quality, and composition, are the meaning of ‘‘model’’ is clear, despite
fewer requirements on vitamin or needed, the comments say that we different dictionary meanings, and that
mineral firms compared to firms that should not regulate dietary supplement the statute is not ambiguous under
make other types of dietary manufacturing in the same manner as Chevron U.S.A. Inc. v. Natural
supplements. drug manufacturing because it would Resources Defense Council, 467 U.S.
837 (1984) (‘‘Chevron’’). One comment with two questions. First, has Congress identical to the original, but instead are
states that, even if the language is directly and unambiguously spoken to contemplated to differ from the original.
ambiguous and our interpretation merits the precise question at issue? (‘‘Chevron Thus, the additional, independent
deference, our interpretation is too step one’’) (see Chevron, 467 U.S. at authority to promulgate CGMP
expansive and not based on a 842.) To find no ambiguity, Congress regulations for dietary supplements that
permissible construction of the statute. must have clearly manifested its Congress provided in section 402(g) of
Another comment states that we did not intention with respect to the particular the act, without delineating what
explain why our interpretation was issue (see Young v. Community requirements such a regulation could or
consistent with our congressional Nutrition Institute, 476 U.S. 974, 980 could not include, left us with
mandate. (1986)). If Congress has spoken directly considerable authority to fill in the gaps
(Response) We agree with the and plainly, we must implement in ways that recognize the differences
comments stating that the dietary Congress’s unambiguously expressed between dietary supplements and other
supplement CGMP requirements in this intent (see Chevron, 467 U.S. at 842– foods that warrant different
final rule need not be identical to the 843). Second, if the act is silent or manufacturing controls. A contrary
existing food CGMP regulations and that ambiguous with respect to a particular interpretation, as some comments
a system of manufacturing controls issue in section 402(g) of the act, is our suggested, that the ‘‘modeled after’’
specific to dietary supplements is interpretation based on a permissible language means the requirements for
needed. We do not agree that we construction of the statute (‘‘Chevron dietary supplement CGMP must be
exceeded the scope of our authority step two’’) (Chevron, 467 U.S. at 843; precisely found in current part 110, or
under section 402(g) of the act in issuing FDA v. Brown & Williamson Tobacco other food CGMP regulations, would so
the proposed requirements for dietary Corp., 529 U.S. 120, 132 (2000))? When narrowly circumscribe our discretion as
supplement CGMP or these final Congress leaves a gap for the agency to to make it impossible to tailor the
requirements. Our interpretation of the fill by regulation, the regulation will regulation to fit the products it is
language in section 402(g) of the act, pass muster so long as it is not designed to address. Such an
including the ‘‘modeled after’’ language, ‘‘arbitrary, capricious, or manifestly interpretation would lead to a rule that
as to what requirements of the act we contrary to the statute’’ (Chevron, 467 would ‘‘frustrate the success of the
have authority to issue, is based on a U.S. at 843–844). regulation undertaken by Congress’’
permissible construction of the statute. We believe that the language in because it would not take into
The comments present the following consideration the characteristics,
section 402(g) of the act provides an
general questions: (1) Whether the hazards, and manufacturing practices
express delegation of authority to us to
statute gives us authority to promulgate specific to dietary supplements
promulgate a regulation to ‘‘prescribe
CGMP requirements for dietary (American Trucking Ass’ns v. U.S., 344
supplements that are not identical to the good manufacturing practices for dietary
supplements’’ so long as those U.S. 298, 311 (1953)).4
requirements in existing CGMP Congress has also spoken to the
regulations for food and (2) if so, regulations are ‘‘modeled after the
current good manufacturing practice precise question of which requirements
whether the requirements in this final CGMP ‘‘regulations for food.’’ The plain
rule that differ from those in existing regulations for food.’’ The express
language in section 402(g) of the act meaning of ‘‘regulations’’ is plural (more
CGMP regulations for food are fairly than one), and the plain meaning of
encompassed within Congress’ direction contemplates broad, but not unlimited,
agency discretion as to what to include ‘‘food’’ is as Congress defined in section
that the dietary supplement regulations 201(f) of the act, including articles
shall be ‘‘modeled after’’ food in a dietary supplement CGMP
regulation. ‘‘used for food or drink.’’ At the time
regulations and, therefore, are based on DSHEA was enacted, there were five
a permissible construction of the statute. Congress has also spoken to the
food CGMP regulations: Those for infant
Under section 402(g)(1) of the act, a precise question of whether the dietary
formula (part 106), thermally processed
dietary supplement is deemed to be supplement CGMP requirements must
low-acid canned food (part 113),
adulterated if it has ‘‘been prepared, be identical to the requirements in
acidified food (part 114), bottled water
packed, or held under conditions that existing food CGMP regulations. If
(part 129), and general food (part 110,
do not meet current good manufacturing Congress had wanted dietary
often referred to as the ‘‘umbrella’’
practice regulations, including supplement CGMP to be identical to
regulations). All of these regulations
regulations requiring, when necessary, food CGMP, it easily could have
appear in Subchapter B of Chapter 1 of
expiration date labeling, issued by the required that by statute. Indeed, if
Title 21 of the Code of Federal
Secretary under subparagraph (2).’’ Congress had intended for CGMPs for
Regulations, entitled ‘‘Food for Human
Section 402(g)(2) of the act authorizes dietary supplements to be the same as
Consumption.’’ Nothing in the language
the Secretary, by regulation, to food CGMPs, there would have been no
of section 402(g) or elsewhere suggests
‘‘prescribe good manufacturing practices need for Congress to have addressed the
that Congress meant to limit the term
for dietary supplements.’’ Congress issue at all; as a type of food, dietary
CGMP ‘‘regulations for food’’ to only the
further provided that such regulations supplements would otherwise be
regulation in part 110. Thus, it is
‘‘shall be modeled after current good governed by the food CGMPs. See
manufacturing practice regulations for section (ff) of the act (21 U.S.C. 321(ff)). 4The Senate Report on DSHEA states that
food’’ and ‘‘may not impose standards Instead, the statute calls for us to issue Congress inserted section 402(g) because it
for which there is no current and regulations that are ‘‘modeled after’’ recognized that ‘‘dietary supplements may require
generally available analytical CGMP regulations for food. The plain different manufacturing and quality controls’’ when
compared to food CGMP (S. Rep. No. 140, 103rd
methodology.’’ meaning of a ‘‘model’’ or ‘‘modeled Cong., 2d Sess., at 31 (1994)). However, the report
In construing the meaning of section after,’’ as discussed in the 2003 CGMP is not considered legislative history. Congress
402(g) of the act, and, in particular, the Proposal (68 FR 12157 at 12165) and in issued a Statement of Agreement (140 Cong. Rec.
language in that section stating that the comments, relates to a pattern, plan, S14801 (Oct. 7, 1994), reprinted in 1994
U.S.C.C.A.N. 3523) that stated ‘‘it is the intent of the
such regulations shall be ‘‘modeled after representation, or simulation. The use of chief sponsors of the bill * * * that no other
current good manufacturing practice the term ‘‘modeled after’’ makes it clear reports or statements be considered as legislative
regulations for food,’’ we are confronted that the regulations need not be history for the bill’’).
consistent with our statutory authority sampling and testing of each batch to §§ 111.95, 111.180(b)(2), 111.260(h),
for us to look to all of our food CGMP ensure nutrient requirements are met 111.325(b)(2), and 111.365(d)). Also
regulations—including infant formula, (§ 106.30); and coding to enable ready similar to the infant formula CGMP
low-acid canned foods, acidified foods, identification of lots during their sale regulation, the dietary supplement
and bottled water, as well as our general and distribution (§ 106.90). CGMP final rule requires manufacturers
food CGMP regulations—after which to The infant formula CGMP regulation to maintain procedures for handling
model our dietary supplement CGMP also includes numerous requirements complaints (final §§ 111.553 and
regulations. that manufacturers maintain records, 111.570(b)(1)); to investigate certain
Congress has not spoken to the e.g., records on certain food-packaging complaints (final § 111.560(a)(2)); and to
precise question of what specific materials; records on nutrient premix keep records of complaints (final
requirements for dietary supplements testing; certificate and guarantees from § 111.570(b)(2)). Required dietary
may be imposed under the ‘‘shall be premix suppliers for required nutrients; supplement records must also, as with
modeled after’’ language. Given this records of results of testing conducted infant formula records, be available for
ambiguity, therefore, under Chevron by suppliers; records of tests to establish inspection by FDA (final § 111.610(a)).
step two, we may determine what the purity of each nutrient, the weight, The ‘‘umbrella’’ food CGMP
requirements to include in this final and amounts of nutrients; records to regulation in part 110 details practices
rule for dietary supplement CGMP, ensure proper nutrient quality control; to ensure ‘‘(1) that food is manufactured,
provided that our interpretation is not records to ensure required nutrient processed, packed, and held under
arbitrary, capricious, or manifestly control at the final product stage; conditions that are sanitary, and (2) that
contrary to the statute (Chevron, 467 distribution records; records on such food is safe, clean, and
U.S. at 844). microbiological quality and purity of wholesome’’ (44 FR 33238 at 33239,
Accordingly, we considered the types raw materials; and records of audits June 8, 1979). Promulgated primarily
of requirements in the existing food (§ 106.100). The infant formula CGMP under the adulteration provisions of
CGMP regulations and used those as regulation also requires manufacturers section 402(a)(3) and (a)(4) of the act, as
models for the dietary supplement to maintain procedures describing how well as section 361 of the Public Health
CGMP requirements. We considered complaints will be handled, to follow Service Act (the PHS Act) (42 U.S.C.
both the objectives and the means of those procedures, and to investigate 264), the umbrella CGMP food
achieving the objectives in the existing when a complaint shows a possible regulation requires a quality control
food CGMP regulations. These CGMP health hazard (§ 106.100(k)). Quality operation whose main purpose is ‘‘to
food regulations include those for infant control records must contain enough provide a systematic procedure for
formula (part 106), general food information to permit a public health taking all actions necessary to prevent
(‘‘umbrella’’ regulations) (part 110), evaluation of any batch of infant food from being adulterated within the
thermally processed low-acid canned formula (§ 106.100(o)). All required meaning of the act’’ (51 FR 22458 at
food (part 113), acidified food (part records must be available for authorized 22461, June 19, 1986), as well as to
114), and bottled water (part 129). Each inspection (§ 106.100(l)). prevent the spread of food-borne
of these food CGMP regulations Many provisions of the dietary communicable diseases (44 FR 33239,
provides objectives and means upon supplement CGMP final rule are similar June 8, 1979) (see § 110.5(a)). Part 110
which we modeled the dietary in objective and means and are also ‘‘specifies requirements that must
supplement CGMP regulations. Just as ‘‘modeled after’’ the provisions of the be met to produce safe and wholesome
the precise requirements of the other infant formula CGMP regulation. For food’’ (51 FR 22461). These umbrella
food CGMP regulations are tailored to example, like the infant formula food CGMP requirements not only
the particular characteristics and regulation, the dietary supplement pertain to food safety, but also are
hazards of the foods and manufacturing CGMP regulation is designed to ‘‘concerned with contamination by filth
processes being addressed, the dietary establish a quality control system to or decomposition which may or may not
supplement CGMP requirements are make sure that dietary supplements are raise safety concerns’’ (51 FR 22458 at
also so tailored. properly manufactured. The dietary 22462).
For example, the infant formula supplement regulation uses similar The detailed requirements of the
CGMP regulation is intended to ensure means to ensure this goal, such as umbrella food CGMP regulation
that the ‘‘safety and nutritional requirements for ingredient control accomplish these objectives through a
potency’’ of a formula are ‘‘built into the (through supplier’s certificate of variety of means. For example, there are
manufacturing process’’ in order to analysis or testing or examination) (final specific personnel provisions requiring
establish a quality control system to § 111.75(a)); preparation of a master employees who may be sources of
make sure that infant formula products manufacturing record (final § 111.205); microbial contamination to be excluded
are properly manufactured (47 FR 17016 in-process batch monitoring (final from certain operations (§ 110.10(a));
at 17017, April 20, 1982). The specific § 111.75(b)) or batch testing or persons working in contact with food,
criteria in the regulations apply in examination (final § 111.75(c)); and food-contact surfaces, and food-
determining whether the infant formula coding to provide a batch, lot, or control packaging materials to follow hygienic
meets the safety, quality, and nutrient number (final § 111.260(a)). Like the practices (§ 110.10(b)); and that certain
requirements of the act (§ 106.1(a)). The infant formula CGMP regulations, the personnel have sufficient education or
means to achieving the objectives in the dietary supplement CGMP final rule experience to produce clean and safe
infant formula regulations include, for contains recordkeeping requirements food (§ 110.10(c)). The umbrella food
example, requirements for ingredient related to packaging materials; CGMP regulation also includes detailed
control (through a supplier’s guarantee certificates of analysis from suppliers; requirements concerning the grounds
or certification or through analysis of results of tests that you conduct, for surrounding a food plant and the design
the ingredient) (§ 106.20); preparation of example, on ingredients or the finished of buildings and structures to protect
a master manufacturing order and a batch; and results of chemical, against contamination or to maintain
system to assure and verify the addition microbiological, or other tests that you sanitary operations and produce safe
of each ingredient (§ 106.25); either in- conduct as necessary to prevent the use food (§ 110.20). Detailed provisions also
process batch testing (§ 106.25(b)) or of contaminated components (final require that physical facilities be
maintained in sanitary condition and in (§ 113.5). Processors of low-acid canned product is free of microorganisms of
sufficient repair to prevent food from foods must have a ‘‘scheduled process’’ potential public health significance, the
being adulterated (§ 110.35). Any water that is established by a qualified person product either must be reprocessed to
that contacts food or food-contact and is ‘‘adequate under the conditions render it commercially sterile or
surfaces must be ‘‘safe and of adequate of manufacture for a given product to destroyed (§ 113.89).
sanitary quality’’ (§ 110.37(a)); achieve commercial sterility’’ (§§ 113.3 All process deviations involving a
plumbing, sewage, and other disposal, and 113.83). ‘‘Commercial sterility’’ of failure to satisfy the minimum
as well as toilet facilities, must also thermally processed food means a requirements of the scheduled process
protect against contamination condition achieved by applying heat to must be recorded and kept in a separate
(§ 110.37(b), (c), and (d)). Similarly, render the food free of certain file detailing the deviations and actions
equipment and utensils must be microorganisms (§ 113.3). Part 113 taken (§ 113.89). Detailed information
designed and maintained to preclude requires that supervisors satisfactorily on processing and production must be
adulteration and food contact surfaces complete training at a school approved entered on forms (§ 113.100(a)). Not
must be maintained to protect food from by FDA (§ 113.10). later than 1 working day after the actual
being contaminated by any source, Part 113 also contains extremely process, and before the food is shipped
including unlawful indirect food detailed requirements on equipment or released for distribution, a qualified
additives (§ 110.40(a)). All operations and procedures. For example, each representative of management must
for receiving, inspecting, transporting, vessel used for pressure processing in review all processing and production
segregating, preparing, manufacturing, steam must be equipped with a mercury records for completeness and to ensure
packaging, and storing food must be thermometer that is tested for accuracy that the product was subjected to the
conducted using adequate sanitation at least once a year, or more frequently scheduled process (§ 113.100(b)).
principles (§ 110.80). Appropriate if necessary, to ensure its accuracy Records to identify the initial
quality control operations must be used (§ 113.40(a)(1)). Critical factors distribution of the finished product
to ensure that food is suitable for human (variation of which may affect the must be kept to facilitate segregation of
consumption and that food-packaging attainment of commercial sterility) must lots that may have become
materials are safe and suitable be specified in the scheduled process contaminated or otherwise rendered
(§ 110.80). Foods must be stored and and must be measured and recorded on unfit for their intended use
transported under conditions to protect processing records frequently enough to (§ 113.100(d)). Records must be
against physical, chemical, and ensure that the factors are within the maintained at the processing plant for at
microbial contamination, as well as specified limits (at least every 15 least 1 year after the date of
against deterioration of the food and the minutes) (§§ 113.40(a)(13) and 113.83). manufacturing and at a reasonably
container (§ 110.93). Observations and measurements of accessible location for another 2 years
The provisions of the umbrella food certain operating conditions must be (§ 113.100(e)).
CGMP regulation serve as the model for made and recorded at intervals of Similarly, the CGMP regulation for
many dietary supplement CGMP sufficient frequency to ensure that acidified food in part 114 requires
provisions. For example, the dietary commercial sterility of the food product supervision by personnel trained at an
supplement CGMP requirements is being achieved (at least every hour) FDA-approved school (§ 114.10);
concerning personnel and microbial (§ 113.40(g)(2)(ii)(c)). There must also be manufacturing in accordance with a
contamination (final § 111.10(a)); a system to stop packaging operations scheduled process established by a
hygienic practices (final § 111.10(b)); (or to segregate products) when the qualified person (§§ 114.80 and 114.83);
and education, training, or experience packaging conditions fall below processing sufficient to destroy the
(final § 111.12) are very similar to scheduled processes vegetative cells of certain
provisions in part 110. In addition, the (§ 113.40(g)(2)(ii)(b)). Regular microorganisms (§ 114.80(a)(1));
dietary supplement CGMP requirements observations of container closures are sufficient control, including frequent
concerning the grounds, physical plant required to be made and recorded testing and recording of results, to
facilities, cleaning materials, pest (§ 113.60). Each container must be ensure that the finished hydrogen-ion
control, water supply, plumbing, sewage coded ‘‘to enable ready identification of concentration (pH) values are not higher
disposal, bathrooms, and trash disposal lots during their sale and distribution’’ than 4.6 (§ 114.80(a)(2)); testing and
(final §§ 111.15 and 111.20) closely (§ 113.60(c)). examinations of containers to ensure
resemble the analogous part 110 Before using raw materials and that the food is suitably protected from
requirements. ingredients susceptible to leakage or contamination
Because of the particular hazards microbiological contamination, the low- (§ 114.80(a)(4)); and coding to enable
associated with low-acid canned foods acid food processor must ensure that ready identification of lots during their
and with acidified foods, the CGMP they are ‘‘suitable for use in processing sale and distribution (§ 114.80(b)).
regulations for these foods contain low-acid food’’ (§ 113.81(a)). Complete Whenever any acidified food process
detailed provisions to ensure safe records covering all aspects of the operation deviates from the scheduled
manufacturing. Specifically, the CGMP establishment of the scheduled process process or the pH of the finished
regulations for these foods protect the and of certain confirmation tests must product exceeds 4.6, the processor must
public health against microbial be maintained permanently (§ 113.83). reprocess it, process it under part 113
contamination from these foods. Part Scheduled processes must be readily requirements, or set it aside for
113 sets out safe manufacturing, available to any duly authorized FDA evaluation as to any potential public
processing, and packaging procedures employee (§ 113.87(a)). Whenever any health significance (§ 114.89). Unless
for low-acid foods in hermetically process is less than the scheduled the evaluation demonstrates that the
sealed containers. The CGMP criteria in process or when critical factors are not food has undergone a process that has
this part apply in determining whether in control, the low-acid food must be rendered it safe, the food must be fully
the facilities, methods, practices, and reprocessed or set aside for further reprocessed to render it safe or be
controls used by commercial processors evaluation as to public health destroyed (§ 114.89).
of such foods are operated ‘‘in a manner significance (§ 113.89). Unless the A record must be made of the
adequate to protect the public health’’ evaluation demonstrates that the procedures used in the public health
evaluation and the results of the factors’’ required to be specified in the bottled drinking water is safe and that
evaluation (§ 114.89). Records must be scheduled process for low-acid and it has been processed, bottled, held, and
kept of examinations of raw materials, acidified foods are akin to the transported under sanitary conditions’’
packaging materials, and finished ‘‘specifications’’ that dietary (§ 129.1). Part 129 requires plant
products, and of suppliers’ guarantees supplement manufacturers must construction and design features, such
or certifications that verify compliance establish for certain points in the as a separate bottling room and an
with our regulations (§ 114.100(a)). manufacturing process (final § 111.70). enclosed room for washing and
Processing and production records Just as low-acid food processors must sanitizing containers, to protect against
showing adherence to scheduled establish procedures to ensure that contamination (§ 129.20). All plant
processes must be maintained and must ingredients are suitable for use, so too equipment and utensils must be suitable
have sufficient additional information must dietary supplement manufacturers for their intended use (§ 129.40(a)).
such as product code, date, container establish component and finished Both the product water supply and
size, and product, to permit a public product specifications (final § 111.70(b) the operations water supply must be of
health hazard evaluation of the and (e)). Just as containers for acidified a ‘‘safe, sanitary quality’’ in
processes applied to each lot, batch, or food must ensure suitable protection conformance with ‘‘the applicable laws
other portion (§ 114.100(b)). Departures from contamination, packaging that and regulations of the government
from scheduled processes having a comes into contact with dietary agency or agencies having jurisdiction’’
possible bearing on public health or the supplements must be safe and suitable (§ 129.35(a)). Samples of source water
safety of the food must be recorded and for use (final § 111.70(d)). Dietary must be analyzed at least once a year for
kept in a separate file or log, along with supplement in-process points, like the chemical contaminants and once every
the action taken to rectify the departure ‘‘critical factors’’ for low-acid and 4 years for radiological contaminants
and the product disposition acidified food, must be monitored to (§ 129.35(a)(3)). Source water from other
(§ 114.100(c)). Records must be kept detect any deviation or unanticipated than a public water system must be
identifying initial distribution of the occurrence that may result in sampled and analyzed for
finished product to facilitate segregation adulteration (final § 111.75(b)(2)). microbiological contaminants at least
of lots that may have become Rejected dietary supplements must once a week (id.). The product water-
contaminated or otherwise unfit for also be held under quarantine (final contact surfaces of all containers and
their intended use. Copies of certain §§ 111.370 and 111.425); dietary equipment must be clean and
required records must be kept at a supplements which have been adequately sanitized and protected from
reasonably accessible location for 3 reprocessed, treated, or which have had contamination (§ 129.37(a) and (b)).
years from the date of manufacture in-process adjustments must meet all Filling, capping, closing, sealing, and
(§ 114.100). The criteria in the part 114 established product specifications and packaging of containers must be done so
regulation, as well as those in part 110, be approved before release (final as to preclude contamination of the
apply in determining whether an article § 111.90(c)). Similar to coding low-acid water (§ 129.37(d)). All product water
of acidified food is adulterated under or acidified foods, dietary supplements contact surfaces must be nontoxic and
section 402(a)(3) of the act in that it has must have assigned batch, lot, or control in compliance with section 409 of the
been manufactured under such numbers (final § 111.415(f)). The design, act (21 U.S.C. 348) (concerning food
conditions that it is unfit for food or calibrations, and cleaning of equipment additives) (§ 129.40(a)(2)).
and utensils must also result in the Numerous production processes and
under section 402(a)(4) of the act in that
equipment and utensils being suitable controls for bottled water are also
it has been prepared, packed, or held
for their intended uses and not result in required. For example, all treatment of
under insanitary conditions whereby it product water must be effective in
contamination of components or dietary
may have become contaminated with accomplishing its intended purpose and
supplements (final § 111.27). Written
filth, or whereby it may have been in accordance with section 409 of the
procedures for the various controls are
rendered injurious to health (§ 114.5). act (§ 129.80(a)). The treatment
required (see, e.g., final §§ 111.8, 111.25,
Many provisions of parts 113 and 114 and 111.103), and required written processes must be performed with
also serve as models for provisions in records (see, e.g., final §§ 111.14, equipment and substances that will not
the dietary supplement final rule. In 111.23, 111.35, and 111.95) must be adulterate the product (§ 129.80).
many instances, the analogous provision kept for 1 year past the shelf life date, Product water samples must be taken
in the dietary supplement final rule if shelf life dating is used, or 2 years before bottling and analyzed as often as
allows more flexibility in the means to after the date of distribution of the last necessary to assure uniformity and
achieve the goal. For example, under associated batch of dietary supplement effectiveness of the processes performed
final § 111.13 qualified personnel must (final § 111.605). All required dietary by the plant (§ 129.80(a)). Cleaning and
be assigned to supervise the supplement CGMP records must be sanitizing solutions must be sampled
manufacturing, packaging, labeling, or readily available for inspection and and tested to assure adequate
holding of dietary supplements. copying by FDA (final § 111.610(a)). performance (§ 129.80(c)).
Although the supervisor must be Finally, the bottled water CGMP Each unit package from a batch or
qualified by education, training, or regulation was promulgated to ensure segment of continuous production run
experience to supervise, the more the safety and sanitary quality of these must be identified by a production code
restrictive requirement of parts 113 and products, which include all water (§ 129.80(e)). The plant must maintain
114 to attend an FDA-approved school processed and bottled for human information on the kind of product,
is not included. The ‘‘scheduled consumption (38 FR 32563, November volume, date, lot code, and distribution
process’’ for low-acid and acidified food 26, 1973). The criteria in part 129, as of finished product to wholesale and
manufacturing, processing, and packing well as in part 110, apply in retail outlets (id.). During the process of
is analogous to the required ‘‘system of determining whether the facilities, filling, capping, or sealing the
production and process controls’’ that methods, practices, and controls used to containers, performance must be
dietary supplement manufacturers must process, bottle, hold, and ship bottled monitored and the filled containers
design and implement (final §§ 111.55 drinking water conform with good inspected to assure that they are sound,
and 111.60(a)). Similarly, the ‘‘critical manufacturing practice ‘‘to assure that properly capped or sealed, and coded
and labeled (§ 129.80(f)). All containers The umbrella food CGMP regulation, for for dietary supplements (see, e.g.,
and closures must be sampled and example, defines the ‘‘plant’’ covered by section 403(s)(2) of the act (a dietary
inspected to ascertain that they are free the requirements of that regulation as supplement is misbranded if its labeling
from contamination (id.). the facility used for, or in connection fails to list the name and quantity of
To assure that the plant’s production with, ‘‘the manufacturing, packaging, each dietary ingredient and if it fails to
of bottled water complies with labeling, or holding of human food’’ have the identity and strength or the
applicable standards, laws, and (§ 110.3(k)). As we have described in quality, purity, or compositional
regulations, the plant must analyze detail, the objectives of the existing food specifications it is represented to meet)).
product samples at specified intervals CGMP regulations and the precise Yet without information about the
(§ 129.80(g)). The methods used to means (or requirements) used to achieve identity, purity, strength, or
analyze the samples must be approved the objectives vary depending on the composition, the manufacturer could
by the government agency with particular hazards and characteristics of not know the final contents of the
jurisdiction (§ 129.80(g)(3)). Records of the products and their manufacturing. dietary supplements it manufactures or
the date of sampling, type of product For example, the umbrella food CGMP whether its processes are reliably and
sampled, production code, and results regulation is specifically designed to consistently producing the correct
of analysis must be maintained ensure that food is manufactured, combination and amounts of ingredients
(§ 129.80(g)(3)). All required records processed, packed, and held under in a dietary supplement. Accordingly,
must be maintained at the plant for at sanitary conditions and that the food is the final rule requires a manufacturer to
least 2 years (§ 129.80(h)) and be safe, clean, and wholesome. Low-acid establish specifications for the identity,
available for official review by FDA at and acidified food CGMP requirements purity, strength, and composition and
reasonable times (id.). focus on facilities, methods, practices, for limits on contaminants of the dietary
Provisions of the bottled water CGMP and controls to protect the public health supplements it manufactures and ensure
regulation also serve as a model for against the particular risks of microbial that such specifications are consistently
provisions of the dietary supplement contamination from these foods. The met in the finished batch of dietary
CGMP regulation. For example, water infant formula CGMP regulation is supplement (§ 111.75(e)). Dietary
that is used in a manner such that the aimed at ensuring both the safety and supplements, like infant formula, are
water may become a component of a nutritional potency of these special relied upon by consumers not only to be
dietary supplement must at a minimum foods. Infant formula is often the sole safe, but also in many instances to
comply with applicable Federal, State, item in the diet. An infant formula that provide specific and important claimed
and local requirements and not does not meet the requirements for health benefits (see, e.g., section 403(r)
contaminate the dietary supplements nutritional potency may cause a hazard of the act). In the preamble to the 2003
(final §§ 111.15(e)(2) and 111.365(c)). to the health of the infant (see 61 FR CGMP Proposal, we discussed a number
Precautions that must be taken to 36154, July 9, 1996). The bottled water of examples illustrating adulteration
prevent contamination of components CGMP regulation embodies and improper formulation of dietary
or dietary supplements include requirements for facilities, methods, supplements caused by manufacturing,
performing chemical, microbiological, practices, and controls used in packaging, or holding practices (68 FR
or other testing (final § 111.365(d)). processing, bottling, holding, and 12157 at 12162 and 12163). These
Filling, assembling, packaging, labeling, shipping of bottled water to ensure its dietary supplement CGMP requirements
and related operations must be safety and sanitary quality. will help to protect consumers against
performed to protect the dietary Like the food CGMP regulations after
similar types of adulteration and against
supplement against adulteration (final which they are modeled, the dietary
reliance on products that are not
§ 111.415). Equipment and utensils supplement CGMP final rule contains
properly formulated.
must be suitable for their intended use criteria for facilities, methods, practices,
(final § 111.27(a)). Safe and adequate and controls used in manufacturing, Generally recognized principles
cleaning compounds and sanitizing packaging, labeling, or holding dietary underlying CGMP also support our
agents must be used (final supplements to ensure the quality of the interpretation of section 402(g) of the
§ 111.15(c)(1)). Representative samples dietary supplement. Quality includes act. Our interpretation of permissible
of each batch must be examined to consistently meeting the established CGMP regulations is reasonable based
ensure that the product meets specifications for identity, purity, on recognized principles for controlling
established specifications (final strength, and composition of the dietary the quality of manufactured products in
§ 111.415(g)). Each lot of packaged and supplement and limits on contaminants, general (Ref. 9). As many comments
labeled dietary supplement must be in addition to manufacturing the dietary asserted, if the dietary supplement
assigned a batch, lot, or control number supplement under conditions to prevent CGMP requirements are to be
(final § 111.415(f)). adulteration. As Congress recognized in meaningful, they must ensure quality in
Moreover, our interpretation of DSHEA, identity, purity, strength, and the finished product (see, for example,
permissible requirements for the dietary composition are essential characteristics the discussion in section X of this
supplement CGMP regulation is also document of comments regarding the
consistent with the use of the terms in the statute (see, e.g., sections 501(a)(2)(B) (drug production and process control system).
CGMP) and 520(f)(1)(A) of the act (device CGMP) Controls to ensure quality include
‘‘good manufacturing practice’’ and (21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A),
‘‘current good manufacturing practice’’ respectively). Case law supports the agency’s view
planning processes to determine desired
in section 402(g) of the act. Although that ‘‘current’’ does not mean ‘‘actually prevailing product features or characteristics, a
these terms are not defined in the act, manufacturing practice’’ in an industry and that system of controls to ensure that the
such a practice need not be accepted by a majority desired product will be consistently
GMP is generally used to refer to of manufacturers (National Ass’n of Pharmaceutical
methods used in, and the facilities and Mfr’s v. Department of Health and Human Services, produced, and making necessary
controls used for, product 586 F. Supp. 740, 752 (S.D.N.Y. 1984)). improvements to the process (section
manufacturing and related activities.5 Nevertheless, the requirements of this final rule 2.6 of Ref. 9). Manufacturers must plan
embody current practices of many food and dietary what they intend to produce, institute
supplement manufacturers, as reflected in the
5Although the act does not define ‘‘current good comments supporting the provisions of the adequate controls to achieve the desired
manufacturing practice,’’ the term is used elsewhere proposed rule. outcome, and ensure that the controls
work so that the desired outcome is different product forms in which these CGMP regulations. Controls that relate
consistently achieved. If the outcome is products will be manufactured. Unlike to certain product forms (e.g., tablets,
not consistently achieved, corrective conventional foods, such as fruit, capsules, powder, softgel) are required
actions need to be implemented in order vegetables, cereals, and dairy products, in this final rule based on the specific
to reach the desired outcome. dietary supplements will be sold in characteristics of dietary supplements
This final rule, like the other food tablet, capsule, powder, or softgel form. and the hazards associated with these
CGMP regulations, embodies the basic They may also be sold as a concentrate, forms, not, as some comments imply,
concepts of controlling quality, i.e., metabolite, constituent, or extract of a based on a desire to emulate drug CGMP
planning, control, and improvement. As vitamin, mineral, herb, botanical, or requirements. The act does not state that
discussed earlier in the ‘‘Overview of dietary substance. Because dietary there may not be similarities between
CGMP’’ (section III.A of this document), supplements are often sold in different the dietary supplement CGMP
we have defined the term ‘‘quality’’ for forms than conventional foods, different requirements and the CGMP
this dietary supplement CGMP processes and controls are needed to requirements for drugs or other non-
regulation to mean ‘‘that the dietary manufacture dietary supplements than food products. Inasmuch as food CGMP
supplement consistently meets the to manufacture conventional foods. For regulations and other CGMP regulations
established specifications for identity, example, equipment must be able to are all based on CGMP principles, it is
purity, strength, and composition and manufacture dietary supplements in neither surprising nor impermissible
has been manufactured, packaged, tablet or softgel form. Therefore, the that there are similarities between the
labeled, and held under conditions to final rule requires that controls be dietary supplement CGMP requirements
prevent adulteration under section established to ensure that the equipment and drug or device CGMP requirements.
402(a)(1), (a)(2), (a)(3), and (a)(4) of the functions in accordance with its Although we do not agree that any of
Federal Food, Drug, and Cosmetic Act.’’ intended use (final § 111.30(e)) and will the CGMP requirements exceed drug
Identifying the desired characteristics of consistently manufacture a product in GCMP requirements, even if a particular
identity, purity, strength, and whatever form is desired. Consistent requirement did, it is not prohibited
composition of a dietary supplement, as with basic CGMP principles, ensuring under the statute. As long as the CGMP
required in this final rule, is an essential the quality of the dietary supplement final rule is ‘‘modeled after’’ the food
part of the planning process to product requires that the manufacturer CGMP regulations, we have satisfied the
manufacture a dietary supplement. establish precisely what it will produce statutory requirements. As noted, our
Without identifying specifications for (specifications for its product), how it interpretation of ‘‘modeled after’’ means
each of these characteristics of a dietary will make the product (processes), and that the dietary supplement CGMP final
supplement, it is not possible to control which process controls and tests it will rule provisions share similar objectives
for, and repeatedly and reliably use to ensure reliable, reproducible and/or use similar means as the existing
produce, the desired end product. results. These CGMP requirements will food CGMP regulations. To the extent
Similarly, requirements for batch testing help to achieve these results. that there are similarities to drug CGMP
ensure that there is consistency from The dietary supplement CGMP regulations, those similarities are
batch to batch. Packaging and labeling requirements are also reasonable when appropriate and not prohibited by
requirements ensure that suitable viewed in the context of the act as a section 402(g) of the act.
packaging is used and that the label whole. See Brown & Williamson, 529 Consistent with our role ‘‘to fill in,
identified in the master manufacturing U.S. at 133. Our mission is, in part, to through interpretation, matters of detail
record for the product is placed on the protect the public health by ensuring related to [the statute’s] administration,’’
finished product. In addition, that foods are safe, wholesome, sanitary, Barnhart v. Walton, 535 U.S. 212, 225
requirements related to consumer and properly labeled (section (2002), we applied our scientific
complaints help to ensure that 903(b)(2)(A) of the act) (21 U.S.C. expertise, policy judgment, and
manufacturers are made aware of 393(b)(2)(A))). Section 701(a) of the act experience to promulgate dietary
problems related to their manufacturing (21 U.S.C 371(a)) gives us the authority supplement CGMP requirements that
processes, including those that may to promulgate regulations for the will protect the public health and
result in illness or injury, so that they efficient enforcement of the act in order effectively implement our statutory
can take corrective actions to prevent to ‘‘effectuate a congressional objective authority to prescribe dietary
any future problems from occurring. expressed elsewhere in the Act’’ supplement CGMP. See United States v.
The procedures for production and (Association of American, Physicians Mead, 533 U.S. 218, 227–228 (2001);
process control in this final rule also and Surgeons, Inc. v. FDA, 226 F. Supp. Nationsbank of North Carolina v.
include as key elements measures to 2d 204 (D.D.C. 2002) (citing Pharm. Variable Annuity Life Ins. Co., 513 U.S.
prevent contamination that could Mfrs. Ass’n. v. FDA, 484 F. Supp. 1179, 251, 256–58 (1995); Chevron, 467 U.S. at
adulterate the product. Requirements to 1183 (D. Del. 1980)). The final rule is 844; Forester v. Consumer Product
protect against contamination during designed to help ensure that dietary Safety Com., 559 F.2d 774, 783 (D.C.
the manufacturing, packaging, labeling, supplements consistently are Cir. 1977).
and holding operations help ensure that manufactured to produce the product
B. Records Authority
this aspect of ‘‘quality’’ is also achieved established by the manufacturer, to bear
for dietary supplements. In sum, this the label identified in the master (Comment 19) Some comments state
final rule embodies principles for manufacturing record, and to prevent that requirements related to record
controlling quality through adulteration. The requirements are keeping and access to such records are
requirements designed to ensure both written to facilitate efficient and necessary to allow our inspectors to
that the dietary supplement meets its effective action to enforce their terms assess the adequacy of a dietary
established specifications for identity, when necessary. supplement manufacturer’s practices.
purity, strength, and composition and Some provisions of the dietary Additional comments state that access
that it is not adulterated. supplement CGMP final rule may be to records is necessary to ensure that
The dietary supplement CGMP similar to the existing drug CGMP CGMP requirements are followed and to
requirements are also reasonable regulations. However, we have not protect the public health. Several
because they take into consideration the modeled these regulations after the drug comments identify specific types of
records we should require in a final One comment cites In the Matter of sufficiently specific authority to us to
rule, including written procedures, Establishment Inspection of Medtronic, promulgate recordkeeping and access
batch and master manufacturing Inc., 500 F. Supp 536 (D. Minn. 1980), regulations (Cf. United States v. Storer
records, distribution records, and lot to support its assertion that we Broadcasting, 351 U.S. 192, 202–03
numbers. Another comment states that exceeded our statutory inspection (1956) (upholding a rule that established
training records should be required authority in the dietary supplement limitations on broadcast licensing that
because the qualifications and training CGMP record requirements. One were ‘‘not specifically authorized by
of employees affects product quality. comment states that a warrantless statute’’)). As stated earlier in this
Other comments, however, state that inspection of dietary supplement CGMP section, the ‘‘modeled after’’ language in
the record retention and access records and criminal consequences that section 402(g) of the act is ambiguous
requirements seem to be modeled after may be imposed under the act for failure with respect to what specific CGMP
drug CGMP and not food CGMP. Other to comply with the act provide a requirements we are to include in this
comments state that, even though ‘‘powerful argument against expanding final rule. At the time Congress enacted
records may be necessary to ensure that the Agency’s inspection authority any section 402(g) of the act there were
CGMP requirements are followed, we do further’’ and raise ‘‘serious several food regulations that contained
not have authority to require access to constitutional concerns.’’ Several recordkeeping and record access
and copying of such records. Some comments ask us to clarify our requirements. We included records
comments assert the authority to jurisdiction for records inspection requirements in the food CGMP
establish regulations for dietary requirements or delete proposed regulations for infant formula (part 106),
supplement CGMP does not imply there § 111.125(c). low acid food (part 113), acidified food
is authority to inspect records. Several Still other comments seek (part 114), and bottled water (part 129).
comments state we cannot rely on confirmation that the confidential and Accordingly, the directive in section
section 701 of the act because there is trade secret information obtained by us 402(g) of the act is sufficient authority
not another section of the act that under the rule would be protected from for our recordkeeping requirements in
authorizes us access to company records disclosure under applicable statutes. this final rule. In addition, our authority
for dietary supplement CGMP and Among other things, the comments cite to establish records requirements has
section 701(a) of the act does not itself the Trade Secrets Act, 18 U.S.C. 1905, been upheld under other provisions of
give us the authority we need to require and the Freedom of Information Act the act, which lacked explicit
records inspection. Another comment (FOIA), 5 U.S.C. 552(b)(4). Some recordkeeping authority for FDA, where
suggests that the absence of an express comments express concern that records we have found records to be necessary
grant of records inspection authority inspection would violate ‘‘rights to (National Confectioners Assoc. v.
privacy of corporate manpower’’ or Califano, 569 F.2d 690, 693–94 (D.C.
means that records inspection is not
would compromise trade secrets. The Cir. 1978) (upholding requirements for
necessary for the efficient enforcement
comments request the rule specifically source coding and distribution records
of the act.
reconfirm our obligations under these based on the statutory scheme as a
Some comments assert that we have laws.
no record inspection authority under whole)).
(Response) We disagree with the
section 704(a) of the act (21 U.S.C comments suggesting that we have no Moreover, records are an
374(a)). A few comments suggest that, authority to require dietary supplement indispensable component of CGMP. The
because records inspection authority manufacturers to maintain records to records required by this final rule
was not expressly granted in DSHEA’s comply with CGMP under section provide the foundation for the planning,
statutory language, as it was for OTC 402(g) of the act; that the absence of an control, and improvement processes
drugs and medical devices, Congress express grant of records authority means that constitute a quality control system.
provided no authority for records records are not needed for the efficient Implementation of these processes in a
inspection for dietary supplement enforcement of the act; and that manufacturing operation serves as the
CGMP. The comments state that we Congress meant, by its silence, that we backbone to CGMP. The records will
have a longstanding interpretation that have no authority to issue records show what is to be manufactured; what
section 704 of the act does not give us requirements. Clearly, just as Congress was, in fact, manufactured; and whether
access to a food manufacturer’s records. is not expected to express ‘‘every single the controls that the manufacturer put
Several comments state that it was evil sought to be corrected’’ in a grant in place to control the identity, purity,
sufficient to have voluntary records of authority to promulgate a rule, it can strength, and composition and limits on
access, stating that many companies are not be expected to articulate every contaminants and to prevent
willing to provide access to records. requirement that is within an agency’s adulteration were effective. Further,
Other comments say that our record delegated authority (American Trucking records will show whether and what
inspection authority for dietary Assoc. v. United States, 344 U.S. 298, deviations from control processes
supplement CGMP is limited to that 309–10 (1953)). occurred, facilitate evaluation and
under section 306(a) of the Public Agencies are expected to bring their corrective action concerning these
Health Security and Bioterrorism expertise to bear on what requirements deviations (including, where necessary,
Preparedness and Response Act of 2002 are necessary that will not ‘‘directly whether associated batches of product
(Bioterrorism Act) (21 U.S.C. 350(c)), frustrate the success of the regulation should be recalled from the
i.e., when we have a ‘‘reasonable belief undertaken by Congress’’ (id. at 311). In marketplace), and enable a
that an article of food is adulterated and this instance, Congress has not manufacturer to assure that the
presents a threat of serious adverse expressed any specific intent regarding corrective action was effective. Written
health consequences * * *’’ Another recordkeeping for dietary supplements procedures also will help ensure that
comment suggests an alternative but has directed FDA to use other food personnel follow hygienic practices;
standard to that in section 306(a) of the CGMP regulations, which require permit evaluation of whether
Bioterrorism Act of a ‘‘reasonable belief recordkeeping and FDA access to equipment, including software that may
that there is a public health hazard’’ for records, as models for these regulations. run the equipment, performs as it is
when we may access records. Congress has delegated substantial and intended; and help ensure that the
equipment is properly maintained and so manufactured to be adulterated as a There is nothing in the Bioterrorism
adequately cleaned. matter of law. The introduction or Act that reflects any Congressional
The CGMP final rule establishes the delivery for introduction into interstate intent to modify section 402(g) of the
parameters for the production and commerce of an adulterated dietary act. In fact, section 414(d)(1) of the act
process control system in which dietary supplement is a prohibited act under (21 U.S.C. 350c(d)(1)), added by section
supplements are to be manufactured. section 301(a) of the act (21 U.S.C. 306(a) of the Bioterrorism Act, shows a
The dietary supplement manufacturer 331(a)), and acts done to an ingredient contrary intent. Section 414(d)(1)
establishes the identity, strength, purity, in a dietary supplement, or to a dietary provides that ‘‘This section shall not be
and composition of the supplement it supplement, while held for sale after construed—(1) to limit the authority of
manufactures (final § 111.70); shipment in interstate commerce that the Secretary to inspect records or to
determines whether the established result in the ingredient or dietary require establishment and maintenance
specifications are met (final § 111,73); supplement being adulterated violates of records under any other provision of
uses the tests it needs to ensure that section 301(k) of the act (21 U.S.C. this Act.’’ Moreover, Congress, in the
those characteristics are consistently 331(k)). Thus, in order for us to legislative history to the Bioterrorism
met (final §§ 111.75 and 111.315); and determine whether the dietary Act, supported our general approach of
identifies the steps necessary to ensure supplement product is adulterated and requiring recordkeeping pursuant to
that any necessary tests or examinations whether a manufacturer has committed authority in section 701(a) of the act in
are completed, reviewed, and recorded a prohibited act, we must have access to combination with other provisions.7 We
in a timely fashion before the dietary the manufacturer’s records that we are are not relying on section 704 of the act
supplement is released for distribution requiring to be kept under section 402(g) for its underlying authority to require
to the public (final §§ 111.110 and of the act. recordkeeping and records access in this
111.325(b)(2)). The CGMP final rule also In light of the foregoing, without final rule. Those comments asserting
requires that the manufacturer establish access to such records, we would not that we do not have such authority and
written procedures for its quality know whether a manufacturer was the underlying references, for example,
control operations to ensure the complying with the procedures and to past hearings on records inspection
personnel performing this function processes required in this final rule. For authority under section 704 of the act,
provide proper review and oversight of example, our investigator must have are not controlling with regard to the
the production and process control access to the test results for the identity action we are taking under sections
system, have the knowledge and of a dietary ingredient to determine 402(g) and 701(a) of the act. When there
experience to identify and anticipate are other bases for jurisdiction and tools
whether such ingredient meets the
possible problems in the manufacturing to protect the public interest, we may
manufacturer’s specification for
of the dietary supplement, and ensure use what ‘‘will be the most effective in
identity. The investigator needs to
corrective measures are taken promptly advancing the Congressional objective’’
understand, by reviewing a record, what
when problems occur (final §§ 111.103 (U.S. v. Midwest Video Corp., 406 U.S.
the software that runs a production
through 111.140). The final rule also 649, 656 (1972)).
operation is set up to do and whether it
requires that the manufacturer establish Some comments stated that our access
performs those functions to achieve the
the ‘‘master recipe(s)’’ for the dietary to dietary supplement records is not
desired product characteristics.
supplement(s) it manufactures so that consistent with constitutional
Observation of these processes alone, by
such recipe(s) can be followed for each jurisprudence. We disagree. The
batch produced (final §§ 111.205 an investigator, would not allow that
investigator to evaluate compliance with comment which expressed concern
through 111.210). In sum, about ‘‘constitutional issues’’ in the
manufacturers cannot operate without this final rule. Moreover, records often
cannot be thoroughly evaluated by the context of an FDA inspection of records
records because critical elements in a during a warrantless FDA inspection
manufacturing process are entirely investigator on site. In such cases,
records must be readily available to food expressed concern about the criminal
dependent on information written or liability that could be imposed on a
captured in the form of a record.6 Such experts at the Center for Food Safety
and Applied Nutrition (CFSAN) and manufacturer under the act (citing
records are also necessary to protect United States v. Dotterweich, 320 U.S.
consumers by enabling manufacturers to agency consultants. We must have
accurate, reliable, and objective data 277 (1944) and United States v. Park,
identify and recall problematic products
about the manufacturing specifications 421 U.S. 658 (1975)). To the extent that
as necessary and make necessary
to be able to achieve an enforceable rule. the comment asserts that the records
corrections to deviations in their
We also disagree with comments access established in this final rule
processes.
The authority granted us under stating our records inspection authority constitutes an improper search and
sections 402(g) and 701(a) of the act not is limited to that provided by section seizure under the Fourth Amendment,
only includes the authority to establish 306(a) of the Bioterrorism Act. There is we disagree.
no basis to conclude that Congress The dietary supplement industry, as
record requirements, but also includes
intended to limit our authority to the food industry as a whole, is a
access to such records. Without such
authority, the dietary supplement CGMP inspect records, to enforce section 7In discussing section 306 of the Bioterrorism Act
requirements are, practically speaking, 402(g) of the act, to the records (Maintenance and Inspection of Records for Foods),
not enforceable. Under section 402(g)(1) inspection authority under the Congress stated, ‘‘The managers did not adopt a
of the act, the failure to meet any CGMP Bioterrorism Act. The Bioterrorism Act, Senate proposal to authorize the Secretary to
requirements, including the failure to enacted almost 8 years after section require the maintenance and retention of other
records for inspection relating to food safety,
have a record that is required by this 402(g), to address credible threats of because the Secretary has authority under section
final rule, renders a dietary supplement serious adverse health consequences or 701(a) of the [act] to issue regulations for the
death to humans and animals, required ‘efficient enforcement of this Act’ and this
6It is also worth noting that standard references
recordkeeping to identify the immediate authority, in combination with other provisions
used in many industries establish clear expectations (such as section 402 [of the act]), gives the Secretary
for documentation and recordkeeping practices for
previous sources and the immediate the authority to require appropriate record keeping
assuring quality control in manufacturing subsequent recipients of food (21 U.S.C. in food safety regulations.’’ (H.R. Conf. Rep. No.
operations (Refs. 9 and 13). 350c). 107–481, at 135 (2002), (Ref. 14)).
pervasively regulated industry that is inspection authority. As already enterohemorrhagic Escherichia coli
subject to warrantless inspections (see, discussed, we are not relying on section 0157:H7 (EHEC), are well-known causes
e.g., United States v. Biswell, 406 U.S. 704 of the act for our authority to of communicable diseases, and may be
311, 315 (1972) (‘‘In the context of a require access to dietary supplement present in dietary supplements and
regulatory inspection system of business CGMP records. Thus, to the extent the their components. There are a number
premises * * * the legality of the search comment cited to Medtronic as an of microorganisms that cause
depends not on consent but on the example of the statutory authority for communicable diseases and that may be
authority of a valid statute.’’); United inspection of device records under found in components or dietary
States v. New England Grocers Supply section 704 of the act, Medtronic is not supplements. These microorganisms
Co., 488 F. Supp. 230, 238 (D. Mass. pertinent to our authority for records cause serious effects and symptoms. For
1980) (holding that a warrantless access in this final rule. example, Salmonella causes
inspection under 21 U.S.C. 374 is ‘‘fully Finally, we disagree that the records salmonellosis, which affects the
consistent with the Fourth access in this final rule will violate any gastrointestinal (GI) tract and is
Amendment’’); United States v. Acri protection a manufacturer has with characterized by diarrhea, fever,
Wholesale Grocery Co., 409 F. Supp. respect to protection of confidential abdominal cramps, headache, nausea,
529, 533 (S.D. Iowa 1976) (holding that commercial or financial information or and vomiting (Ref. 16). In a small
a warrantless inspection, which trade secrets. Trade secrets and portion of healthy people (1 to 4
includes photographic activities, commercial or financial information percent), infection spreads from the GI
conducted under 21 U.S.C. 374 does not that is privileged or confidential are tract into the blood stream, which can
violate the Fourth Amendment); United protected from disclosure under FOIA be life-threatening. Persons with
States v. Business Builders, Inc., 354 F. and other laws (see, e.g., 21 U.S.C. immune compromising conditions (such
Supp. 141, 143 (N.D. Okla. 1973) (‘‘the 331(j), 18 U.S.C. 1905). Further, our as cancer, Acquired Immunodeficiency
statute takes the place of a valid search FOIA regulations set forth the specific Syndrome (AIDS), autoimmune
warrant’’); United States v. Del Campo procedures for assuring such protection. disorders) are at greater risk of blood
Baking Mfg. Co., 345 F. Supp. 1371 (D. It was not clear from the comments stream infection (Ref. 16).
Del 1972) (finding warrantless what was meant by ‘‘rights to privacy of Campylobacteriosis, often due to
inspection of food establishment lawful corporate manpower.’’ We note that infection with Campylobacter jejuni, is
under 21 U.S.C. 374)). §§ 20.63 and 20.64 contain provisions characterized by diarrhea, fever, and
As explained earlier in this section, for the protection of personal privacy. abdominal cramps, which can be severe
we have ample authority, under sections (Ref. 17). These symptoms frequently
C. Public Health Service Act Authority
402(g) and 701(a) of the act, to require relapse, and the disease may become
that certain records be kept and (Comment 20) One comment chronic in immune compromised
accessible to us upon inspection. acknowledges that we have authority persons. People with
Records access is imperative to the under the PHS Act to regulate intrastate campylobacteriosis are also at increased
efficient enforcement of the dietary activities that may cause the spread of risk of developing certain post-
supplement CGMP final rule, and we communicable diseases. The comment infectious complications, which will
are not prohibited from requiring access states that, in any situation in which we prolong their recovery.
to these records under sections 402(g) need to exercise our authority over any EHEC may cause infections with a
and 701(a) of the act (See Permian Basin disease-causing substance within the very low infectious dose (as low as 2 to
Area Rate Cases, 390 U.S. 747, 780 State where a component or dietary 45 organisms), and may result in non-
(1968) (‘‘in the absence of compelling supplement is manufactured, packed, or bloody and bloody diarrhea, hemolytic-
evidence that such was Congress’ held, we can and should exercise our uremic syndrome (a cause of red blood
intention * * * [the court should not] authority under the PHS Act. However, cell destruction, damage of blood vessel
prohibit administrative action the comment asserts that nothing in the walls, and, in severe cases, kidney
imperative for the achievement of an preamble clearly states whether we failure (especially in young children)),
agency’s ultimate purposes.’’)). believe that the final rule will be, in its thrombotic thrombocytopenic purpura
We also disagree with the comment entirety, binding on manufacturers, (i.e., a blood disorder characterized by
suggesting that voluntary records access packers, and holders of dietary low platelets, low red blood cell count,
is sufficient. In our experience, many supplements who are engaged solely in abnormalities in kidney function, and
manufacturers are not willing, as the intrastate commerce, and that we have neurological abnormalities (especially
comments suggest, to provide records not requested comment on this specific in adults)), and death (Ref. 18).
voluntarily to us (Ref. 15). Moreover, it issue. The comment requests that we Animal tissues (e.g., organs from
is often the case that the most clearly state that the final rule applies livestock), as well as botanicals, used as
uncooperative manufacturers are the only to interstate commerce, except for components in dietary supplements
very ones whose records and processes activities that may spread may contain EHEC, Salmonella, and
are deficient. Without mandatory communicable diseases. Campylobacter jejuni. In addition,
requirements for agency access to (Response) We address each of these because the same microorganisms are
records required by the final rule, we issues in turn. also present in the environment, they
could not enforce and there would be may contaminate components during
minimal incentives for manufacturers to 1. The Communicable Disease Risk manufacturing activities. Moreover,
comply with the rule, which would Posed by Dietary Supplements people who harbor those pathogens
frustrate Congressional intent in There are communicable disease risks could transmit them to components and
enacting section 402(g) of the act. related to the manufacture of dietary dietary supplements during processing.
We also disagree with the comment supplements that are appropriately Therefore, components and dietary
that cited In the Matter of Establishment addressed not only under the act, but, supplements, as potential sources of
Inspection of Medtronic, Inc., 500 F. as the comment acknowledges, also communicable diseases, may be
Supp. 536 (D. Minn. 1980), to suggest under the PHS Act. Microorganisms, regulated under the PHS Act.
that our proposed recordkeeping including Salmonella enterica For these microorganisms (e.g., EHEC,
requirements exceed our statutory (Salmonella), Campylobacter jejuni, and Salmonella, and Campylobacter jejuni)
humans carry and transmit infections the tablet production process and diseases. If, for example, a dietary
through their feces or by direct contact thereby expose consumers (Ref. 25). supplement manufacturer purchased an
with other persons. For other The industry is aware of the dangers animal-derived ingredient that harbored
microorganisms, domestic and wild of using components contaminated with Salmonella enterica, but failed to take
animals serve as the reservoir, and Salmonella and other microorganisms. the steps necessary to inactivate the
humans become infected when For example, in 2001, a component pathogen, the consumption of the
contaminated tissues of infected manufacturer recalled 2,400 pounds of dietary supplement could lead to the
animals are used in dietary pepsin contaminated with Salmonella. spread of salmonellosis.
supplements. For both categories of As a result, a number of dietary The final rule also requires firms to
microorganisms, dietary supplements supplement manufacturers issued take measures to exclude from certain
can also become contaminated recalls for their dietary supplements operations any sick persons who might
indirectly by human and animal fecal that contained the pepsin. In the press contaminate material, including
contamination of water or through the releases accompanying the recalls, the components, dietary supplements, and
production or processing environment. dietary supplement manufacturers contact surfaces used to manufacture,
Dietary supplements may contain a warned consumers of the possible package, label, or hold a dietary
variety of components derived from dangers of Salmonella contamination, supplement.
domestic and wild animals, such as and encouraged consumers to either
destroy or return the supplements (Ref. D. The Interstate Commerce Nexus for
powders prepared from whole or partial the Final Rule
gecko, deer antler velvet, and organs, 26).
such as cow liver and brain, pork Therefore, because of the 1. The PHS Act
stomach, or sheep spleen from common communicable disease concerns
associated with dietary supplements, we (Comment 21) Several comments
domestic livestock. Each of these tissues assert that, although the PHS Act may
may be contaminated with are asserting legal authority under the
PHS Act in support of the final rule. As extend to some intrastate activities, its
microorganisms such as Salmonella, reach is very limited. The comments
discussed in the following section of
Campylobacter jejuni, and EHEC. Even appear to conclude that the reach of the
this document, our authority under the
clinically normal animals obtained from PHS Act and the act extends only to
PHS Act is not limited to interstate
safe sources may harbor these situations in which the finished dietary
activities. It also covers intrastate
communicable pathogens and result in supplement is shipped in interstate
activities.
contaminated products (Ref. 19). commerce.
(Information on these animals and 2. Activities For Which We Are (Response) We do not agree that this
potential pathogens can be accessed at Asserting Legal Authority Under the view is correct. The PHS Act extends to
http://www.fsis.usda.gov/Science/ PHS Act intrastate commerce. Under section 361
Microbiology/index.asp). Dietary There are many opportunities for of the PHS Act (42 U.S.C. 264), we may
supplements also may contain components and dietary supplements to ‘‘make and enforce such regulations as
crustacean or molluscan shellfish or become contaminated with in [our] judgment are necessary to
components prepared from them, such microorganisms that spread prevent the introduction, transmission,
as glucosamine from shrimp communicable diseases. The final rule or spread of communicable diseases
exoskeletons and oyster extract, that requires firms to take all the necessary from foreign countries into the States or
may be contaminated with Vibrio precautions during the manufacture of a possessions, or from one State or
species, including V. parahaemolyticus. dietary supplement to prevent such possession into any other State or
Vibrio species are natural inhabitants of contamination. possession.’’
shellfish harvest waters, and shellfish These precautions, for example, In Louisiana v. Mathews, 427 F. Supp.
are commonly naturally contaminated, include: Performing manufacturing 174, 176 (E.D. La. 1977), the court
especially during times of the year when operations under conditions and upheld FDA’s regulation that banned
harvest waters are warm (Refs. 20 controls that protect against potential the sale of small turtles to prevent the
through 23). V. parahaemolyticus most microorganism growth; washing or spread of disease caused by turtles
often causes gastroenteritis cleaning components that contain soil harboring Salmonella and Arizona
characterized by diarrhea, abdominal or other contaminants; performing microorganisms. The ban covered both
cramps, nausea, vomiting, and fever microbiological testing, as necessary, to interstate and intrastate sales. The court
(Ref. 24). prevent the use of contaminated held that the intrastate ban is not only
Dietary supplements may also contain components; sterilization, authorized by the law, but, under
botanicals (plants) that may harbor pasteurization, freezing, refrigeration, modern conditions of transportation and
microorganisms, including organisms and controlling pH, humidity, and water commerce ‘‘is clearly reasonable to
from animal feces (Salmonella and activity (aw), or using other effective prevent the interstate spread of disease’’
Shigella spp., Escherichia coli), and means to remove, destroy, or prevent (id.).
organisms arising from handling the growth of microorganisms and We are authorized under the PHS Act
(Staphylococcus aureus), harvesting, decomposition; and holding to regulate conduct that occurs within a
processing, and transportation. components and dietary supplements State to the extent necessary to prevent
Components contaminated with that can support the growth of the interstate spread of communicable
microorganisms must be treated to infectious microorganisms of public diseases. Such is the present case with
prevent the finished dietary health significance in a manner that respect to the provisions of the dietary
supplements from being contaminated. prevents them from becoming supplement CGMP final rule for which
The processes used to manufacture adulterated. section 361 of the PHS Act provides
dietary supplements do not, by Failure to properly clean components, authority.

themselves, always eliminate the or take any other appropriate steps, such
microorganisms. Studies show, for as those listed in the previous 2. The Act
example, that microorganisms, such as paragraph, could lead to pathogen The act extends to the sale of a dietary
EHEC and Salmonella, can even survive growth and the spread of communicable supplement that was manufactured and
distributed entirely in one State, if the connection with interstate commerce will be enforced. The comments focus
supplement contains any ingredient or required for jurisdiction in such action on provisions containing words such as
uses any component that came from shall be presumed to exist.’’)). ‘‘adequate,’’ ‘‘qualified,’’ ‘‘readily
outside of that State. Such a dietary In conclusion, the final rule covers accessible,’’ ‘‘convenient,’’ ‘‘suitable,’’
supplement is subject to section 301(k) not only finished products that have ‘‘appropriate,’’ and ‘‘necessary.’’ For
of the act, which prohibits ‘‘[t]he moved in interstate commerce but also example, one comment notes that
alteration, mutilation, destruction, products made from ingredients or proposed § 111.15(e) would require
obliteration, or removal of the whole or components that have moved in physical plant plumbing to be of an
any part of the labeling of, or the doing interstate commerce. This is true adequate size and design and to be
of any other act with respect to, a food, regardless of the amount of the adequately installed and maintained.
drug, device, or cosmetic, if such act is ingredient or component in the product The comment objects to the section on
done while such article is held for sale and regardless of whether the finished the ground that ‘‘what constitutes
(whether or not the first sale) after dietary supplement has itself moved in ‘adequate’ in those contexts is left
shipment in interstate commerce and interstate commerce. The final rule also undefined.’’
results in such article being adulterated covers products, components, and (Response) We disagree these terms
or misbranded.’’ (emphasis added). See ingredients that may contribute to the are vague or that the identified terms
also 21 U.S.C. 321(b)(3) (defining food spread of communicable disease, should be deleted from the final rule.
to include articles used as components regardless of whether the component, The qualifying terms objected to in the
of food). ingredient, or product has itself moved comments have been in use since the
The interstate commerce prerequisite in interstate commerce. umbrella food CGMP rule (part 110) was
under section 301(k) or section 304(a) first promulgated in 1969. For example,
3. Commerce Clause
(21 U.S.C. 334(a)) of the act is this regulation included requirements
established when one or more (Comment 22) One comment states that: ‘‘[p]lant buildings and structures
components used in the manufacture of that we must be ‘‘mindful of the limits’’ shall be suitable in size;’’ there must be
the product have crossed State lines. imposed on the regulation of intrastate ‘‘sufficient space’’ for equipment and
This principle is known as ‘‘component commerce by the Supreme Court in storage materials; there must be
jurisdiction’’ (See, e.g., Baker v. United United States v. Lopez, 514 U.S. 549 ‘‘adequate lighting;’’ and protection
States, 932 F.2d 813, 814–15 (9th Cir. (1995). The comment asserts that we against pests must be provided ‘‘where
1991); United States v. Article of Food may only regulate intrastate activity that necessary’’ (see 34 FR 6977 at 6978,
* * * Coco Rico, Inc., 752 F.2d 11, 14 has a ‘‘substantial effect’’ on interstate April 26, 1969). The court in National
(1st Cir. 1985); United States v. commerce and activity that ‘‘exerts a Association of Pharmaceutical
Dianovin Pharmaceuticals, Inc., 475 substantial economic effect on interstate Manufacturers. v. Department of Health
F.2d 100, 103 (1st Cir.), cert. denied, 414 commerce.’’ & Human Services, 586 F.Supp. 704
U.S. 830 (1973) (‘‘appellants’ use of (Response) The final rule is consistent (S.D.N.Y 1986), addressed the very
components shipped in interstate with the Lopez decision. Among the question of whether terms such as
commerce to make vitamin K for cases cited by the Court in Lopez as ‘‘adequate,’’ ‘‘appropriate,’’ ‘‘proper,’’
injection brought their activities within support for its decision is Wickard v. ‘‘sufficient,’’ and ‘‘suitable,’’ in the drug
§ 331(k)’’); United States v. Cassaro, Filburn, 317 U.S. 111 (1942), which CGMP regulation were vague. The court
Inc., 443 F.2d 153, 155–56 (1st Cir. involved the production and found that the drug CGMP regulation
1971); United Statesv. Detroit Vital consumption of homegrown wheat. In containing such terms was ‘‘sufficiently
Foods, Inc., 330 F.2d 78, 81–82 (6th that case, the Court explained: definite to give notice of the required
Cir.), cert. denied, 379 U.S. 832 (1964); ‘‘although Filburn’s own contribution to conduct to one who would avoid [their]
United States v. Allbrook Freezing & the demand for wheat may have been penalties, and to guide the judge in
Cold Storage, Inc., 194 F.2d 937, 939 trivial by itself, that was not enough to [their] application * * *’’ (Id. at 753).
(5th Cir. 1952); United States v. Varela- remove him from the scope of federal The court so held, in part, in light of the
Cruz, 66 F.Supp.2d 274, 277–281 (D. regulation where, as here, his fact that the drug CGMP statute was
P.R. 1999)). contribution, taken together with that of upheld against a constitutional
Nor does it matter that the interstate many others similarly situated, is far vagueness attack in United States v. Bel-
product component comprises only a from trivial’’ (Lopez, 514 U.S. at 556). Mar Laboratories, Inc., 284 F. Supp.
minute part of the article, United States The same is true for dietary supplement 875, 883 (E.D.N.Y. 1968) (‘‘the phrase
v. Miami Serpentarium Laboratories, manufacturers. Therefore, the ‘current good manufacturing practice’ is
[1981—1982 Transfer Binder] Food requirements of the final rule are not strange to those in the trade to
Drug Cosm. L.Rep. (CCH) paragraph consistent with the Commerce Clause of whom the subject section is directed.’’).
38,164 at 38,930 (S.D. Fla. 1982); United the Constitution. Furthermore, the use of such ‘‘ordinary
States v. 14 Cases * * * Naremco, 374 terms to express ideas which find
F.Supp. 922, 925 (W.D. Mo. 1974), or if E. Fifth Amendment
adequate interpretation in common
the interstate ingredient combines with (Comment 23) Several comments usage and understanding’’ are not the
others to form a different product. allege a number of the sections of the types of terms that have been held to be
Detroit Vital Foods, 330 F.2d at 81; proposed regulation are unconstitutionally vague (Boyce Motor
United States v. 40 Cases * * * unconstitutionally vague and violate the Lines v. United States, 342 U.S. 337, 342
Pinocchio Brand * * * Oil, 289 F.2d Administrative Procedure Act (APA) (1952)). Some of these very terms have
343, 346 (2d Cir.), cert. denied, 368 U.S. because the rule would be ‘‘contrary to been in use for over 30 years in food
831 (1961). constitutional right, power, privilege, or CGMP regulations.
Finally, we note that section 709 of immunity.’’ The comments express No comments were submitted
the act creates a presumption of concern that if such terms are not objecting to the use of such terms, when
interstate commerce (see 21 U.S.C. 379a defined or deleted, there would be no the umbrella food CGMP rule was
(‘‘In any action to enforce the fair notice on what conduct is revised in 1986 (see 51 FR 22458, June
requirements of this Act respecting a prohibited and would result in 19, 1986). Also, when we began work on
device, food, drug, or cosmetic the ‘‘unbridled discretion’’ in how the rule the dietary supplement CGMP rule, we
received and published for comment an F. Supp. at 883 (rejecting a vagueness detect and avoid adulteration through
industry draft of a CGMP regulation for challenge to the CGMP requirements for CGMP, the proposed rule created a
dietary supplements. The industry draft drugs, noting that ‘‘[a]s a matter of fact, presumption that dietary supplements
used many of the same terms. For there are responsible segments of are adulterated until proven otherwise.
example, it provides in part: ‘‘Plumbing opinion within the industry itself which (Response) The final rule does not
shall be of adequate size and design and oppose a greater degree of specificity in violate section 402(f) of the act. Section
adequately installed and maintained’’ this area.’’). 402(f) and (g) of the act provide two
(62 FR 5700 at 5703, February 6, 1997). Finally, it is important to understand independent bases under which we may
Thus, there has been sufficient common that rules are not unconstitutionally take enforcement action against dietary
usage of these terms in the food industry vague simply because they require supplements. A dietary supplement may
and, in particular, the dietary interpretation by regulated persons. For be adulterated either because a
supplement industry to enable example, courts have held that the term manufacturer has failed to follow a
manufacturers, and those who enforce ‘‘insanitary conditions’’ in the act is not CGMP requirement, or because a dietary
the requirements, to comprehend and unconstitutionally vague (See Golden supplement presents an unreasonable
apply such terms ‘‘with a reasonable Grain Macaroni Co. v. United States, risk of illness or injury, or both. There
degree of certainty’’ to their particular 209 F.2d 166, 168 (9th Cir. 1953) (citing would be no reason to assert a second
operations (Boyce Motor Lines v. United Boyce Motor Lines, supra); Berger v. basis for adulteration under section
States, 342 U.S. at 340 (‘‘[F]ew words United States, 200 F.2d 818 (8th Cir. 402(g) of the act if one always had to
possess the precision of mathematical 1952)). In Berger, the court rejected the demonstrate adulteration under section
symbols, most statutes must deal with claim that the term ‘‘insanitary 402(f) of the act as a prerequisite.
untold and unforeseen variations in condition’’ is unconstitutionally vague We also disagree with the comment
factual situations, and the practical on the ground that it does not specify that the proposed rule creates a
necessities of discharging the business the ‘‘degree of insanitation’’ required for presumption that the dietary
of government inevitably limit the a violation (id. at 822). A law may supplement is adulterated simply
specificity with which legislators can require a person to make ‘‘estimates of because the proposed requirements
spell out prohibitions [and therefore] no the degree of dirtiness and lack of would enable a manufacturer to detect
more than a reasonable degree of sanitation’’ which may result in a and avoid adulteration. The
certainty can be demanded.’’)). The violation (id., see alsoBoyce Motor Lines requirements for CGMP are prophylactic
same reasoning applies here. It v. United States, 342 U.S. at 340 (It is and are designed in part to ensure that
addresses ‘‘untold and unforeseen not ‘‘unfair to require that one who all aspects of manufacturing, from
variations in factual situations’’ and, as deliberately goes close to an area of receipt through distribution, provide the
proscribed conduct shall take the risk necessary controls and monitoring to
such, ‘‘no more than a reasonable degree
that he may cross the line’’)). There are ensure the quality of the dietary
of certainty can be demanded.’’
sufficient protections under the act to supplement, including that it is
Agencies are permitted to, and indeed overcome any concerns related to how manufactured, packaged, labeled, and
must, use such qualifying terms to it will be criminally enforced. We held in a manner to prevent
address the variety of conditions that disagree that such terms will lead to adulteration.
exist at different companies. We do not ‘‘unbridled discretion’’ on how the rule (Comment 25) One comment states
need to, nor could we, predict with is enforced. that, if there is reduced competition
mathematical precision how many In short, we find that the rule is not through the enforcement of the rule,
inches or feet, for example, would be unconstitutionally vague, and does not there will be a secondary effect of
‘‘adequate space’’ to allow for cleaning violate section 706(2)(B) of the APA (5 elimination of speech on dietary
a particular piece of equipment that U.S.C. 706(2)(B)). supplement innovative uses.
could be applied to every size of facility (Response) The comment seems to
and every operation (id.). Moreover, F. Miscellaneous conclude that, if a dietary supplement
defining such terms too precisely would (Comment 24) One comment states manufacturer is not able to stay in
unduly restrict the application of the that the proposed rule violates section business due to adverse enforcement
regulation to a very narrow, limited set 402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act actions against it by us, or elects to not
of circumstances and not provide (21 U.S.C. 342 (f)(1)(A)(i) and go into business based on the possibility
industry with the needed flexibility to (f)(1)(A)(ii)), which deems a dietary of enforcement action by us, there will
address the number and variety of types supplement adulterated if it contains a be reduced competition due to fewer
of manufacturing operations that dietary ingredient that presents an products, less labeling, and
Congress intended for this rule to cover unreasonable risk of illness or injury ‘‘elimination of speech on innovative
(see Freeman United Coal Mining under conditions of use in labeling or uses.’’ To the extent that the comment
Company v. Federal Mine Safety and ordinary conditions of use, if none are is suggesting that the dietary
Health Review Commission, 108 F.3d suggested or recommended in labeling. supplement CGMP requirements are
358, 363 (D.C. Cir. 1997) (citations Under section 402(f) of the act, the unconstitutionally overbroad, this
omitted) (upholding a regulation that Government bears the burden of proof to argument is wholly without merit (Cf.
required equipment to be ‘‘maintained show that a dietary supplement is Wisconsin v. Mitchell, 508 U.S. 476,
in good repair,’’ the court rejected the adulterated. The comment states that 488–89 (1993) (finding no merit to an
vagueness challenge: ‘‘specific the proposed rule reversed the overbreadth argument that the
regulations cannot begin to cover all of presumption under section 402(f) of the possibility of enhanced sentences based
the infinite variety of [conditions at act, and would revise the rule to require on prior racially motivated speech or
firms and that] * * * [b]y requiring us to first show a violation under associations constitutes an
regulations to be too specific [courts] section 402(f) of the act before we could impermissible chill on free speech)).
would be opening up large loopholes take any enforcement action under Manufacturing a dietary supplement in
allowing conduct which should be section 402(g). Another comment states a manner that violates the CGMP
regulated to escape regulation.’’); United that, because the rule was intended to requirements causes the product to be
States v. Bel-Mar Laboratories, Inc., 284 enable manufacturers to be able to adulterated, and therefore, unlawful.
The fact that a manufacturer may not dietary supplements do not apply to you distinguish label operations from the
stay in business, or elects not to enter if you are holding those dietary broader context of manufacturing.
business, due to: (1) Our supplements at a retail establishment for In any case, to correct such
implementation of CGMP requirements the sole purpose of direct retail sale to misinterpretation, we have revised
or (2) our enforcement against a product individual consumers. This section also § 111.1 to include the word ‘‘label.’’
that violates CGMP requirements, does states that a retail establishment does Thus, under final § 111.1(a), you are
not mean that we are somehow not include a warehouse or other storage subject to the dietary supplement CGMP
prohibiting speech. In any event, there facility for a retailer or a warehouse or requirements if you ‘‘manufacture,
is no First Amendment protection for other storage facility that sells directly package, label, or hold a dietary
speech that concerns unlawful activity to individual consumers. supplement.’’ We also have made
under the first prong of the test set out This exclusion represents specific corresponding changes to other sections
in Central Hudson Gas & Electric Corp. changes sought by the comments. We in this final rule; for example, we have
v. Public Service Commission, 447 U.S. provide detail on the comments and our revised the definition of ‘‘you’’ in final
557 (1980). Therefore, the comment’s reasons for revising final § 111.1 in the § 111.3 to state that ‘‘you’’ means ‘‘a
suggestion that there is elimination of following paragraphs. person who manufactures, packages,
speech based on the rulemaking is not (Comment 26) Some comments labels, or holds’’ a dietary supplement,
supportable. The requirements in the interpret the proposal as not applying to and we also have inserted the word
final rule do not infringe on a persons who perform labeling ‘‘labeling’’ in the title to this final rule.
manufacturer’s right to lawfully label operations. For example, one comment We have not explained this change in
and market a dietary supplement. claims that proposed § 111.35(e), which the preamble each time it is made in the
would require manufacturers, codified provision.
VI. What Comments Did We Receive on packagers, and persons who hold In addition, we refer to ‘‘label’’ and
the General Provisions? (Subpart A) dietary supplements to establish ‘‘labeling’’ in the context of CGMP
A. Organization of Final Subpart A specifications, did not apply to requirements related to operations for
‘‘labelers’’ because the proposed ensuring the correct label is on the
Proposed subpart A contained five definition of ‘‘you’’ did not expressly product. To help clarify that we are
provisions regarding the scope of the mention persons who label dietary referring to labeling requirements in this
proposed rule, definitions, and supplements. final rule for labeling operations and
exclusions. Table 2 of this document (Response) We disagree with the not, for example, to the labeling
lists the sections in final subpart A and comments. Various provisions in the requirements in part 101, we inserted
identifies the proposed sections that proposal expressly mentioned or the word ‘‘operations’’ in the title of part
form the basis of the final rule. pertained to labels and labeling 111 to read ‘‘Current Good
operations (see, e.g., proposed Manufacturing Practice in
TABLE 2.—DERIVATION OF §§ 111.20(c)(6) (which would require Manufacturing, Packaging, Labeling, or
SECTIONS IN FINAL SUBPART A your physical plant to have separate or Holding Operations for Dietary
defined areas for packaging and label Supplements.’’
2003 operations), 111.30(a) (which would (Comment 27) Several comments ask
Final Rule CGMP impose certain requirements on for clarification about the rule’s
Proposal
automatic, mechanical, or electronic applicability to different types of
§ 111.1 Who is subject § 111.1 equipment used to ‘‘manufacture, businesses and practices. Some
to this part? package, label, and hold’’ a dietary comments ask for a clear listing of who
supplement), 111.35(a) (which would is subject to the rule, stating that it is
§ 111.3 what definitions § 111.3 require you to implement a system of difficult to apply the rule’s specific
apply to this part? production and process controls that provisions. According to these
cover, among other things, all stages of comments, the rule’s level of detail and
§ 111.5 Do other statu- § 111.5
labeling dietary supplements), 111.37(a) inflexibility does not account for
tory provisions and
regulations apply?
(which would require you to use a variations in manufacturing needs
quality control unit to ensure, among within the entire industry.
other things, your label operations are Several comments on various
B. Who Is Subject to This Part? (Final
performed in a manner that prevents proposed sections ask who would be
§ 111.1)
adulteration and misbranding), responsible for complying with CGMP
Section 111.1 explains who is subject 111.40(b) and (c) (which would impose requirements if more than one party was
to the dietary supplement CGMP certain requirements on packaging and involved in the manufacturing,
requirements. In brief, final § 111.1(a) labels you receive and on persons who packaging, labeling, or holding of the
states that you are subject to the dietary perform label requirements), and 111.70 dietary supplement. For example, some
supplement CGMP requirements if you (which would impose various comments ask whether consultants are
manufacture, package, label, or hold a requirements on packaging and label subject to a specific proposed section;
dietary supplement. This requirement operations)). Although the proposed others ask who would be responsible if
includes a dietary supplement you definition of ‘‘you’’ and proposed a firm employed another firm to handle
manufacture but that is packaged or § 111.1 did not include the word ‘‘label’’ packaging or labeling operations.
labeled by another person, and a dietary or ‘‘labeling,’’ we considered label Other comments request clarification
supplement that is imported, offered for operations to be part of a broader regarding the rule’s applicability to
import in any State or Territory of the manufacturing process, and it would be distributors. Some comments claim that
United States, the District of Columbia, illogical to interpret the proposal’s a person who holds and sells packaged
or the Commonwealth of Puerto Rico. specific references to label operations as products should not be subject to
Final § 111.1(b), however, excludes somehow being inapplicable to labelers dietary supplement CGMP
certain persons from the rule. simply because a proposed definition of requirements. Other comments state that
Specifically, § 111.1(b) states that the ‘‘you’’ or a general ‘‘scope’’ provision dietary supplement CGMPs should
requirements pertaining to holding did not mention labels or otherwise apply to distributors as well as
manufacturers. These comments assert this rule may apply to various persons, applicable CGMP requirements related
many supplement distributors are we provide some examples in the to the operations that they perform. The
merely marketers who employ contract following paragraphs. manufacturer would not be responsible
manufacturers. The comments said that, A manufacturer that manufactures a for the oversight of the packager/labeler,
because marketers are the parties dietary supplement, and then packages since the packager/labeler is not under
providing supplements to consumers, and labels and distributes the dietary the control of the manufacturer and has
we should hold marketers responsible supplement, is subject to all the control over the release of the packaged
for their products and require marketers requirements in this final rule. If that and labeled dietary supplement.
to ensure that their contract manufacturer contracts with another A manufacturer may decide to hire a
manufacturers adhere to CGMP person to package and label the dietary contractor or a consultant for specific
requirements. These comments argue supplement, then the packager/labeler is operations within the scope of the
we should not permit marketers to responsible for complying with the manufacturer’s responsibilities under
transfer their responsibilities in requirements for packaging and labeling the final rule. For example, a
delivering safe supplements. Other operations, in addition to other relevant manufacturer may hire a person to
comments assert questions about the requirements. The packager/labeler, in calibrate its equipment. The
rule’s applicability are underscored by this example, would need to comply, manufacturer is responsible for
typical dietary supplement labeling not only with the specific requirements complying with the requirements
practices where the contact information related to packaging and labeling related to its responsibilities, e.g.,
listed on the product label pertains to operations in subpart L, but also with calibration requirements in this
the distributor/marketer instead of the the general requirements related to example, even though the manufacturer
actual manufacturer. personnel, physical plant, quality has hired another person to perform that
Collectively, these comments raise a control, and other requirements that job task.
basic question as to which party or apply to that firm’s operations. However In another example, a distributor who
parties are responsible for complying the packager/labeler would not need to purchases a packaged and labeled
with the dietary supplement CGMP comply with requirements that do not dietary supplement and who then holds
requirements where more than one apply to it; for example, the packager/ the product in a warehouse for
party is involved in the manufacture, relabeler would not have to conduct distribution to another physical location
packaging, labeling, or holding of that testing on the finished batch of dietary is subject to the requirements related to
dietary supplement. supplement since it does not its operations. The codified uses the
(Response) In the 2003 CGMP manufacture the finished batch of word ‘‘hold’’ since it is a broad term
Proposal, we stated that it would apply dietary supplement. which encompasses the activities of a
to a wide variety of activities associated A manufacturer who contracts with a distributor. Thus, the distributor would
with the manufacture, packaging, and person to do packaging and labeling, but be responsible for complying with
holding of a dietary supplement, who later distributes the packaged and requirements in subpart M, Holding and
including labeling, testing, quality labeled product, is ultimately Distributing, in addition to other
control, holding, and distribution (68 FR responsible for the dietary supplement requirements related to its operations
12157 at 12175). We stated under it releases for distribution. The (e.g., Personnel, Physical Plant and
proposed part 111 you would need to manufacturer would be responsible for Grounds).
comply with those regulations directly the CGMP requirements for the In cases where a distributor contracts
applicable to the operations that you operations that it performs, including with a manufacturer to manufacture a
perform and provided examples (id.). those related to the release of the dietary supplement that the distributor
All activities may not be performed by product for distribution. For example, then distributes under its own label, the
the same person. For example, a the manufacturer must determine distributor has an obligation to know
manufacturer may contract with another whether the packaged and labeled what and how manufacturing activities
firm to package and label the dietary dietary supplement it receives from the are performed so that the distributor can
supplement in the containers used for packager/labeler conforms to applicable make decisions related to whether the
distribution to consumers. specifications (final § 111.127(d)), and packaged and labeled product conforms
Alternatively, a distributor may contract must approve the release of the to its established specifications and
with one firm to manufacture a dietary packaged and labeled dietary whether to approve and release the
supplement, and another firm to supplement for distribution (final product for distribution.
package and label the dietary § 111.127(h)). Although the (Comment 28) Some comments state
supplement that the distributor manufacturer is not performing the that the proposed rule requirements
ultimately distributes under its own specific activities related to the would require the manufacturer to
name. packaging and labeling operations done report adverse events to us, but would
Under this final rule, you must by another person, the manufacturer has not require those who distribute the
comply with the CGMP requirements an obligation to know what and how product and whose name is likely to be
that apply to your operations related to such activities are performed so that it on the product label, to report adverse
the manufacture, packaging, labeling, can make decisions related to whether events to us. The comments state that
and holding of dietary supplements. It the packaged and labeled product reports of adverse events submitted by
is not practical to list all possible conforms to applicable specifications consumers to those who distribute, but
contractual relationships that persons and whether to approve and release the do not make, dietary supplements could
may enter into in the manufacture of a product for distribution. be hidden from the public if such
dietary supplement, or to list all Some manufacturers may sell their persons are not required to submit those
businesses or practices that may be finished batch of dietary supplement to reports to us.
subject to the requirements of this final a packager/labeler that the packager/ (Response) The comments may have
rule in order for persons to know labeler may package, label, and then misinterpreted the proposed rule. The
whether they are subject to hold and distribute. The manufacturer requirement to review and investigate a
requirements of this final rule. To and packager/labeler would each be product complaint is distinct from any
provide additional clarity about how responsible for complying with the report about the product complaint to
us. Reporting a complaint to us is not proposed rule to limit the rule’s including those that may not appear in
covered by these CGMP requirements applicability to dietary supplements. the finished batch of the dietary
and would be voluntary, unless the In contrast, other comments say the supplement. Component includes
complaint is subject to the statutorily rule should apply to dietary ingredient dietary ingredients (as described in
mandated reporting requirements for manufacturers as well as to dietary section 201(ff) of the act) and other
‘‘significant adverse events’’ pursuant to supplement manufacturers. The ingredients’’ (final § 111.3). The
the ‘‘Dietary Supplement and Non- comments state that excluding those proposed rule, § 111.3, recognized that
Prescription Drug Consumer Protection who provide or supply dietary ‘‘dietary ingredients’’ are ‘‘components’’
Act’’ (Public Law 109–462), signed into ingredients would mean those who have (68 FR 12157 at 12176) (describing how
law on December 22, 2006 (see the greatest expertise in these goods dietary ingredients would fall within
discussion in section XX of this would not be subject to dietary the proposed definition of
document). supplement CGMP requirements and ‘‘component’’).
Under the procedures that are set thus fail to cover a crucial step in There are specific requirements in
forth in subpart O, Product Complaints preventing the adulteration or this final rule that relate to components,
(see section XX of this document), a contamination of dietary supplements. and thus dietary ingredients, that are
distributor and a manufacturer are both The comments argue that, for some used in the manufacture of a dietary
subject to the requirements related to dietary ingredients (especially raw supplement. For example, final
the review and investigation of a botanical and agricultural goods), the § 111.70(b) requires you to establish
product complaint that they receive. most critical point in ensuring an certain component specifications. Such
(Comment 29) Some comments argue ingredient’s quality and purity is at time requirements would include
against including minimum CGMPs of harvest or creation, and that this is specifications for dietary ingredients as
necessary for activities related to particularly true with new or original ‘‘components.’’ It is important to control
manufacturing, packaging, labeling, or ingredients. the components used in the
holding dietary ingredients in the final The comments state problems with manufacture of dietary supplements to
rule. Several comments argue the dietary supplements often arise from ensure consistency and to ensure the
proposed rule is overly broad and substandard ingredients, and the quality of the dietary supplement. Since
inconsistent with congressional intent. difficulty in testing the properties of dietary ingredients are considered
These comments question whether some botanical and other dietary components, the various requirements
Congress intended that CGMP apply to ingredients at the in-process or finished apply to dietary ingredients as part of
persons involved in the manufacture, product stage makes it necessary to the production and process control.
packaging, labeling, and holding of include dietary ingredient Therefore, we disagree to the extent
dietary ingredients. The comments also manufacturers in the final rule. comments were suggesting that there
argue that, if the rule applies to dietary Furthermore, these comments assert a should be no CGMP requirements
ingredient manufacturers, we would be flexible testing scheme that they related to the dietary ingredients used
establishing precedent and that we lack recommend (which emphasizes by a manufacturer in the manufacture of
legal authority to regulate ingredients establishing specifications for dietary supplements.
rather than the finished products components, relying on certificates of Dietary ingredients are included
themselves. The comments state that analysis from qualified suppliers, within the meaning of ‘‘component.’’ In
neither food CGMP nor drug CGMP qualifying component suppliers, and those requirements in the proposed rule
offers precedent or guidance on establishing written procedures, with where ‘‘component’’ encompasses
regulating ingredients. The comments testing of finished batches serving as a ‘‘dietary ingredient’’ we are, in the final
argue those who provide dietary check on the overall manufacturing rule, removing ‘‘dietary ingredient’’ in
ingredients should be subject to the process) makes it important to regulate those requirements and only refer to
existing general food CGMP dietary ingredient manufacturers. ‘‘component.’’ Given the scope of the
requirements in part 110 rather than to Other comments suggest we issue a final rule, it is redundant to refer to both
the dietary supplement CGMP separate or modified set of CGMP ‘‘component’’ and ‘‘dietary ingredient’’
requirements. requirements that would apply to where the latter is subsumed in the
Several comments argue that many persons who manufacture, package, former.
dietary ingredients are used in regular label, or hold dietary ingredients. These In response to comments that
foods and in drugs as well as in dietary comments say the proposed rule does questioned the need to include
supplements. The comments argue, for not work for all dietary ingredients, manufacturers of dietary ingredients
some dietary ingredients, their use in especially those converted from non- within the scope of part 111, we have
dietary supplements represents a very food grade to food grade during the made changes to the scope of the rule,
small percentage of the dietary manufacturing process. These as applied to dietary ingredient
ingredient’s worldwide usage. The comments said the rule should be manufacturers. As we explain more
comments say we should allow those modified for dietary ingredients. fully in our discussion of final
who deal only with dietary ingredients (Response) Two issues seem to be §§ 111.70, 111.73, 111.75, and 111.77
to operate under one set of regulations, raised by these comments: (1) Whether (see section X of this document), after
such as the general food CGMP dietary ingredients are within the scope considering comments about the overall
requirements in part 110. According to of this final rule and (2) whether dietary production and process control system,
these comments, we have not ingredient manufacturers are subject to we revised the final rule’s approach to
demonstrated either a failure of the this final rule. Dietary ingredients are ensuring product quality. This approach
current system or a compelling need to included within the scope of this final emphasizes that it is important to
create different regulations for raw rule but dietary ingredient ensure the quality of the dietary
materials common to both the food and manufacturers are not necessarily supplement throughout the production
dietary supplement industries. The subject to this rule. The definition of and process control system. This
comments would revise the title of part ‘‘component’’ in this final rule includes approach emphasizes establishing
111 and proposed § 111.1 and make ‘‘any substance intended for use in the specifications for components and
conforming revisions throughout the manufacture of a dietary supplement ensuring those specifications are met.
You may rely on a certificate of analysis consumers as a dietary supplement, you Some comments expressed concern
for specifications (except for the identity would be subject to the dietary about dietary ingredient manufacturers
of the dietary ingredient) only if you supplement CGMP requirements, as a having to comply with proposed
satisfy certain criteria, which include manufacturer, for the product sold to § 111.95 on product complaints. If a
qualifying the supplier of the consumers and not subject to an dietary ingredient manufacturer receives
components. With this approach, the exclusion under final § 111.1(b), a product complaint, we encourage the
goal of ensuring the quality of dietary discussed in this section. In other manufacturer to evaluate the complaint
supplements can be achieved without words, final § 111.1(a) refers to the to determine if it may involve a problem
applying the rule specifically to persons nature of your activity, and simply with the manufacture of the dietary
who manufacture, package, label, or engaging in some activities that do not ingredient. In addition, we encourage
hold dietary ingredients that will be bring you within the scope of the final the dietary ingredient manufacturer to
further processed as a dietary rule does not necessarily mean that all notify the dietary supplement
supplement by other persons. your activities are outside the scope of manufacturer so that it can review the
Consequently, we revised § 111.1 by the final rule. complaint and investigate, as needed.
deleting ‘‘dietary ingredient.’’ Therefore, We do not agree, as some comments (Comment 31) Several comments
those who manufacture, package, label, suggested, that we need to issue a question the proposal’s applicability to
or hold dietary ingredients are not separate or modified set of CGMP persons who sell packaged products or
subject to the final rule. To illustrate, requirements for dietary ingredients. seek clarification as to whether the rule
assume you manufacture a dietary That is because there are adequate applies to dietary supplement
ingredient and sell that bulk dietary controls established in this final rule for manufacturers that operate from homes
ingredient to Company X. Company X the use of dietary ingredients used by and those that distribute product to
then utilizes the bulk dietary ingredient the manufacturer of a dietary other distributors.
in a dietary supplement. Under final supplement. However, if you (Response) To the extent that the
§ 111.1(a), you would not be subject to manufacture, package, label, or hold comments question whether retailers or
these dietary supplement CGMP dietary ingredients that will be further individuals who sell dietary
requirements because you are not processed as a dietary supplement by supplements directly to individual
manufacturing a dietary supplement, another person, you must comply with consumers are subject to the dietary
rather you are manufacturing a dietary food CGMP requirements in part 110. A supplement CGMP requirements, we
ingredient for further incorporation into dietary ingredient is a food under have revised the final rule by creating a
a dietary supplement by Company X. If, section 201(f) of the act, as a food, or as new § 111.1(b) which states that: ‘‘The
however, you sell herbs in bulk to a component of food. Because the final requirements pertaining to holding
Company X, and Company X simply rule gives manufacturers an incentive to dietary supplements do not apply to you
packages the herbs into smaller units for qualify suppliers of dietary ingredients, if you are holding those dietary
sale as a dietary supplement, you would persons who manufacture, package, supplements at a retail establishment for
be subject to the dietary supplement label, or hold dietary ingredients may the sole purpose of direct retail sale to
CGMP requirements because you are wish to familiarize themselves with individual consumers. A retail
manufacturing a dietary supplement these dietary supplement CGMP establishment does not include a
that Company X is simply packaging requirements and use them in warehouse or other storage facility for a
and labeling, and not further processing manufacturing, packing, labeling, or retailer or a warehouse or other storage
into a dietary supplement. In other holding operations for dietary facility that sells directly to individual
words, in the latter example, you would ingredients. consumers. ’’ This means, for example,
have acted as a manufacturer whose (Comment 30) Some comments argue if you operate a storefront retail
finished product is simply repackaged if the final rule ultimately covers dietary establishment where you stock dietary
or relabeled. ingredient suppliers then we should supplements on your shelves for
Under final § 111.1(a) persons clarify what constitutes a ‘‘consumer.’’ purchase by individual consumers, we
engaged solely in activities relating to According to these comments, dietary do not consider you to be ‘‘holding’’
the harvesting, storage, or distribution of ingredient suppliers do not typically those dietary supplements in a manner
raw agricultural commodities that will supply their products directly to those that would require you to comply with
be incorporated into a dietary individuals who will ultimately the holding provisions in this final rule.
supplement by others are not included consume or ingest them. Thus, Sale to individual consumers, where
within the scope of the rule as a dietary ‘‘consumers’’ of dietary ingredients are you are not storing bulk dietary
supplement manufacturer. This is other companies, not individuals. The supplements as one would in a
because those persons simply ‘‘supply’’ comments express concern about the warehouse or storage facility, does not
a component (i.e., the raw agricultural possible application of proposed fall within the manufacturing,
commodity) that another person will § 111.95 which would require packaging, labeling, or holding activities
process into a dietary supplement; thus procedures for handling complaints. that would subject you to dietary
you do not manufacture, package, label, (Response) The final rule applies only supplement CGMP requirements.
or hold a dietary supplement. to persons who manufacture, package, However, if you operate storefront
Note, too, that if you manufacture and label, or hold dietary supplements and retail establishments, and those retail
supply a component directly to are not subject to an exclusion in final establishments obtain their stocks from
consumers as a dietary supplement, you § 111.1. However, as explained in the your warehouse, we would consider
would be considered a dietary previous response to comment 29, if a your warehouse operations to be
supplement manufacturer within the dietary ingredient manufacturer also ‘‘holding’’ dietary supplements and
scope of final § 111.1(a). Likewise, if supplies or sells a dietary ingredient as expect your warehouse operations to
you manufacture a component and sell a dietary supplement, such a comply with the rule’s holding
part of the batch to another person who, manufacturer would be subject to final requirements. Such distribution is no
in turn, will further process the § 111.1(a) and subject to all relevant different than other warehouse
component as a dietary supplement and dietary supplement CGMP operations that are normally subject to
sell the remainder of the batch to requirements. CGMP requirements. Consequently, to
distinguish between ‘‘holding’’ dietary adulteration are not eliminated just be considered to be dietary supplements
supplements for retail sale to consumers because the practitioner is an herbalist, (e.g., certain products used by
and ‘‘holding’’ dietary supplements in a and therefore, such an exemption traditional Asian medicine
warehouse for further distribution, final should not be included in this final rule. practitioners). Further, we are not
§ 111.1(b) limits the exclusion to However, after further consideration, we considering exercising our enforcement
persons holding dietary supplements have determined that it would be discretion with respect to practitioners
‘‘at a retail establishment for the sole appropriate for us to consider the who prepare batches of herbs and sell
purpose of direct retail sale to exercise of our enforcement discretion them to individual consumers without
individual consumers.’’ Final § 111.1(b) in deciding whether to apply the determining whether the dietary
also makes it clear that a retail requirements of this final rule to certain supplement is appropriate for each
establishment does not include a health care practitioners, such as consumer’s needs in a one-on-one
warehouse or other storage facility that herbalists, acupuncturists, naturopaths, personal consultation, or those that
a retailer uses to hold the dietary and other related health care providers. prepare batches of a dietary supplement
supplements or an operation that sells We find it noteworthy that the for which there is a known or suspected
directly to consumers, but that itself comments identified two potential safety concern.
distributes the product to the consumer safeguards that could support the (Comment 33) Several comments
from a warehouse or storage facility and exercise of our enforcement discretion asked us to exempt academic
not from a storefront retail on whether to apply the requirements of institutions that provide training for
establishment. the final rule to certain practitioners: (1) therapeutic disciplines that use, for
(Comment 32) Many comments Adequate training in the professional example, herbal formulas in their
question the rule’s applicability to practice and (2) an individual client and practice regardless of whether the
various practitioners such as herbalists, practitioner relationship. For example, dietary supplements they produce enter
acupuncturists, naturopaths, and other comments claimed that the practitioners into interstate commerce. Specifically,
health care providers who prepare receive adequate training to formulate these comments would revise the final
individualized herbal formulas for dietary supplements and that they rule to state that it does not apply ‘‘to
specific individuals on a case-by-case provide the dietary supplements to academic institutions that provide
basis. Most comments say such individuals in the course of a one-on- training in dispensing of nutritional or
practitioners should not be covered by one consultation on the premises of the herbal products and formulas related to
the rule. These comments give various practitioner. One comment from a courses in therapeutic disciplines that
reasons to justify their position, practitioner states that she received her provide such products and formulas as
including: training from an accredited 4-year a part of their therapy, for example,
• These practitioners do not broadly university and it included didactic and naturopathy, herbalism, traditional
sell products; clinical training in acupuncture and Chinese medicine, and acupuncture.’’
• These practitioners make very small Chinese herbs. Another comment from (Response) Similar to what we stated
quantities of individualized formulas, an organization provides detailed in response to comment 32, we believe
and can therefore be very selective as to training guidelines for practitioners, that it may be appropriate to consider
the quality of ingredients used; including 1,600 hours of training, 400 the exercise of our enforcement
• The testing and storage hours of which should include clinical discretion in circumstances where an
requirements of each finished batch work. Moreover, many comments also academic institution’s actions are
cannot apply to a small dispensary assert that the practitioners are different similar to those of a practitioner who is
where several different modified herbal from dietary supplement manufacturers adequately trained in their profession
formulas are prepared each day; because they formulate the dietary and who provides dietary supplements
• Based on the projected costs to supplements in the course of a one-on- within the context of an individual
implement CGMPs, it would be virtually one consultation at their premises. That client and practitioner relationship. In
impossible for an individual enables them to ensure the formulations general, it is not our policy to inspect
practitioner or university clinic to are made to meet the specific needs of an academic institution that provides
develop the necessary quality control the individuals. training for therapeutic disciplines that
unit, maintain reserve samples, We believe that a one-on-one use, for example, dietary supplements
maintain the required paperwork, or consultation by a practitioner who is in their practice. We intend to consider
retrofit clinics to comply with the rule; adequately trained in their profession the exercise of our enforcement
• Many States regulate or license may not necessitate the same types of discretion in those situations where
these practitioners, so further Federal controls as we are establishing in this there is a one-on-one consultation that
regulation is unnecessary; final rule for manufacturing activities includes a practitioner with adequate
• Some practitioners do not consider that are on a larger scale. Such a training. We intend to issue guidance to
themselves to be manufacturers; practitioner may make some further clarify how the agency intends
• In an analogous situation, formulations in advance of the to exercise its enforcement discretion on
compounding pharmacists are not consultation and still make the the application of this final rule to
required to comply with drug CGMPs; formulations in very limited quantities certain academic institutions.
and for the individual client. We believe that (Comment 34) Several comments
• Despite the growing number of such it would be appropriate to consider the discuss the position taken by certain
practitioners, there is no proof that exercise of our enforcement discretion, nations, notably Australia and Canada,
greater harm has occurred to the general on a case-by-case basis, to determine that have developed CGMP
public from the herbs these practitioners whether to apply the requirements of requirements and related guidance for
sell. this final rule to such persons. botanicals. According to these
(Response) We stated in the 2003 We do not expect the number of those comments, these nations recognize that
CGMP Proposal (68 FR 12157 at 12175) subject to the consideration of our there are various types of practitioners
that we declined to exempt herbalist enforcement discretion to be very large. who sell herbs and herbal preparations
practitioners from the proposed rule. Many products that are manufactured in a clinical setting, and do not consider
We continue to believe that the risks of by practitioners would not necessarily such persons to be manufacturers. The
comments ask us to follow the example otherwise participate in the rulemaking foreign firms, we explain our position as
of these nations. process. Consequently, we decline to follows. Section 801(a) of the act (21
(Response) We intend to consider the provide yet another opportunity for U.S.C. 381a) authorizes us to refuse
positions taken by other nations to comment. admission of an imported food if it
inform us in our decisionmaking in any (Comment 37) The preamble to the appears from the examination of such
future guidance on how we intend to 2003 CGMP Proposal noted that samples or otherwise that such article
exercise our enforcement discretion on comments submitted in response to our is, among other things, adulterated. A
the application of this final rule to 1997 ANPRM state we should not foreign firm’s refusal to allow us to
certain practitioners. distinguish between dietary obtain records via an inspection for
(Comment 35) Many comments say supplements made in the United States CGMP purposes, as required by final
we should define when a dietary and those made in a foreign country (68 § 111.610 (for the dietary supplements
supplement will be said to have entered FR 12157 at 12174). Although we agreed the foreign firm offers for import into
interstate commerce. The comments with the comments and made no the United States), would create the
state herbal practitioners (and academic distinction between foreign and appearance that such imported dietary
institutions) often purchase source domestic firms in the proposed rule, we supplements are adulterated under
herbs from outside their State, even if invited comment on how we might section 402(g) of the act, and thus, could
they prepare these herbs for their ensure dietary ingredients and dietary lead to a refusal of admission under
specific customers within the State. supplements exported to the United section 801(a) of the act.
These comments request we clarify that States have been manufactured, Foreign firms who ship to the United
the rule does not apply to herbs packaged, labeled, and held consistent States must operate under conditions
purchased out of State if prepared for with part 111 (68 FR 12157 at 12175). that satisfy our regulations, including
local use. Other comments request Several comments argue the rule the requirement that records be made
clarification regarding clients who have should apply to foreign firms as well as available during the course of an FDA
moved across State lines, yet maintain domestic manufacturers to ensure a inspection. We note that except in
a relationship with an herbalist ‘‘level playing field’’ and to protect circumstances where there is a public
practitioner. American consumers. Some comments health emergency or we receive
(Response) In section V of this say we should work with foreign information that would indicate the
document we explain the interstate and countries to harmonize our appearance of adulteration of products
intrastate issue related to the final rule. requirements and thus avoid potential shipped to the United States, foreign
(Comment 36) A few comments assert trade disputes under international trade inspections are generally scheduled
individual practitioners and practitioner agreements such as the General well, e.g., weeks, in advance. Thus, we
organizations often are unaware of the Agreement on Tariffs and Trade. Other believe that taking action under section
opportunity to comment on CGMP or comments suggest compliance by 801 of the act is appropriate if
regulatory issues. Therefore, the foreign firms could be achieved through companies do not accommodate our
comments say these practitioners and the use of third party certification inspectional request.
organizations often fail to provide programs, such as the dietary
comment or otherwise participate in C. What Definitions Apply to This Part?
supplement verification program
rulemaking and say we should give (Final § 111.3)
administered by USP, or the adoption of
these practitioners and practitioner importer verification provisions similar Section 111.3 defines various terms
organizations a chance to comment. to those used in our HACCP that we use in the final rule and notes
(Response) We provided many requirements for seafood (see § 123.12). that definitions or interpretations of
opportunities for comment and, In contrast, another comment says we terms in section 201 of the act also
therefore, we decline to adopt the should inspect foreign firms to ensure apply. In general, we adopted the
comments’ suggestion. As we discuss in compliance, whereas other comments definitions that we proposed, although,
section I of this document, we claim we lack jurisdiction over foreign in some cases, we deleted words or
published an ANPRM concerning firms. concepts as a result of other changes we
dietary supplement CGMPs on February (Response) We are amending made to the final rule. We have added
6, 1997 (62 FR 5700); the 1997 ANPRM proposed § 111.1 to clarify the a definition of ‘‘quality’’ for purposes
provided an opportunity for public regulation’s applicability to foreign only of this final rule.
comment. On March 7, 2003, we issued firms. We explain in this section how A recurring change we made is the
a Talk Paper, along with other we may enforce the rule against foreign deletion of the words ‘‘dietary
background documents, announcing the firms. We, however, are not making any ingredient’’ in several definitions. In
issuance of a proposed dietary changes in response to the comments some cases, the use of the words
supplement CGMP rule. We made the calling for the harmonization of the rule ‘‘dietary ingredient’’ was redundant to
proposed rule available when it went on with foreign rules because this request the use of ‘‘component’’ and thus not
display (before it published) in the is beyond the scope of the final rule. necessary in the final rule. Because a
Federal Register on March 13, 2003 (68 In response to comments, and for ‘‘dietary ingredient’’ is subsumed within
FR 12157), and, again, provided an clarification, we have revised final the definition of ‘‘component,’’ as
opportunity for public comment. We § 111.1(a) to clarify that the regulation explained in our response to comment
also held public meetings on April 29, applies to the extent that you 29, we deleted ‘‘dietary ingredient’’ in
2003, in College Park, MD and on May manufacture, package, label, or hold a those definitions where ‘‘component’’
6, 2003, in Oakland, CA. We also held dietary supplement, including a dietary was used to avoid redundancy.
a public meeting (via satellite downlink) supplement imported or offered for In other provisions, we deleted
on May 9, 2003, with viewing sites at import in any State or Territory of the ‘‘dietary ingredient’’ from the definition
our district and regional offices United States, the District of Columbia, because the use of those words was no
throughout the country. Thus, we or the Commonwealth of Puerto Rico. longer necessary given the narrowing of
provided numerous opportunities for With respect to the comments the scope of the rule as it applies to
interested persons to learn about the requesting that we make clear our dietary ingredient manufacturers
rule and to submit comments or position for enforcing the rule against (explained in the response to comments
29 and 30). For example, we deleted the same product made with the same supplement. Component includes
‘‘dietary ingredient’’ from the proposed lot(s) of raw materials regardless of how dietary ingredients (as defined in
definition of ‘‘ingredient’’ that referred many days it took to produce the batch, section 201(ff) of the act) and other
to the ‘‘manufacture of a dietary or if it meant a quantity produced in 1 ingredients.’’
ingredient or dietary supplement’’ and day. The comment also asks whether The definition of component now
the ‘‘finished batch of the dietary batches produced on consecutive days, refers only to the manufacture of a
ingredient or dietary supplement.’’ We using the same formula, can be dietary supplement (whereas the
did not need to state ‘‘manufacture of considered to be the same batch with proposal also referred to the
the dietary ingredient’’ or refer to respect to the proposed testing manufacture of dietary ingredients). We
‘‘finished batch of dietary ingredient’’ requirements if the quality control unit also made a nonsubstantive, editorial
because dietary ingredient determined that different lots of raw revision in the last sentence to put
manufacturers that only supply such materials are equivalent (e.g., by parentheses around the reference to
ingredients to other persons for meeting all specifications). section 201(ff) of the act and to change
processing into a dietary supplement are (Response) The ‘‘same cycle of the word order so that ‘‘component’’
not subject to the final rule. manufacture’’ refers to a process during includes ‘‘dietary ingredients * * * and
We discuss changes to the definitions, which equipment remains dedicated to other ingredients.’’ (The proposed
other than the changes we have made the manufacture of the batch. The terms definition had ‘‘components’’ including
globally such as the deletion of ‘‘dietary do not limit you to any particular time ‘‘ingredients and dietary ingredients.’’)
ingredients,’’ the change from ‘‘include, period or require you to operate (Comment 39) Some comments would
but not limited to’’ to ‘‘includes’’ or equipment continuously until you have distinguish among ‘‘raw material,’’
‘‘include,’’ the addition of labels and completed the ‘‘same cycle of ‘‘components,’’ and ‘‘starting material’’
labeling, and the deletion of the word manufacture.’’ The ‘‘same cycle of because the comments said that defining
‘‘quality’’ from the phrase ‘‘identity, manufacture’’ also does not limit the ‘‘component’’ to include all these
purity, quality, strength, and number of lots of components you use. materials is confusing. One comment
composition,’’ as well as comments You may consider, as one batch, a adds that many starting materials are
asking us to define more terms or to product produced using different lots of not food grade or approved food
delete certain definitions, in more detail raw materials where the production of ingredients until they have been
in the following paragraphs. the batch is a continuous process on a processed. One comment states the term
dedicated line. However, for each ‘‘raw material’’ is typically used to
1. Actual Yield component that you use in the describe the materials (such as dietary
The final rule defines ‘‘actual yield’’ manufacture of the batch of dietary ingredients, fillers, and processing aids)
as ‘‘the quantity that is actually supplement, you would need to that will be used to make the final
produced at any appropriate step of establish specifications under final product. The comment further states
manufacture or packaging of a particular § 111.70, determine whether these ‘‘component’’ is typically used to
dietary supplement.’’ specifications are met under final describe the specific items used to
We received no substantive comments § 111.73, and ensure that these assemble the finished product for the
to the proposed definition. component specifications are met using end user. The components would
the criteria under final § 111.75. include packaging components such as
2. Batch bottles, caps, and labels, as well as the
Further, you may not consider different
The final rule defines ‘‘batch’’ as ‘‘a batches of product produced on bulk dietary supplement. This comment
specific quantity of a dietary consecutive days using the same also suggests that we use the term
supplement that is uniform, that is formula to be the same batch for ‘‘starting material’’ to distinguish
intended to meet specifications for purposes of testing requirements. The substances used in the manufacture of
identity, purity, strength, and term ‘‘different batches’’ suggests that dietary ingredients from substances
composition, and that is produced the production is not a continuous used in the manufacture of dietary
during a specified time period according process on a dedicated line. supplements.
to a single manufacturing record during (Response) We decline to revise the
the same cycle of manufacture.’’ 3. Batch Number, Lot Number, or rule as suggested by the comments.
This definition differs from the Control Number There may be differences in how
proposed definition of ‘‘batch’’ by The final rule defines these terms as components are referred to by certain
stating that a batch is a specific quantity ‘‘any distinctive group of letters, manufacturers and how we refer to it in
of a dietary supplement that is numbers, or symbols, or any this final rule. However, for purposes of
‘‘uniform.’’ combination of them, from which the this final rule we refer to all substances
We inserted the word ‘‘uniform’’ in complete history of the manufacturing, used in the manufacture of dietary
response to comments asking that we packaging, labeling, and/or holding of a supplements as ‘‘components,’’ whether
define ‘‘lot’’ to be consistent with batch or lot of dietary supplements can or not those substances appear in the
‘‘batch.’’ We explain our reasons for be determined.’’ finished product.
harmonizing the definitions and for We received no substantive comments Please note that, although ingredients
inserting ‘‘uniform’’ into the definition on the definition. We added the word are ‘‘components’’ under our definition,
of ‘‘batch’’ in the response to comment ‘‘and’’ before ‘‘or’’ to emphasize that the not all components are ingredients. For
42 of this document. history of each activity must be able to example, a solvent used to make an
We discuss the comments on our be determined. herbal extract is not an ingredient when
proposed definition of ‘‘batch’’ and our it is removed from the extract by a
changes to the definition in our 4. Component process such as drying, because the
responses to the following comments. The final rule defines ‘‘component’’ as solvent was not intended to be present
(Comment 38) Several comments ask ‘‘any substance intended for use in the in the finished dietary supplement.
us to clarify what the ‘‘same cycle of manufacture of a dietary supplement, However, the solvent would be a
manufacture’’ is in the definition of including those that may not appear in ‘‘component’’ because it was used in the
‘‘batch.’’ One comment asks if it meant the finished batch of the dietary manufacture of the dietary supplement.
As for materials that might not be considered a component, because We did not receive any substantive
food grade or approved food ingredients ‘‘rosehips’’ is not what you added. comments on the proposed definition.
until processing, see the discussion in
5. Contact Surface 8. Lot
response to comment 240 in section XII
of this document. The final rule defines ‘‘contact The final rule defines ‘‘lot’’ as ‘‘a
(Comment 40) Several comments surface’’ as ‘‘any surface that contacts a batch, or a specific identified portion of
express concern that ‘‘component’’ component or dietary supplement, and a batch, that is uniform and that is
could be interpreted to mean any those surfaces from which drainage onto intended to meet specifications for
constituent present in a botanical the component or dietary supplement, identity, purity, strength, and
extract or other natural product. The or onto surfaces that contact the composition; or, in the case of a dietary
comments say a single botanical can component or dietary supplement, supplement produced by continuous
contain tens of thousands of occurs during the normal course of process, a specific identified amount
constituents or metabolites and that operations.’’ The final rule lists produced in a specified unit of time or
chemists have not identified all containers, utensils, tables, contact quantity in a manner that is uniform
constituents of a single botanical. surfaces of equipment, and packaging as and that is intended to meet
According to the comments, the cost of examples of ‘‘contact surfaces.’’ specifications for identity, purity,
testing for all constituents would exceed We did not receive any substantive strength, and composition.’’
comments on the proposed definition. The final rule differs from the
a product’s total annual revenues.
We deleted ‘‘ordinarily’’ from proposed definition in that the proposed
(Response) In general, we would definition of ‘‘lot’’ would have the batch
‘‘ordinarily occurs during the normal
consider the botanical extract or the or specific identified portion of a batch
course of operations’’ because
other natural product to be the be intended to have ‘‘uniform identity,
‘‘ordinarily’’ is redundant to ‘‘normal.’’
‘‘component’’ as defined in this final purity, quality, strength, and
rule rather than consider that all the 6. Ingredient composition.’’
various chemical substances contained The final rule defines ‘‘ingredient’’ as (Comment 42) One comment agrees
in the botanical extract or other natural ‘‘any substance that is used in the with the proposed definition for ‘‘lot,’’
product are components. Thus, if you manufacture of a dietary supplement but several other comments would
are manufacturing a dietary supplement and that is intended to be present in the revise the definition to be more
that is intended to provide a certain finished batch of the dietary consistent with the proposed definition
substance (e.g., vitamin C ) and you add supplement. An ingredient includes, but of ‘‘batch.’’ Specifically, the comments
a natural product which is intended to is not necessarily limited to, a dietary note the proposed definition of ‘‘batch’’
supply the vitamin C (e.g., vitamin C in ingredient as defined in section 201(ff) would refer to a quantity of dietary
the form of rosehips), we would of the act.’’ We did not receive any supplement that is ‘‘intended to meet
consider the natural product (e.g. substantive comments on this specifications for identity, purity,
rosehips that contain a certain amount definition. We made a nonsubstantive, quality, strength and composition,’’
of vitamin C) to be a component which editorial change to replace ‘‘finished whereas the proposed definition of ‘‘lot’’
must be listed in the master dietary supplement’’ with ‘‘finished would refer to a batch or specific
manufacturing record. The component batch of the dietary supplement.’’ identified portion of a batch that is
specifications for the rosehips must (Comment 41) One comment says we ‘‘intended to have uniform identity,
include a specification for the strength should define ‘‘ingredient’’ better to purity, quality, strength, and
of the substance (e.g., vitamin C) in ensure consistent interpretation of composition.’’ The comments would
whatever amount you determine is CGMP at all levels throughout the revise the definition of ‘‘lot’’ by deleting
necessary to meet the specification for dietary supplement industry. the phrase ‘‘intended to have uniform’’
the strength of the vitamin C in the (Response) We disagree with the and inserting the phrase ‘‘intended to
finished batch of dietary supplement. comment. We believe the definition is meet specifications for’’ in order to
Under final § 111.70, we expect you to adequate, including as it does both make the definitions of ‘‘batch’’ and
establish specifications for the natural dietary ingredients as described in ‘‘lot’’ consistent.
product and ensure that the section 201(ff) of the act and other (Response) We agree that the
specifications are met. As an example ingredients that do not fit that definitions for ‘‘batch’’ and ‘‘lot’’ should
relevant to an extract, if you are description, such as an emulsifier used be consistent, but we disagree with the
manufacturing a dietary supplement to establish a uniform dispersion in a comments’ suggestion to delete the term
that is intended to provide a certain liquid dietary supplement or a color ‘‘uniform’’ from the definition of ‘‘lot.’’
amount of vitamin C that derives from additive used to color a capsule. The attributes of a lot or batch should
the natural product rosehips, and the Moreover, the comment did not explain be uniform throughout the lot or batch
substance that you purchase from a or specify which aspects of the and meet established specifications for
supplier to add as a component is a proposed definition should be revised those attributes. If samples from a lot or
purified extract of rosehips (rather than or explain why the proposed definition batch were tested for appropriate
rosehips themselves), we would would lead to inconsistent specifications of identity, purity,
consider the purified extract to be a interpretations of CGMP. strength, and composition, the attributes
component (as an ingredient). The should be consistent throughout the
component specifications for the 7. In-Process Material sample and be uniform from sample to
purified extract must include a The final rule defines ‘‘in-process sample regardless of whether the test
specification for the strength of the material’’ as ‘‘any material that is samples are taken from the beginning,
substance (i.e., vitamin C) in whatever fabricated, compounded, blended, middle, or end of the lot or batch.
amount you determine is necessary to ground, extracted, sifted, sterilized, Consequently, we revised the definition
meet the specification for the strength of derived by chemical reaction, or of ‘‘lot’’ to state, in relevant part, that a
the vitamin C in the finished batch of processed in any other way for use in ‘‘lot’’ is a batch or specific identified
dietary supplement. However, in this the manufacture of a dietary portion of a batch that ‘‘is uniform and
example ‘‘rosehips’’ would not be supplement.’’ that is intended to meet specifications
for identity, purity, strength, and accordingly. The comment further (Response) We decline to revise the
composition’’ or, for dietary discusses the difficulties in ‘‘sterilizing’’ rule as suggested by the comment. The
supplements produced by a continuous botanicals to render them free of comment’s revision would undermine
process, a specific identified amount microorganisms associated with the reasons for issuing a rule. Rules
produced in a specified unit of time or insanitary conditions. The comment create enforceable requirements. It is not
quantity in a manner that is uniform notes that some international clear, nor did the comment discuss, how
and that is intended to meet organizations have established ‘‘upper we could enforce the requirements in
specifications for identity, purity, limits’’ for these organisms for botanical this final rule if firms were able to avoid
strength, and composition.’’ supplements, which, in the comment’s a particular requirement by declaring
Similarly, we revised the definition of opinion, represent more realistic them to be ‘‘inapplicable’’ or
‘‘batch’’ so that it states, in relevant part, standards than trying to attain a substituting alternatives which they felt
that a ‘‘batch’’ is a specific quantity of ‘‘sterile’’ botanical supplement. they had demonstrated were ‘‘at least an
a dietary supplement ‘‘that is intended (Response) We disagree with the equivalent level of quality assurance.’’
to meet specifications for identity, comment. We do not interpret the There would be inconsistency in the
purity, strength, and composition.’’ definition of ‘‘microorganism’’ as general CGMP practices used within the
These revisions make the definitions making the presence of nonpathogenic dietary supplement industry and
of ‘‘batch’’ and ‘‘lot’’ consistent. microorganisms that are not a public uncertainty as to whether the process
9. Microorganisms health risk a ‘‘sanitary concern’’ that and production controls ensure the
would render a product adulterated. quality of the dietary supplement.
The final rule defines
Instead, we interpret the definition as Consequently, we decline to revise the
‘‘microorganisms’’ as ‘‘yeasts, molds,
saying that microorganisms of public rule as suggested by the comment.
bacteria, viruses, and other similar We have, however, made a
microscopic organisms having public health significance and microorganisms
presenting sanitary concerns are nonsubstantive, editorial change to the
health or sanitary concern.’’ It adds that
‘‘microorganisms’’ under this rule. definition so that ‘‘must’’ is used to state
the definition includes species that: (1)
These are the types of microorganisms ‘‘a requirement.’’ The proposed
May have public health significance; (2)
that may cause a component or dietary definition had referred to ‘‘mandatory
may cause a component or dietary
supplement to become adulterated. requirements.’’ Since a requirement by
supplement to decompose; (3) indicate
As for upper limits on microbial its nature is mandatory, the word
that the component or dietary
contamination, the comment offered no ‘‘mandatory’’ is unnecessary.
supplement is contaminated with filth;
or (4) otherwise may cause the suggested limits, and we decline to 11. Pest
component or dietary supplement to be establish such limits in this rule. The
final rule requires manufacturers to The final rule defines ‘‘pest’’ as ‘‘any
adulterated. objectionable insect or other animal,
(Comment 43) One comment would establish limits for those types of
contamination that may adulterate or including birds, rodents, flies, mites,
revise the definition to identify specific and larvae.’’
microorganisms that have public health lead to adulteration of components or
We did not receive any substantive
or sanitary concern (i.e., Salmonella dietary supplements. Thus, for example,
comments on this definition. However,
species, Escherichia coli, Pseudomonas a manufacturer of a botanical dietary
on our own initiative, we made
aeruginosa, and Staphylococcus supplement would have to determine
nonsubstantive, editorial changes to
aureus). The comment says this would what, if any, microorganisms are likely
delete the words, ‘‘but not limited to’’
be consistent with USP requirements. or certain to be present and establish
after ‘‘including’’ and to place the word
(Response) We disagree with the limits, as appropriate to prevent
‘‘animals’’ in the singular.
comment. A list of specific adulteration of the finished batch of the
microorganisms could easily become dietary supplement. 12. Physical Plant
outdated as new pathogens emerge, and We have modified the word ‘‘have’’ The final rule defines ‘‘physical
constantly issuing new rules to revise with the word ‘‘may’’ to indicate that plant’’ as ‘‘all or any part of a building
the list would be both inefficient and the determination or evaluation of or facility used for or in connection with
impractical. whether there is a ‘‘public health manufacturing, packaging, labeling, or
(Comment 44) One comment significance’’ is not made after the fact. holding a dietary supplement.’’
expresses concern that the proposed There does not have to be a factually We received no substantive comments
definition for microorganisms would established determination of public on this definition. The final rule is
include microorganisms that are a health significance for you to conclude substantially similar to the proposed
natural part of the ecology of all natural that the microorganisms ‘‘may rule’s definition of ‘‘physical plant.’’ We
products. The comment says certain adulterate’’ the dietary supplement. The added ‘‘any’’ and placed ‘‘part’’ in the
levels of microorganisms are expected change from ‘‘could cause’’ to ‘‘may singular to clarify that individual parts
on botanical raw materials (i.e., those cause’’ is to be consistent with the of a building or facility are subject to the
naturally occurring or introduced previous change to ‘‘may have.’’ CGMP requirements.
through organic cultivation techniques)
10. Must 13. Product Complaint
and that many do not present a public
health risk. The comment expresses The final rule explains that the word The final rule defines ‘‘product
concern that nonpathogenic ‘‘must’’ is ‘‘used to state a requirement.’’ complaint’’ as ‘‘any communication that
microorganisms that are not a public (Comment 45) One comment would contains any allegation, written,
health risk would be a ‘‘sanitary’’ revise the definition to say that the term electronic, or oral, expressing concern,
concern that would render a product ‘‘must’’ be used to state mandatory for any reason, with the quality of a
adulterated. The comment argues there requirements ‘‘unless shown to be dietary supplement, that could be
should be little concern about the inapplicable or replaced by an related to current good manufacturing
presence of microorganisms that present alternative demonstrated to provide at practice. Examples of product
no public health consequence, and so least an equivalent level of quality complaints are: Foul odor, off taste,
we should revise the definition assurance.’’ illness or injury, disintegration time,
color variation, tablet size or size receive or they, themselves, generate defined ‘‘consumer complaints.’’ The
variation, under-filled container, foreign that may relate to operations outside the comments say we should delete this
material in a dietary supplement packagers’, labelers’, or distributors’ definition and deal with consumer
container, improper packaging, control. For example, a distributor who complaints separately as part of the new
mislabeling, or dietary supplements that purchases a dietary supplement in bulk CFSAN Adverse Event Reporting
are superpotent, subpotent, or contain for packaging and labeling may System (CAERS).
the wrong ingredient, or contain a drug complain about product quality to the One comment states we should define
or other contaminant (e.g., bacteria, dietary supplement manufacturer. The the term ‘‘serious adverse dietary
pesticide, mycotoxin, glass, lead).’’ manufacturer who receives the supplement experience.’’ The comment
This definition modifies the proposed complaint must then take appropriate would define a ‘‘serious adverse dietary
rule’s definition of ‘‘consumer action to determine whether the supplement experience’’ as ‘‘any
complaint,’’ which would define such a complaint involves a possible failure of adverse dietary supplement experience
complaint as any ‘‘communication that a dietary supplement to meet any CGMP occurring at any dose that results in any
contains any allegation, written or oral, requirements. Thus, the final rule of the following outcomes: death, a life-
expressing dissatisfaction with the revises the term ‘‘consumer complaint’’ threatening adverse dietary supplement
quality of a dietary supplement related to ‘‘product complaint’’ to emphasize experience, inpatient hospitalization or
to good manufacturing practices. that the complaint is about the product prolongation of existing hospitalization,
Examples of product quality related to regardless of the complaint’s source. a persistent or significant disability/
good manufacturing practices are: Foul (Comment 47) One comment incapacity, or a congenital anomaly/
odor, off taste, superpotent, subpotent, disagrees that ‘‘disintegration time’’ and birth defect. Important medical events
wrong ingredient, drug contaminant, ‘‘tablet size’’ are appropriate examples that may not result in death, be life-
other contaminant (e.g., bacteria, of complaints about product quality threatening, or require hospitalization
pesticide, mycotoxin, glass, lead), specifications. may be considered a serious adverse
disintegration time, color variation, (Response) We disagree with this dietary supplement experience and,
tablet size or size variation, under-filled comment. Complaints about based upon appropriate medical
container, foreign material in a dietary disintegration time or tablet size could judgment, they may jeopardize the
supplement container, improper indicate a problem with the production patient or subject and may require
packaging, or mislabeling. For the and process control system that may medical or surgical intervention to
purposes of this regulation, a consumer affect the quality of the dietary prevent one of the outcomes listed in
complaint about product quality may or supplement. this definition.’’
may not include concerns about a (Comment 48) Some comments (Response) We decline to include in
possible hazard to health. However, a disagree with the proposed definition of the definition of ‘‘product complaint’’
consumer complaint does not include ‘‘consumer complaint’’ because it an adverse event related to the safety of
an adverse event, illness, or injury excluded an adverse event, illness, or a particular dietary ingredient. The final
related to the safety of a particular injury related to the safety of a rule establishes CGMP requirements for
dietary ingredient independent of particular dietary ingredient. The dietary supplements and does not focus
whether the product is produced under comments say there should be a on whether dietary ingredients that
good manufacturing practices.’’ consistent approach for handling all manufacturers may use in their dietary
We explain the reasons for revising complaints, including adverse events. supplements are inherently safe.
the proposed definition in our response One comment states consumers will not Nevertheless, we encourage firms to
to the following comments. be able to determine whether a product investigate all complaints, regardless of
(Comment 46) Some comments would quality issue related to CGMP caused an whether the complaints relate to CGMP.
broaden the definition of consumer adverse event. This comment expresses Furthermore, mandatory reporting to
complaint to include complaints from concern that not classifying adverse FDA of serious adverse events is now
dietary ingredient suppliers. One events as consumer complaints could required as a result of the enactment of
comment would change ‘‘consumer lead manufacturers to avoid the ‘‘Dietary Supplement and Non-
complaint’’ to ‘‘customer complaint.’’ investigating certain adverse events and, Prescription Drug Consumer Protection
(Response) As discussed in section VI therefore, prevent them from Act’’ (Public Law 109–462), signed into
of this document, the final rule does not determining the appropriate cause and law on December 22, 2006. In any event,
apply to those who only manufacture implementing the associated corrective consistent with these CGMP
dietary ingredients. However, we action. The comments stress we should requirements, manufacturers must
encourage such firms that receive not treat complaints related to CGMP establish limits on contamination, as
complaints about a dietary supplement issues differently from other complaints needed, for all ingredients or any
to share those complaints with those in and urged us to classify all adverse component they use in manufacturing a
the manufacturing chain associated with events as consumer complaints, whether dietary supplement.
that dietary supplement’s manufacture or not they might have been caused by We agree it may be unclear whether
so others may take corrective action as a particular dietary ingredient. a particular product complaint is related
needed. Those who engage in the A few comments state the proposal, to CGMP. Final § 111.560, relating to
manufacture of a dietary supplement, which did not specifically address product complaints, applies in
including manufacturing, packaging, adverse event reporting, but did address situations where the product complaint
labeling, and holding operations, are the broader category of consumer involves a ‘‘possible failure of a dietary
responsible for complying with this complaints and would require supplement to meet any of its
final rule’s product complaint companies to investigate ‘‘adverse event specifications or any other requirements
requirements. reports,’’ may simply create more of this part.’’ Thus, if a firm is unclear
Furthermore, we encourage packagers, confusion and may contradict the whether a particular complaint it
labelers, and distributors who receive a overall objective of a comprehensive receives relates to a CGMP issue, we
product complaint to notify those in a adverse event reporting system. The would consider that complaint to be
dietary supplement’s manufacturing comments also state neither the food related to a ‘‘possible failure’’ to meet
chain about product complaints they CGMP regulations nor the 1997 ANPRM CGMP. Consequently, the firm must
comply with the requirements in (now ‘‘product complaint’’ in the final of complaints for a certain time period,
subpart O, unless the firm affirmatively rule). These sentences explained, in and the inclusion of specific
determines that the complaint is not part, that a consumer complaint does information in the record of a
related to a ‘‘possible failure’’ to meet not include an adverse event, illness, or complaint.
CGMP, and therefore, is not a ‘‘product injury related to the safety of a
14. Quality
complaint.’’ To make this clear, we particular dietary ingredient
revised the definition so that it applies independent of whether the product is For purposes solely of this final rule
to any ‘‘communication * * * that produced under CGMP. We deleted we have decided to define ‘‘quality.’’
could be related to good manufacturing those sentences because they are Quality means that the dietary
practice’’ rather than to be any unnecessary to include in the definition supplement consistently meets the
‘‘communication * * * that is related to and can be included as further established specifications for identity,
good manufacturing practice.’’ explanation of what the definition of purity, strength, and composition and
We disagree with comments that ‘‘product complaint’’ means in the limits on contaminants and has been
suggested that the requirements for preamble discussion. manufactured, packaged, labeled, and
product complaints would somehow The proposed definition of ‘‘consumer held under conditions to prevent
contradict the overall objective of the complaint’’ used the phrase ‘‘expressing adulteration under section 402(a)(1),
CAERS. This final rule has no effect on dissatisfaction with the quality of a (a)(2), (a)(3), and (a)(4) of the act.
the mandatory or voluntary reporting of dietary * * * supplement;’’ the final (Comment 49) Some comments asked
adverse events. We agree some adverse rule uses the phrase ‘‘expressing that we define ‘‘quality.’’ Some
events may be related to a failure to concern, for any reason, with the quality comments claimed the proposal
ensure the quality of the dietary of a dietary supplement.’’ This change is described ‘‘quality’’ in terms of
supplement as required by the final to ensure that even if the consumer is ‘‘identity,’’ ‘‘purity,’’ and
rule. To the extent that an adverse event not actually dissatisfied with the ‘‘composition.’’ One comment would
is associated with CGMP, it would be product, but has a concern with the define ‘‘quality’’ as ‘‘the total
considered a ‘‘product complaint’’ product, this is still handled as a characteristics of a product that bear on
under the final rule. The fact that it is product complaint. its ability to satisfy stated (i.e., labeled)
considered a product complaint does We made several editorial or or implied needs of identity, purity,
not mean that such complaint could not grammatical changes to the definition of strength and composition.’’ Another
be voluntarily reported as an adverse product complaint in this final rule for comment would define ‘‘quality’’ as
event through CAERS. Such a complaint simplicity and revised the order of the ‘‘having the appropriate identity, purity,
may be required to be reported under listed examples of product complaints. and strength for the intended purpose.’’
the mandatory reporting requirements of For example, the proposed definition of Another comment would define quality
the ‘‘Dietary Supplement and Non- ‘‘consumer complaint’’ states the term using all the other attributes of identity,
Prescription Drug Consumer Protection ‘‘means communication that contains purity, strength and composition.
Act’’ (Public Law 109–462), signed into any allegation * * *.’’ The final rule (Response) For purposes only of this
law on December 22, 2006. We have defines ‘‘product complaint’’ as final rule, we have added a definition of
added ‘‘illness or injury’’ to the final meaning ‘‘any communication that quality. This definition is not intended
rule’s definition of ‘‘product complaint’’ contains any allegation * * *.’’ Another to apply to CGMP requirements other
as an example of a product problem nonsubstantive change was to insert the than those that apply to dietary
relating to CGMP to help clarify that words ‘‘dietary supplements that are’’ supplements. In section III of this
there may be some overlap in the type before ‘‘superpotent, subpotent’’ to give document, in the overview discussion,
of complaints related to product quality the reader a clear understanding as to we discuss the concept of ‘‘quality’’ as
that may also be considered an adverse the article that is superpotent or it applies to these dietary supplement
event. subpotent. CGMP requirements and the distinction
As for defining ‘‘serious adverse Finally, we added ‘‘electronic’’ as an between the use of the term in the final
dietary supplement experience,’’ we example of how a product complaint rule and in the proposed rule.
decline to add such a definition to the could be communicated to ensure that Because we have defined ‘‘quality’’ as
final rule. We define certain terms in a all forms of communication are encompassing identity, purity, strength,
rule to give those terms a clear and included and added ‘‘current’’ to modify and composition, we have revised each
consistent meaning. None of the ‘‘good manufacturing practice’’ for section with requirements for the
provisions in this rule addresses or even consistency. ‘‘identity, purity, quality, strength, and
mentions ‘‘serious adverse dietary We discuss in section V of this composition’’ to remove the word
supplement experiences,’’ so there document, our general response to the ‘‘quality.’’ The affected sections in this
would be no advantage in codifying a comment that stated that neither the final rule are: § 111.3 (definition of
definition for the term in this final rule. food CGMP regulations nor the 1997 batch); § 111.3 (definition of lot);
If, however, the comment meant to ANPRM contains a definition of § 111.65 (‘‘What are the requirements for
narrow the definition of ‘‘consumer ‘‘consumer complaint,’’ is in our quality control operations?’’); § 111.70
complaint’’ to ‘‘serious’’ illness, or discussion of whether this final rule (‘‘What specifications must you
injury, we decline to do so. If a exceeds our authority or it has to be establish?’’); § 111.75 (‘‘What must you
consumer reports an illness or injury, identical to the food CGMP regulations. do to determine whether specifications
which he or she attributes to consuming More specifically, we acknowledge that are met?’’); § 111.80 (‘‘What
a dietary supplement, the report may the industry draft that we published in representative samples must you
indicate a problem with the production the 1997 ANPRM did not define collect?’’); § 111.95 (‘‘Under this subpart
and process control system for that ‘‘consumer complaint.’’ The industry E, what records must you make and
dietary supplement, even if the injury or draft did contain provisions that would keep?’’); § 111.105 (‘‘What must quality
illness is not ‘‘serious’’ or severe. be directed to ‘‘complaint files.’’ The control personnel do?’’); § 111.455
We have, however, decided to delete provisions for complaint files would (‘‘What requirements apply to holding
the last two sentences in the proposed require the use of written procedures to components, dietary supplements,
definition of ‘‘consumer complaint’’ handle complaints, retention of records packaging, and labels?’’); and § 111.515
(‘‘When must a returned dietary comments would clarify the definition other operation. In addition, the quality
supplement be bestroyed, or otherwise by indicating that a distinct or separate control operations may be performed by
suitably disposed of?’’). unit need not perform the quality someone outside the organization (such
control function. These comments say as a contractor).
15. Quality Control To clarify these points and to prevent
the quality control function is best
The final rule defines ‘‘quality performed by a person or persons potential misinterpretation of quality
control’’ as ‘‘a planned and systematic qualified by training, education, or control operations, we revised the
operation or procedure for ensuring the experience in the different processing definition of ‘‘quality control unit.’’
quality of a dietary supplement.’’ The areas. Instead of a unit, quality control
proposed rule defined ‘‘quality control’’ Many comments say we should personnel who perform quality control
as ‘‘a planned or systematic operation consider any individual carrying out a operations may be a person, persons, or
for preventing a dietary ingredient or quality control function to be part of the group and may be ‘‘within or outside of
dietary supplement from being quality control unit for purposes of this your organization.’’ We also added a
adulterated.’’ rule. new § 111.12(b) to require you to
(Comment 50) One comment suggests (Response) We agree that the quality identify who is responsible for your
revising the definition to use more control function is best performed by a quality control operations. Under final
positive language. Specifically, the person or persons qualified by training, § 111.12(b) each person who is
comment would define ‘‘quality education, or experience in relevant identified to perform quality control
control’’ as ‘‘a planned and systematic areas. To the extent that the comments operations must be qualified to do so
operation or procedure for ensuring the interpreted the proposed definition as and have distinct and separate
quality of dietary supplement requiring firms to have a separate responsibilities related to performing
products.’’ person or group whose sole function in such operations from those
(Response) We agree that the the company is to perform quality responsibilities that the person
comment’s suggested language conveys control operations or that the quality otherwise has when not performing
a positive concept about quality control functions are limited to those such operations. Throughout the
control’s role and value and adopt the who are employed within the firm, we codified, we use the term ‘‘quality
language in part. The final rule’s quality disagree. As discussed in the preamble control personnel’’ when referring to the
control requirements will help ensure to the proposal, the quality control unit performance of specific quality control
compliance with other CGMP should consist of as many people as operations. The term ‘‘quality control
requirements and, therefore, will help necessary to perform the quality control personnel’’ refers to the person or
ensure the quality of the dietary operations (68 FR 12157 at 12252). We persons designated to perform the
supplement and that the dietary have reconsidered the use of the term particular quality control operation.
supplement is packaged and labeled as ‘‘unit.’’ In order to clarify that we do not
specified in the master manufacturing intend to require a separate division or 17. Representative Sample
record. We have defined the term office be created, we instead use the The final rule defines ‘‘representative
‘‘quality’’ in this final rule as including term ‘‘personnel.’’ Although we have sample’’ as ‘‘a sample that consists of an
preventing a dietary supplement from eliminated references to ‘‘unit,’’ we still adequate number of units that are drawn
being adulterated. Consequently, we agree that personnel can be a person, based on rational criteria, such as
revised the definition of ‘‘quality persons, or a group, and as many random sampling, and that are intended
control’’ to state that ‘‘quality control’’ persons as necessary, who perform the to ensure that the sample accurately
means a planned and systematic quality control operations. The portrays the material being sampled.’’
operation or procedure ‘‘for ensuring the manufacturer must identify the This definition is similar to the
quality of a dietary supplement.’’ We appropriate person or persons to be proposed definition of ‘‘representative
deleted ‘‘for preventing a dietary responsible for the quality control sample.’’ We have added ‘‘an adequate’’
ingredient or dietary supplement from operations associated with a particular before ‘‘number’’ to emphasize that the
being adulterated’’ in the proposed manufacturing operation. For example, sample must be sufficient for its
definition since the concept of quality the manufacturer may designate one purpose. We also made nonsubstantive
includes preventing adulteration. individual as a packaging expert who is grammatical changes to insert ‘‘that are’’
responsible for the quality control between ‘‘and’’ and ‘‘intended.’’
16. Quality Control Personnel operations related to packaging, (Comment 52) Some comments note
The final rule defines ‘‘quality control designate a second individual as an the proposed rule would use the terms
personnel’’ as ‘‘any person, persons, or expert in deciding whether to accept or ‘‘representative sample,’’ ‘‘reserve
group, within or outside your reject incoming components, and sample,’’ and ‘‘representative reserve
organization, who you designate to be designate a third individual as an expert sample’’ but would only define
responsible for your quality control in deciding whether in-process ‘‘representative sample.’’ The comments
operations.’’ specifications are met at certain control ask us to clarify the distinction, if any,
(Comment 51) Some comments seem points. The definition does not limit the between these terms.
to suggest that the reference in the 2003 other activities that these designated (Response) A ‘‘reserve sample’’ is a
CGMP Proposal to a ‘‘quality control individuals may perform within the sample that is to be held or kept for a
unit’’ mandates a separate unit or manufacturing operations; thus, for designated time. It differs from a
department with responsibility for all example, the packaging expert who ‘‘representative sample’’ in the sense
quality control operations. One performs the quality control function for that a representative sample is not
comment explains many companies do packaged dietary supplements could always kept; for example, one might
not have one quality control unit with also have responsibilities in the actual take a representative sample to test
oversight of all operations within the packaging operation. Quality control product quality, but one would not
facility. This comment states companies responsibilities and specific activities necessarily keep every tested sample.
commonly have each separate section of are distinct and separate from any other To clarify this distinction, the final
an operation perform both its function responsibilities and specific activities rule now defines a ‘‘reserve sample’’ as
and its own quality control. A few that an employee might perform for any ‘‘a representative sample of product that
is held for a designated period of time.’’ appropriate oversight of the treatment, manufacturer or may obtain a written
We also revised the rule to refer solely in-process adjustments, and scientific evaluation of a process,
to a ‘‘reserve sample’’ rather than use reprocessing so the dietary supplement especially in cases where two or more
both ‘‘reserve sample’’ and will still meet required specifications. control measures are used to accomplish
‘‘representative reserve sample.’’ Therefore, we added a conforming the 99.999 percent reduction in the
requirement to final §§ 111.90(b) and target pathogen, to ensure the process is
18. Reprocessing
111.140(b)(3)(vi) to require oversight by adequate to destroy microorganisms of
The final rule defines ‘‘reprocessing’’ quality control personnel for any public health significance or to prevent
as ‘‘using, in the manufacture of a reprocessing, treatment, or in-process their growth.
dietary supplement, clean, adjustment of a dietary supplement that (Comment 54) Many comments object
uncontaminated components or dietary have been previously removed from to the proposed text concerning the
supplements that have been previously manufacturing and that have been made application of heat or chemicals to a
removed from manufacturing and that suitable for use in the manufacture of a food contact surface to yield a reduction
have been made suitable for use in the dietary supplement (see sections X and of 5 logs or 99.999 percent of
manufacture of a dietary supplement.’’ XI of this document). representative disease organisms of
We modified the definition that, in part, public health significance. The
read ‘‘* * * dietary supplements that 19. Reserve Sample
comments state the aspect of the
have been previously removed from The final rule contains a new proposed definition is overly
manufacturing for reasons other than definition of ‘‘reserve sample.’’ ‘‘Reserve prescriptive, beyond our legal authority,
insanitary conditions’’ by removing ‘‘for sample’’ is defined as ‘‘a representative and would not provide additional
reasons other than insanitary sample of product that is held for a public health benefits. Many comments
conditions’’ to expand the scope of what designated period of time.’’ We explain say it is inappropriate to use the
may be reprocessed. We explain the our reasons for creating this definition
definition of sanitization from our Food
reason for the latter change in our in this section under the definition of
Code because retail and manufacturing
response to the following comments. We ‘‘representative sample.’’
operations are distinct. A few comments
also changed ‘‘unadulterated’’ to
20. Sanitize assert the process of manufacturing
‘‘uncontaminated’’ to be consistent with
The final rule defines ‘‘sanitize’’ as dietary supplements shares more in
the revisions we have made in other
‘‘to adequately treat cleaned equipment, common with food or drug
sections, including the definition of
containers, utensils, or any other manufacturing than with retail
quality.
(Comment 53) Some comments ask us cleaned contact surface by a process that operations. Most comments recommend
to clarify whether components or is effective in destroying vegetative cells that we define ‘‘sanitize’’ in the manner
dietary supplements that have been of microorganisms of public health that was presented in the 1997 ANPRM
successfully treated to reduce microbial significance, and in substantially and consistent with the current food
levels to acceptable levels can be reducing numbers of other CGMP definition at § 110.3 so that
reprocessed. Some comments object to microorganisms, but without adversely ‘‘sanitize’’ means ‘‘to adequately treat
the proposed definition of affecting the product or its safety for the dietary product contact surfaces by a
‘‘reprocessing’’ because it did not consumer.’’ process that is effective in destroying
include components or dietary The final rule’s definition of vegetative cells of microorganisms of
supplements removed for insanitary ‘‘sanitize’’ differs from the proposal in public health significance, and in
conditions, and several comments object that the proposed definition would have substantially reducing numbers of other
to the restrictions to reprocessing specified a reduction of 5 logs or 99.999 undesirable microorganisms, but
described in proposed percent reduction of ‘‘representative without adversely affecting the product
§§ 111.35(i)(4)(iii) and 111.50(f), disease microorganisms of public health or its safety for the consumer.’’
because, they argue, the definition and significance’’ and ‘‘other undesirable One comment states that consistently
sections associated with reprocessing microorganisms’’ and would have validating the effectiveness of the
would not permit the reprocessing of specified the use of heat or chemicals. sanitizing procedure is impractical and
previously insanitary ingredients even if The preamble to the 2003 CGMP recommended we state instead that
there are processes available that are Proposal explained that we based the equipment, utensils, etc., should be
safe and effective in removing foreign proposed definition of ‘‘sanitize’’ on the cleaned and sanitized in a manner that
matter, microorganisms, or chemicals definition of ‘‘sanitization’’ in the ‘‘Food keeps undesirable microorganisms and
that may have rendered the ingredient Code’’ (which is a model that gives food other adulterants from contaminating all
‘‘insanitary.’’ One comment would control authorities a scientifically sound components, ingredients, in-process
revise the definition as follows: technical and legal basis for regulating materials, and finished product. The
‘‘Reprocessing means using, in the the retail and food service segment of comment claims that, by this approach,
manufacture of a dietary supplement, the industry) because dietary the microbial and analytical test results
clean, unadulterated components * * * supplements are often consumed of product produced on a facility’s
or dietary supplements that have been without further processing, similar to equipment, coupled with random
previously removed from manufacturing foods consumed in retail outlets (68 FR testing of final rinse water after cleaning
for reasons other than insanitary 12157 at 12179). The preamble to the and sanitizing equipment and utensils,
conditions or that have been 2003 CGMP Proposal also explained would provide sufficient and
successfully reconditioned so that they that, to achieve the reduction levels in continuous evidence of a proper and
are suitable for use.’’ the proposed definition, one would effective cleaning and sanitizing plan.
(Response) We agree that materials need to validate control measures to Two comments claim that the
can be treated, subjected to in-process ensure they are both appropriate to their proposed definition for sanitize denotes
adjustments, or reprocessed when there operation and scientifically sound. The ‘‘validation methodology’’ found in drug
are suitable processes available, and we preamble explained that in many cases, CGMP, and that we must base dietary
revised the definition of ‘‘reprocessing’’ manufacturers may rely on a written supplement CGMP on food rather than
to reflect this. However, there must be certification from the equipment on drug standards.
Other comments express concern separate definitions for ‘‘sanitize’’ and We note that the Environmental
about validating control measures to ‘‘sanitizing agent.’’ The comments Protection Agency has regulatory
ensure that they are scientifically sound would define ‘‘sanitize’’ as meaning ‘‘to authority over certain uses of sanitizers
and appropriate to operations and the adequately treat equipment, containers, as pesticide chemicals and we have
economic burden to do the testing. A utensils, or any other dietary product regulatory authority over certain uses of
few comments state it would be difficult contact surface by applying a sanitizing sanitizers as food additives. Under
to show a 100,000-fold reduction on an agent on cleaned food contact surfaces.’’ section 201(q)(1)(B) of the act, as
already cleaned surface, particularly if One comment would define ‘‘sanitizing amended by the Food Quality Protection
the pre-sanitization level is at or near agent’’ as ‘‘cumulative heat or chemicals Act (FQPA) (Public Law 104–170) and
the lower limit of the test method that, when evaluated for efficacy, yield the Antimicrobial Regulation Technical
employed. a reduction of 5 logs, which is equal to Corrections Act (ARTCA) (Public Law
One comment states the definition 99.999 percent reduction, of 105–324), certain substances used as
required the manufacturer to representative disease microorganisms food contact surface sanitizing solutions
demonstrate a 100,000-fold reduction in of public health significance and are subject to the Environmental
microbial count every time a food substantially reduce the numbers of Protection Agency’s regulatory authority
contact surface is sanitized. A few other undesirable microorganisms, but as pesticide chemicals. The
comments express concern that without adversely affecting the product Environmental Protection Agency
processing lines would have to be or its safety for the consumer.’’ Another recently codified tolerance exemptions
closed down each time they are comment would define ‘‘sanitizing under section 408 of the act (21 U.S.C.
sanitized in order to test them, creating agent’’ in a similar manner, except it 346a) for those food contact surface
a financial hardship especially on would omit references to a 5-log sanitizing solutions that were
smaller operations. Other comments ask reduction. previously subject to our authority at
us to give companies the flexibility § 178.1010 and transferred to the
(Response) The proposed definition of
necessary to monitor sanitation needs Environmental Protection Agency’s
‘‘sanitize’’ was intended to give firms
based on individual products and authority under FQPA and ARTCA (see
the flexibility to monitor sanitation
manufacturing operations to be 40 CFR 180.940 (69 FR 23113, April 28,
needs based on their products and
consistent with existing industry 2004). Such pesticide chemicals must
operations. We did not intend to suggest
practices and food and drug CGMPs. comply with the Pesticide Tolerance
One comment requests we clarify that that manufacturers had to demonstrate a
100,000-fold reduction in microbial regulations in 40 CFR 180.940.
a sanitizing agent for use on food Sanitizers used on food packaging must
processing equipment must be approved count every time they sanitized a
contact surface, nor did we intend, as comply with our regulations at
in accordance with part 178, Indirect § 178.1010. For an in depth discussion
Food Additives: Adjuvants, Production some comments claimed, to have firms
close down processing lines every time of appropriate sanitizers for food contact
Aids, and Sanitizers (21 CFR part 178) surface use, see the Environmental
and our expectations with respect to they were sanitized to test them for
microbial reduction. Rather, the Protection Agency’s Pesticides;
what documentation would be Tolerance Exemptions for Active and
necessary to prove the effectiveness of language of the proposed rule was
intended to make it clear that processes Inert Ingredients for Use in
the sanitizer used. Two comments say Antimicrobial Formulations (Food
the proposed definition of sanitize used to sanitize contact surfaces should
be effective. However, we recognize that Contact Surface Sanitizing Solutions)
means that manufacturers must perform (69 FR 23113, April 28, 2004) and DIS/
validation studies to demonstrate that the proposed definition caused
confusion as to our intent. The proposed TSS–4 Efficacy Data Requirements
the sanitizers they are using reduce the Sanitizing Rinses (for previously
microbial load on equipment by definition may have been interpreted as
proposing validation to ensure an area cleaned food-contact surfaces) (January
100,000-fold, a requirement for a 30, 1979) (Ref. 27) (available on the
‘‘sanitizer’’ under regulations issued by was sanitized; however our intent was
simply to require that effective Internet at http://www.epa.gov/
the Environmental Protection Agency. oppad001/dis_tss_docs/dis-04.htm).
The comments say a sanitizer should sanitizers and sanitizing processes be
not be held to this standard for the used, just as in food establishments. 21. Theoretical Yield
purpose of reducing microbial loads on Therefore, in order to clarify the The final rule defines ‘‘theoretical
food product contact surfaces, and that provision, we have revised the yield’’ as ‘‘the quantity that would be
manufacturers of a solid dosage form definition of ‘‘sanitize’’ to be consistent produced at any appropriate step of
may not need to ‘‘sanitize’’ their with § 110.3(o). The final rule defines manufacture or packaging of a particular
equipment because the processing ‘‘sanitize’’ as adequately treating dietary supplement, based upon the
environment is not suitable for ‘‘cleaned equipment, containers, quantity of components or packaging to
microbial growth due to the low water utensils, or any other cleaned contact be used, in the absence of any loss or
activity. One comment recommended surface by a process that is effective in error in actual production.’’
using the approach in the Food Code, destroying vegetative cells of We received no substantive comments
which specifies conditions under which microorganisms of public health on the proposed definition.
chemical sanitizers listed in § 178.1010 significance, and in substantially
may be used, including the requirement reducing numbers of other 22. Water Activity
that they be used in accordance with the microorganisms, but without adversely The final rule defines ‘‘water activity’’
Environmental Protection Agency- affecting the product or its safety for the as ‘‘a measure of the free moisture in a
approved manufacturer’s label use consumer.’’ The final definition of component or dietary supplement and is
instructions, and be used for dietary sanitize does not include any statements the quotient of the water vapor pressure
supplements rather than imposing a about mechanisms that you may use to of the substance divided by the vapor
validation requirement on achieve compliance because including pressure of pure water at the same
manufacturers. such nonbinding information is temperature.’’
Some comments would divide the inconsistent with our current practices We received no substantive comments
definition of ‘‘sanitize’’ by creating for establishing regulations. on the proposed definition.
23. We composition’’ means that the production many tests that could be used to identify
The final rule explains that ‘‘we’’ on a batch-by-batch basis is consistent the botanical constituents, but that it
means the United States Food and Drug with the master manufacturing record would be economically exhausting
Administration. and is what it is represented on the label considering the number of botanical
The final rule’s definition is identical to be (identity); is without impurities constituents, and it would not
and is the desired product (purity); is contribute to quality or safety.
to the proposed definition. We received
the identity, purity, and strength for its (Response) We decline to revise the
no substantive comments on the
intended purpose (quality); is the rule to define identity, purity, strength,
proposed definition. or composition. The exact way in which
concentration, that is, the amount per
24. You unit of use intended (strength); and is the dietary supplement industry uses
the intended mix of product and these terms may vary, and defining
The final rule defines ‘‘you’’ as a
product-related substances these terms could limit the flexibility
‘‘person who manufactures, packages,
(composition) (68 FR 12157 at 12176). that is needed to accommodate such
labels, or holds dietary supplements.’’
One comment says ‘‘identity’’ should variations.
25. What Other Terms Did the mean ‘‘a substance or product is what it Nevertheless, to elaborate on our
Comments Want Defined? is represented on the label to be.’’ interpretation of identity, purity,
One comment says that it does not strength, and composition, and to
(Comment 55) Some comments ask us
seem appropriate to define the term respond to the particular concerns
to define ‘‘adulteration’’ (based on the
‘‘purity’’ to mean ‘‘without impurities.’’ raised by some comments, we provide
provisions of section 402 of the act),
The comment states it would be difficult the following information.
‘‘dietary ingredient,’’ and ‘‘dietary a. Identity. The ‘‘identity’’ of a dietary
to consider an herbal extract as being
supplement’’ (based on the definition in supplement refers to the dietary
‘‘pure’’ because it is a mixture of
section 201(ff) of the act). supplement’s consistency with the
naturally occurring compounds in a
(Response) We decline to revise the master manufacturing record and/or that
solvent. Another comment suggests the
rule as suggested by the comments. The it is the same as described in the master
term ‘‘purity’’ be defined to mean ‘‘free
terms have meaning within the context manufacturing record.
from objectionable and/or deleterious
of the act and case law. Further, under b. Purity. The ‘‘purity’’ of a dietary
levels of impurities including, but not
final § 111.3 the act’s definitions and supplement refers to that portion or
limited to, heavy metals, pesticides,
interpretations ‘‘apply to such terms mycotoxins, radioactivity, filth, percentage of a dietary supplement that
when used in this part.’’ Thus, there is extraneous material, molds, yeasts and represents the intended product. For
no need for us to define the terms as bacteria.’’ Another comment suggests example, amino acids generally can
requested by the comments. defining the term ‘‘purity’’ as ‘‘having exist in two forms (i.e., dextro (D-, or
(Comment 56) Proposed § 111.35(e)(2) the intended identity and composition right) and levo (L-, or left) forms) called
would require a person to establish a and being without significant enantiomers. Enantiomers have the
specification for any point, step, or stage impurities.’’ However, the comment same chemical formula and the same
in the manufacturing process where does not explain what is meant by chemical structure, but differ in their
control is necessary to prevent ‘‘without significant impurities.’’ three-dimensional orientation. If you
adulteration, and proposed § 111.35(f) One comment suggests defining the manufacture a dietary supplement to
would require monitoring of the in- term ‘‘strength’’ as ‘‘having the intended provide the amino acid L-arginine, and
process control points, steps, or stages concentration, that is, the amount of the you determine that 90 percent of the
to ensure these established dietary ingredient per unit of use (tablet, manufactured product is L-arginine and
specifications are met and to detect any capsule, soft gel, teaspoon, or other 10 percent of the manufactured product
unanticipated occurrence that may unit).’’ Another comment expresses is D-arginine, you could describe your
result in adulteration. Some comments concern about the use of the term L-arginine product as ‘‘90 percent
ask us to define the term ‘‘control point’’ ‘‘strength’’ in relationship to pure.’’ As another example, if you
as ‘‘any point, step or stage in the nonstandardized herbals because there manufacture a mixture of triglycerides
manufacturing process where control is are no current industry standards for that provides polyunsaturated fatty
necessary to prevent adulteration.’’ these products. This comment suggests acids in the diet, the manufactured
(Response) We decline to add a we clarify the term ‘‘strength’’ so it triglycerides may contain small amounts
definition of ‘‘control point’’ as refers to having the correct amount of a of free fatty acids and sterols. The free
requested by the comments. Instead, we stated ingredient. One comment notes fatty acids and sterols could derive, for
revised final § 111.75(b) (formerly St. Johns wort has a composition of example, from the source of the
proposed § 111.35(f)) to state that you approximately 40 different constituents triglycerides or could be byproducts of
must monitor the in-process points, in addition to the essential oil that the manufacturing process. If you
steps, or stages where control is contains numerous constituents. The determine that 95 percent of the
necessary to ensure the quality of the comment asks which constituent it manufactured product is the mixture of
finished batch of dietary supplement; should use to determine ‘‘strength.’’ the triglycerides that provides the
this revision eliminates the need to Another comment would use the term polyunsaturated fatty acids, and 5
define ‘‘control point.’’ ‘‘quantity’’ instead of ‘‘strength.’’ percent of the product is free fatty acids
(Comment 57) Several comments One comment would define and sterols, you could describe the
would have us define one or more of the ‘‘composition’’ as ‘‘having the intended purity of your product as ‘‘95 percent
following terms: Identity, purity, mix of components or ingredients, pure.’’
strength, and composition. Some including dietary ingredients.’’ Another Just as we use the term ‘‘purity’’ to
comments suggest specific text for the comment would delete ‘‘composition’’ refer to the identity and amount of a
definitions. from the rule because, the comment dietary supplement that is the desired
Similarly, some comments suggest claimed, an FDA investigator might product, we use ‘‘impurity’’ to refer to
codifying the preamble description that conclude that ‘‘composition’’ refers to the identity and amount of a dietary
we used for these terms, i.e., the phrase every constituent of every botanical. supplement that is not the desired
‘‘identity, purity, quality, strength, and According to this comment, there are product. In the previous examples, we
view the D-arginine that is present in If the comments were concerned that comment would define ‘‘manufacturer’’
the product that is intended to be L- the ‘‘strength’’ of a dietary supplement as ‘‘a person who formulates or changes
arginine as an ‘‘impurity,’’ and we view meant that you need to establish the the composition or physical
the free fatty acids and sterols that are quantitative amount per unit of measure characteristics of a dietary supplement
present in the product that is intended of each constituent in a dietary or who packages or labels the product
to be a mixture of triglycerides that ingredient, such as a botanical extract or in a container for distribution’’ to clarify
provide polyunsaturated fatty acids in natural product, we do not consider that a company that does not
the diet as ‘‘impurities.’’ For the such constituents to be ‘‘components’’ manufacture a specific dietary
purposes of these examples, we do not of a dietary supplement, unless you add supplement, but purchases a dietary
view these ‘‘impurities’’ as such constituents as components (as in supplement in bulk and then packages
‘‘contaminants.’’ an extract) (see discussion of the or labels the bulk dietary supplement
If the comments were concerned that definition of component in this section). for sale to consumers, is still subject to
the dietary supplement CGMP We do not consider the rule’s dietary supplement CGMP
requirements regarding a dietary requirements on dietary supplement requirements. The comment cites our
supplement’s ‘‘purity’’ mean that we strength as necessarily relating to the proposed definition of ‘‘manufacturer’’
expect you to characterize each individual constituents of such in our infant formula CGMP proposal
constituent of a natural product to products. Whether the requirements (see 61 FR 36154 at 36209, July 9, 1996
determine whether each constituent is regarding dietary supplement strength (proposing to define a ‘‘manufacturer’’
present in a certain pre-established apply to one or more constituents of as ‘‘a person who prepares, re-
quantity (i.e., purity specification) to dietary ingredients in a dietary constitutes or otherwise changes the
determine whether it contributes to the supplement depends on what you are physical or chemical characteristics of
‘‘purity’’ of the dietary supplement or manufacturing. For example, if you are an infant formula or packages or labels
would be considered as an ‘‘impurity,’’ manufacturing vitamin C, and your the product in a container for
we do not consider such constituents to source of vitamin C is rosehips, you distribution’’)).
be ‘‘components’’ of a dietary would establish a strength specification Other comments would define
supplement (see discussion of the for vitamin C in the finished batch of ‘‘manufacturer’’ to exclude a health care
definition of component in this section). the dietary supplement (e.g., ‘‘x practitioner or herbalist and noted the
For example, if you manufacture a milligrams (mg) of vitamin C per Canadian Natural Health Product
tablet’’). You are required to ensure that regulations do not apply to health care
dietary supplement containing fish oil,
the dietary supplement does in fact practitioners.
we would not consider the triglycerides,
contain ‘‘x mg of vitamin C per tablet.’’ (Response) We decline to define
which are constituents of the fish oil, to ‘‘manufacturer’’ in the final rule. In
Alternatively, if you are manufacturing
be components. Likewise, we would not section III, footnote 1 of this document,
rosehips and not vitamin C from
consider particular fatty acids (such as we explain that ‘‘manufacture’’ is a
rosehips, the strength specification that
the polyunsaturated fatty acids broad term and is not limited to
you establish for the finished batch of
docosahexaenoic acid (DHA) and production, packaging, or labeling
the dietary supplement is the strength of
eicosapentaenoic acid (EPA)), which are activities. Consequently, we prefer to
the rosehips themselves (i.e., the
constituents of the triglycerides, to be explain our interpretation of the final
concentration of rosehips in the final
components of the dietary supplement. rule in this preamble and to have the
product, such as ‘‘x mg of rosehips per
In this example, you would be required codified provisions state general
tablet’’). You are required to ensure that
to establish a purity specification for the principles rather than attempt to capture
the product does in fact contain ‘‘x mg
amount of triglycerides in the fish oil. subtleties in a definition of
of rosehips per tablet.’’
(Note that if you are manufacturing fish We discuss the requirements to ‘‘manufacturer.’’
oil to provide the fatty acids DHA and establish and meet specifications in our (Comment 59) Proposed § 111.35(e)(1)
EPA in the dietary supplement, the discussion of subpart E (see section X of through (e)(3) would require you to
component specifications for the fish oil this document). establish specifications for identity,
must include a strength specification for d. Composition. A dietary purity, quality, strength, and
DHA and EPA in whatever amount you supplement’s ‘‘composition’’ refers to composition at receipt, in-process, and
determine is necessary to meet the the specified mix of product and finished batch stages, while proposed
specification for strength of DHA and product-related substances in a dietary § 111.35(g)(1) would require you to test
EPA in the dietary supplement.) We do, supplement. For example, a dietary each dietary supplement at the finished
however, expect you to set appropriate supplement manufactured to provide batch stage before release for
limits on contaminants (e.g., toxic vitamin C may contain, in addition to distribution to confirm that
substances) that are known to be vitamin C, a tablet coating agent and specifications are met, provided that
constituents of botanical extracts or substances used as binders. The there are scientifically valid analytical
other natural products that are likely or composition could be described as the methods available to perform such
certain to contain constituents that are percent of the dietary supplement that testing. If your quality control unit
harmful. is vitamin C, the tablet-coating agent, determined that finished batch testing
c. Strength. The strength of a dietary and each binder. could not be completed for any
supplement relates to its concentration. e. Other terms. specification because a scientifically
By concentration, we mean the (Comment 58) Several comments valid analytical method was not
quantitative amount per serving (for would revise the rule to define available, proposed § 111.35(g)(2) and
example, weight/weight, weight/ ‘‘manufacturer.’’ Many comments ask (g)(3) would require you to perform
volume, or volume/volume). Therefore, whether the rule applies to certain types testing on components and at the in-
for purposes of this final rule, strength of companies or professionals and said process stage to determine whether that
does not refer simply to the quantity of a definition of ‘‘manufacturer’’ would specification is met. The preamble to
an ingredient, rather it refers to the clarify the rule’s applicability. the 2003 CGMP Proposal explained that
amount of a stated ingredient per a Some comments suggest specific text a scientifically valid analytical method
specified unit of measure. for a definition. For example, one is one that is based on scientific data or
results published in, for example, The preamble to the 2003 CGMP enable manufacturers and FDA
scientific journals, references, text Proposal acknowledged that compendia investigators to comprehend and apply
books, or proprietary research (68 FR can have a role in establishing tests used such terms to a particular operation, we
12157 at 12198). to determine whether specifications are do not believe a definition for these
Several comments agree that met. For example, we noted that terms is necessary.
scientifically valid analytical methods compendial standards may be (Comment 61) Several comments
are those that are based on scientific appropriate reference materials for use would define the terms ‘‘certificate of
data or results published in scientific in conducting tests or examinations (68 analysis,’’ ‘‘certificate of compliance/
journals, references, textbooks, or FR 12157 at 12208). However, we did conformance,’’ and ‘‘continuing product
proprietary research. However, several not list specific compendia that would guarantee.’’ Most comments include
comments ask us to define or better be suitable sources or scientifically these terms in a list of terms that they
explain the terms ‘‘test’’ or valid analytical tests, and are not listing want us to define to ensure consistent
‘‘scientifically valid analytical method’’ such compendia in this final rule. The interpretation of the rule throughout the
as used in the dietary supplement compendia identified in the comments, industry. One comment says a standard
CGMP final rule. One comment argues i.e., INA, ANSI, AHP, and USP, may for documentation, such as a certificate
that, because of the evolving nature of include some methods that are based on of analysis, would put greater emphasis
methodology for ingredients used in scientific data or results published in on the firm’s responsibility to comply
dietary supplements, we should give the scientific journals, references, textbooks, with CGMP.
industry more guidance as to what can or proprietary research, but also contain (Response) We decline to define these
be considered authoritative for the some methods that are not based on terms as suggested by the comments. We
purpose of compliance with CGMP. such data or results. Thus, whether or have included, in the codified, the use
Some comments state we should not a method is scientifically valid is of a certificate of analysis as an option
acknowledge methods from the Institute not determined solely by its inclusion in to determine whether certain
for Nutraceutical Advancement (INA), a compendium. Rather, it is the specifications have been met. The final
American Herbal Pharmacopoeia (AHP), responsibility of quality control § 111.75(a)(2)(ii)(B) requires that certain
European Pharmacopoeia, and the personnel to approve the use of those information be provided in a ‘‘certificate
World Health Organization (WHO) as scientifically valid tests that will ensure of analysis.’’ This provision states that
scientifically valid analytical methods. a product’s identity, purity, strength, the certificate of analysis must include
One comment notes the USP establishes and composition whether or not such a description of the test or examination
scientifically valid procedures in its tests are contained in a particular method(s) used, limits of the test or
compendia and encouraged us to compendium. examinations, and actual results of the
We also decline to define ‘‘validation’’ tests or examinations, provided you
designate compendial procedures as
and ‘‘verification’’ because the final rule satisfy certain other criteria.
‘‘scientifically valid’’ by defining
does not establish any requirements that As for the claim that a standard for
‘‘scientifically valid’’ to include
use these terms. documentation, such as a certificate of
compendial procedures. The comment (Comment 60) One comment asks us analysis, would emphasize a firm’s
further argues that failure to to define the terms ‘‘adequate,’’ responsibility to comply with CGMP,
acknowledge compendial procedures as ‘‘sufficient,’’ and ‘‘qualified’’ and argues we encourage firms who are excepted
scientifically valid would be that, without these definitions, an FDA from the scope of the rule in final
inconsistent with section 403(s)(2)(D) of investigator may assert that something § 111.1 and who supply dietary
the act, which acknowledges the role of or someone is not adequate, sufficient, ingredients and other components to
compendia, by considering a dietary or qualified. follow dietary supplement CGMP
supplement misbranded if the (Response) We decline to define requirements.
supplement is covered by the ‘‘adequate,’’ ‘‘sufficient,’’ or ‘‘qualified’’ We decline to define ‘‘certificate of
specifications of an official in this final rule. Deciding what is compliance/conformance’’ or
compendium, is represented as ‘‘adequate’’ or ‘‘sufficient,’’ or who is ‘‘continuing product guarantee’’ because
conforming to the specifications of an ‘‘qualified’’ must be done on a case-by- the final rule does not establish any
official compendium, and fails to so case basis, depending on the operations requirements that use these terms.
conform. and the particular facts. As explained in
Other comments would define section V of this document, we do not 26. What Definitions Did the Comments
‘‘validation’’ and ‘‘verification’’ and need to, nor could we, predict with Want Us to Delete?
directed us to ‘‘ANSI Standard A8402– mathematical precision how many (Comment 62) Some comments would
1994’’ (a description of validation and inches or feet, for example, would be delete certain definitions (e.g.,
verification standards). ‘‘adequate space’’ to allow for cleaning ‘‘component’’ and ‘‘ingredient’’) because
(Response) We decline to define a particular piece of equipment that these terms do not appear in the food
‘‘test,’’ ‘‘scientifically valid analytical could be applied to every size of facility CGMP, the 1997 ANPRM, or both.
method,’’ or ‘‘scientifically valid and every operation. Furthermore, (Response) We decline to delete any
method’’ in this final rule. As the defining ‘‘adequate,’’ as defined in part definition for the reasons stated by the
comments recognized, the analytical 110, as ‘‘that which is needed to comments. As discussed in section V of
methods for components are evolving. A accomplish the intended purpose in this document, Congress did not require
regulatory definition for ‘‘test,’’ keeping with good public health dietary supplement CGMP requirements
‘‘scientifically valid analytical method,’’ practice’’ would still require context to to be identical to the food CGMP
or ‘‘scientifically valid method’’ could determine whether, in a particular requirements, so the mere fact that a
become obsolete if we based it on operation and based on a particular set definition may not appear in a food
specific sources such as INA, AHP, or of facts the particular practice was CGMP regulation does not mean we
USP that may or may not themselves ‘‘adequate.’’ Moreover, for terms such as must delete that definition from this
stay current or that may be modified in ‘‘adequate,’’ ‘‘sufficient,’’ and final rule, especially when the
a manner that did not enjoy widespread ‘‘qualified,’’ where there has been comments offered no other justification
support. common usage in the food industry to for deleting the definition. Definitions
provide clarity and consistency in comments’ arguments prompted us to supplement CGMP requirements could
interpreting various terms in a rule. reconsider whether proposed § 111.2 be ‘‘modified by manufacturer product
was necessary at all, and, in the end, we specifications’’ would create uncertainty
D. Do Other Statutory Provisions and
decided to delete the proposed section. over whether manufacturers could
Regulations Apply? (Final § 111.5)
We describe the comments on proposed unilaterally ‘‘modify’’ their product
Final § 111.5 states: ‘‘In addition to § 111.2 in the following paragraphs. specifications to fit a batch that failed to
this part, you must comply with other (Comment 63) Several comments meet specifications or claim that a
applicable statutory provisions and argue the proposed rule went beyond violation was ‘‘cured’’ by a
regulations under the act related to the ‘‘minimum standards’’ mentioned in manufacturer’s new product
dietary supplements.’’ Proposed § 111.5 proposed § 111.2. These comments also specification. In any event, given that
stated that, in addition to the dietary assert the proposed rule lacked we decided to omit proposed § 111.2
supplement CGMP requirements, ‘‘you flexibility. altogether, the change sought by the
must comply with other applicable (Response) We disagree with the comment is moot.
statutory provisions and regulations comments. In several instances, the
under the act related to the proposed requirement is practically 2. ‘‘Exclusions’’ (Proposed § 111.6)
manufacturing, packaging or holding of identical to requirements in the As we stated earlier in this section,
dietary ingredients or dietary umbrella food CGMP regulations. For proposed § 111.6 would exclude from
supplements.’’ example, most of the proposed the dietary supplement CGMP
Section 111.5 reminds you that other requirements for personnel, physical requirements persons who engage solely
statutory or regulatory requirements, not plants, and equipment and utensils in activities related to the harvesting,
included in the dietary supplement correspond to long-established, similar storage, or distribution of raw
CGMP requirements, may apply to your requirements in the umbrella food agricultural commodities that would be
particular products, operations, or CGMP regulations in part 110. In other incorporated into a dietary supplement
activities. In our further review of this instances, the proposed rule would by other persons. However, as we
provision, we determined that we do require a particular action or result explained in our response to comment
not need to elaborate on the individual (such as establishing specifications for 27 of this document, we decided that
operations and have shortened the components, in-process controls, the exclusion was not necessary, given
provision to eliminate the references to manufactured dietary supplements, and the changes that we made to final
particular operations. You are required packaged and labeled dietary § 111.1(a).
to comply with other applicable supplements under proposed Nevertheless, we received several
statutory and regulatory requirements, § 111.35(e)), but gave firms the comments on proposed § 111.6, and we
and we have retained this provision to flexibility and the responsibility to address those comments here.
ensure you understand that this final decide what those specifications will be. (Comment 65) One comment would
rule does not relieve you of your We have included flexibility where it is revise the rule to exclude or use
responsibilities to comply with other appropriate to do so, and, after we different requirements for small
applicable statutory and regulatory revised parts of the rule in response to businesses. The comment suggested we
requirements related to dietary the comments, the final rule provides categorize small businesses by
supplements. more flexibility than the proposal. For employment levels or dollar sales and
example, final § 111.75 sets forth criteria adopt a tiered enforcement strategy
E. What Sections Did We Remove From for relying on a certificate of analysis to similar that used in other government
the Rule, and Why? ensure that certain specifications for programs, such as those under the
The final rule omits sections that were components are met and for when you Occupational Safety and Health Act, the
in the proposed rule. Proposed § 111.2, can test a subset of finished batches for Americans with Disabilities Act, and the
‘‘What Are These Regulations Intended a select number of specifications; this Family Leave Act. Another comment
to Accomplish,’’ would have described differs considerably from the proposal would exempt small businesses from
the rule’s purpose as establishing the which would have required testing all the specific requirements for testing if
minimum CGMP you must use to the batches for all specifications. those businesses produce annual batch
extent that you manufacture, package, or (Comment 64) One comment would runs of 25,000 capsules and tablets.
hold a dietary supplement. Proposed revise proposed § 111.2 to read as (Response) We decline to exclude
§ 111.6, ‘‘Exclusions,’’ would have follows: ‘‘These regulations recommend small businesses from the final rule or
excluded ‘‘persons engaged solely in general minimum current good to have different criteria for such
activities related to the harvesting, manufacturing practices that, when businesses. As we stated in our response
storage, or distribution of raw modified by manufacturer product to comments 1, 3, and 16, there is no
agricultural commodities that will be specifications, will extend to the reason to assume that Congress meant to
incorporated into a dietary supplement manufacture, package, or holding of apply different or lesser CGMP
by other persons’’ from the dietary dietary ingredients or dietary requirements, or no CGMP requirements
supplement CGMP requirements. supplements for that manufacturer.’’ at all, to dietary supplements made by
(Response) We decline to revise the small businesses. Dietary supplement
1. ‘‘What Are These Regulations rule as suggested by the comment. CGMP requirements help to ensure the
Intended to Accomplish?’’ (Proposed Section 402(g) of the act states that ‘‘The quality of the dietary supplement and,
§ 111.2) Secretary may by regulation prescribe among other things, that a dietary
We elected to remove proposed good manufacturing practices for dietary supplement meets its specifications,
§ 111.2 from the final rule because we supplements.’’ If a dietary supplement that it contains the ingredients specified
realized that it created no enforceable has been prepared, packaged, labeled, or in its master manufacturing record, and
obligations and provided little, if any, held under conditions that do not meet that it is not contaminated. Consumers
helpful information. The few comments the final rule’s requirements, the dietary should be able to expect that the dietary
that address proposed § 111.2 either supplement is deemed to be adulterated supplements they purchase meet CGMP
disagreed with its general statement or under section 402(g)(1) of the act. Here, requirements regardless of the
sought to weaken the provision; the the comment’s suggestion that dietary manufacturer’s size. However, to help
businesses comply with dietary (Response) As explained in our will be further processed as a dietary
supplement CGMPs, we are giving responses to comments 29 and 30, supplement by others are not subject to
businesses with fewer than 500 persons who only manufacture or the final rule. If you manufacture and
employees but 20 or more employees a supply a component that will be further sell dietary supplements, in addition to
compliance date of 24 months after the processed as a dietary supplement by supplying components to others, you
date of publication of this final rule, and another person are not within the scope would be subject to this final rule under
we are giving businesses with fewer of this final rule. Thus, a ‘‘consolidator’’ § 111.1(a).
than 20 employees a compliance date of who simply buys raw agricultural
commodities and then sells them to As for potential safety issues arising
36 months after the date of publication
dietary ingredient manufacturers would from the early stages of manufacturing,
of this final rule.
not be subject to this final rule. such as the use of improper handling of
We carefully considered the size of a
Similarly, persons engaged in drying, agricultural commodities and the risk of
business when developing these
chopping, cutting, size reduction, adulteration, the final rule, at § 111.75,
regulations. The most common Small
Business Association size standard sifting, and grinding of raw agricultural describes criteria that enable a
applicable to manufacturers covered by commodities which they then sell to manufacturer of a dietary supplement to
this final rule is 500 employees. Based others for processing into a dietary rely on a certificate of analysis. One
on comments and our knowledge of the supplement would not be subject to this criterion is that the manufacturer must
dietary supplement industry, we know final rule. We note, however, that such first qualify the firm providing the
that there are a number of dietary persons are not exempt from other component by establishing the
supplement manufacturers who fall regulatory requirements. We remind reliability of the firm’s certificate of
significantly below the standard of 500 readers that a dietary ingredient is a analysis through confirmation of the
employees. To accommodate these food under section 201(f)(3) of the act. results of the firm’s tests or
manufacturers, we have established Consequently, a raw agricultural examinations. Firms that improperly
different compliance dates as noted. commodity that is a dietary ingredient handle raw agricultural commodities,
(Comment 66) One comment would is still subject to the umbrella food such that the commodities that they
CGMP requirements in part 110, and provide are adulterated, are not likely to
exempt ‘‘consolidators’’ (whom it
activities such as drying, chopping, and be qualified as suppliers of those
described as individuals who purchase
cutting are what we have long commodities.
raw agricultural commodities for sale to
considered to be types of food
raw ingredient manufacturers) from the In the future, we will consider the
processing.
rule. Some comments suggest expanding As for ‘‘wildcrafters,’’ if they package requests to develop guidance for subsets
the exclusion pertaining to harvesting, and label raw agricultural commodities of agricultural and post-harvest
storage, and distribution of raw as dietary supplements or sell them to activities (such as for hygienic practice
agricultural commodities to include consumers for use as a dietary for wildcrafters, identifying botanicals)
other common and basic raw botanical supplement, we would consider them to associated with dietary supplement
processing activities, such as drying, be manufacturers of a dietary manufacturing, along with other
chopping, cutting, size reduction, supplement and subject to the rule. If, guidance we may find useful as they
sifting, grinding, and storage. One however, the wildcrafter simply sells relate to certain CGMP requirements for
comment would delete the word the raw agricultural commodity to dietary supplements.
‘‘solely’’ to make the rule more flexible another for incorporation into a dietary
and make it possible to exclude supplement, it would not be subject to VII. Comments on Personnel (Final
producers, who do not manufacture a this final rule, but might be subject to Subpart B)
distinct product, from the CGMP rule. the CGMP requirements in part 110.
Another comment expresses concern A. Organization of Final Subpart B
Persons engaged in the harvesting,
about potential safety issues that can storage, or distribution of raw Proposed subpart B contained three
arise from the early stages of agricultural commodities, whether for provisions regarding personnel. Table 3
manufacturing, such as the use of distribution as a dietary supplement or of this document lists the sections in
improper handling of agricultural for distribution as a dietary ingredient to final subpart B and identifies the
commodities and the risk of a dietary supplement manufacturer, may proposed sections that form the basis of
adulteration; the comment says want to read our guidance entitled the final rule.
businesses involved in producing or ‘‘Guide to Minimize Microbial Food
distributing raw agricultural Safety Hazards for Fresh Fruits and
commodities should be subject to some TABLE 3.—DERIVATION OF
Vegetables’’ available at http://
requirements under the rule. A few www.cfsan.fda.gov/~dms/
SECTIONS IN FINAL SUBPART B
comments ask us to draft guidance prodguid.html (Ref. 28). This guidance
documents to address activities such as 2003
addresses common areas of food safety Final Rule CGMP
wildcrafting, plant identification, good concern in the growing, harvesting, Proposal
agricultural practices, and good sorting, packing, and distribution of
hygienic practices for wildcrafters fresh produce, and contains principles § 111.8 What are the re- N/A
(persons who harvest plants grown in that would apply to raw agricultural quirements under this
the wild), and growers and brokers and commodities, such as herbs and subpart B for written
specific service providers (millers, botanicals. procedures?
extractors). Some comments would As for the comment that would delete
exempt individual wildcrafters because § 111.10 What require- § 111.10
the word ‘‘solely’’ from proposed
ments apply for pre-
wildcrafters deal in relatively small § 111.6, we note that such a change is venting microbial con-
amounts of material at a time and sell no longer necessary since we are tamination from sick or
their material to larger brokers who deleting § 111.6. However, we caution infected personnel and
combine materials from different that only those persons or entities that for hygienic practices?
pickers together. manufacture or supply components that
TABLE 3.—DERIVATION OF SEC- unconstitutionally vague under the Fifth to ensure that we can evaluate firms’
TIONS IN FINAL SUBPART B— Amendment and arbitrary and compliance with their written
Continued capricious under section 706(2)(B) of procedures, final § 111.14 requires that
the Administrative Procedure Act (APA) a person who manufactures, packages,
2003 and therefore should be deleted. The labels, or holds dietary supplements
Final Rule CGMP comments focus on: make and keep records of such
Proposal • Proposed § 111.12(a) which would procedures. Such records would be
require ‘‘qualified employees’’ and available to us under subpart P.
§ 111.12 What personnel § 111.12 • Proposed § 111.13(a) which would
qualification require- require ‘‘qualified personnel to E. What Requirements Apply for
ments apply? Preventing Microbial Contamination
supervise.’’
In general, these comments say the From Sick or Infected Personnel and for
§ 111.13 What super- § 111.13 Hygienic Practices? (Final § 111.10)
visor requirements proposal’s failure to define the term
apply? ‘‘qualified’’ means that persons who are The title of this provision has been
subject to the rule could not discern the changed from proposed § 111.10 to
§ 111.14 Under this sub- N/A meaning of the term. These comments clarify that the requirements are related
part B, what records also say the proposal imposes no limits to the prevention of microbial
must you make and on enforcement officers as to what contamination due to the health
keep? would satisfy the requirements and, condition of personnel and not other
thus would represent an exercise of sources.
B. Highlights of Changes to the unbridled discretion and disparate
Proposed Requirements for Personnel 1. Final § 111.10(a)
decisionmaking. These comments argue
1. Revisions proposed § 111.12(b), which would Final § 111.10(a) requires you to take
require employees to have ‘‘the training measures to exclude from any
The final provisions in subpart B operations any person who might be a
and experience to perform the person’s
include revisions that clarify that the source of microbial contamination, due
duties,’’ and proposed § 111.13(b),
final rule applies only to persons who to a health condition, where such
which would require supervisors to be
manufacture, package, label, or hold contamination may occur, of any
‘‘qualified by training and experience to
dietary supplements unless subject to an material including components, dietary
supervise,’’ would suffice.
exclusion in § 111.1. (Response) We are not deleting supplements, and contact surfaces used
The final provisions also include in the manufacture, packaging, labeling,
§§ 111.12(a) and 111.13(a) as requested
revisions that clarify the applicability of or holding of a dietary supplement. This
by these comments. As discussed in
the rule to persons who perform provision is similar to proposed
section V of this document, we disagree
labeling operations for dietary § 111.10. We added ‘‘due to a health
that the terms in question are
supplements. condition’’ for clarity.
unconstitutionally vague, need to be
2. Changes After Considering Comments defined, or may result in discriminatory (Comment 68) Several comments
enforcement. There has been sufficient suggest that employees who are sick
The final rule:
• Requires you to establish and common usage of these terms in the should be allowed to work in areas
follow written procedures to fulfill the food industry to enable manufacturers, where they will not come into contact
requirements of subpart B; and those who enforce the with components, dietary supplements,
• Provides flexibility regarding the requirements, to comprehend and apply or contact surfaces, and that the
requirement to exclude personnel who such terms ‘‘with a reasonable degree of requirements of proposed § 111.10 are
might be a source of microbial certainty’’ to their particular operations too strict. These comments say proposed
contamination (e.g., due to illness or (see Boyce Motor Lines v. United States § 111.10(a) is too broad in stating that
open lesions) so that such personnel 342 U.S. at 340). Further, agencies are such persons be excluded ‘‘from
must be excluded only from operations permitted to use qualifying terms to working in any operation.’’ These
where such contamination may occur; enable them to address a wide variety of comments explain that such persons
• Clarifies that the qualification of conditions at companies. For these may be suitable for performing other
personnel and supervisors may be done reasons, we have retained the use of the tasks, such as warehouse functions or
through education, training, or terms in the final rule. The provisions administrative work. These comments
experience; at issue also give firms the flexibility to would revise proposed § 111.10(a) so
• Sets forth a new requirement that determine how to comply with the that it is acceptable for such persons to
you identify qualified personnel to regulations. We also explain in section work so long as they will not be a vessel
perform quality control operations and V of this document that the final rule for microbial contamination.
requires that such personnel have does not violate the APA. Other comments agree with proposed
distinct and separate responsibilities § 111.10(a), and state that employees
D. What Are the Requirements Under who are sick should be excluded from
related to performing quality control
This Subpart for Written Procedures? the plant, even from areas where
operations from those responsibilities
(Final § 111.8) products are not processed. These
that the person otherwise has when not
performing quality control operations; We received many comments that comments state excluding such
and recommended written procedures for personnel should be mandatory as the
• Sets forth a new requirement to various provisions. We address the need microbes from an open sore, wound, or
make and keep records that document for written procedures generally in other source of contamination could
training of personnel. section IV. We also respond to contaminate the surrounding air,
individual comments on specific personnel, etc. For example, if the

C. General Comments on Proposed provisions in the same section. Final production area is a closed loop air
Subpart B § 111.8 requires you to establish and handling system, then contamination
(Comment 67) Some comments assert follow written procedures to fulfill the could spread to the other areas through
one or more proposed requirements are requirements of subpart B. Additionally, the common air handling units/ducts.
(Response) We agree that some tasks are moving and modifying the exposed or where contact surfaces are
may be suitable for a person who might prepositional phrase concerning washed), and § 111.10(b)(9) (taking any
be a source of microbial contamination. ‘‘working in any operation.’’ We also other precautions necessary to protect
Certain warehouse functions or have added the word ‘‘infection’’ to against contamination).
administrative tasks may be appropriate clarify the sources of potential abnormal Proposed § 111.10(b)(5) would require
for such a person to do, provided that contamination. the hygienic practices that you use to
these functions or tasks do not expose (Comment 69) Several comments include maintaining gloves used in
components, dietary supplements, or suggest employees who may be the handling components, dietary
contact surfaces to microbial source of microbial contamination ingredients, or dietary supplements in
contamination from the person, and should be permitted to work in areas of an intact, clean, and sanitary condition
provided that the person would not the plant where they pose no risk of and ensuring that gloves be of an
infect others who would then expose contamination, and therefore should not impermeable material.
components, dietary supplements, or be excluded unless they pose such a (Comment 70) One comment asks us
contact surfaces to microbial risk. to clarify the requirements for the use of
contamination. (Response) We agree with the gloves in proposed § 111.10(b)(5). The
A requirement to exclude employees comments and are revising proposed comment says there are situations in
from being present at work would limit § 111.10(a)(1) accordingly. Therefore, which gloves are ineffective or
potential microbial contamination, you may allow persons with certain cumbersome. The comment provides as
which is the basis of the point made by health conditions to work in areas of a an example, if a person is packaging a
some comments that employees who are plant where they pose no risk of bulk material in fiber packs with metal
sick should be excluded from the plant. contamination even though they must ring lids, bulky gloves can interfere with
However, the comments do not be excluded from other areas where they the finer work such as attaching security
persuade us to deny firms the flexibility would pose such a risk. tabs, and thin, flexible gloves can be
to determine whether it would be Final § 111.10(a)(2) requires you to easily damaged by the sharp edges of
appropriate for an employee who may instruct your employees to notify their the metal rings on the lid.
be a source of microbial contamination supervisor(s) if they have, or if there is (Response) Final § 111.10(b)(5)
to work in some areas of the physical a reasonable possibility that they have, requires you to maintain gloves in an
plant that are sufficiently separated a health condition stated in intact, clean, and sanitary condition; it
from areas where product § 111.10(a)(1) that could contaminate does not require you to use gloves in
contamination could occur. When any components, dietary supplements, any specific situation. Although there is
considering whether an employee may or any contact surface. no requirement for wearing gloves while
be permitted to work and whether he/ We did not receive comments specific performing specific operations, you
she represents a potential source of to proposed § 111.10(a)(2). must wear gloves when they are
microbial contamination, one should necessary to protect against
2. Final § 111.10(b)
look beyond the obvious potential contamination of any components,
sources of contamination, and consider Final § 111.10(b) requires, if you work dietary supplements, or contact
possibilities such as the forms of in an operation during which surfaces.
indirect contamination discussed by the adulteration of the component, dietary (Comment 71) Proposed § 111.10(b)(8)
comments. Therefore, we are revising supplement, or contact surface may would require that the hygienic
proposed § 111.10(a) to require you to occur, you to use hygienic practices to practices that you use, to the extent
take measures to exclude ‘‘from any the extent necessary to protect against necessary to protect against
operations any person who might be a contamination of components, dietary contamination, include not eating food,
source of microbial contamination, due supplements, or contact surfaces. Final chewing gum, drinking beverages, or
to a health condition, where such § 111.10(b) lists nine hygienic practices, using tobacco products in areas where
contamination may occur, of any such as wearing outer garments in a components, dietary ingredients, dietary
material including components, dietary manner that protects against supplements, or any contact surfaces are
supplements, and contact surfaces used contamination, washing hands exposed, or where contact surfaces are
in the manufacture, packaging, labeling, thoroughly, and wearing, where washed.
or holding of a dietary supplement.’’ appropriate, hair nets, caps, beard One comment would substitute the
As one measure to reduce potential covers, or other effective hair restraints. word ‘‘processed’’ for the word
microbial contamination, final We did not receive any comments ‘‘exposed’’ in proposed § 111.10(b)(8).
§ 111.10(a)(1) requires you to exclude, concerning proposed § 111.10(b)(1) The comment says, although areas
from working in any operations that (wearing outer garments in a manner where components, dietary
may result in contamination, any person that protects against contamination), supplements, and contact surfaces are
who, by medical examination, the § 111.10(b)(2) (maintaining adequate exposed pose the greatest risk,
person’s acknowledgement, or personal cleanliness), § 111.10(b)(3) adulteration is also possible where these
supervisory observation, is shown to (washing hands thoroughly), items are held (i.e., stored in containers
have, or appears to have an illness, § 111.10(b)(4) (removing all unsecured and, thus, not exposed). Furthermore,
infection, open lesion, or any other jewelry and other objects that might fall the comment explains the use of the
abnormal source of microbial into components, dietary supplements, word ‘‘processed,’’ rather than
contamination, that may result in equipment, or packaging and removing ‘‘exposed,’’ would cover all areas
microbial contamination of components, hand jewelry that cannot be adequately intended to be covered by CGMPs and
dietary supplements, or contact sanitized), § 111.10(b)(6) (wearing, would alleviate the need to specify that
surfaces, until the health condition no where appropriate, hair nets, caps, the requirement applies to areas where
longer exists. Final § 111.10(a)(1) is beard covers, and other effective hair contact surfaces are washed.
similar to proposed § 111.10(a)(1). We restraints), § 111.10(b)(7) (not storing (Response) We decline to revise the
have added that the person can clothing or other personal belongings rule as suggested by the comment. We
acknowledge that he or she may be a where components, dietary believe the word ‘‘exposed’’ covers all
source of microbial contamination. We supplements, or contact surfaces are areas intended to be covered by the
requirement, including areas where functions do not need to be performed from training, in that ‘‘experience’’ is
contact surfaces are washed. We by a distinct or separate unit or person knowledge that a person gains over
consider an area where contact surfaces and that a person who is qualified by time, e.g., as he or she becomes
are washed to ‘‘expose’’ the contact training, education, or experience can increasingly familiar with a particular
surface. To avoid any confusion, we are serve a quality control function. action or piece of equipment.
modifying § 111.10(b)(8) to say ‘‘* * * Therefore, we are adding a new These comments persuade us that the
any contact surfaces are exposed, or § 111.12(b) to clarify that you must
rule would be clearer if we added
where contact surfaces are washed.’’ As identify who is responsible for quality
‘‘education’’ to the list of attributes that
written, the requirement to not eat, control operations. Under final
are used to qualify an employee. We
chew gum, drink, or use tobacco § 111.12(b) each person identified must
products in areas where components, be qualified to perform such operations, also agree there are some employees
dietary supplements, and contact and must have distinct and separate who could be qualified based solely on
surfaces are exposed gives firms responsibilities related to performing their education or experience and other
appropriate flexibility to determine such operations from those employees who would become qualified
areas where employees may or may not responsibilities that the person through, for example, on-the-job
eat, chew gum, drink, or use tobacco otherwise has when not performing training before they are left on their own
products. such operations. The quality control to perform their assigned duties. Rather
personnel can have dual functions than revise the rule to list all three
F. What Personnel Qualification attributes and then explain that an
within the facility but should separately
Requirements Apply? (Final § 111.12) employee can be qualified by any
perform the different responsibilities.
Final § 111.12(a) requires you to have Final § 111.12(c) requires that each combination of the attributes, we have
qualified employees who manufacture, person engaged in manufacturing, changed the conjunction from ‘‘and’’ to
package, label, or hold dietary packaging, labeling, or holding, or in ‘‘or.’’ Additionally, on our own
supplements. Final § 111.12(a) is similar performing any quality control initiative, we have replaced ‘‘person’s
to proposed § 111.12(a), except that the operations, have the education, training, duties’’ with ‘‘person’s assigned
final rule includes an editorial change to or experience to perform the person’s functions.’’ This change reinforces the
clarify that the requirement is to have assigned functions. Final § 111.12(c) principle that the employee’s training
the qualified employees do the work includes a revision associated with final relates to the functions that he or she is
rather than merely to have qualified § 111.12(b) by including persons who assigned to perform.
employees. perform quality control operations as
(Comment 72) The 2003 CGMP We will consider whether it would be
persons who also need to have the
Proposal invited comment on whether education, training, or experience for useful to provide guidance on what type
there is a minimum number of the assigned functions. of education, training, or experience
employees needed to manufacture (Comment 74) Several comments state would be sufficient for an employee to
dietary supplements (68 FR 12157 at we should revise the rule to allow for be properly qualified. We believe that
12183). Several comments state the final any combination of ‘‘training or such education, training, or experience
rule should not include such a experience.’’ These comments explain it may vary by job function and that it
minimum number because firms should is not always possible for an employee would be difficult to provide generic
be able to decide for themselves how to have both ‘‘training and experience.’’ guidance that would be sufficient for all
many qualified personnel they need. These comments would revise proposed specific job tasks. We decline to suggest
(Response) The final rule does not § 111.12(b) to read, ‘‘each person that training should be limited, as the
stipulate a minimum number of engaged in the manufacture of a dietary comments suggest, to the particular
employees. However, there should be product should have the proper operation(s) that the employee performs
enough employees to manufacture, education, training, and experience (or as they relate to the person’s functions.
package, label, and hold dietary any combination thereof) needed to These CGMP requirements apply to
supplements to ensure compliance with perform the assigned functions. many types of manufacturing operations
the final rule. In general, CGMP suggests Training should be in the particular of various size and complexity, so the
the need for a minimum of two persons: operations(s) that the employee training may vary depending on the
One to perform the work, and a second performs as they relate to the circumstances and may include more
to check the work performed to ensure employee’s functions.’’ Another than the employee’s assigned functions.
that a manufacturing deviation or an comment asks for guidance as to what (Comment 75) One comment states we
unanticipated occurrence is not type of education, training, or should provide training materials such
overlooked. experience is required for an employee as texts, videos, Internet training, or
(Comment 73) Some comments about to be considered qualified. seminars, to help companies properly
the proposed definition of ‘‘quality (Response) We agree with the point
train their employees.
control unit’’ say the quality control made by the comments. We
function need not be performed by a acknowledge that some positions will (Response) We have no plans at this
distinct or separate unit. These require an appropriate educational time to provide companies with training
comments say the quality control background in addition to any on-the- materials for their employees. We
function is best performed by a person job training. In the preamble to the 2003 expect that most companies already
or persons qualified by training, CGMP Proposal (68 FR 12157 at 12183) have trained or will train their
education, or experience in the different we noted ‘‘training’’ may be considered employees and that where additional
processing areas. a form of ‘‘education’’ and elected to training is needed to comply with these
(Response) As discussed, we have require that employees be qualified by regulations, companies will develop the
revised the proposed definition and ‘‘training and experience’’ rather than training materials that are appropriate
substituted the term ‘‘personnel’’ for ‘‘education, training, and experience.’’ for the functions their employees
‘‘unit.’’ (For the definition of quality The 2003 CGMP Proposal used the perform. We may consider providing
control personnel, see section VI of this conjunction ‘‘and’’ because we guidance in the future if circumstances
document.) We agree the quality control considered ‘‘experience’’ to be different warrant such guidance.
G. What Supervisor Requirements Thus, final § 111.13(b) states, ‘‘Each (Comment 79) Several comments state
Apply? (Final § 111.13) supervisor whom you use must be employee training records are critical
Final § 111.13(a) requires you to qualified by education, training, or and should be required under the final
assign qualified personnel to supervise experience to supervise.’’ rule. The comments explain that these
the manufacturing, packaging, labeling, (Comment 78) Several comments say records should show the content of the
or holding of dietary supplements. Final the term ‘‘to supervise’’ is ambiguous training, the date of the training, and the
§ 111.13(a) derives from proposed and would revise the rule to clarify signature of the employee trained. These
§ 111.13(a). what a supervisor must be qualified to comments assert that a formal (written)
We did not receive comments specific supervise: The manufacture, packaging, GMP training program is necessary to
to proposed § 111.13(a). or holding of dietary ingredients and track which employees have been
Final § 111.13(b) requires each dietary supplements. Another comment trained in the CGMP requirements.
supervisor you use to be qualified by would revise proposed § 111.13(b) to These comments add, without a written
education, training, or experience to clarify what type of training and and documented training program, it is
supervise. Final 111.13(b) derives from experience are required so that firms likely that some employees may not
proposed § 111.13(b) which would would have more guidance as to what receive sufficient training, or in some
require you and your supervisors to be is expected to confirm that personnel cases, any CGMP training at all. These
qualified by training and experience to are qualified. comments say successful quality control
supervise. (Response) We decline to revise the programs are inextricably connected to
(Comment 76) Several comments ask rule as suggested by the comments. We appropriate training programs, and
us to revise the rule so that supervisors disagree that the term ‘‘to supervise,’’ written documentation of employee
may be qualified by any combination of which is commonly used in the training is an important safeguard to
training or experience. These comments industry, is ambiguous. These CGMP ensuring safe and accurately labeled
would revise proposed § 111.13(b) to requirements apply to many types of dietary supplements. These comments
read, ‘‘supervisors must be qualified by manufacturing operations of various also state it is already an industry
education, training, and experience (or size and complexity, and the training standard to document training.
any combination thereof) to supervise must be suited to the circumstances. Other comments question our ability
the manufacturing, packaging, or to evaluate whether a firm’s employees
H. Under This Subpart, What Records have been adequately trained without
holding of dietary ingredients and Must You Make and Keep? (Final
dietary supplements in compliance with written documentation of the training.
§ 111.14)
this rule.’’ One comment, however, (Response) As discussed more fully in
would make an exception for quality As discussed in this section, the final the discussion of subpart E in section X
control and sanitation supervisors, rule contains a new § 111.8 requiring of this document, the final rule focuses
stating we should require these you to establish and follow written on ensuring the quality of the dietary
supervisors to have both training and procedures to fulfill the requirements of supplement at every stage of the
experience. subpart B. Those written procedures are production and process control system.
(Response) Consistent with the records. Therefore, we are adding a new Such a system begins with the proper
change we made to proposed § 111.14(a) requiring you to make and training. We agree that documentation
§ 111.12(c), we are revising proposed keep records in accordance with subpart of employee training is necessary to
§ 111.13(b) to require the supervisors P. Final § 111.14(b)(1) requires you to track which employees have been
you use to be qualified by ‘‘education, make and keep a record of the written trained in which operations. Therefore,
training, or experience.’’ We procedures for fulfilling the final § 111.14(b)(2) requires you to keep
acknowledge that some supervisory requirements of subpart B. documentation of training, including
personnel may need a different range of The preamble to the 2003 CGMP the date of the training, the type of
education, training, or experience than Proposal invited comment on whether training, and the person(s) trained.
others, and expect firms to determine we should require documentation and (Comment 80) One comment says we
the appropriate balance of education, records regarding each employee’s should not require manufacturers to
training, and experience. training (68 FR 12157 at 12183). After document and keep records regarding
(Comment 77) Several comments say considering comments and for the each employee’s training. The comment
our use of the phrase ‘‘you and the reasons discussed in the following says the rule should focus on end
supervisors you use’’ in proposed paragraphs, § 111.14(b)(2) requires you results and not on process.
§ 111.13(b) was unclear. According to to make and keep documentation of (Response) We disagree with the
these comments, the term ‘‘you’’ as training, including the date of training, comment. As we have explained in this
defined in the proposal, is quite the type of training, and the person(s) section, each person engaged in an
expansive and could be read so broadly trained. activity covered by these CGMP
as to require the Chief Executive Officer We also invited comment on whether regulations must have the education,
(CEO) of a company be ‘‘qualified’’ to the final rule should contain training, or experience to perform the
supervise. requirements for documentation about person’s assigned functions. Some
(Response) We agree that the phrase consultants that you use (68 FR 12157 employees will be considered qualified
‘‘you and the supervisors you use’’ at 12183). We specifically suggested any based in part on training taken as
could be clearer. Therefore, we are such requirement include the company employees. To show that such
revising proposed § 111.13(b) to say that consultant’s name, address, training is appropriate to the employee’s
‘‘each supervisor whom you use’’ must qualifications, and a description of functions and has in fact occurred, the
be qualified to supervise. Section services provided. After considering the training must be properly documented.
111.13(b) applies to any person who comments and for the reasons discussed This documentation is an important
supervises the manufacturing, in the following paragraphs, the final aspect of ensuring adequate training
packaging, labeling, or holding of rule does not include any requirements and, therefore, helping to ensure the
dietary supplements, even if that person to make and keep records regarding result of having qualified employees
also is an executive such as the CEO. consultants. who perform their functions properly.
(Comment 81) Several comments state VIII. Comments on Physical Plant and • Modifies the minimum
the documentation of the training Grounds (Final Subpart C) requirements for water that is used in a
program should include the title of the manner such that the water may become
A. Organization of Final Subpart C
person doing the training, an evaluation a component of the dietary supplement,
of the employee’s understanding of the Proposed subpart C contained two e.g., when such water contacts
training, and recommendations for the provisions regarding physical plants. components, dietary supplements, or
frequency of refresher training. One Table 4 of this document lists the any contact surface. Such water must, at
comment describes a specific method sections in final subpart C and identifies a minimum, comply with applicable
for training and for tracking training. the corresponding proposed sections Federal, State, and local requirements
The comments state an evaluation of the that form the basis of the final rule. and not contaminate the dietary
employee’s understanding of the supplement.
training would ensure that employees TABLE 4.—DERIVATION OF • Simplifies the sanitation
who receive training understand what SECTIONS IN FINAL SUBPART C requirements for toxic materials,
bathroom facilities, and hand-washing
they have been taught.
Final Rule 2003 CGMP facilities.
(Response) We decline to require Proposal • Simplifies and clarifies the design
specific additional documentation of requirements for floors, walls, and
employee training. We believe a firm § 111.15 What sanitation § 111.15
requirements apply to ceilings; fans and other air-blowing
should have some flexibility in how it your physical plant equipment; equipment that controls
wants to document training. and grounds? temperature and humidity; and the use
(Comment 82) Several comments of safety-type glass or glass-like
respond to our question as to whether § 111.16 What are the N/A materials.
the final rule should require
requirements under • Requires written procedures for
this subpart C for writ- cleaning the physical plant and for pest
documentation about consultants, ten procedures?
including each consultant’s name, control.
address, qualifications, and a § 111.20 What design § 111.20 • Requires that you make and keep
description of services provided. and construction re- records of the written procedures.
Several comments say that documenting quirements apply to
C. General Comments on Proposed
your physical plant?
this information is useful and could be Subpart C
done on a voluntary basis, but that such § 111.23 Under this sub- § 111.15(d)(3) (Comment 83) Several comments say
information is not necessary to ensure part C, what records and (e)(2) we should have different sanitation
safe and accurately labeled supplements must you make and
keep?
requirements for dietary ingredient
and, thus, should not be required. One manufacturers than for dietary
comment notes that recommendations supplement manufacturers. These
from consultants may or may not be B. Highlights of Changes to the
comments state that the manufacture of
used, and that a company should not Proposed Requirements for Physical
synthetic or highly processed dietary
have to explain at a later date why such Plant and Grounds
ingredients includes extensive
decisions were made. Another comment 1. Revisions purification steps, especially toward the
asserts that we and the company may end of the manufacturing process, and
The final rule:
have different opinions on whether a that these steps remove contaminants
consultant is qualified and that the • Reflects that the rule applies to that may have been introduced at earlier
consultant’s qualification is not our persons who manufacture, package, stages in the manufacturing process.
label, or hold dietary supplements These comments consider some stages
concern if a product is not adulterated.
unless subject to an exclusion in of the dietary ingredient manufacturing
One comment says documenting the
§ 111.1. process to not be subject to the same
name and services of the GMP
• Requires you to have strict controls as those used for
consultants should be required to
documentation or otherwise be able to manufacturing finished dietary
facilitate contact in case of need.
show that water that is used in a manner supplements.
(Response) The proposal noted such that the water may become a (Response) As discussed in section VI
documentation of the name, address, component of the dietary supplement, of this document (subpart A), the final
qualifications, and services rendered for e.g., when such water contacts rule applies to persons who
each consultant may help you know components, dietary supplements, or manufacture, package, label, or hold
whom to contact and if questions arise any contact surface, meets applicable dietary supplements and who are not
concerning the advice that the Federal, State, and local requirements subject to an exclusion in § 111.1, and
consultant has given. Thus, our intent in and does not contaminate the dietary does not apply to establishments that
suggesting such documentation was to supplement. only manufacture dietary ingredients.
help you rather than to make the 2. Changes After Considering Comments We addressed this comment in the
information available for us to response to comment 29.
determine whether we agreed with you The final rule: (Comment 84) Some comments assert
that a particular individual was • Includes requirements similar to the that one or more proposed requirements
qualified to be a consultant. However, food CGMP requirements in § 110.20(a) are unconstitutionally vague under the
the comments persuade us that such for keeping the grounds bordering your Fifth Amendment and are arbitrary and
information is not necessary to help physical plant in a condition that capricious under section 706(2)(B) of
ensure dietary supplement quality. protects against contamination. the APA. The comments would delete
Therefore, the final rule does not require • Clarifies that sanitation supervisors the following proposed requirements:
documentation regarding consultants. can be qualified by education, training, • § 111.15(e), which would require
or experience. plumbing to be ‘‘of an adequate size and
design and be adequately installed and dietary supplements, or contact supplements. Although some
maintained;’’ surfaces. The methods for adequate requirements in § 110.20(a) are not
• § 111.15(g), which would require ground maintenance include: strictly limited to drainage and trash
bathrooms to be ‘‘adequate’’ and • Properly storing equipment, disposal, the comment suggesting the
‘‘readily accessible; ’’ removing litter and waste, and cutting requirements to maintain grounds be
• § 111.15(h), which would require weeds or grass within the immediate limited to drainage and trash disposal
hand-washing facilities ‘‘to be adequate, vicinity of the physical plant so that it did not explain why, for example, it
convenient, and furnish running water does not attract pests, harbor pests, or would not be as important for a facility
at a suitable temperature;’’ provide pests a place for breeding; that manufactures dietary supplements
• § 111.15(h)(i), which would require • Maintaining roads, yards, and to maintain roads, yards, and parking
hand-washing and, where appropriate, parking lots so that they do not lots so that they do not become a source
hand-sanitizing facilities ‘‘at each constitute a source of contamination in of contamination as it already is for
location in your physical plant’’ where areas where components, dietary facilities that manufacture conventional
good hygienic practices require supplements, or contact surfaces are foods. Therefore, the final rule is adding
employees to wash or to sanitize or both exposed; § 111.15(a), which is similar to
wash and sanitize their hands; • Adequately draining areas that may § 110.20(a) with editorial revisions
• § 111.20(a), which would require contribute to the contamination of consistent with the rest of this final rule.
your physical plant to ‘‘be suitable in components, dietary supplements, or
contact surfaces by seepage, filth or any 2. Final § 111.15(b)(1)
size, construction, and design to
facilitate maintenance, cleaning, and other extraneous materials, or by Final § 111.15(b)(1) (proposed
sanitizing operations;’’ and providing a breeding place for pests; § 111.15(a)) requires you to maintain
• § 111.20(d)(6), which would require • Adequately operating systems for your physical plant in a clean and
aisles or working spaces between waste treatment and disposal so that sanitary condition. Final § 111.15(b)(2)
equipment and walls to be adequately they do not constitute a source of requires you to maintain your physical
unobstructed and of adequate width. contamination in areas where plant in repair sufficient to prevent
In general, these comments assert the components, dietary supplements, or components, dietary supplements, or
2003 CGMP Proposal did not define contact surfaces are exposed; and contact surfaces from becoming
terms or phrases (such as ‘‘adequately’’ • If your plant grounds are bordered contaminated.
or ‘‘at each location’’) in a way that by grounds not under your control, and We did not receive comments specific
persons who are subject to the rule can if those other grounds are not to proposed § 111.15(a).
discern the meaning of the term or maintained in the manner described in
this section, you must exercise care in 3. Final § 111.15(c)
phrase. These comments argue that the
the plant by inspection, extermination, Final § 111.15(c) (proposed
proposed rule imposes no limitations on
or other means to exclude pests, dirt, § 111.15(b)) sets forth requirements for
enforcement officers on the exercise of
and filth or any other extraneous cleaning compounds, sanitizing agents,
their discretion and, thus, invites
material that may be a source of pesticides, and other toxic materials.
exercise of unbridled discretion and Final § 111.15(c) includes changes
disparate decisionmaking. contamination.
(Comment 85) Several comments say that we are making for clarity and
(Response) As discussed in section V
the final rule should require the consistency. We added other ‘‘toxic’’
of this document, we disagree that the
maintenance of external areas similar to materials because some paragraphs
terms that the comments objected to in
the food CGMP requirement at within final § 111.15(c) simply refer to
the 2003 CGMP Proposal are
§ 110.20(a) for keeping the grounds the cleaning compounds, sanitizing
unconstitutionally vague, need to be
outside the facility adequately agents, and pesticides as ‘‘toxic
defined, or may result in discriminatory
maintained. These comments state that materials,’’ and because proposed
enforcement. We are retaining the terms
such a requirement is basic, is equally § 111.15(b)(2) addressed the use and
in the final rule.
important to facilities that manufacture storage of toxic materials that are not
D. What Sanitation Requirements Apply conventional foods and to facilities that within the general category of cleaning
to Your Physical Plant and Grounds? manufacture dietary supplements, and compounds, sanitizing agents, or
(Final § 111.15) that there is no reason why this pesticides.
requirement should differ from food Final § 111.15(c)(1) requires you to
1. Final § 111.15(a) use cleaning compounds and sanitizing
CGMPs. One comment asserts such a
The preamble to the 2003 CGMP requirement is basic to the industry and agents that are free from microorganisms
Proposal (68 FR 12157 at 12184) stated it should not be dismissed as a burden of public health significance and that
that we were not proposing to the industry. Some comments also are safe and adequate under the
requirements similar to the food CGMP assert that a provision similar to conditions of use. Final § 111.15(c)(1) is
requirements found in § 110.20(a) for § 110.20(a) would help train staff and similar to proposed § 111.15(b)(1),
keeping the grounds bordering your would explain to plant maintenance except that we inserted ‘‘that are’’ before
physical plant in a condition that personnel what is required and why. ‘‘safe and adequate.’’ We consider this
protects against contamination of One comment says there should be to be a nonsubstantive, editorial change.
components or dietary supplements in some minimum requirement for Proposed § 111.15(b)(1) was, itself,
order to limit the burden to sanitation and cleanliness in the area patterned after § 110.35(b)(1), which: (1)
manufacturers. However, we invited surrounding the plant and that Requires cleaning compounds and
comment on whether we should include requirements for drainage and trash sanitizing agents used in cleaning and
such requirements in a final rule. After removal should be adequate. sanitizing procedures to be free from
considering the comments, we have (Response) We agree that a undesirable microorganisms and safe
drafted final § 111.15(a) to require you requirement to maintain grounds is and adequate under the conditions of
to keep the grounds of your physical equally important for facilities that use and (2) provides that compliance
plant in a condition that protects against manufacture conventional foods and for may be verified by any effective means
the contamination of components, facilities that manufacture dietary including purchase of these substances
under a supplier’s guarantee or ‘‘cleaning compounds,’’ and added Therefore, although you do not have to
certification or examination of these ‘‘other toxic materials.’’ enclose your outside equipment, you
substances for contamination. must take measures to exclude pests
(Comment 86) Several comments ask 4. Final § 111.15(d)
from areas outside of the plant.
us to clarify our expectations with Final § 111.15(d) (proposed
respect to substantiating that a cleaning § 111.15(c)) sets forth requirements for 5. Final § 111.15(e)
compound or sanitizing agent is free pest control. Section § 111.15(d) is Final § 111.15(e) (proposed
from microorganisms of public health almost identical to proposed § 111.15(c). § 111.15(d)) sets forth requirements for
significance and is safe and adequate Final § 111.15(d)(1) requires you to the water supply of your physical plant.
under conditions of use. Some not allow animals or pests in any area Final § 111.15(e)(1) requires that you
comments suggest proposed of your physical plant. Final must provide water that is safe and
§ 111.15(b)(1) provide for the use of § 111.15(d)(1) allows guard or guide sanitary at suitable temperatures and
certifications or guarantees from a dogs in some areas of your physical under pressure as needed for all uses
supplier because our investigators plant if the presence of the dogs will not where water does not become a
otherwise may not recognize such result in contamination of components, component of the dietary supplement.
documents as evidence of compliance. dietary supplements, or contact We did not receive comments specific
Several comments say it is not necessary surfaces. Final § 111.15(d)(2) requires to proposed § 111.15(d)(1). We have
for a manufacturer to test these types of that you take effective measures to modified the phrase ‘‘safe and of
products, and that a continuing product exclude pests from your physical plant adequate sanitary quality’’ to read ‘‘safe
guarantee, combined with a statement of and to protect against the contamination and sanitary.’’ To avoid confusion with
intended use from the manufacturer of of components, dietary supplements, the definition of ‘‘quality’’ we have
the cleaning compound or sanitizing and contact surfaces on the premises by adopted solely for purposes of this final
agent, should satisfy the requirements. pests. Final § 111.15(d)(3) requires that rule, we deleted the references to
(Response) When assessing you not use insecticides, fumigants, ‘‘quality’’ as it applies to water
compliance with final § 111.15(c)(1), we fungicides, or rodenticides unless you standards. We consider this change to
would not treat a firm that take precautions to protect against the be nonsubstantive and still require
manufactures, packages, labels, or holds contamination of your components, water that is not a component of a
a dietary supplement differently than dietary supplements, or contact dietary supplement to meet a safe and
we would treat a facility that surfaces. sanitary standard.
manufactures, packages, labels, or holds (Comment 87) Several comments Final § 111.15(e)(2) requires that
conventional foods. Therefore, we claim proposed § 111.15(c) would water used in a manner such that the
intend to accept, as the comments require that sealed equipment outside of water may become a component of the
request, a supplier’s guarantee or the plant (e.g. storage tanks, vessels, dietary supplement, e.g., when such
certification that a cleaning compound piping) be enclosed to prevent pests water contacts components, dietary
or sanitizing agent is free from from roaming around these areas. The supplements, or any contact surface,
microorganisms of public health comments say there is no need to shelter must, at a minimum, comply with
significance and is safe and adequate outdoor equipment if it is properly applicable Federal, State, and local
under the conditions of use for the sealed. These comments state that requirements and not contaminate the
purpose of determining compliance dietary supplements are sometimes dietary supplement. Final § 111.15(e)(2)
with final § 111.15(c)(1). manufactured in extensive, highly derives from proposed § 111.15(d)(2)
Final § 111.15(c)(2) requires you to automated facilities in which large tanks which would require that water that
not use or hold toxic materials in a and vessels are interconnected via contacts components, dietary
physical plant in which components, piping, and that in these cases ‘‘the supplements, or any contact surfaces
dietary supplements, or contact surfaces physical plant’’ and ‘‘the equipment in must, at a minimum, comply with the
are manufactured or exposed, unless the plant’’ converge so that some or applicable National Primary Drinking
those materials are necessary: (1) To much of the equipment is effectively Water (NPDW) regulations and any State
maintain clean and sanitary conditions, located outdoors. Thus, the comments and local government requirements.
(2) for use in laboratory testing ask us to revise proposed § 111.15(c) to Final § 111.15(e)(2) includes changes we
procedures, (3) for maintaining or clarify that it applies only to interior are making after considering comments
operating the physical plant or areas of the physical plant. discussed in the following paragraphs.
equipment, or (4) for use in the plant’s (Response) Equipment such as that (Comment 88) Several comments state
operations. described by the comments, if properly the water quality that is required for
We did not receive comments specific sealed, should protect components, conventional foods is sufficient for
to proposed § 111.15(b)(2). We have dietary supplements, and contact dietary supplements. The comments
made a nonsubstantive edit to surfaces from contamination with pests. argue that no additional water standards
§ 111.15(c)(2) by moving ‘‘contact Final § 111.15(d) does not require that are listed in the CGMPs for low-acid
surfaces’’ to be the last item on the list. sealed equipment outside of the plant, canned foods in part 113 or in the
Final § 111.15(c)(3) requires you to such as storage tanks, vessels, or piping, CGMPs for acidified foods in part 114.
identify and hold cleaning compounds, be enclosed, e.g., inside a building. These comments argue that, if ‘‘safe and
sanitizing agents, pesticides, pesticide Final § 111.15(d)(2) requires that you of adequate sanitary quality’’ is
chemicals, and other toxic materials in take effective measures to exclude pests sufficient to ensure the quality of the
a manner that protects against from your physical plant and to protect water used in most food products, then
contamination of components, dietary against the contamination of it is also adequate to ensure the quality
supplements, or contact surfaces. Final components, dietary supplements, or of the water used in dietary
§ 111.15(c)(3) is similar to proposed contact surfaces on the premises by supplements.

§ 111.15(b)(3). pests. Moreover, final § 111.15(a) Other comments would revise the
We did not receive comments specific includes several requirements designed final rule to allow different standards
to proposed § 111.15(b)(3), but replaced to limit or exclude pests around all parts and requirements for water that contacts
‘‘toxic cleaning compounds’’ with of the exterior of your physical plant. or is used in dietary supplements
compared to water that contacts prescribed in the Environmental sanitary would not necessarily comply
components, including dietary Protection Agency’s NPDW regulations with, for example, the NPDW
ingredients. These comments state in 40 CFR part 141. regulations. A requirement stating ‘‘safe
current food CGMP regulations require We would consider it to be a rare and of adequate sanitary quality’’ or, as
only that water supplies that contact situation where a dietary supplement stated in the final rule, the requirement
food (defined to include ingredients and manufacturer uses well water and has of ‘‘safe and sanitary’’ could be seen as
raw materials) be ‘‘safe and of adequate no access to municipal water. a lesser standard than water that
sanitary quality.’’ These comments say Nonetheless, to the extent that a complies with ‘‘applicable Federal,
that this would be consistent with the manufacturer uses water that is not State, and local requirements.’’ We want
act’s basis for CGMP requirements for subject to Federal oversight, the to make clear that you must comply
foods, i.e., that food is not prepared manufacturer would have to comply with applicable Federal, State, and local
‘‘under unsanitary conditions whereby with any State or local regulations that requirements related to the water that
it may have become contaminated with apply to food manufacturing facilities you use for food processing that would
filth, or whereby it may have been using such water in food processing. otherwise be required of you, and not to
rendered injurious to health’’ (section Manufacturers that use water from a some lesser standard that you may
402(a)(4) of the act). Several comments municipal source, which is subject to consider is ‘‘safe and sanitary’’ when
state the final rule should adopt a the Environmental Protection Agency water is used in a manner such that the
similar rationale for components, NPDW regulations, should not be water may become a component of the
including dietary ingredients. These subject to a lesser standard in this final dietary supplement, e.g., when such
comments explain that components, rule than what is already required of water contacts a component, dietary
including dietary ingredients, are not in them by the Environmental Protection supplement, or any contact surface.
a form in which they will be consumed Agency. Thus, to accommodate Foreign manufacturers would need to
and are subject to further processing manufacturers subject to the comply with the water standard
prior to consumption. Environmental Protection Agency’s required in this final rule and achieve
Several comments say that requiring NPDW regulations for the water that the same level of performance as is
water used for cleaning contact surfaces they use in the manufacture of dietary required of domestic manufacturers.
to meet Environmental Protection supplements, as well as those dietary The water used in domestic or foreign
Agency regulations is an unnecessary supplement manufacturers who are not manufacturing must not contaminate
burden for companies that do not have subject to the Environmental Protection the dietary supplement. To clarify that
access to municipal water. According to Agency’s NPDW regulations, we are the water used, whether by a domestic
these comments, potable water should modifying the rule to state water that is or foreign manufacturer, must not be a
be sufficient. used in a manner such that the water source of contamination, we are adding
(Response) In the preamble to the may become a component of the dietary the words ‘‘and not contaminate the
2003 CGMP Proposal (68 FR 12157 at supplement, e.g., when such water dietary supplement’’ in final
12185), we stated that water should, at contacts components, dietary § 111.15(e)(2). We also want to make it
a minimum, be potable and that water supplements, or any contact surface, clear that water includes what is in the
that is ‘‘safe and of adequate sanitary must, at a minimum, comply with water, e.g., any of its contaminants in
quality’’ should be potable. We also said applicable Federal, State, and local addition to H2O. For example, when we
water that contacts components, dietary requirements and not contaminate the speak of drinking water, we do not just
supplements, or contact surfaces dietary supplement. We decline to use mean the H2O, we mean the iron, lead,
should, at a minimum, meet the ‘‘safe and of adequate safety’’ that some sulfur, and any other contaminants
Environmental Protection Agency’s comments state is sufficient because it contained in the water.
NPDW regulations and State, and local is for conventional foods. We believe (Comment 90) Several comments
requirements. We proposed to require that requiring that water comply with suggest water should meet some or all
that water used in operations where Federal, State and local requirements standards of the USP monograph for
water contacts components, dietary and not contaminate dietary sterile, purified water and say that the
supplements, or any contact surfaces supplements provides a clear standard standard in the USP monograph is a
meet the NPDW regulations because of as to what is required. higher, and presumably safer, standard
the potential for contamination if water (Comment 89) Some comments assert than the NPDW standard. The
were used that did not adhere to the that water that is used to manufacture comments state the USP’s water
microbial standards, for example, in the components or dietary ingredients deionization and purification systems
NPDW regulations. Finally, we stated where such components or dietary requirements are already common in the
these requirements were minimum ingredients are subject to further industry.
requirements and that water that is more processing prior to consumption, should (Response) We do not discourage
pure than that required under the be subject to the ‘‘safe and of adequate firms from using water in dietary
NPDW regulations may be desired. sanitary quality’’ standard in § 110.37. supplement manufacturing that meets
The comments stated some (Response) We acknowledge that such USP standards, including deionized or
manufacturers may not have access to components and dietary ingredients are purified water, but we do not require, as
municipal water, and therefore, that subject to the requirement in § 110.37. If a CGMP, the use of USP standards. This
meeting the NPDW regulations for the manufacturers do not fall within the final rule sets forth minimum
cleaning contact surfaces would be too scope of final § 111.1, such requirements for persons who
burdensome. These comments asserted manufacturers would be subject to the manufacture, package, label, or hold a
that potable water would be sufficient. CGMP requirements in part 110. dietary supplement. Thus, firms may
The comments do not provide a To the extent that such comments use water that exceeds our minimum
definition of ‘‘potable water.’’ We have request the ‘‘safe and of adequate requirements.
defined ‘‘potable water,’’ in the sanitary quality’’ language apply to (Comment 91) The preamble to the
regulations on interstate conveyance water used in the manufacture of a 2003 CGMP Proposal recognized that
sanitation in 21 CFR part 1250 to be, in dietary supplement, we decline to make foreign firms might not be subject to
part, water that meets the standards that change. Water that is safe and Environmental Protection Agency water
requirements or adhere to such (Response) We disagree that proposed standard for purified water and point
requirements, but also stated that water § 111.15(d)(1) and (d)(2) were out that the USP standard provides an
quality is an important part of CGMP redundant. For example, as described in assurance of the water’s consistency and
(68 FR 12157 at 12185). Thus, in the the proposed sections, nonpotable water provides a system that can be
preamble to the 2003 CGMP Proposal, that would have been ‘‘safe and of monitored.
we invited comment on how we might adequate sanitary quality’’ for use in Several comments suggest we include
ensure that foreign firms meet the same flushing toilets may not have been ‘‘safe timetables for water testing or describe
water quality requirements as domestic and of adequate sanitary quality’’ for use water testing frequency requirements.
firms. Several comments respond to our in the manufacture of a liquid dietary These comments state we should apply
request for comments specific to the supplement. something analogous to the proposed
applicability of the water standards to Final § 111.15(e)(1) requires that you requirements for infant formula which
foreign firms. Several comments provide water that is safe and sanitary, would require manufacturers to conduct
recommend we not distinguish between at suitable temperatures, and under the tests with sufficient frequency to
domestic and foreign firms with regard pressure as needed, for all uses where ensure that the water meets the
to water quality. The comments claim water does not become a component of Environmental Protection Agency’s
all firms must compete on a ‘‘level the dietary supplement. Final NPDW standard, but not less frequently
playing field.’’ These comments state § 111.15(e)(2) requires that water that is than annually for chemical
water quality standards vary from used in a manner such that the water contaminants, every 4 years for
country to country, and many countries may become a component of the dietary radiological contaminants, and weekly
do not have requirements that are supplement, e.g., when such water for bacteriological contaminants. Other
comparable to those in the United contacts components, dietary comments refer to the amendments to
States. The comments say foreign supplements, or any contact surface, the bottled water regulations at
manufacturers should not be permitted must, at a minimum, comply with § 165.110 which require a minimum
to import products into the United applicable Federal, State, and local yearly monitoring of source water and
States that do not meet the same safety requirements and not contaminate the finished bottled water products for
standards as domestic goods. dietary supplement. As an example of chemical contaminants for which
Other comments ask us to consider how the requirements would apply, allowable levels have been established
the water quality requirement to be met water that contains lead at a level that in the bottled water quality standard.
if the water complies with the NPDW is 20 times higher than the maximum (Response) Final § 111.23(c) requires
standard or any equivalent water quality accepted level in the Environmental you to have documentation that water,
standard that is ensured by a foreign Protection Agency’s NPDW standards when used in a manner such that the
public agency. for lead may not be safe for use in the water may become a component of the
(Response) We agree that foreign firms manufacture of dietary supplement that dietary supplement, e.g., when such
should be required to meet the water is consumed in four 2-ounce portions water contacts a component, dietary
safety and sanitary requirements per day, but may be safe for use in supplement, or contact surface, meets
required of domestic firms and achieve cleaning the floors of the physical plant. the requirements of final § 111.15(e)(2).
the same level of performance of Therefore, to emphasize that water that You must meet the requirement for final
domestic firms. As discussed in this is ‘‘safe and sanitary’’ may be different § 111.15(e)(2) at the point of use, rather
section, foreign firms are required to depending on its use, the final rule than at the point of delivery, i.e., at the
meet all requirements and would need continues to separate § 111.15(e)(1) and point the water may become a
to comply with their own national or (e)(2) (formerly proposed § 111.15(d)(1) component of the dietary supplement,
local water safety requirements and not and (d)(2)). such as when the water contacts
contaminate the dietary supplement. Additionally, to emphasize the components, dietary supplements, or
(Comment 92) One comment would importance of the water that is used in any contact surface (such as when the
combine proposed § 111.15(d)(1) and the manufacture of a dietary water comes out of the faucet or comes
(d)(2) into a single paragraph. The supplement, where the water is used in out of a spigot from a holding tank
comment says the two proposed a manner such that the water may where you store water). Thus, you must
paragraphs are redundant. Proposed become a component of the dietary ensure that the water used in a manner
§ 111.15(d)(1) would require that you supplement, final § 111.23(c) (proposed such that the water may become a
provide water that is safe and of § 111.15(d)(3)) requires you to have component of the dietary supplement,
adequate sanitary quality, at suitable documentation and keep records that not the water source before it enters
temperatures, and under pressure as such water meets the requirements of your facility, meets the NPDW
needed, in all areas where water is final § 111.15(e)(2). In contrast, there is regulations, or if not subject to the
necessary for: (1) Manufacturing dietary no corresponding requirement for NPDW regulations, that it meets any
ingredients or dietary supplements; (2) documentation in final § 111.23 that other applicable Federal, State, and
making ice that comes in contact with other water, such as water that is used local requirements and does not
components, dietary ingredients, dietary to clean floors or used in employee contaminate the dietary supplement.
supplements, or contact surfaces; (3) bathrooms, meets requirements of final For example, if the water that enters
cleaning any surface; and (4) employee § 111.15(e)(1). your facility is subject to the
bathrooms and hand-washing facilities. (Comment 93) Several comments Environmental Protection Agency
Proposed § 111.15(d)(2) would require state, if we retain a water standard NPDW regulations, then the water must
that water that contacts components, requirement based on the comply with such requirements at the
dietary ingredients, dietary Environmental Protection Agency point of use, i.e., when it contacts the
supplements, or any contact surface NPDW standard, then it is important to components, dietary supplement, or any
must at a minimum comply with the include provisions recognizing the contact surface (such as when the water
NPDW regulations prescribed by the acceptability of municipal water sources comes out of the faucet or out of a spigot
Environmental Protection Agency under and the frequency of testing required for from a holding tank where you store
40 CFR part 141 and any State and local other water sources. Some comments water). You could rely on a certificate of
government requirements. recommend water should meet the USP analysis under final § 111.75(a)(2)(ii)
from the supplier of the water (e.g., the meets the requirements of final that discharge waste water or sewage
municipality) to ensure that the water § 111.15(e)(2). We also recommend that and piping systems that carry water
entering your facility complies the you requalify your facility at the point used for manufacturing dietary
applicable Federal, State, and local of use at appropriate intervals. supplements, for cleaning contact
requirements. However, you must If you use water from a private source, surfaces, or for use in bathrooms and
ensure that nothing happens to the you must use water that complies with hand-washing facilities.
water that may contaminate the water any State and local requirement and We did not receive comments specific
once it enters your facility and before does not contaminate the dietary to proposed § 111.15(e), other than
the water may become a component of supplement. You may need to perform comments arguing that certain text was
the dietary supplement at the point of appropriate water treatment procedures, unconstitutionally vague and arbitrary
use. Certain contaminants or including filtration, sedimentation, and and capricious. We address those
microorganisms may be introduced into chlorination to satisfy final comments in section V of this
the water from the facility. Thus, you § 111.15(e)(2). document.
may need to establish specifications and (Comment 94) Several comments
would delete proposed § 111.15(d)(2), 7. Final § 111.15(g)
procedures to prevent contamination
arguing that it is unnecessary to state a Final § 111.15(g) (proposed
from pipes through which the water
requirement that water meet the § 111.15(f)) sets forth requirements for
travels in the facility or from vessels in
Environmental Protection Agency’s sewage disposal and requires you to
which the water is held in the facility
NPDW standards. These comments state dispose of sewage into an adequate
prior to use. You may need to test for
that if water is used in processing or at sewage system or through other
certain contaminants, e.g., lead or adequate means.
critical points in the cleaning process,
microorganisms, at point of use to then a manufacturer will already have We did not receive comments specific
ensure there is no contamination of the established specifications for its to proposed § 111.15(f).
water within your facility. Such tests appropriate use.
may not need to include all of the 8. Final § 111.15(h)
(Response) We agree that a
chemical, microbiological, or manufacturer will need to establish Final § 111.15(h) (proposed
contaminant testing already certified by specifications, under final § 111.70(a), § 111.15(g)(1)) sets forth requirements
the supplier to determine whether the for any point, step, or stage in the for the bathrooms of your physical
water entering your facility complies manufacturing process where control is plant. Final § 111.15(h) requires you to
with Federal, State and local necessary to ensure the quality of the provide your employees with adequate,
requirements. Rather, you would need dietary supplement, and for water that readily accessible bathrooms, and that
to evaluate what, if any, introductions of is used in a manner such that the water the bathrooms be kept clean and not be
contaminants are likely to occur within may become a component of the dietary a potential source of contamination to
your facility and determine whether supplement. For reasons set forth in your components, dietary supplements,
additional tests are needed to verify that response to comment 88, final or contact surfaces.
the water, at point of use, will comply § 111.15(e)(2) establishes the minimum (Comment 95) Several comments state
with Federal, State, and local standards for water that will be used in companies should be given flexibility in
requirements and not contaminate the a manner such that the water may designing their bathrooms. These
dietary supplement. Alternatively, you become a component the dietary comments assert the food CGMP
may decide not to rely on a certificate supplement, e.g., when such water requirements allow flexibility in
of analysis and instead conduct your contacts components, dietary bathroom design, so the dietary
own testing at point of use to determine supplements, or any contact surface. supplement CGMP rule should do the
if the water complies with applicable Thus, we disagree that proposed same. The comments would delete
Federal, State, and local requirements. § 111.15(e)(2) be eliminated. proposed § 111.15(g)(1) through (g)(3),
We decline to set out testing which pertained to: (1) Keeping the
requirements or frequency of testing in 6. Final § 111.15(f) bathrooms in good repair at all times; (2)
this final rule in lieu of giving Final § 111.15(f) (proposed providing self-closing doors; and (3)
manufacturers the flexibility to decide §111.15(e)) sets forth requirements for providing doors that do not open into
on the appropriate testing and frequency the plumbing of your physical plant. areas where components, dietary
of such testing to ensure that the water Final § 111.15(f) requires your ingredients, dietary supplements, or
meets the requirements in final plumbing to be of an adequate size and contact surfaces are exposed to airborne
§ 111.15(e)(2). We may consider issuing design and be adequately installed and contamination, except where alternate
guidance, as needed, on our maintained to: (1) Carry sufficient means have been taken to protect
recommendation for testing based on amounts of water to required locations against contamination.
water sources and the purposes for throughout the physical plant; (2) (Response) We agree that it is
which the water is used. If you rely on properly convey sewage and liquid unnecessary to require specific
a certificate of analysis from the disposable waste from your physical bathroom features such as those in
supplier of the water, we recommend plant; (3) avoid being a source of proposed § 111.15(g)(1) through (g)(3)
that you qualify your facility by contamination to components, dietary because you may be able to achieve
conducting appropriate tests at the point supplements, water supplies, or any compliance through other means better
of use to verify that no other tests are contact surface, or creating an suited to your operations. Accordingly,
necessary or that any additional tests unsanitary condition; (4) provide we are revising the rule by deleting
you have chosen are sufficient to adequate floor drainage in all areas proposed § 111.15(g)(1) through (g)(3) as
establish that the water that is used in where floors are subject to flooding-type requested by the comments. However,
a manner such that the water may cleaning or where normal operations we continue to believe that mechanisms
become a component of the dietary release or discharge water or other such as self-closing doors and doors that
supplement, e.g., when such water liquid waste on the floor; and (5) not do not open onto areas where
contacts components, dietary allow backflow from, or cross- components, dietary supplements, or
supplements or any contact surface, connection between, piping systems contact surfaces are exposed to
contamination will help protect against 10. Final § 111.15(j) develop and supervise sanitation
contamination. Final § 111.15(j) (proposed § 111.15(i)) procedures. As we also stated in
sets forth requirements for trash response to comment 76, we
9. Final § 111.15(i)
disposal at your physical plant. Final acknowledge that some supervisory
Final § 111.15(i) (proposed § 111.5(h)) § 111.15(j) requires that you convey, personnel may need a different range of
sets forth requirements for the hand- store, and dispose of trash to: (1) education, training, or experience than
washing facilities of your physical Minimize the development of odors; (2) others. However, we have decided to
plant. Final § 111.15(i) requires you to minimize the potential for trash to give firms the flexibility to decide the
provide hand-washing facilities that are attract, harbor, or become a breeding appropriate amount of education,
designed to ensure that an employee’s place for pests; (3) protect against training, or experience for a given job
hands are not a source of contamination contamination of components, dietary function. If that includes a combination
of components, dietary supplements, or supplements, any contact surface, water of attributes, the firm should select and
any contact surface, by providing supplies, and grounds surrounding your train employees accordingly.
facilities that are adequate, convenient, physical plant; and (4) control
and furnish running water at a suitable E. What Are the Requirements Under
hazardous waste to prevent This Subpart for Written Procedures?
temperature. contamination of components, dietary
Final § 111.15(i) differs from the (Final § 111.16)
supplements, and contact surfaces.
proposal in that the proposal would list (Comment 97) One comment suggests We received many comments that
six specific features of a hand-washing deleting proposed § 111.15(i)(1) recommend written procedures for
facility, such as effective hand-cleaning concerning minimizing the
and sanitizing preparations (proposed various provisions. We address the need
development of odors, because, the for written procedures generally in
§ 111.15(h)(2)), air driers, sanitary towel comment claimed, minimizing odors is
service, or other suitable drying devices section IV of this document. We also
not a ‘‘true’’ CGMP requirement. respond to comments on specific
(proposed § 111.15(h)(3)), and trash bins (Response) We disagree that
that are constructed to protect against provisions in the same section.
minimizing the development of odors is
recontamination (proposed not part of CGMP. Odor from trash is We are adding a new final § 111.16
§ 111.15(h)(4)). often an indication of problems with entitled ‘‘What Are the Requirements
(Comment 96) Several comments state microbial contamination, such as Under This Subpart for Written
we should give firms the flexibility to decomposition, decay, and the growth Procedures?,’’ to require you to establish
design their hand-washing facilities. of harmful bacteria. In addition, odor and follow written procedures for
According to these comments, from trash can attract pests. By fulfilling certain requirements of
substituting the word ‘‘may’’ for the conveying, storing, and disposing of subpart C. You must establish and
word ‘‘must’’ would accomplish this. trash to minimize the development of follow written procedures for cleaning
The comments argue that, as with odors, you will help reduce the the physical plant and for pest control.
bathrooms, an overall sanitation potential for problems with microbial F. What Design and Construction
requirement should be sufficient, and contamination and pests. Requirements Apply to Your Physical
that, as long as there is a strong and
11. Final § 111.15(k) Plant? (Final § 111.20)
enforceable standard, firms should have
the flexibility to adopt only those Final § 111.15(k) (proposed Final § 111.20 addresses physical
measures that are needed to meet the § 111.15(j)) sets forth requirements for plant design and construction
underlying requirement. sanitation supervisors at your physical requirements.
(Response) We agree that it is plant. Final § 111.15(k) requires that you
unnecessary to require specific hand- assign one or more employees to 1. Final § 111.20(a) and (b)
washing mechanisms because you may supervise overall sanitation. Each Final § 111.20(a) and (b) require that
be able to achieve compliance through supervisor must be qualified by any physical plant that you use in the
other means better suited to your education, training, or experience to
manufacturing, packaging, labeling, or
operations. However, we disagree that develop and supervise sanitation
holding of dietary supplements: (1) Be
an overall sanitation requirement would procedures. Final § 111.15(k) differs
be sufficient, because such a suitable in size, construction, and
from proposed § 111.15(j) in that the
requirement would not clearly state the design to facilitate maintenance,
proposal would require that each
purpose of the requirement, which is to cleaning, and sanitizing operations and
supervisor be qualified by training and
ensure that an employee’s hands are not (2) have adequate space for the orderly
experience.
a source of contamination of placement of equipment and holding of
(Comment 98) Several comments
components, dietary supplements, or materials as is necessary for
suggest revising proposed § 111.15(j) to
any contact surface. maintenance, cleaning, and sanitizing
state that sanitation supervisors may be
We are revising proposed § 111.15(h) qualified by education, training, or operations and to prevent
(final § 111.15(i)) in the final rule in two experience (or any combination thereof) contamination and mixups of
respects. First, the final rule states that to develop and supervise sanitation components and dietary supplements
the hand-washing facilities are to be procedures. In contrast, several during manufacturing, packaging,
designed to ensure that an employee’s comments say that sanitation labeling, or holding.
hands are not a source of contamination. supervisors should be qualified by both We did not receive comments specific
Second, final § 111.15(i) states that the training and experience. to proposed § 111.20(a) or (b), other than
hand-washing facilities are to be (Response) Consistent with our comments arguing that certain text in
adequate, convenient, and furnish response to comment 76 in section VII proposed § 111.20(b) was
running water at suitable temperatures of this document, final § 111.15(k) unconstitutionally vague and arbitrary
but does not provide the specific hand- provides that sanitation supervisors, and capricious. We address those
washing mechanisms detailed in the like other supervisors, must be qualified comments in this section and section V
2003 CGMP Proposal. by education, training, or experience to of this document.
2. Final § 111.20(c) that is intended under proposed odors and vapors (including steam and
Final § 111.20(c) requires that any § 111.20(c) when it referred to ‘‘separate noxious fumes) in areas where they may
physical plant you use in the or defined areas’’ of a physical plant. contaminate components, dietary
manufacturing, packaging, labeling, or These comments state that it is unclear supplements, or contact surfaces; (4)
holding of dietary supplements provide if we expect a firm not to manufacture equipment that controls temperature
for the use of proper precautions to multiple products in a single room or and humidity, when such equipment is
reduce the potential for mixups or area. The comments state that, if this is necessary to ensure the quality of the
contamination of components, dietary the case, this would be equivalent to the dietary supplement; and (5) aisles or
supplements, or contact surfaces, with drug CGMP requirements and would be working spaces between equipment and
excessive. The comments argue that, if walls that are adequately unobstructed
microorganisms, chemicals, filth, or
the proper controls are in place, and of adequate width to permit all
other extraneous material.
Under final § 111.20(c) your physical manufacturing and packaging of persons to perform their duties and to
plant must have, and you must use, multiple products is possible in a single protect against contamination of
room or area without compromising components, dietary supplements, or
separate or defined areas of adequate
product identity, quality, strength, contact surfaces with clothing or
size or other control systems, such as
purity, and composition. personal contact.
computerized inventory controls or (Response) Final § 111.20(c) states Final § 111.20(d)(1)(i) through
automated systems of separation, to that you must have and use separate or (d)(1)(v) is similar to proposed
prevent contamination and mixups of defined areas of adequate size or other § 111.20(d)(1), (d)(2), (d)(3), (d)(5), and
components and dietary supplements control systems, such as computerized (d)(6), respectively. Additionally, as
during the following operations: (1) inventory controls or automated systems explained in the following paragraphs,
Receiving, identifying, holding, and of separation. The preamble of the 2003 we have made other changes to
withholding from use, components, CGMP Proposal explained that if your proposed § 111.20(d)(1) (final
dietary supplements, packaging, and physical plant does not allow for § 111.20(d)(1)(i)) and proposed
labels that will be used in or during the physically separate areas, you could § 111.20(d)(5) (final § 111.20(d)(1)(iv)).
manufacturing, packaging, labeling, or develop an alternative approach for (Comment 101) Several comments
holding of dietary supplements; (2) segregating components and dietary argue that the requirement of proposed
separating, as necessary, components, supplements at points when they are § 111.20(d)(1) that floors, walls, and
dietary supplements, packaging, and received, stored, and rejected (68 FR ceilings be made of ‘‘smooth and hard
labels that are to be used in 12157 at 12188). We interpret the surfaces,’’ if read literally, could be
manufacturing from components, comments as asking whether alternative interpreted to prohibit the use of
dietary supplements, packaging, or approaches for segregating products ceilings with drop-in tiles. These
labels that are awaiting material review could be used, even if physically comments assert that, while there may
and disposition decision, reprocessing, separate areas were available in a be areas in a manufacturing plant where
or are awaiting disposal after rejection; facility, so that different materials could drop-in ceilings are inappropriate given
(3) separating the manufacturing, be processed in the same area. Final the height of the ceiling, the nature of
packaging, labeling, and holding of § 111.20(c) allows you to use ‘‘separate the product, or the type of operation
different product types including or defined areas of adequate size or conducted in that area, such ceilings are
different types of dietary supplements other control systems;’’ thus, you can adequate in many areas of a
and other foods, cosmetics, and comply with this requirement by manufacturing facility, and certainly are
pharmaceutical products; (4) performing manufacturing multiple products in the appropriate in places where product is
laboratory analyses and holding same room or area instead of using a labeled or stored. The comments argue
laboratory supplies and samples; (5) physically separate location, as long as that replacing such ceilings with
cleaning and sanitizing contact surfaces; you have systems in place to prevent surfaces that are ‘‘smooth and hard’’ is
(6) packaging and label operations; and contamination and mixups of unnecessary. Several other comments
(7) holding components or dietary components and dietary supplements. argue that they could find no precedent
supplements. in any food CGMP regulations for a
(Comment 99) Several comments 3. Final § 111.20(d) provision specifying ‘‘smooth and hard
would change ‘‘computerized inventory Final § 111.20(d) requires that any surfaces’’ for ceilings, but did identify a
controls’’ to ‘‘adequate inventory physical plant you use in the precedent in the section of drug CGMP
controls’’ in proposed § 111.20(c). The manufacturing, packaging, labeling, or requirements relating to ‘‘aseptic
comments say that a requirement to use holding of dietary supplements be processing.’’ The comments state that
a computerized system is too designed and constructed in a manner adopting such a drug CGMP
prescriptive and that inventory controls that prevents contamination of requirement is inappropriate for dietary
that are not computerized may be components, dietary supplements, or supplements.
equally effective in achieving contact surfaces. The comments say the overall
compliance with proposed § 111.20(c). Final § 111.20(d)(1) requires the purpose of proposed § 111.20(d)(1)
(Response) These comments may have design and construction to include: (1) should be to ensure that facilities can be
misinterpreted proposed § 111.20(c). Floors, walls, and ceilings that can be kept in a clean and sanitary condition.
Computerized inventory controls are an adequately cleaned and kept clean and The comments would revise proposed
example of the type of system that may in good repair; (2) fixtures, ducts, and § 111.20(d)(1) to require physical plants
be appropriate; § 111.20(c) does not pipes that do not contaminate to have surfaces that can be adequately
require you to have a computerized components, dietary supplements, or cleaned, but would give manufacturers
system in the first instance. Thus, final contact surfaces by dripping or other the flexibility to use appropriate
§ 111.20(c) continues to use leakage or condensate; (3) adequate surfaces in different parts of a plant.
computerized inventory controls as an ventilation or environmental control The comments also argue that the
example of a central system. equipment, such as air flow systems, rule’s specificity establishes a
(Comment 100) Several comments ask including filters, fans, and other air- conundrum for certain manufacturers to
us to clarify the degree of separation blowing equipment, that minimize conform to other Federal regulations,
e.g., Occupational Safety and Health unprocessed botanical ingredients or requiring fans and air-blowing
Administration (OSHA) noise levels. animal-derived ingredients, but there is equipment. These comments state this
The comments argue that firms should no proven issue with the powdered type of equipment is not always needed
be allowed to simultaneously conform botanical and animal derived and may, in some instances, be more
to both OSHA and FDA requirements. ingredients used by the dietary likely to cause adulteration than prevent
(Response) We agree that a smooth supplement industry. it. The comments ask us to clarify that
and hard surface may not be necessary Several comments argue against fans and other air-blowing equipment
in every case to prevent contamination requiring temperature and heat controls, are only required when they are
of the dietary supplement. However, asserting that most equipment used to necessary to prevent adulteration.
you may need floors, walls, and ceilings manufacture dietary supplements is (Response) Proposed § 111.20(d)(4)
that are constructed of smooth and hard often cleaned with large amounts of hot was intended to require that any fans
surfaces to prevent contamination of the water, and therefore temperature and and other air-blowing equipment you
dietary supplement when, for example, humidity controls are not practical. use be located and operated in a manner
physical attributes of components (e.g., (Response) We agree that controls for that minimizes the potential for
particle size or electrostatic charge) temperature and humidity should only microorganisms and particulate matter
would make it difficult to keep floors, be required when necessary to ensure to contaminate components, dietary
walls, and ceilings clean. Consequently, the quality of the dietary supplement, supplements, or contact surfaces.
we conclude that a requirement that the and we are revising final § 111.20(d) Nevertheless, given the comments’
physical plant have floors, walls, and accordingly. However, we disagree that misinterpretation, we are revising
ceilings that can be adequately cleaned there is adequate evidence that proposed § 111.20(d)(4) (final
and kept clean and in good repair to temperature and humidity do not § 111.20(d)(2)) to state that, ‘‘When fans
prevent contamination of the dietary stimulate reproduction of and other air-blowing equipment are
supplement is sufficient. We are microorganisms in dietary supplements. used,’’ those fans and equipment must
revising final § 111.20(d)(1) to remove It is well-recognized that be located and operated in a manner
the language concerning smooth and microorganisms such as bacteria will that minimizes the potential for
hard surfaces. The final rule gives you grow in a warm environment and that contamination by microorganisms and
the flexibility to determine how best to microorganisms, such as molds, will particulate matter. This should clarify
construct your facility in order to grow in a moist environment. In that the rule does not mandate the use
prevent contamination and to ensure the addition, if the comments are suggesting of fans and air-blowing equipment.
quality of the dietary supplements you that this final rule should only include (Comment 104) Some comments state
manufacture, package, label, or hold. requirements that derive from specific, that exhaust and venting equipment
Section 111.20(d)(1)(ii) of the final already known examples that the can, under certain circumstances, be a
rule (proposed § 111.20(d)(2)) requires absence of a requirement directly led to source of microbial contamination. The
your physical plant design and a problem with a dietary supplement, comments would revise proposed
construction to have fixtures, ducts, and we disagree. CGMP requirements can § 111.20(d)(4) to read: ‘‘Fans and other
pipes that do not contaminate help prevent products from becoming air-blowing or exhaust and venting
components, dietary supplements, or adulterated during the manufacturing equipment located and operated in a
contact surfaces by dripping or other process, and, in certain cases, manner that minimizes the potential for
leakage, or condensate. Final controlling temperature and humidity microorganisms and particulate matter
§ 111.20(d)(1)(iii) (proposed may be necessary to ensure the quality to contaminate components, dietary
§ 111.20(d)(3)) pertains to adequate of the dietary supplement. ingredients, dietary supplements, or
ventilation or environmental control With respect to the comments stating contact surfaces.’’
equipment. We added ‘‘or other that using hot water to clean equipment (Response) We decline to revise the
leakage’’ to clarify that the requirement makes control of temperature and rule as suggested by these comments as
relates to ‘‘leakage’’ regardless of humidity impractical, we advise that a there is no need to do so. We consider
whether the leakage is in the form of firm unable to control temperature and exhaust equipment and venting
‘‘dripping.’’ humidity in those parts of its facility equipment to be types of fans or air-
(Comment 102) Proposed where control is necessary to ensure the blowing equipment and therefore
§ 111.20(d)(5) would require your quality of the dietary supplement covered by the term ‘‘fans and other air-
physical plant design and construction because it uses hot water to clean blowing equipment.’’
to include equipment that controls equipment would not be in compliance
temperature and humidity. Several with final § 111.20(c). The provision 4. Final § 111.20(e)
comments suggest adding a qualifier to requires that your physical plant have, Final § 111.20(e) (proposed
the temperature and humidity control and that you use, separate and defined § 111.20(e)) requires that any physical
requirements so that controls are only areas of adequate size, or other control plant that you use in the manufacturing,
required as necessary to prevent systems, to prevent contamination packaging, labeling, or holding of
adulteration. The comments state there during operations such as cleaning dietary supplements provide adequate
is adequate evidence that temperature contact surfaces (final § 111.20(c)(5)). light in: (1) All areas where components
and humidity do not stimulate Final § 111.20(d)(2) (proposed or dietary supplements are examined,
reproduction of microorganisms and § 111.20(d)(4)) requires that, when fans processed, or held; (2) all areas where
pests in dietary supplements. The and other air-blowing equipment are contact surfaces are cleaned; and (3)
comments also argue that retesting older used, such fans and equipment be hand-washing areas, dressing and locker
ingredients stored in an uncontrolled located and operated in a manner that rooms, and bathrooms.
environment and subjected to heat, minimizes the potential for We did not receive any comments
cold, and ambient humidity produced microorganisms and particulate matter specific to proposed § 111.20(e).
no evidence of reproduction of to contaminate components, dietary
microorganisms. According to the supplements, or contact surfaces. 5. Final § 111.20(f)
comments, temperature and humidity (Comment 103) Several comments Final § 111.20(f) (proposed
may present issues with raw, interpret proposed § 111.20(d)(4) as § 111.20(f)) requires that any physical
plant you use in the manufacturing, effective means’’ with ‘‘effective’’ before this document. The absence of a
packaging, labeling, or holding of the word protection and ‘‘including provision in drug CGMP requirements
dietary supplements use safety-type consideration of’’ with ‘‘by, for does not preclude us from requiring it
light bulbs, fixtures, skylights, or other example:’’. in this final rule establishing CGMP
glass or glass-like materials when the requirements for dietary supplements
7. Final § 111.20(h)
light bulbs, fixtures, skylights, or other for which we have no pre-approval
glass or glass-like materials are Final § 111.20(h) (proposed scheme for ingredients used in such a
suspended over exposed components or § 111.20(h)) requires that any physical product.
dietary supplements in any step of plant you use in the manufacturing, (Comment 107) Several comments ask
preparation, unless your physical plant packaging, labeling, or holding of us to clarify that, if a municipal water
is otherwise constructed in a manner dietary supplements use adequate supply is used in a facility, the
that will protect against contamination screening or other protection against municipal water report is acceptable
of components or dietary supplements pests, where necessary. documentation of water quality. These
in case of breakage of glass or glass-like (Comment 105) One comment argues comments say that a city’s yearly report
materials. that proposed § 111.20(h) should be of its municipal water quality should be
We did not receive any comments deleted because it is redundant when sufficient documentation, and that
specific to proposed § 111.20(f). On our compared to proposed § 111.15(c) which independent testing should not be
own initiative, we are making clarifying would require you to not allow animals required. Several comments claim that
changes to final § 111.20(f) by: or pests in any area of your physical our officials made statements to this
• Adding ‘‘or glass-like materials’’ plant, except for guard or guide dogs in effect during a public meeting held on
after the word ‘‘glass.’’ Although certain circumstances. May 6, 2003.
proposed § 111.20(f) only specified (Response) We disagree that final The comments also assert that water
glass, its intent was to cover any § 111.20(h) is redundant to proposed quality in a community is typically well
material that could shatter and § 111.15(c) (final § 111.15(d)). Although known due to public notification that is
contaminate components, dietary both paragraphs deal with pests, final required by the Environmental
supplements, or contact surfaces. § 111.20(h) establishes a design Protection Agency or due to other
Therefore, we are adding glass-like requirement (i.e., a specific requirement resources. These comments say that
material to final § 111.20(f) to cover to use adequate screening or other municipal water supplies are also well
fixtures and skylights that use non-glass protection), while final § 111.15(d) sets controlled as a result of Environmental
materials (such as acrylic and forth a sanitation requirement (i.e., to Protection Agency regulations, and that,
polycarbonate materials) but could still not allow animals or pests in your if water quality in a community or
contaminate components, dietary physical plant). Therefore, we are country is suspect, we can move
supplements, or contact surfaces if retaining § 111.20(h) in the final rule. aggressively to enforce the standards.
shattered or broken. The comments argue that, overall, our
Further, we are stating that the G. Under This Subpart, What Records enforcement burden would be less than
requirement applies when the light Must You Make and Keep? (Final requiring every company in the industry
bulbs, fixtures, skylights, or other glass § 111.23) to maintain and produce documentation
or glass-like materials are suspended Final § 111.23(a) requires you to make related to water quality.
over exposed components or dietary and keep records required under this (Response) A yearly municipal report
supplements in any step of preparation. subpart in accordance with subpart P. is a good starting point for documenting
We made this change to prevent the rule Final § 111.23(b) requires that you water meets the requirements of final
from being misinterpreted as requiring make and keep records of the written § 111.15(e), however, such a report
firms to suspend light bulbs, fixtures, procedures for cleaning the physical cannot stand on its own as the only
skylights, or other glass over plant and for pest control. This assurance that the water of the regulated
components or dietary supplements in provision was added to ensure that the body (such as persons subject to this
every step of preparation. written procedures now required under final rule) complies with these
final § 111.16 are maintained as regulations. A municipal water report
6. Final § 111.20(g) required under subpart P. offers reasonable assurance that the
Final § 111.20(g) (proposed Final § 111.23(c)(1) (proposed water entering your plant satisfies the
§ 111.20(g)) requires that any physical § 111.15(d)(3)) requires that you make requirements of the Environmental
plant you use in the manufacturing, and keep records that water, when used Protection Agency’s NPDW regulations.
packaging, labeling, or holding of in a manner such that the water may However, as discussed previously, the
dietary supplements provide effective become a component of the dietary requirement to show that the water that
protection against contamination of supplement, meets the requirements of is used in a manner such that the water
components and dietary supplements in final § 111.15(e)(2). may become a component of the dietary
bulk fermentation vessels. Such (Comment 106) Several comments supplement, e.g., when such water
protection includes: (1) Use of state there is no documentation contacts components, dietary
protective coverings; (2) placement in requirement for water in the food or supplements, or any contact surface,
areas where you can eliminate drug CGMPs. The comments, therefore, meets the requirements of § 111.15(e)(2),
harborages for pests over and around the say there should be not be such a applies to water at the point of use, i.e.,
vessels; (3) placement in areas where requirement in this final rule for dietary after it has passed through your
you can check regularly for pests, pest supplements. plumbing system.
infestation, filth or any other extraneous (Response) To the extent that the If you use a municipal water supply,
materials; and (4) use of skimming comments assert we cannot include you should take steps to ensure that you
equipment. such a requirement for documentation are at all times aware of problems, such
We did not receive comments specific in the dietary supplement CGMP as an acute problem with microbial
to proposed § 111.20(g). We have made because there is no corollary contamination or a long-term problem
nonsubstantive, grammatical changes to requirement in part 110, we have associated with lead pipes that are
the provision by replacing ‘‘by any responded to this issue in section V of present in some parts of the city water
supply, that may not be reflected in the 3. Changes After Considering Comments thus, invite exercise of unbridled
municipal water report. The final rule: discretion and disparate
• Requires you to establish and decisionmaking.
IX. Comments on Requirements Related (Response) As discussed in section V
to Equipment and Utensils (Subpart D) follow written procedures to fulfill the
of this document, we disagree that the
requirements of subpart D, including
A. Organization of Final Subpart D terms are unconstitutionally vague,
written procedures for:
Proposed subpart D contained two need to be defined, may result in
Æ Calibrating instruments and
provisions regarding equipment, discriminatory enforcement, or violate
controls;
utensils, and automatic, mechanical, or Æ Calibrating, inspecting, and the APA. There has been sufficient
electronic equipment. Table 5 of this checking automated, mechanical, usage of these terms in the food industry
document lists the sections in the final and electronic equipment; and to enable manufacturers, and those who
rule and identifies the corresponding Æ Maintaining, cleaning, and enforce the requirements, to
sections in the 2003 CGMP Proposal sanitizing, as necessary, equipment, comprehend and apply such terms.
that form the basis of the final rule. utensils, and other contact surfaces; Agencies are permitted to use qualifying
• Requires you to keep records of the terms to enable them to address a wide
TABLE 5.—DERIVATION OF SECTIONS maintenance, cleaning, and sanitizing of variety of conditions at companies.
IN SUBPART D equipment either in equipment logs or D. What Are the Requirements Under
in batch records; This Subpart for Written Procedures?
Final Rule 2003 CGMP • Requires that quality control (Final § 111.25)
Proposal personnel periodically review records of We received many comments that
calibrations, inspections, or checks of recommend written procedures for
§ 111.25 What are the § 111.25(c)(1)
requirements under § 111.25(e)(1)
automated, mechanical, or electronic various provisions. We address the need
this subpart D for writ- equipment rather than approve such for written procedures generally in
ten procedures? records when they are made; section IV of this document. We also
• Specifies that software for a respond to comments on specific
§ 111.27 What require- § 111.25(a), (b), computer controlled process is included provisions in the same section. We are
ments apply to the (d), and (e) under automated, mechanical, or
equipment and uten- adding final § 111.25 that requires you
electronic equipment; and to establish and follow written
sils that you use? • Clarifies that the requirement to procedures for certain requirements.
§ 111.30 What require- § 111.30 retain backup files of software programs
ments apply to auto- and of data entered into computer E. What Requirements Apply to the
mated, mechanical, or systems is for computer systems that Equipment and Utensils That You Use?
electronic equipment? you use in the manufacture, packaging, (Final § 111.27)
labeling, or holding of dietary Final § 111.27 (proposed § 111.25)
§ 111.35 Under this sub- §§ 111.25(c)(1), supplements. sets forth various requirements for
part D, what records (c)(2), (d),
must you make and and (f), C. General Comments on Proposed equipment and utensils.
keep? § 111.30(b)(2), Subpart D 1. Final § 111.27(a)
(b)(5), and (c)
§ 111.50(c)(4)
(Comment 108) Some comments a. Final § 111.27(a). Final § 111.27(a)
claim one or more proposed (proposed § 111.25(a)(1)) requires you to
requirements are unconstitutionally use equipment and utensils that are of
B. Highlights of Changes to the
vague under the Fifth Amendment and appropriate design, construction, and
Proposed Requirements for Equipment
arbitrary and capricious under workmanship to enable them to be
and Utensils
§ 706(2)(B) of the APA. These proposed suitable for their intended use and to be
1. Revisions requirements include: adequately cleaned and properly
The final rule includes revisions that • § 111.25(a)(1), which would require maintained. In order to correct the
reflect the final rule applies to persons that equipment and utensils be ‘‘of misnumbering of this provision in the
who manufacture, package, label, or appropriate design, construction, and 2003 CGMP Proposal, this general
hold dietary supplements unless subject workmanship to enable them to be requirement has been broken out from
to an exclusion in § 111.1. suitable for their intended use and to be the remaining requirements of final
adequately cleaned and properly § 111.27(a).
2. Revisions Associated With the maintained’’; and Final § 111.27(a)(1)(i) through (a)(1)(v)
Reorganization • § 111.25(a)(2), which would require provide examples of such equipment,
The revisions associated with the you to ‘‘use equipment and utensils of such as equipment used to hold or
reorganization include: appropriate design and construction so convey (§ 111.27(a)(1)(i)), equipment
• Renumbering proposed § 111.25 as that use will not result in the using compressed air or gas
final § 111.27 and correcting the contamination of components, dietary (§ 111.27(a)(1)(iii)), and equipment used
numbering of the sections misnumbered ingredients, or dietary supplements.’’ in automated, mechanical, or electronic
in the 2003 CGMP Proposal; In general, these comments assert the systems (§ 111.27(a)(1)(v)).
• Requiring documentation and proposed sections did not define terms Final § 111.27(a)(1) is similar to
backup files in a separate section for or phrases (such as ‘‘suitable’’ or proposed § 111.25(a)(1) except for two,
recordkeeping requirements; and ‘‘appropriate design’’) in a way that nonsubstantive editorial changes. The
• A nonsubstantive editorial change persons who are subject to the rule can first change replaces ‘‘automatic
to refer to ‘‘automated equipment’’ discern the meaning of the term. These equipment’’ with ‘‘automated
rather than ‘‘automatic equipment.’’ comments also assert the proposed equipment’’ in what is now
Although there is no practical difference sections do not limit enforcement § 111.27(a)(1)(v) (proposed
between these two terms, the term officers’ exercise of their discretion as to § 111.25(a)(1)(5)). Although there is no
‘‘automated’’ is the customary term. what will satisfy the requirements and, practical difference between
‘‘automatic’’ and ‘‘automated,’’ the latter sanitizing agents; and (5) maintained to supplements: (1) Be fitted with an
is the customary term. protect components and dietary indicating thermometer, temperature-
(Comment 109) Some comments argue supplements from being contaminated measuring device, or temperature-
that the proposal’s use of terms such as by any source. recording device that indicates, and
‘‘appropriate design, construction, and We did not receive comments specific records, or allows for recording by hand,
workmanship to enable them to be to proposed § 111.25(a)(3). We have the temperature accurately within the
suitable for their intended use’’ and substituted the phrase ‘‘in which they compartment and (2) have an automated
‘‘adequately cleaned and properly are used’’ for ‘‘of their intended use’’ to device for regulating temperature or an
maintained’’ are unconstitutionally make clear the requirement applies to automated alarm system to indicate a
vague under the Fifth Amendment and equipment actually used in the significant temperature change in a
arbitrary and capricious under the APA. manufacture, packaging, labeling, or manual operation.
(Response) We discuss those holding of dietary supplements. (Comment 112) The preamble to the
comments generally in section V of this d. Final § 111.27(a)(4). Final 2003 CGMP Proposal invited comment
document and, because we disagree that § 111.27(a)(4) (proposed § 111.25(a)(4)) as to whether we should require specific
the final rule violates either the Fifth requires that the equipment and utensils target temperatures for dietary
Amendment of the Constitution or the you use have seams that are smoothly ingredients or dietary supplements held
APA, we have not revised § 111.27(a)(1) bonded or maintained to minimize in freezers or cold storage (68 FR 12157
except for the changes mentioned in the accumulation of dirt, filth, organic at 12190). Several comments assert there
previous paragraphs. material, particles of components or is no need for us to specify storage
b. Final § 111.27(a)(2). Final dietary supplements, or any other temperatures for dietary ingredients or
§ 111.27(a)(2) (proposed § 111.25(a)(2)) extraneous materials or contaminants. dietary supplements. The comments
requires you to use equipment and Final § 111.27(a)(4) is similar to state most dietary supplements and
utensils of appropriate design and proposed § 111.25(a)(4) and is analogous dietary ingredients are shelf stable based
construction so that use will not result to § 110.40(b) which requires that seams on their low water activity control,
in the contamination of components or on food-contact surfaces be smoothly which limits and slows chemical
dietary supplements with: (1) bonded or maintained so as to minimize degradation and microbiological growth.
Lubricants, (2) fuel, (3) coolants, (4) accumulation of food particles, dirt, and Other comments say target temperatures
metal or glass fragments, (5) filth or any organic matter and thus minimize the are not required where freezing is used
other extraneous material, (6) opportunity for growth of only to enhance the milling properties
contaminated water, or (7) any other microorganisms. We have deleted the (fracturing) of dried botanicals and not
contaminants. phrase ‘‘to minimize the opportunity for to prevent microbial contamination.
(Comment 110) Several comments growth of microorganisms’’ as (Response) We have not included any
state we should recognize that unnecessary in this context as the specific target temperature requirements
lubricants are an integral part of the remaining wording of the provision in the final rule. Consequently, firms
encapsulation of gelatin-enrobed encompasses this concept. In should determine for themselves what
products and other dosage forms. These nonsubstantive editorial changes to final temperatures are needed to ensure that
comments state lubricants are not § 111.27(a)(4) we substitute ‘‘particles of the their dietary supplements are not
potential contaminants, and in fact, help components or dietary supplements’’ for adulterated (see final § 111.70 regarding
move gelatin ribbons through ‘‘component or dietary supplement the specifications you must establish).
encapsulating machines. The comments particles’’ to improve clarity, and re- f. Final § 111.27(a)(6). Final
would revise proposed § 111.25(a)(2) to order the list of extraneous materials or § 111.27(a)(6) (proposed § 111.25(a)(6))
read, ‘‘lubricants not intended for contaminants. requires the instruments or controls you
product contact,’’ to clarify the rule’s (Comment 111) Several comments use in the manufacturing, packaging,
intent. argue that proposed § 111.25(a)(4) is labeling, or holding of a dietary
(Response) We decline to revise the overly restrictive by requiring supplement, and instruments or
final rule as suggested by the comments. equipment and utensils to ‘‘have seams controls that you use to measure,
Final § 111.27(a)(2) states that the use of that are smoothly bonded or regulate, or record temperatures, pH, aw,
equipment and utensils must not result maintained’’ to minimize or other conditions, to control or
in the contamination of components or contamination. The comments would prevent the growth of microorganisms
dietary supplements with lubricants. If revise the rule as follows: ‘‘Equipment or other contamination, be accurate and
a lubricant used for encapsulation does and utensils you use must be of proper precise, adequately maintained, and
not result in contamination of the design and maintained to minimize adequate in number for their designated
components or dietary supplements accumulation * * *.’’ uses.
then the encapsulating machine (Response) We disagree that proposed (Comment 113) One comment states
complies with final § 111.27(a)(2). § 111.25(a)(4) (final § 111.27(a)(4)) is that proposed § 111.25(a)(6)(i)’s
c. Final § 111.27(a)(3). Final overly restrictive or that it requires a requirements that instruments and
§ 111.27(a)(3) (proposed § 111.25(a)(3)) particular design. Final § 111.27(a)(4) controls be ‘‘accurate and precise’’ goes
requires all equipment and utensils you requires seams that are smoothly beyond ‘‘typical’’ calibration, and would
use to be: (1) Installed and maintained bonded or maintained to minimize require full validation of all instruments
to facilitate cleaning the equipment, accumulation of dirt and gives firms the and controls. The comment argues that
utensils, and all adjacent spaces; (2) flexibility to use any design they it is unnecessary to require both
corrosion-resistant if the equipment or choose, provided that the seams, by accuracy and precision for all
utensils contact components or dietary design or maintenance, minimize instruments and controls, and would
supplements; (3) made of nontoxic accumulation of contaminants. require precision only when necessary
materials; (4) designed and constructed e. Final § 111.27(a)(5). Final to prevent contamination. The comment
to withstand the environment in which § 111.27(a)(5) (proposed § 111.27(a)(5)) states calibration to ensure accuracy of
they are used, the action of components requires that each freezer, refrigerator, instruments and controls is usually
or dietary supplements, and, if and other cold storage compartment you sufficient to ensure control or
applicable, cleaning compounds and use to hold components or dietary prevention of the growth of
microorganisms or other contaminants now has paragraphs (b) and (b)(1) (Comment 115) Several comments
in most situations. The comment gives through (b)(3). claim requirements relating to
an example where thermometers are Final § 111.27(b)(1) through (b)(3) calibration of instruments and controls
used to monitor temperature in a (proposed § 111.25(b)(1) and (b)(2)) should be limited to those instruments
warehouse where dietary supplements requires you to calibrate before first use, and controls that directly affect the
are stored. and at the frequency specified in writing identity, purity, quality, strength, and
(Response) We disagree that proposed by the manufacturer of the instrument composition of a dietary supplement.
§ 111.27(a)(6) requires full validation of or control, or at routine intervals, or as According to the comments, in most
all equipment and controls. As otherwise necessary to ensure the manufacturing facilities, there are many
discussed in the preamble to the 2003 accuracy and precision of the instruments and controls that do not
CGMP Proposal (68 FR 12157 at 12190), instrument and control. directly affect identity, purity, quality,
accuracy means that the recorded (Comment 114) Several comments strength, and composition, and that
measurements are equal to the (true object to the level of detail regarding the calibrating all instruments and controls
value) of the thing being measured and proposed calibration. Specifically, the could easily become unduly
precision means that individual comments object to requiring that burdensome. The comments also would
measurements should be close to each manufacturers calibrate instruments and limit the requirement for periodic
other when made under the same controls ‘‘as specified in writing by the calibration of instruments and controls
conditions. manufacturer of the instrument and to those instruments and controls
We also disagree that instruments control.’’ The comments say this directly involved in the critical control
need not be precise. An instrument that requirement is more prescriptive than parameters of the process, i.e., those
gives widely varying readings from one drug CGMP requirements. The parameters needed to meet
use to the next cannot ensure product comments acknowledge that following specifications or to ensure identity,
quality over time. The degree of manufacturer specifications is likely to purity, quality, strength, and
accuracy and precision is determined by be part of the calibration procedure, but composition. The comments suggest
the nature of the instrument or control state that firms should have the that critical control parameters would
and the process to which it relates. We flexibility to modify their procedures as have to be established.
have, however, made several (Response) We decline to revise the
necessary. These comments would
nonsubstantive, editorial changes to rule as suggested by the comments. The
couple proposed § 111.25(b) with a
§ 111.27(a)(6) as well as other edits to requirement to calibrate instruments
requirement to establish and follow
conform to changes made throughout and controls is limited to those
written procedures for calibrating
the final rule. These are the instruments and controls that you use in
instruments and controls and redraft
nonsubstantive editorial changes: testing a component or dietary
proposed § 111.25(b) to mirror the drug
• Inserting a hyphen between supplement or in manufacturing a
CGMP requirements, using language
‘‘hydrogen’’ and ‘‘ion’’ and dietary supplement. Any such
• Revising the end of the paragraph such as ‘‘You must routinely calibrate equipment has the potential to affect,
so that it discusses ‘‘instruments and instruments and controls that control or directly or indirectly, the quality of the
controls that you use * * * to control monitor critical parameters that you use dietary supplement.
or prevent the growth of in manufacturing or testing a (Comment 116) Some comments
microorganisms or other contamination component or dietary supplement.’’ would revise proposed § 111.25(b)(1) to
* * *.’’ The proposal stated (Response) We disagree that proposed state that ‘‘calibration should be done,
‘‘instruments and controls that you use § 111.25(b) is overly prescriptive, where standards are available or where
* * * that control or prevent the growth exceeds drug CGMP requirements, or it is necessary to meet product
of microorganisms or other requires what is claimed by the specifications.’’
contamination * * *’’. (In other words, comments. We discuss, generally, the (Response) We decline to revise the
the final rule replaces ‘‘that’’ with ‘‘to’’.) issue of whether this final rule ‘‘exceeds rule as suggested by the comments. It
g. Final § 111.27(a)(7). Final drug CGMPs’’ in section V of this would be customary for an equipment
§ 111.27(a)(7) (proposed § 111.25(a)(7)) document. It is standard practice to manufacturer to have standards that can
requires that the compressed air or other calibrate an instrument before using it be used to calibrate the equipment,
gases you introduce mechanically into for the first time. A requirement that irrespective of the specific composition
or onto a component, dietary you calibrate as specified by the of the dietary supplement that is
supplement, or contact surface or you manufacturer of the equipment, or at manufactured using that equipment.
use to clean any contact surface be routine intervals, or as otherwise Equipment that is not or cannot be
treated in such a way that the necessary to ensure the accuracy and calibrated is unlikely to be in
component, dietary supplement, or precision of the instrument and control, compliance with the requirement of
contact surface is not contaminated. provides ample flexibility. Calibration, final § 111.27(a)(6)(i) which requires
We received no comments specific to whether for instruments and controls instruments used in the manufacturing,
proposed § 111.25(a)(7). used in manufacturing or testing drugs, packaging, labeling, and holding of
devices, conventional foods, or dietary dietary supplements, and instruments
2. Final § 111.27(b) supplements, helps ensure the accuracy and controls that you use to perform
Final § 111.27(b) (proposed and precision of the instrument and certain operations, be accurate and
§ 111.25(b)(1)) requires you to calibrate control. We do not prescribe how precise.
instruments and controls that you use in frequently such calibration must be (Comment 117) Some comments
manufacturing or testing a component done, but it must be done often enough would revise proposed § 111.25 from
or dietary supplement. In order to to ensure that instruments and controls the active voice to the passive voice.
correct the misnumbering of this are operating within the correct These comments claim that the active
provision in the 2003 CGMP Proposal, parameters. We are revising the 2003 voice—i.e., requiring that ‘‘you’’
this general requirement has been CGMP Proposal (at § 111.27(b)(2)) to calibrate instruments and controls—
broken out from the remaining clarify that the requirement relates to requires that the dietary supplement
requirements of final § 111.27(b) and the frequency of calibration. manufacturer perform the calibration,
when in fact such calibrations are often i.e., a process, that is designed to ensure § 111.25(e)(1). Some comments
performed by an outside service. the quality of the dietary supplement. suggested calibrating sanitation
(Response) You may use an outside The final rule gives firms the flexibility operations based on risk. The final rule
service. We would not consider that to use different calibration methods as largely leaves it up to firms to decide
calibration done for you by an outside long as the method used is established whether to sanitize or to just clean
service is any different than calibration in a written procedure. without sanitizing, based on the risks
done by your employees, and it is you associated with the materials and
(rather than an outside service) whom 3. Final § 111.27(c) process used. However, under final
we will hold responsible to ensure that Final § 111.27(c) (proposed § 111.27(d)(3), if you use wet
the calibration is performed. § 111.25(d)) requires that you repair or processing, if you determine that it is
Accordingly, we decline to revise the replace instruments or controls that necessary to clean a contact surface, you
provisions as suggested. cannot be adjusted to agree with the must also sanitize that surface.
(Comment 118) Several comments say reference standard. (Comment 122) Several comments
calibration before first use should not be We received no comments specific to state the final rule should include a
required for certified, precalibrated proposed § 111.25(d). requirement for validating cleaning
instrumentation. The comments state procedures. The comments argue that
4. Final § 111.27(d)
precalibrated instrumentation is much testing requirements for finished dietary
more expensive than noncalibrated Final § 111.27(d) (proposed supplements might not test for certain
instrumentation, with the additional § 111.25(e)) requires you to maintain, contaminants that could arise as a result
expense attributed to the precalibration. clean, and sanitize, as necessary, all of cleaning. One comment asserts these
Several comments would revise equipment, utensils, and any other potential contaminants would be
proposed § 111.25(b)(2) to read, ‘‘you contact surfaces used to manufacture, discovered in a properly designed and
must calibrate, or be able to verify that package, label, or hold components or executed cleaning validation protocol,
the calibration has been completed, dietary supplements. In order to correct and that including these written
before first use,’’ instead of ‘‘you must the misnumbering of this provision in cleaning procedures in the final rule
calibrate before first use.’’ The the 2003 CGMP Proposal, this general would help prevent adulteration and
comments state that performance test requirement has been broken out from help ensure the identity, purity, quality,
results could be made available for this the remaining requirements of final strength, and composition of dietary
verification. § 111.27(d) and now has paragraphs (d) supplements.
(Response) As written, the and (d)(1) through (d)(7). (Response) We decline to require
requirement that equipment be a. Final § 111.27(d)(1). Final specific cleaning validation procedures
calibrated before first use includes § 111.27(d)(1) requires that the in the final rule. Final § 111.27(d) and
calibration performed by a third party as equipment and utensils be taken apart the requirements for written procedures
a precalibration because we would as necessary for thorough maintenance, under final § 111.25(c) are sufficient to
consider that calibration performed by a cleaning, and sanitizing. ensure the use of cleaning procedures to
third party as no different from (Comment 121) Some comments argue ensure the quality of the dietary
calibration performed by one of your that individual manufacturing supplement.
own employees. Under final operations will determine when b. Final § 111.27(d)(2). Final
§ 111.35(b)(3) you must have sanitizing agents are needed after § 111.27(d)(2) (proposed § 111.25(e)(2))
documentation of the calibration. cleaning because of the wide variety of requires you to ensure that all contact
If you purchase a precalibrated processes in the industry. The surfaces, used for manufacturing or
instrument, we strongly recommend comments also say widespread use of holding low-moisture components or
that the vendor conduct the certification sanitizing agents is creating resistant dietary supplements, are in a dry and
onsite after installation. If not, we microbial strains, and incorporating sanitary condition when in use. When
strongly recommend that you verify that unnecessary sanitization processes the surfaces are wet-cleaned, you must
the instrument remains calibrated after would contribute to this health concern. sanitize them, when necessary, and
it has been installed. Some comments recommend allow them to dry thoroughly before you
(Comment 119) Several comments ask manufacturers calibrate sanitizing use them again.
whether the proposed requirement to procedures to the particular process in We received no comments specific to
calibrate ‘‘before first use’’ refers to the a declared fashion depending upon the proposed § 111.25(e)(2). We have
first use after installation or the first use risk factors of their process and substituted the phrase ‘‘when in use’’
after each start-up. materials. The comments set out several for ‘‘at the time of use’’ for clarity.
(Response) Final § 111.27(b)(1) refers standards for sanitation procedures. c. Final § 111.27(d)(3). Final
to the first use after installation and (Response) Final § 111.27(d) requires § 111.27(d)(3) (proposed § 111.25(e)(3))
does not require calibration after each you to maintain, clean, and sanitize, as requires you, if you use wet processing
start-up. necessary, equipment, utensils, and any during manufacturing, to clean and
(Comment 120) Some comments other contact surfaces, used to sanitize all contact surfaces, as
would require that instruments and manufacture, package, label, or hold necessary, to protect against the
controls be calibrated, but argue that the dietary supplements. The final rule thus introduction of microorganisms into
final rule should not include detailed gives you discretion to decide when components or dietary supplements.
procedures specifying calibration sanitizers or sanitizing treatments, such Final § 111.27(d)(3) also requires that:
methods. The comments said the rule as heat, are necessary and does not • When cleaning and sanitizing is
should stay focused on end results and mandate the incorporation of necessary, you clean and sanitize all
not process. unnecessary sanitization processes. contact surfaces before use and after any
(Response) We disagree that the Additionally, under final § 111.27(d) interruption during which the contact
regulations should not focus on process. you have flexibility to determine when surface may become contaminated and
The essence of the CGMP requirements sanitizing is appropriate and to sanitize • If you use contact surfaces in a
established by these regulations is a only as necessary. We note that this continuous production operation or in
production and process control system, flexibility was also present in proposed consecutive operations involving
different batches of the same dietary (such as utensils intended for one-time Additionally, on our own initiative,
supplement, you must adequately clean use, paper cups, and paper towels) be: we have made two editorial,
and sanitize the contact surfaces, as (1) Stored in appropriate containers and nonsubstantive changes to final
necessary. In this provision, we (2) handled, dispensed, used, and § 111.27(d)(6). The final rule now states
substituted ‘‘consecutive’’ for ‘‘back-to- disposed of in a manner that protects that the cleaning compounds and
back,’’ a nonsubstantive change. We also against contamination of components, sanitizing agents must be adequate for
inserted ‘‘adequately’’ to make clear that dietary supplements, or any contact ‘‘their’’ intended use and safe under
cleaning and sanitizing must be surface. ‘‘their conditions’’ of use.
adequate. We received no comments specific to g. Final § 111.27(d)(7). Final
(Comment 123) Several comments proposed § 111.25(e)(5). § 111.27(d)(7) (proposed § 111.25(e)(7))
argue against using the term ‘‘sanitize’’ f. Final § 111.27(d)(6). Final requires you to store cleaned and
in proposed § 111.25(e)(3). The § 111.27(d)(6) (proposed § 111.25(e)(6)) sanitized portable equipment and
comments state that, based on the requires your cleaning compounds and utensils that have contact surfaces in a
proposed definition of ‘‘sanitize,’’ sanitizing agents to be adequate for their location and in a manner that protects
§ 111.25(e)(3) would require evaluation intended use and safe under their them from contamination. We received
of any sanitation steps to ensure that the conditions of use. no comments specific to proposed
level of log reduction is reached, for (Comment 124) One comment would § 111.25(e)(7).
example, by taking ‘‘before and after’’ delete proposed § 111.25(e)(6), stating it
swab samples. The comments would F. Reorganization of Certain Paragraphs
is redundant to proposed § 111.15(b), in Proposed § 111.25
revise proposed § 111.25(e)(3) to state which would require you to use
that equipment, utensils, etc. shall be cleaning compounds and sanitizing Proposed § 111.25 would impose
cleaned and sanitized in a manner that agents that are free from microorganisms certain requirements relating to written
keeps microorganisms and other of public health significance and safe procedures for calibrating instruments
adulterants from contaminating all and adequate under the conditions of and controls (proposed § 111.25(c) and
components, ingredients, in-process use. (d)) and keeping calibration records
materials, and finished goods. (proposed § 111.25(f)). The final rule
(Response) The final rule now defines (Response) We disagree with this
comment. Proposed §§ 111.15(b)(1) and now contains a new recordkeeping
‘‘sanitize’’ as ‘‘to adequately treat section (§ 111.35) that combines
cleaned equipment, containers, utensils, 111.25(e)(6) (now final §§ 111.15(b)(1)
and 111.27(d)(6), respectively) differed elements of proposed § 111.25(c), (d),
or any other cleaned product contact and (f), as well as other sections. We
surface by a process that is effective in in their requirements and their
applicability. Proposed § 111.15(b)(1) discuss comments on proposed
destroying vegetative cells of § 111.25(c), (d), and (f) and describe
microorganisms of public health would apply to cleaning compounds
and sanitizing agents used in the final § 111.35 in this section.
significance, and in substantially
reducing numbers of other physical plant and would require them G. What Requirements Apply to
microorganisms, but without adversely to be ‘‘safe and adequate under the Automated, Mechanical, or Electronic
affecting the product or its safety for the conditions of use.’’ In contrast, Equipment? (Final § 111.30)
consumer.’’ The definition no longer proposed § 111.25(e)(6) would apply to Final § 111.30 sets forth requirements
specifies a level of log reduction, so the cleaning compounds and sanitizing for automated, mechanical, or electronic
revised definition should eliminate the agents used on equipment, utensils, and equipment that you use to manufacture,
comments’ concern as to any possible contact surfaces used to manufacture, package, label, or hold a dietary
need for ‘‘before and after’’ samples. package, or hold components, dietary supplement.
d. Final § 111.27(d)(4). Final ingredients, or dietary supplements, and
§ 111.27(d)(4) (proposed § 111.25(e)(4)) it would require such cleaning 1. Comments on the Organization and
requires you to clean surfaces that do compounds or sanitizing agents to be Framework of Proposed § 111.30
not come into direct contact with ‘‘adequate for intended use and safe (Comment 125) Some comments
components or dietary supplements as under condition [sic] of use.’’ By using would revise proposed § 111.30(a) to
frequently as necessary to protect the phrase ‘‘adequate for intended use,’’ replace ‘‘equipment to manufacture,
against contamination. Final proposed § 111.25(e)(6) would have you package, label, and hold’’ with
§ 111.27(d)(4) relates to final consider whether a particular cleaning ‘‘equipment to manufacture, package,
§ 111.27(d)(2) and (d)(3). For example, compound or sanitizing agent was label, or hold.’’ The comments said that
you would not have to clean your appropriate for the particular use to the same piece of equipment will not
ceilings as often as you clean your which it was being applied. serve to manufacture, package, label,
contact surfaces because your ceilings Furthermore, depending on the and hold components or dietary
normally do not touch components or situation, a cleaning compound or supplements.
dietary supplements. However, you sanitizing agent that is appropriate for (Response) We agree, and have
would have to clean your ceilings as use on a physical plant may be revised § 111.30 accordingly. Final
frequently as necessary to prevent dust inappropriate for use on equipment, § 111.30 also contains the following
or other contaminants from falling onto utensils, and contact surfaces. For changes:
your components, dietary supplements, example, a powdered cleaning • ‘‘Automatic’’ (as in ‘‘automatic
and contact surfaces. compound might be suitable for equipment’’) is replaced with
We received no comments specific to cleaning your physical plant’s floors, ‘‘automated’’ as an editorial,
proposed § 111.25(e)(4). We substituted but inappropriate for cleaning nonsubstantive change;
‘‘do not come into direct contact with’’ equipment that mixes components. In • The phrase ‘‘determine the
for ‘‘do not touch’’ as a nonsubstantive other words, the ‘‘conditions of use’’ can suitability of your equipment’’ has been
editorial revision. also vary between final §§ 111.15(e)(1) revised to read ‘‘determine the
e. Final § 111.27(d)(5). Final and 111.27(d)(6) and lead to different suitability of the equipment * * *’’ in
§ 111.27(d)(5) (proposed § 111.25(e)(5)) conclusions regarding use of the same § 111.30(b) and has no substantive
requires that single-service articles cleaning compound. impact; and
• We have substituted the word inspections, and checks, and proposed proposed §§ 111.25 and 111.30
‘‘met’’ for ‘‘achieved’’ to comply with § 111.30(b)(5) which would require you pertained to equipment, they differed in
‘‘plain language’’ initiatives and to be to make and keep backup files of their focus. Proposed § 111.25 would
consistent with other provisions. software programs and data, are now focus on equipment design,
We describe other changes to incorporated into final § 111.35, and we construction, maintenance, cleaning,
proposed § 111.30 in the following discuss these provisions later in this sanitizing, and calibration. In contrast,
paragraphs. section. proposed § 111.30 would focus on the
(Comment 126) Several comments (Comment 127) Several comments equipment’s operation or suitability
support proposed § 111.30 particularly would limit proposed § 111.30(a) and within your manufacturing process. For
with respect to computers. The (b) to automatic, mechanical, or example, proposed § 111.30(a)(2) would
comments state computers are electronic equipment that actually require you to determine the suitability
susceptible to erroneous data input, are affects product specifications. The of your equipment by ensuring that your
subject to malfunctions and software comments argue that, in a modern equipment is capable of operating
problems, and thus should be regulated manufacturing facility, most, if not all, satisfactorily ‘‘within the operating
under the final rule. equipment used to manufacture, limits required by the process.’’ In
One comment questions why we package, label, or hold any food product contrast, proposed § 111.25 had no
organized proposed § 111.30 into two is automatic, mechanical, or electronic. comparable suitability requirement
paragraphs (a) and (b). The comment The comments say that equipment, such insofar as your manufacturing processes
claims there was no meaningful as forklifts, should not be required to be were concerned. Thus, the proposed
difference between the two paragraphs. designed or selected in a manner that sections are not redundant, and the final
Other comments say some proposed ensures that product specifications are rule retains both § 111.27 (proposed
requirements for automatic, mechanical, met, as would be required in proposed § 111.25) and § 111.30.
and electronic equipment, such as the § 111.30(a)(1), or to be calibrated, as
proposed requirement for maintaining would be required in § 111.30(b)(1). 2. Comments Specific to Proposed
backup files of data entered into (Response) As we stated previously, § 111.30
computer systems, would apply to we have revised § 111.30 so that it a. Final § 111.30(a) and (b). Final
automatic, mechanical, and electronic applies to equipment ‘‘that you use to § 111.30(a) (proposed § 111.30(a)(1))
equipment that are not related to manufacture, package, label, or hold a requires you, for any automated,
CGMPs. The comments argue that dietary supplement.’’ This revision mechanical, or electronic equipment
proposed § 111.30(b) would apply to should prevent the rule from being you use to manufacture, package, label,
computers on which payroll records are interpreted as applying to forklifts or or hold a dietary supplement, to design
maintained, and that such a requirement other equipment that have no bearing on or select the equipment to ensure that
does not belong in these CGMPs. the manufacture, packaging, labeling, or dietary supplement specifications are
(Response) We agree, in part, and holding of dietary supplements. consistently met.
disagree, in part, with the comments. (Comment 128) Several comments Final § 111.30(b) (proposed § 111.30
We agree that computers used in the argue that proposed § 111.30 is (a)(2)) requires you, for any automated,
manufacture, packaging, labeling, or redundant to proposed § 111.25 and mechanical, or electronic equipment
holding of dietary supplements should could be removed without meaningful that you use to manufacture, package,
be, and are, subject to final § 111.30. effect. One comment argues that label, or hold a dietary supplement, to
We disagree, however, with those proposed § 111.30(a) and (b) (i.e., that determine the suitability of the
comments that interpreted proposed all automatic, mechanical, and equipment by ensuring that the
§ 111.30(a) and (b) as being the same or electronic equipment be designed or equipment is capable of operating
interpreted proposed § 111.30 as selected to ensure that product satisfactorily within the operating limits
applying to equipment that has no specifications are consistently achieved required by the process.
direct bearing on dietary supplements. and operate satisfactorily within (Comment 129) Some comments argue
Proposed § 111.30(a) differed from operating limits required by the process) that the requirements of proposed
proposed § 111.30(b) in that paragraph are redundant to proposed § 111.25(a)(1) § 111.30(a) might be impossible to meet
(a) would pertain to the operation and (which would require that all because, in many instances, dietary
suitability of your equipment within equipment be of appropriate design, supplement manufacturers cannot
your manufacturing process. In contrast, construction, and workmanship to predict, at the time of purchase, the
proposed § 111.30(b) would apply to enable them to be suitable for their entire range of ingredients and products
calibration of your equipment and intended use) and proposed for which a particular piece of
controls you establish for your § 111.25(a)(1)(v) (which would state that equipment might be used. The
equipment. ‘‘equipment’’ includes automatic, comments argue that a particular piece
We disagree with those comments mechanical, or electronic systems). The of equipment’s suitability for a
that would interpret proposed comment states that, for equipment to particular ingredient or product must be
§ 111.30(b) as applying to payroll be suitable for its intended use, the evaluated at the time the need arises.
computers or other equipment that has equipment must operate satisfactorily The comments would revise proposed
no CGMP function. To prevent within operating limits and, by § 111.30(a)(1). The words ‘‘Design and
misinterpretations of final § 111.30, we extension, ensure that product select equipment to ensure’’ would be
have revised it to apply to equipment specifications are consistently achieved. replaced with the words ‘‘Use
‘‘that you use to manufacture, package, The comment states the separate equipment that ensures;’’ and proposed
label, or hold a dietary supplement’’ and regulations for automatic equipment in § 111.30(a)(2) would be revised to
renumbered proposed § 111.30(a)(1), the drug CGMPs is less detailed despite replace the words ‘‘is capable of
(a)(2), (b)(1), (b)(3), and (b)(4) as our efforts to present the 2003 CGMP operating’’ with the word, ‘‘operates.’’
§ 111.30(a) through (e), respectively. Proposal in ‘‘simplified language.’’ (Response) We disagree with the
Proposed § 111.30(b)(2) which would (Response) We disagree that proposed comments. Although a company may
require you to make and keep written § 111.30 is redundant to proposed not know the entire range of products
records of equipment calibrations, § 111.25 (final § 111.27). Although both that a machine may be used for,
proposed § 111.30(a)(1) and (a)(2) would § 111.30(b) involves considerations of (Comment 134) Several comments
neither require you to determine all uses how the equipment would be affected urge us to develop a separate guidance
of equipment at the time of purchase by environmental conditions, whether document with respect to determining
nor prevent you from evaluating an old the equipment is appropriate for its the suitability and capability of
machine for a new use (these provisions intended use, and whether the equipment used in the manufacture of
are renumbered as final § 111.30(a) and equipment can be maintained properly dietary supplements.
(b), respectively). Thus, even if you to ensure satisfactory operation. (Response) We believe that firms have
chose to use old equipment for a new (Comment 132) Several comments sufficient experience to determine
use, you still must select that equipment argue that the requirement of proposed whether equipment is suitable and
to ensure that dietary supplement § 111.30(a)(2) to ‘‘determine the capable of performing its intended
specifications are consistently met with suitability of your equipment by function. However, if we find that
the new equipment use and determine ensuring that your equipment is capable guidance will be helpful, we will
the suitability of the new equipment use of operating satisfactorily within the consider whether to issue guidance at a
by ensuring that the equipment is operating limits required by the later date.
capable of operating satisfactorily process’’ is vague and subject to many b. Final § 111.30(c). Final § 111.30(c)
within the operating limits required by interpretations. These comments assert (proposed § 111.30(b)(1)) requires you,
the new process. that this may cause an uneven playing for any automated, mechanical, or
(Comment 130) Several comments field among companies as they apply electronic equipment you use to
express concern that facilities and much differing standards to this requirement. manufacture, package, label, or hold a
equipment in the industry are old and The comments also argue that the dietary supplement, to routinely
lack historical documentation. These vagueness of this requirement could calibrate, inspect, or check the
comments ask us to clarify whether potentially cause uneven enforcement, equipment to ensure proper
manufacturers would have to establish depending on the experience and performance. Final § 111.30(c) also
baseline information for old facilities understanding of individual inspectors. requires quality control personnel to
and equipment. (Response) We disagree that proposed periodically review these calibrations,
(Response) All equipment that you § 111.30(a)(2) (final § 111.30(b)) is vague inspections, or checks.
use, regardless of whether it is old or or may result in uneven enforcement. (Comment 135) Several comments
new, must be capable of doing what you There has been sufficient common usage claim the requirement for the quality
intend it to do. Just as you could of terms such as ‘‘suitable,’’ ‘‘capable,’’ control unit to approve calibrations,
evaluate old equipment for a new use, and ‘‘satisfactorily’’ in the industry to inspections, or checks of equipment is
you can demonstrate that old equipment enable firms, and those who enforce the too prescriptive and that qualified
does, in fact, do what you intend it to requirements, to comprehend and apply persons outside of the quality control
do for uses that you developed before such terms to particular operations. unit should be able to approve these
these CGMP requirements were Agencies may use qualifying terms to calibrations, inspections, or checks. The
established, and thereby comply with enable them to address a wide variety of comments also state the quality control
final § 111.30(a) and (b). conditions, and such terms provide the unit should perform audits of the
(Comment 131) Several comments flexibility needed for various records generated to ensure the
argue that our statement in the preamble operations. appropriate calibrations, inspections, or
to the 2003 CGMP Proposal that (Comment 133) Several comments checks are being adequately performed
‘‘systems need to be installed in a assert that proposed § 111.30(a)(2) is at the required intervals.
manner that takes into account the without justification and overly Other comments refer to related
inherent limitations of the system, prescriptive when compared to requirements in proposed § 111.37(b)(8)
tested under conditions that reflect conventional food CGMPs. that the quality control unit review all
actual conditions of use’’ (68 FR 12157 (Response) As discussed in section V records for equipment calibrations,
at 12193) is vague and subject to of this document, the mere fact that a inspections, or checks. The comments
multiple interpretations. dietary supplement CGMP requirement state the requirements for oversight by
(Response) We disagree with the has no counterpart in the food CGMP the quality control unit in proposed
comment. The statement in question regulations, or has more detail than a § 111.37(b)(8) are excessive and go
should be read in context because the counterpart in such regulations, does beyond requirements for both the drug
preamble to the 2003 CGMP Proposal not mean that it is overly prescriptive. CGMPs and food CGMPs. One comment
described several conditions for Rather, what is important is whether would revise proposed § 111.37(b)(8) to
consideration. The preamble to the 2003 proposed § 111.30(a)(2) (final require a review of all records when
CGMP Proposal stated, in relevant part: § 111.30(b)) is necessary to ensure the there is a negative impact on the dietary
‘‘Some systems may work properly only quality of the dietary supplements. For supplement due to a calibration failure.
within a narrow range of environmental example, the preamble to the 2003 (Response) Final § 111.12(b) requires
conditions, such as temperature and CGMP Proposal (68 FR 12157 at 12193) that you identify who is responsible for
humidity, and some might be discussed how the incorporation of your quality control operations, and
particularly sensitive to electromagnetic software into the operation of automatic each person who is designated to
interference. The actual conditions of equipment has both increased the perform quality control operations must
use of a system should be considered as complexity of such equipment and be qualified to do so and have distinct
early as possible in its design and resulted in a process that may operate and separate responsibilities related to
development. Systems need to be differently for each execution, because a performing such operations from those
installed in a manner that takes into software-based control system can be responsibilities that the person
account the inherent limitations of each configured at will by the operator or by otherwise has when not performing
system, tested under conditions of use, the system itself. Therefore, it is such operations. Thus, you may identify
and properly maintained to ensure that essential that you ensure that automated any person whom you believe is
they continue to function as expected equipment is capable of operating qualified to approve calibrations,
during their lifetime’’ (68 FR 12157 at satisfactorily within the operating limits equipments, or checks to perform
12193.) Thus, suitability under final required by the process. quality control operations.
We disagree that the review by quality complexity, and computerization in types of changes that must be approved
control personnel should be limited to manufacturing equipment (68 FR 12157 and instituted. This shift in emphasis is
circumstances when there has been a at 12194). appropriate given that the final rule
calibration failure. One function of Several comments state that addresses responsibilities of the quality
quality control personnel is to provide computers are susceptible to erroneous control personnel elsewhere.
oversight to prevent problems with the data input and subject to malfunctions d. Final § 111.30(e). Final § 111.30(e)
product that you distribute by finding and software problems and, thus, (proposed § 111.30(b)(4)) requires you,
any problems with the equipment that should be regulated under the final rule. for any automated, mechanical, or
you use to produce the product rather (Response) We agree that computers electronic equipment you use to
than to investigate the cause of a used in the manufacturing processes manufacture, package, label, or hold a
problem with a product that you already should be regulated under the final rule. dietary supplement, to establish and use
distributed. However, we agree that it is As the preamble to the 2003 CGMP appropriate controls to ensure that the
sufficient to periodically review the Proposal stated the incorporation of equipment functions in accordance with
records of calibrations, inspections, or software into the operation of automatic its intended use. Quality control
checks of automated, mechanical, or equipment has increased the complexity personnel must approve these controls.
electronic equipment, for example, on of such equipment and resulted in a We did not receive comments specific
an annual basis, rather than to approve process that may operate differently for to proposed § 111.30(b)(4).
each record when it is made. A periodic each execution, because a software-
based control system can be configured 3. Reorganization of Certain Paragraphs
review can uncover trends in the
at will by the operator or by the system in Proposed § 111.30
performance of the equipment that have
the potential to adversely affect the itself (68 FR 12157 at 12193). As we explained earlier in this
quality of the dietary supplement and Additionally, final § 111.35(b)(5) section, proposed § 111.30 would
that may not be obvious by merely requires you to make and keep backup impose certain requirements relating to
approving each record when it is made. files of software programs and data to written records of equipment
Seeing such trends would enable quality keep them secure from alterations, calibrations, inspections, or checks
control personnel to recommend inadvertent erasures, or loss. The issue (proposed § 111.30(b)(2)) and making
corrective actions. This periodic review in the preamble to the 2003 CGMP and keeping backup files of software
is consistent with proposed Proposal, however, was whether programs and data (proposed
§ 111.37(b)(8) which would require the computerized systems should be § 111.30(b)(5)). The final rule now
quality control unit to ‘‘review’’ all regulated separately from other contains a new recordkeeping section,
records for equipment calibration, equipment; in the absence of comments final § 111.35, that combines elements
inspections, or checks rather than supporting separate treatment for of proposed § 111.30(b)(2) and (b)(5), as
‘‘approve’’ these records. Therefore, we computerized systems, we have well as other sections.
have revised the requirement that the included computerized systems as Additionally, proposed § 111.30(c)
quality control unit approve ‘‘equipment’’ in final § 111.30(d). would require you to keep records in
calibrations, inspections, or checks of We are, however, revising final accordance with the written procedure
automatic, mechanical or electronic § 111.30(d) in the following manner: and recordkeeping requirements in
equipment so that final § 111.30(c) • We are inserting the words ‘‘for proposed § 111.125. Section 111.35 of
requires that quality control personnel automated, mechanical, and electronic the final rule now incorporates
periodically review such operations equipment (including software for a proposed § 111.30(c) as well. We
rather than approve them when they are computer controlled process)’’ after discuss final § 111.35 in the following
made. ‘‘Establish and use appropriate paragraphs.
Additionally, we have made a minor controls.’’ This change simply reiterates
change to § 111.30(c). The change the types of equipment for which H. Under This Subpart, What Records
inserts the words ‘‘the equipment’’ after appropriate controls must be established Must You Make and Keep? (Final
‘‘Routinely calibrate, inspect, or check and used, and makes it clear that § 111.35)
* * *.’’ This insertion simply reiterates software is included under the rule and Final § 111.35 describes the
that ‘‘the equipment’’ must be routinely • We are rephrasing the purpose of recordkeeping requirements. It
calibrated, inspected, or checked. § 111.30(d). The proposal stated that represents a combination of proposed
c. Final § 111.30(d). Final § 111.30(d) you must establish and use appropriate §§ 111.25(c)(1) through (c)(2), (d)(1)
(proposed § 111.30(b)(3)) requires you, controls ‘‘to ensure that your quality through (d)(7), and (f); 111.30(b)(2),
for any automated, mechanical, or control unit approves changes in the (b)(5), and (c); and 111.50(c)(4).
electronic equipment you use to master manufacturing record batch
manufacture, package, label, or hold a control records, packaging operations, 1. Final § 111.35(a)
dietary supplement, to establish and use and label operations, or changes to other Final § 111.35(a) states that you must
appropriate controls for the equipment operations related to the equipment that make and keep records required under
(including software for a computer- you use and that only authorized subpart D in accordance with subpart P.
controlled process) to ensure that any personnel institute the changes.’’ The Subpart P deals with records and
changes to the manufacturing, final rule states that you must establish recordkeeping.
packaging, labeling, holding, or other and use appropriate controls for your Final § 111.35(a) is broader than
operations are approved by quality equipment ‘‘to ensure that any changes proposed § 111.25(f), which stated that
control personnel and instituted only by to the manufacturing, packaging, you ‘‘must keep calibration records as
authorized personnel. labeling, holding, or other operations required by this section in accordance
(Comment 136) The preamble to the are approved by quality control with’’ the 2003 CGMP Proposal’s
2003 CGMP Proposal invited comment personnel and instituted only by recordkeeping section, and compared to
on whether we should regulate authorized personnel.’’ proposed § 111.30(c), which stated that
computerized systems separately from As revised, final § 111.30(d) shifts its you must keep ‘‘automatic, mechanical,
other automatic equipment, given the emphasis from the person(s) who must or electronic equipment records
broad range in sophistication, approve or institute the changes to the required by this section in accordance
with’’ the 2003 CGMP Proposal’s Final § 111.35(b)(2) (proposed approach will be awkward for some
recordkeeping section. However, final § 111.50(c)(4)) requires you to make and companies to comply with and would
§ 111.35(a) has the same effect as keep documentation, in individual not result in collection of information in
proposed §§ 111.25(f) and 111.30(c). equipment logs, of the date of the use, a logical order or location where it can
We did not receive any substantive maintenance, cleaning, and sanitizing of be easily referenced and reviewed, such
comments on proposed §§ 111.25(f) or equipment, unless such documentation as on the production floor, or to provide
111.30(c). is kept with the batch record. data for trend analysis. The comments
(Comment 137) Proposed also contend requiring all information to
2. Final 111.35(b)(1) and (b)(2)
§ 111.50(c)(4) would require that the be maintained in the batch record will
Final § 111.35(b) combines the batch record include the date and time be difficult in practice and place an
various recordkeeping requirements that of the maintenance, cleaning, and enormous burden on companies.
were in proposed §§ 111.25(c) (written sanitizing of the equipment and (Response) We agree that
procedures for calibrating instruments processing lines used in producing the documenting the cleaning, sanitizing,
and controls and documentation that batch. The preamble to the 2003 CGMP and maintenance of equipment is
those procedures were followed and Proposal also invited comment on important. However, we have revised
that the calibration was performed), whether the person performing the the provision so that these records need
111.25(d) (written procedures or maintenance, cleaning, and sanitizing of not be part of the batch record. Instead,
documentation for calibration, such as portable equipment and utensils should final § 111.35(b)(2) requires you to make
the instrument or control calibrated and document at the time of performance and keep documentation of the date of
the calibration date), 111.30(b)(2) and the maintenance, cleaning, and use, maintenance, cleaning, and
(b)(5) (written records of equipment sanitizing (68 FR 12157 at 121928). sanitizing of equipment in individual
calibrations, inspections, or checks, and Several comments argue that the final equipment logs, unless such
backup files of software and data, rule should require documentation at documentation is kept with the batch
respectively), and 111.50(b)(4) the time of performance of equipment, record. By ‘‘equipment log,’’ we mean a
(inclusion of date and time of utensil, and contact surface written record that includes information
maintenance, cleaning, and sanitizing of maintenance, cleaning, and sanitation about the history of a piece of
equipment and processing lines in the and should also require this equipment. This history includes items
batch record). documentation to be kept as records. such as date of installation, routine
Specifically, final § 111.35(b)(1) states The comments explain that such maintenance, repairs, and cleaning.
that you must make and keep records of recordkeeping is common practice in Additionally, final § 111.260 requires
‘‘written procedures for fulfilling the the industry, is an important part of you to identify the equipment and
requirements of this subpart,’’ including batch history, and omitting such a processing lines used in producing the
written procedures for: requirement would diminish the batch and either provide a cross-
• Calibrating instruments and industry standard. In addition, the reference that will make it possible to
controls that you use in manufacturing comments state that written records are find the applicable equipment log as
or testing a component or dietary an effective way to ensure that there is needed or include documentation that
supplement. This paragraph is similar to consistency in how employees are equipment was cleaned, sanitized, or
proposed § 111.25(c). Although we did trained and to assess compliance. maintained (we discuss final § 111.260
not receive any substantive comment on Several comments agree that in section XIV of this document). For
proposed § 111.25(c), we are rephrasing equipment maintenance, cleaning, and example, you may keep records
the paragraph due to its reorganization sanitizing records should be kept and documenting that you cleaned
as part of final § 111.35. Additionally, state that this information should be containers you will use for holding a
although proposed § 111.25(c) would kept with individual pieces of finished batch either in records
require you to document that the equipment, rather than in the batch associated with the equipment you use
written procedures for calibration were record as proposed § 111.50(c)(4) would for cleaning, or with the applicable
followed each time a calibration is require. The comments say it is easier batch record, depending on what is
performed, we are moving the and more efficient for some companies most convenient and practical for your
documentation requirement to final to maintain equipment logs that can be operations.
§ 111.35(b)(3) which we discuss later in referenced when necessary. (Comment 138) Several comments
this section. Other comments say manufacturers state documenting the cleaning of
• Calibrating, inspecting, and should have flexibility to design a contact surfaces would be unnecessarily
checking automated, mechanical, and recordkeeping program suited to their labor-intensive because the term is so
electronic equipment. This paragraph is operations, and should have the option broadly defined. Other comments argue
similar to proposed § 111.30(b)(2), of using an equipment log as it provides that documenting the cleaning of
although we are rephrasing the an efficient way to document, trace, and utensils is unnecessary and
paragraph due to its reorganization as review equipment use, maintenance, inappropriate. These comments support
part of final § 111.35. cleaning, and sanitization of equipment. requiring documentation for the
• Maintaining, cleaning, and According to these comments, because cleaning of large equipment, but claim
sanitizing, as necessary, all equipment, the 2003 CGMP Proposal would require that requiring manufacturers to
utensils, and any other contact surfaces batch production records to identify all uniquely identify each spoon, spatula,
that are used to manufacture, package, equipment used during production, this container, and hose (or other general
label, or hold components or dietary will allow for cross-referencing with the cleaning) in order to document each
supplements. This paragraph relates to equipment log, should the need occur. cleaning would be inappropriate and
final § 111.25(c) which requires you to The comments argue that the proposed create an enormous burden on the
establish and follow written procedures manufacturer. According to these

for such activities. 8Although the preamble to the 2003 CGMP
comments, such a requirement would
We did not receive any comments Proposal discussed this issue in relation to slow and complicate the cleaning
proposed § 111.25 (‘‘What Requirements Apply to
specific to proposed §§ 111.25(c) or the Equipment and Utensils You Use?’’), the same process, making proper cleaning more
111.30(b)(2). principle applies to proposed § 111.50(c)(4). cumbersome. The comments assert that
contamination from these sources has calibration requirements would not be and those guidances offered advice on
not caused any recalls and is not needed if the final rule included various drug CGMP issues. With respect
justified. requirements to establish and follow to calibration, for example, the
(Response) We disagree with these written procedures. December 1997 edition dealt with the
comments. The final rule requires you (Response) The information required question of whether the drug CGMP
to document the work that was done, under final § 111.35(b)(3) (proposed regulations require equipment to be
but gives you the flexibility to decide § 111.25(d)) is the minimum amount labeled with calibration dates. The
how to document that work was done. necessary to provide sufficient guidance identified various regulations
For contact surfaces such as containers information concerning equipment that would be applicable and also said
you use to hold a finished batch, you calibration. For example, some firms that: ‘‘During an inspection a firm
could, for example, record the cleaning may have more than one machine to should be able to document when a
either on a single line that you provide perform a given function; in those specific piece of equipment was last
in your batch record, or as a line entry situations, documentation that calibrated/maintained, the results or
in the log of the equipment that you use identified the exact machine that was action, and when its next calibration/
to clean the containers, or in some other calibrated would distinguish it from maintenance is scheduled. The absence
way that suits your needs. These are not other, seemingly identical, but of such documentation is a CGMP
labor-intensive requirements. noncalibrated machines. Likewise, if the deviation’’ (see CDER, ‘‘Human Drug
It is important that you have maintenance instructions for a machine CGMP Notes,’’ December 1997, at page
procedures in place to know that small called for calibration checks every 3 (Ref. 29)).
items, such as spatulas, are clean when month, documenting the date of This advice is comparable, in several
you use them. For example, if you have calibration would show you whether respects, to the information required by
a log where you designate equipment calibrations were done on schedule. As final § 111.35(b)(3). For example, it
that has been cleaned, your batch record another example, if a machine required refers to a ‘‘specific piece of
could simply have a place to check that calibration according to a particular equipment,’’ which is similar to final
you used equipment designated as standard, identifying the reference § 111.35(b)(3)(i)’s requirement to
clean. standard would help verify that the identify the instrument or control
3. Final § 111.35(b)(3) calibration was done correctly. calibrated. It refers to the time when
Thus, we disagree with those calibration occurred; this is similar to
Final § 111.35(b)(3) (proposed comments claiming that proposed final § 111.35(b)(3)(ii)’s requirement to
§ 111.25(d)(1) through (d)(7)) requires § 111.25(d) was too prescriptive. If, for provide the calibration date. Although
you to make and keep documentation of example, the final rule simply directed public distribution of ‘‘Human Drug
any calibration, each time the you to document calibration, without CGMP Notes’’ ended in 2003, and the
calibration is performed, for instruments specifying what information should be document was circulated only within
and controls that you use in contained in that documentation, then FDA from 2001 to 2003 (but was
manufacturing or testing a component the resulting documentation could have available through FOIA), the guidances
or dietary supplement. In the little or no value. For example, assume offered the drug industry advice on
documentation you must: (1) Identify that you have two identical pieces of complying with the drug CGMPs, and
the instrument or control calibrated; (2) equipment, but only one had been we have retained the guidances on our
provide the calibration date; (3) identify calibrated. If the documentation simply Internet site. In other words, the drug
the reference standard used, including said, ‘‘machine was calibrated,’’ you CGMP regulations did not have to be as
the certification of accuracy of the would not know which machine had ‘‘prescriptive’’ because the drug
known reference standard and a history been calibrated. As another example, if industry learned about our
of recertification of accuracy; (4) you had a machine that had to be interpretations or expectations of the
identify the calibration method used, recalibrated every year, and the drug CGMPs through guidance.
including appropriate limits for documentation merely said, Here, in contrast, there is no
accuracy and precision of instruments ‘‘recalibration completed,’’ you would comparable history of issuing periodic
and controls when calibrating; (5) not know whether the machine had guidance to inform the dietary
provide the calibration reading or been recalibrated yesterday, last month, supplement industry about specific
readings found; (6) identify the last year, or 4 years ago. CGMP issues.
recalibration method used, and reading With respect to the argument that Yet, even if final § 111.35 is more
or readings found, if accuracy or proposed § 111.25(d) should be revised ‘‘prescriptive’’ than the drug CGMPs,
precision or both accuracy and to resemble the drug CGMPs, we that difference does not mean that we
precision limits for instruments and disagree. We recognize that the drug must revise the rule to ‘‘mirror’’ the
controls were not met; and (7) include CGMPs are less detailed with respect to drug CGMPs. The dietary supplement
the initials of the person who performed documentation; for example, 21 CFR industry is more diverse compared to
the calibration and any recalibration. 211.68(a), ‘‘Automatic, mechanical, and the drug industry, and so, at least with
(Comment 139) Some comments electronic equipment,’’ simply states, in respect to documenting calibration,
support proposed § 111.25(d). However, relevant part, ‘‘If such equipment is so more—rather than less—detail is
other comments argue that the used, it shall be routinely calibrated, appropriate.
documentation requirements are unduly inspected, or checked according to a We do note, however, that final
prescriptive. Some comments would written program designed to assure § 111.35(b)(3) differs from proposed
revise proposed § 111.25(d) to more proper performance’’ and ‘‘Written § 111.25(d) in the following respects:
closely mirror the requirements in drug records of those calibration checks and • § 111.25(d) would require you to
CGMPs. Some comments suggest the inspections shall be maintained.’’ identify specific calibration-related
requirement to maintain written records However, the comments overlook the information ‘‘in any written procedure
of calibrations should simply state ‘‘You fact that, from 1993 to 2003, the Center or at the time of performance,’’ final
must maintain written records of for Drug Evaluation and Research § 111.35(b)(3) requires documentation
calibrations according to Sec. 111.125.’’ (CDER) issued periodic guidance, in the ‘‘each time the calibration is
Other comments suggest detailed form of ‘‘Human Drug CGMP Notes,’’ performed.’’ Final section 111.35(b)(1)
requires you to have records of the ‘‘you’’ can refer to someone with whom manufacture, package, label, or hold
written procedures for calibrating you contract, but you are responsible for dietary supplements.
instruments and controls, but does not ensuring that the calibration (Comment 142) Several comments
specify the contents of such written requirements are met, and to have argue that many software programs are
procedures; documentation of the calibration, even in a near constant state of revision and
• § 111.25(d) would refer to though the steps may be performed that it is not a common business
‘‘instruments and controls.’’ Final offsite. practice for a firm in any industry to
§ 111.35(b)(3) now refers to maintain records of outdated software
‘‘instruments and controls that you use 4. Final § 111.35(b)(4) programs, at least if the firm is still able
in manufacturing or testing a Final § 111.35(b)(4) (proposed to use a revised program to access data
component or dietary supplement.’’ § 111.30(b)(2)) requires you to make and it entered using an outdated program.
This change clarifies the instruments keep written records of calibrations, The comments assert that, although the
and controls that are subject to final inspections, and checks of automated, drug CGMPs require the maintenance of
§ 111.35(b)(3) and is consistent with mechanical, and electronic equipment certain backup files of data entered into
final § 111.27(b), which requires you to that is used to manufacture, package, computer systems, they do not require
calibrate instruments and controls; label, or hold a dietary supplement. the maintenance of backup files of
• The type of information that must We did not receive comments specific software programs.
be documented under § 111.35(b)(3)(i) to proposed § 111.30(b)(2). We have (Response) Keeping backup copies of
through (b)(3)(vii) is essentially made nonsubstantive editorial changes software helps ensure that data can be
identical to that in proposed to the rule. For example, proposed retrieved if the primary software
§ 111.25(d)(1) through (d)(7), but we § 111.30(b)(2) would require you to develops a problem. When we use the
revised the sentence structure due to the ‘‘make and keep’’ written records; final term ‘‘backup,’’ we mean a second copy
manner in which we reorganized final § 111.35(b)(4) omits the words ‘‘ make of the software in question rather than
§ 111.35; and keep’’ because that requirement a copy of previous versions of the
• § 111.25(d)(6) would have you software that are outdated, provided
appears earlier in § 111.35.
identify the recalibration method used. that data can be retrieved. However, if
Final § 111.35(b)(3)(vi) requires you to 5. Final § 111.35(b)(5) the data collected using outdated
identify the recalibration method used software cannot be retrieved by the
Final § 111.35(b)(5) (proposed
‘‘and reading or readings found.’’ The newer software, there would still be a
§ 111.30(b)(5)) requires you to make and
addition of ‘‘reading or readings found’’ need to maintain a primary copy and a
keep backup file(s) of current software
is consistent with the remainder of backup copy of the outdated software
proposed § 111.25(d)(6) (final programs (and of outdated software that
is necessary to retrieve records that you used to collect or manage the data.
§ 111.35(b)(3)(vi)) which is a We have narrowed the requirement to
simplification of the phrase ‘‘accuracy are required to keep in accordance with
retain backup files of software to current
or precision or both accuracy and subpart P, when current software is not
software and of outdated software that
precision limits for instruments and able to retrieve such records) and of data
is necessary to retrieve records that you
controls were not met.’’ One would only entered into computer systems that you
are required to keep in accordance with
know that limits were not met based on use to manufacture, package, label, or
subpart P, when current software is not
a reading or readings; and hold dietary supplements. Under final
able to retrieve such records.
• § 111.25(d)(7) would require the § 111.35(b)(5)(i), your backup file (e.g., a (Comment 143) Some comments
initials of the person who performed the hard copy of data you have entered, claim that, although the drug CGMPs
calibration. Final § 111.35(b)(3)(vii) diskettes, tapes, microfilm, or compact require the maintenance of certain
requires the initials of the person who disks) must be an exact and complete backup files of data entered into
performed the calibration and any record of the data you entered. Under computer systems, they do not require
recalibration. Arguably, recalibration is final § 111.35(b)(5)(ii), you must keep the maintenance of backup files of
a type of calibration, but we have added your backup software programs and data software programs. Several comments
‘‘any recalibration’’ to final secure from alterations, inadvertent also assert that it is not always possible
§ 111.35(b)(3)(vii) to ensure that erasures, or loss. to keep backup files of the software
recalibrations are included in the rule. (Comment 141) Several comments programs used in certain pieces of
(Comment 140) Several comments would limit the requirement for equipment, because the equipment
would revise proposed § 111.25(d) to maintaining backup files of data entered manufacturer may be the only one
read, ‘‘The following must be identified into computer systems to those data having access to the programming of its
* * *’’, rather than ‘‘you must entered into computer systems that are equipment. The comments would delete
identify.’’ The comments explain that relied upon for compliance with the words ‘‘software programs and’’
calibrations and recalibrations are often CGMPs. These comments argue that the from proposed § 111.30(b)(5).
performed by the equipment paragraph, as written, calls for a firm to (Response) In most cases, we
manufacturer, vendor, or other outside make and keep backup files of data anticipate that firms will have access to
service, rather than by the dietary entered into computers on which backup copies of their software
supplement manufacturer. The personnel payroll records are programs. We acknowledge that in rare
comments argue that the proposal maintained, and state that no such instances, backup copies may not be
requires that the calibration or requirement should be imposed. available and in these situations, we
recalibration must be performed onsite Therefore, these comments would will take that into account in reviewing
(i.e., at the plant manufacturing the replace the words ‘‘your computer compliance with this provision. We
dietary ingredient or supplement) when system’’ with the words ‘‘any of your decline to revise the provision as
in fact many calibrations can, or even computer systems that are relied upon suggested.
must, be performed offsite. for compliance with this part.’’
(Response) We decline to revise the (Response) We have modified the 6. Final § 111.35(b)(6)
paragraph as requested. As we discuss provision to clarify that the requirement Final § 111.35(b)(6) states that you
in section VI of this document, the term is for computer systems that you use to must make and keep ‘‘documentation of
the controls that you use to ensure that Several comments argue that request for comments as a suggestion
equipment functions in accordance with proposed § 111.30(a)(1) and (a)(2) have that we were considering such formal
its intended use.’’ the effect of establishing unnecessarily validation requirements. At this time,
The preamble to the 2003 CGMP formal, stringent, and expensive we are not requiring formal process
Proposal stated that we were not validation requirements on equipment validation for equipment. However, we
proposing verification requirements for design, selection, and capability. The will monitor the development of
automatic, mechanical, or electronic comment states that this language systems that evolve within this diverse
equipment (68 FR 12157 at 12194). represents a de facto ‘‘IQ/OQ/PQ’’ industry.
However, we invited comment on (installation qualification/operational
We disagree that proposed
whether the final rule should require qualification/performance qualification)
such verification (id.). Verification § 111.30(a)(1) and (a)(2) would have the
requirement. According to these
would ensure that the processes using effect of establishing unnecessarily
comments, emphasis should instead be
automatic, mechanical, and electronic formal, stringent, and expensive
directed to actual use and operation.
equipment consistently produce an In contrast, several comments argue validation requirements on equipment
outcome that meets a predetermined we should require manufacturers to design, selection, and capability, and
specification and any predetermined develop and maintain data that that the language would represent a de
quality characteristics. Verification demonstrate that equipment is suitable facto ‘‘IQ/OQ/PQ’’ requirement for
would show whether your automatic, and that the production process equipment. Final § 111.30(e) requires
mechanical, or electronic processes will consistently delivers expected results. you to ensure equipment operates in
consistently operate as they should. The comments argue that one key CGMP accordance with its intended use. We
(Comment 144) Several comments element is the requirement for systems agree with the comments that argued
argue against including equipment to operate consistently and to produce that data demonstrating that equipment
verification requirements. The an outcome that meets a predetermined is suitable, and that the production
comments argue that the verification specification. According to these process consistently delivers expected
discussion in the preamble to the 2003 comments, demonstration of system results, are a key element of CGMP.
CGMP Proposal is difficult to capability is best achieved through Therefore, final § 111.35(b)(6) requires
distinguish from drug validation. The systems verification. The comments you to make and keep documentation of
comments argue that validation should explain that, in an industry where the the controls that you use to ensure that
be allowed to evolve in the dietary complexity of finished products often the equipment functions in accordance
supplement industry as it evolved in precludes finished product testing, the with its intended use. Examples of such
drug CGMPs. According to these capability of the systems employed is of controls include temperature settings,
comments, the dietary supplement paramount importance. The comments fill rates, and blending times that must
industry, being largely self regulated in state if the processes used fail to be set, checked, and adjusted as
CGMPs to date and not generally produce a product meeting necessary.
practicing verification, would be more predetermined specifications and
readily adaptable to, and better quality characteristics, then the product X. Comments on Requirement to
controlled by, strict operating controls should not be sold. The comments add Establish a Production and Process
and quality control checks including that, although verification imposes Control System (Final Subpart E)
sufficient input and output checks on additional costs on manufacturers, A. Reorganization of Proposed § 111.35
computer operated systems, than having frequently rejected product, adequate Into Final Subpart E
to digest the concept of verification and rework procedures, and extensive in-
implement verification processes. The process and finished product testing In the 2003 CGMP Proposal, the
comments state that, in the future, also would be costly. requirements for a production and
verification may be a means of offsetting Several comments also claim the use process control system were set forth in
some of the extensive testing of finished of an appropriate verification system § 111.35. As shown in table 6 of this
products. may, under certain circumstances, allow document, we are reorganizing
Other comments state we should not for lot testing as opposed to batch proposed § 111.35 into subpart E. Table
require verification of processes that use testing. These comments state that, with 6 lists the sections in final subpart E and
automatic, mechanical, or electronic process verification and an appropriate identifies the sections in the 2003
equipment given the different processes testing scheme, a manufacturer could CGMP Proposal that form the basis of
that dietary supplement manufacturers demonstrate that lot testing provides the final rule.
use. The comments argue that although sufficient assurance of quality and lack
dietary supplement manufacturers, of adulteration. The comments ask us to TABLE 6.—DERIVATION OF SECTIONS
depending on the unique circumstances address these alternatives in the final IN FINAL SUBPART E
of a particular manufacturing process, rule. Many comments said written
may choose to verify processes using a records of verification should be 2003 CGMP
sound verification system, we should maintained. The comments offer several Final Rule Proposal
not require verification. suggestions on how this could be
Several comments ask us to clarify accomplished, including using § 111.55 What are the § 111.35(a)
whether we intended to require full statistical process control techniques or requirements to imple-
validation of equipment used to process other appropriate statistical tools. ment a production and
dietary supplements because terms such (Response) We used the term process control sys-
as ‘‘suitability’’ and ‘‘capable,’’ which ‘‘verification’’ rather than ‘‘validation’’ tem?
we used in proposed § 111.30(a)(1) and to signal that we did not expect that a
§ 111.60 What are the § 111.35(b)
(a)(2), might be interpreted to require final rule would include requirements design requirements
validation. These comments state for formal process validation for the production and
validation is unnecessary and overly requirements, such as an IQ/OQ/PQ process control sys-
burdensome for equipment used in requirement, for equipment. Regardless, tem?
manufacturing dietary supplements. several comments interpreted our
TABLE 6.—DERIVATION OF SECTIONS comments assert the 2003 CGMP should be permitted for finished batches
IN FINAL SUBPART E—Continued Proposal does not encourage rather than the proposed requirement
development of such specifications. for testing every batch for every
2003 CGMP Several comments assert that a more specification.
Final Rule appropriate balance is needed between Many comments note that section
Proposal
an effective process control system and 402(g)(2) of the act directs us to develop
§ 111.65 What are the § 111.35(c) a reasonable testing scheme that is dietary supplement CGMP requirements
requirements for qual- calculated to confirm the quality of that are modeled after the CGMP
ity control operations?
dietary supplements, and that it is regulations for food. These comments
§ 111.70 What specifica- § 111.35(e), (f), important to provide companies with point out that, because the food CGMPs
tions must you estab- (g), and (k) more flexibility in developing a specific allow the use of a verified certificate of
lish? CGMP program that satisfies the analysis, it is unfair and illogical to
requirements. The comments stress it is disallow a certificate of analysis in the
§ 111.73 What is your § 111.35 (f), (g), important to build quality into a dietary supplement CGMP final rule.
responsibility for deter- and (h) product throughout the entire One comment states the proposed
mining whether estab- production process by relying on strong requirements for production and
lished specifications process controls rather than by testing at process controls are more stringent than
are met?
the finished batch stage. One comment the requirements for drug products.
§ 111.75 What must you § 111.35(e), (f), asserts that, in an appropriate process Several comments stress that the most
do to determine (g), (h), (i), control system, testing is a means to critical aspect of a successful CGMP
whether specifications (k), and (l) monitor and ensure that the control system is effective process control,
are met? § 111.37 system is functioning as intended. Many which includes a requirement for
(b)(11)(iv) comments recommend the final rule written procedures and documentation
§ 111.40(a)(2) include rigorous in-process controls for all key processing operations. Many
plus a requirement for one identity test comments argue that effective process
§ 111.77 What must you § 111.50(d)(2), of incoming components to ensure control, including extensive written
do if established spec- (f), and (g) procedures, should allow for a
quality and safety.
ifications are not met? § 111.35(i)(4)(i)
Many comments assert a certificate of decreased testing burden with respect to
and (i)(4)(ii)
analysis can be a key element of the the finished product. One comment
§111.80 What represent- § 111.37(b)(11) manufacturing process provided that a suggests we exempt manufacturers from
ative samples must manufacturer certifies that a vendor the requirement to test each batch of
you collect? consistently supplies suitable product finished product if they have a qualified
through a combination of vendor audits manufacturing process that meets
§ 111.83 What are the § 111.37(b)(12) and product testing. (A certificate of certain basic criteria, including a
requirements for re- § 111.50(h) analysis is a document, provided by the requirement for written procedures for
serve samples? § 111.83(b)(2) supplier of a component prior to or each stage of the process and a written
§ 111.87 Who conducts § 111.35(i) and upon receipt of the component, that plan for qualifying this process.
a material review and (n) documents certain characteristics and Several comments urge us to build
makes a disposition § 111.37(b)(5) attributes of the component.) Comments more flexibility into the testing
decision? and (b)(14) also assert that, with use of a certificate requirements, in both the type and
§ 111.40(a)(3) of analysis from a properly qualified number of tests required and the
§ 111.50(d)(1) supplier, the amount of required testing point(s) in the supply chain at which
§ 111.85(a) and could be reduced. One comment notes they would be required. Some
(c) that, although a certificate of analysis comments recommend that the
may not be relied upon completely to frequency of testing be established
§ 111.90 What require- § 111.35(i)(4) under a statistically valid method to
ments apply to treat- § 111.50(d)(1),
forgo testing of a received ingredient,
ment, in-process ad- (f), and (g) the extent of testing could be reduced to ensure that in-process controls are
justments, and reproc- § 111.65(d) take into account the history of the adequate to guarantee production of a
essing when there is a supplier in providing quality safe and effective dietary supplement or
deviation or unantici- ingredients. This and other comments ingredient. Several comments
pated occurrence or recommend the dietary supplement recommend we require manufacturers to
when a specification manufacturer conduct identity tests to test incoming ingredients and raw
established in accord- ensure that the correct component has materials, in lieu of testing each
ance with § 111.70 is been received. A few comments note finished batch of product. These
not met? that the drug CGMP regulations permit comments state it is more prudent to
§ 111.95 under this sub- § 111.35(m) and the use of a supplier’s certificate of test to ensure that the materials used in
part E, what records (o) analysis based upon certification of the formulating a product are appropriate
must you make and supplier by a program of complete and safe than to risk making an
keep? testing for conformance with the adulterated product and, in so doing,
certificate of analysis. contaminate manufacturing equipment.
B. General Comments on Proposed Several comments support the use of Several comments recommend we
§ 111.35 a qualified supplier’s certificate of allow manufacturers to employ skip-lot
analysis in lieu of testing at the finished testing as an alternative to testing each
(Comment 145) Several comments batch stage. One comment recommends finished batch of product. One comment
emphasize the first step in ensuring testing be strategically employed to states that, with adequate process
safe, high quality products is to use high verify that other control procedures controls in place, periodic or skip-lot
quality components that meet well- have accomplished their intended testing is sufficient, and notes that skip-
defined specifications. Some of these result; if other controls are adequate, a lot testing is acceptable under the
statistically-based testing program regulatory frameworks for herbal
products in other countries, including each company must confirm other to use. This requirement is similar to the
Canada and countries in the European required specifications for components proposed requirement set forth by
Union. prior to use, either by relying upon a industry in both the 1997 ANPRM and
In summary, the comments suggest an certificate of analysis or by testing or in the January 2004 industry comment
approach that stresses the importance of examining the component. to the proposed rule. Firms may not rely
establishing specifications for As the comments have suggested, upon a certificate of analysis provided
components, relying on a certificate of specifications for the ‘‘identity’’ of by suppliers to determine the identity of
analysis from a qualified supplier for components of dietary supplements are a dietary ingredient before use. We
certain specifications with qualification critically important. These comments recognize, however, that it may be
of the suppliers, and establishing and included references to industry possible for a manufacturer to
following written procedures. This proposals that supported identity demonstrate, through various methods
overall approach would focus on testing. The 1997 ANPRM (62 FR 5700) and processes in use over time for its
building quality into a dietary included an industry proposed outline particular operation, that a system of
supplement throughout the production of CGMP provisions which contained a less than 100 percent identity testing
and process control system. The role of provision that required identity testing would provide no material diminution
testing at the finished batch stage would as follows: ‘‘(iv) Each lot of raw material of assurance of the identity of the
become a check on whether the overall shall undergo at least one test by the dietary ingredient as compared to the
manufacturing process is, in fact, under manufacturer to verify its identity. Such assurance provided by 100 percent
control. tests may include any appropriate test identity testing. To provide an
(Response) Based upon a review of with sufficient specificity to determine opportunity for a manufacturer to make
the comments, we have reconsidered identity, including chemical and such a showing and reduce the
the approach taken in the 2003 CGMP laboratory tests, gross organoleptic frequency of identity testing of
Proposal. The 2003 CGMP Proposal analysis, microscopic identification, or components that are dietary ingredients
would require that all finished batches analysis of constituent markers.’’ (60 FR from 100 percent to some lower
of dietary supplements be tested at the 5700 at 5705). frequency, we decided to provide, in an
finished batch stage to ensure that the In January 2004, a group of trade interim final rule published elsewhere
products met specifications for identity, associations representing dietary in this issue of the Federal Register, a
purity, strength, and composition. The supplement manufacturers and others procedure that allows for submission to,
2003 CGMP proposal recommended, but submitted text of proposed CGMP and review by, FDA of an alternative to
would not require, testing of incoming requirements to the docket as an the required 100 percent identity testing
components to ensure that component alternative to the 2003 CGMP Proposal. of components that are dietary
specifications, including identity, were This submission also included a ingredients, provided certain conditions
met. However, if a specification (such as provision which required identity are met.
identity) could not be tested at the testing as follows:
finished batch stage, the proposed rule In the preamble to the 2003 CGMP
(1) For components, dietary ingredients, or Proposal (68 FR 12157 at 12198), we
would require a firm to test incoming dietary supplements that you receive, you
components for that specification and to explained that we would not permit
must:
test for that specification at the in- (i) conduct at least one test or examination firms to rely upon supplier
process stage as necessary to ensure that to verify that the specifications for identity certifications. The decision was based,
products met specifications. We are are met; * * * in large part, on problems that have
persuaded that, as an alternative to (1996N–0417, EMC000261–02 at 20). occurred with faulty certificates in the
testing each finished batch of product, Both the 1997 ANPRM industry past. We have, however, reconsidered
we can allow for the use of a statistically outline and the January 2004 industry our position on certificates for
sound sampling and testing program for docket submission included provisions specifications, other than for the
finished batches of dietary supplements that allowed certificates of analysis to identity of the dietary ingredients, based
unless a manufacturer chooses to test establish specifications other than for on comments discussing how firms have
every batch. Such a sampling and identity for ingredients and taken steps to ensure that their
testing program is feasible when components. certificates are reliable. We believe that
controls are implemented earlier than In the preamble to the 2003 CGMP the minimum criteria that we are
the final product stage in the Proposal (68 FR 12157 at 12162) we establishing for a certificate of analysis,
manufacturing process. Controls include discussed a case in which Digitalis together with the requirement that a
the use of a certificate of analysis from lanata was labeled as plantain and, as firm relying on a certificate of analysis
a qualified supplier for specifications a result, a young woman experienced a must qualify a supplier and periodically
other than the identity of a dietary life-threatening abnormal heart function repeat that qualification process, can
ingredient, and the establishment and after consuming a dietary supplement prevent the problems that have occurred
monitoring of in-process manufacturing containing D. lanata in lieu of plantain. with faulty certificates in the past.
controls. We agree with the comments The problem occurred notwithstanding Therefore, for component specifications,
that if we reduce the requirements for the fact that certificates of analysis other than the identity of a dietary
testing at the finished batch stage, then furnished by the supplier provided ingredient, including confirming the
it is critical that you determine whether assurances that the component was identity of components that are not
components meet specifications. We indeed plantain. dietary ingredients, we are permitting
address this issue in the following two Because of the critical importance of firms to rely upon certificates of
ways: (1) Each manufacturer must ensuring the proper identity of dietary analysis provided by suppliers, if the
confirm the identity of each component ingredients—they are the central certificates meet the requirements of the
prior to use (you must test or examine defining ingredients of a dietary final rule. Under final § 111.75(a), a firm
dietary ingredients to verify the identity, supplement—we are requiring each firm may rely upon a certificate of analysis
but may rely on a certificate of analysis that uses a dietary ingredient to perform from its supplier of a component,
to confirm the identify of components its own testing or examination for provided that certain criteria are met
other than dietary ingredients) and (2) identity of each dietary ingredient prior which include the following: (1) The
firm first qualifies the supplier by dietary ingredients and the appropriate dietary supplements. We decline to
establishing the reliability of the reliance on a certificate of analysis for include codified language that may not
supplier’s certificate of analysis through components other than dietary capture all of the possible relationships
confirmation of the results of the ingredients is found in this section in that exist in a given operation.
supplier’s tests or examinations; (2) the response to comment 174.
E. What Are the Design Requirements
certificate of analysis includes a
C. Final Subpart E and Highlights of for the Production and Process Control
description of the test or examination
Changes to the Proposed Regulations System? (Final § 111.60)
method(s) used, limits of the test or
examinations, and actual results of the The provisions in final subpart E Final § 111.60(a) requires that your
tests or examinations; (3) the firm reflect that the final rule applies only to production and in-process control
maintains documentation of how it persons who manufacture, package, system be designed to ensure that the
qualified the supplier; (4) the firm label, or hold a dietary supplement dietary supplement is manufactured,
periodically reconfirms the supplier’s unless subject to an exclusion in final packaged, labeled, and held in a manner
certificate of analysis; and (5) the firm’s § 111.1. The approach that we are that will ensure the quality of the
quality control personnel review and incorporating into the final rule requires dietary supplement and that the dietary
approve the documentation setting forth changes in most of the individual supplement is packaged and labeled as
the basis for qualification (and paragraphs of proposed § 111.35. specified in the master manufacturing
requalification) of any supplier. record. Final § 111.60(b) requires that
D. What Are the Requirements to
As we discussed in the preamble to the production and in-process control
Implement a Production and Process
the 2003 CGMP Proposal, in-process system include all requirements of
Control System? (Final § 111.55)
controls are necessary to ensure that subparts E through L of part 111 and be
dietary supplements are manufactured Final § 111.55 requires you to reviewed and approved by quality
in accordance with their specifications implement a system of production and control personnel. Final § 111.60(a) and
(68 FR 12157 at 12197). Under final process controls that covers all stages of (b) derive from proposed § 111.35(b).
§ 111.75(b), firms must monitor the in- manufacturing, packaging, labeling, and As discussed in section III of this
process points, steps, or stages where holding of the dietary supplement to document, we are clarifying a number of
control is necessary to ensure the ensure the quality of the dietary provisions that did not explicitly
quality of the finished batch of the supplement and that the dietary identify labeling as an operation that is
dietary supplement to: (1) Determine supplement is packaged and labeled as covered by the rule. Final § 111.60 is
whether the in-process specifications specified in the master manufacturing one such provision. Under proposed
are met and (2) detect any deviation or record. Final § 111.55 derives from § 111.35(a) we would require that you
unanticipated occurrence that may proposed § 111.35(a). implement a system of production and
result in a failure to meet specifications. (Comment 146) A few comments say process controls that covers all stages of
In addition, we have strengthened the the production and process controls manufacturing, packaging, labeling, and
requirements for in-process controls by outlined in proposed § 111.35 are holding of the dietary supplements. In
requiring that quality control personnel critical in ensuring that dietary an oversight, proposed § 111.35(b)
conduct all required material reviews supplements meet specifications for would require your production and in-
and make all required disposition identity, purity, quality, strength, and process control system to be designed to
decisions using written procedures to composition. One comment ensure that the dietary supplement is
ensure that deviations or unanticipated recommends proposed § 111.35(a) be manufactured, packaged, and held—but
occurrences that occur are consistently revised to state ‘‘* * * that covers all not labeled—in a manner that would
handled. stages of manufacturing, packaging, prevent adulteration of the dietary
Because of the strengthened labeling, and holding of * * * dietary supplement. To correct this oversight,
requirements regarding component and supplements that occur in your facility final § 111.60 explicitly identifies
in-process specifications, the final rule or for which you otherwise have labeling as an operation that the design
permits testing of a subset of finished responsibility.’’ This comment explains of your production and process control
batches rather than requiring testing of that the production of dietary system must address.
each finished batch. Consistent with supplements is often broken up into (Comment 147) A few comments
several suggestions in the comments, we several stages which are under the recommend that the phrase ‘‘designed to
built more flexibility into the testing control of different entities. The ensure’’ in proposed § 111.35(b) be
requirements so that a firm may test a comment gives the following examples: deleted because it requires that formal,
subset of finished dietary supplement A marketing company may manufacture prospective studies (similar to a process
batches that the firm identifies through and package a product itself; or it may validation) must be performed and such
a sound statistical sampling plan for contract with one company to a requirement would be unduly
selected specifications rather than test manufacture and package the product; burdensome.
every batch of the finished dietary or it may contract with one company to (Response) We disagree with the
supplement for every specification. manufacture the product and another comments’ interpretation of the
Finally, quality control personnel must company to package the product; and proposed regulation and decline the
review and approve any exceptions contract manufacturers and packagers request. Final § 111.60(a) relates to the
from testing requirements that are may subcontract portions of the overall design of your production and
allowed under the rule and the basis for manufacturing or packaging. process control system. It does not
such exceptions. This approach is (Response) We decline to revise the require validation based on scientific
consistent with the comments that we rule as suggested by the comments. As studies, but rather that your process
received and will achieve a high degree we discussed in response to comment contain all the controls necessary to
of integrity in the manufacturing 37 in section VI of this document, you ensure the quality of your dietary
process, while at the same time provide must comply with the CGMP supplements and that the dietary
flexibility to the industry. requirements that apply to your supplement is packaged and labeled as
Additional discussion on the operations related to the manufacturing, specified in the master manufacturing
requirements for identity testing of packaging, labeling, and holding of record. The process, for example, must
ensure that the dietary supplement for identity, purity, quality, strength, practicable or necessary to require
meets all specifications established and composition as appropriate to testing for all possible contaminants for
under § 111.70(e). protect the public health; and quality, every dietary supplement, or for every
strength, and composition as component used to manufacture a
F. What Are the Requirements for
appropriate for the * * * product.’’ dietary supplement. As we explained in
Quality Control Operations? (Final
This comment states it is confusing and the 2003 CGMP Proposal (68 FR 12157
§ 111.65)
unnecessary to require that all five of at 12199 through 12200), the
Final § 111.65 requires that you these attributes be addressed for all manufacturer has the responsibility to
implement quality control operations in dietary supplements. The comment also determine what types of contamination
your manufacturing, packaging, states the term ‘‘purity’’ requires are likely or certain to contaminate a
labeling, and holding operations for explanation because not all ingredients given product and to determine what
producing the dietary supplement to or supplements are subject to the same types of tests to conduct and when to
ensure that these operations are types of contamination. test for such contamination. We
performed in a manner that ensures the (Response) We are not making any explained that botanicals are likely or
quality of the dietary supplement and changes in the provision as suggested by certain to contain filth and
that the dietary supplement is packaged this comment. The comment provides microorganisms of public health
and labeled as specified in the master no basis for the assertion that the significance based on the areas in which
manufacturing record. Final § 111.65 proposed requirement to use a quality they are harvested (id.). As another
derives from proposed § 111.35(c). control unit to ensure that a dietary example, fungal growth on a botanical
Proposed § 111.35(c) referred to the supplement meets specifications for component can provide the
role of the quality control unit in identity, purity, strength, and environment for mycotoxin production,
manufacturing, packaging, and label composition is confusing and especially aflatoxin (id.). If fungal
operations—but not in holding unnecessary. In section VI of this growth is present, the manufacturer
operations. This was an oversight. We, document, we explain that purity means would need to perform an appropriate
therefore, revised proposed § 111.35(c) that portion or percentage of a dietary test that can detect the toxic substance.
to include ‘‘holding’’ as an operation supplement that represents the intended We stated that the manufacturer must be
that is subject to the oversight of quality product. aware of potential contamination,
control personnel for consistency with regardless of whether due to filth,
G. What Specifications Must You
final § 111.105 (proposed § 111.37(a)), insects, microorganisms, or toxins and
Establish? (Final § 111.70)
which provides for the performance of to test or examine, as appropriate, the
quality control operations to ‘‘ensure Final § 111.70 derives from proposed
components and dietary supplements
that your manufacturing, packaging, §§ 111.35(e), (f), (g), and (k),
111.37(b)(11)(iv), and 111.70(c). for those types of contamination that
label, and holding operations ensure the may adulterate or that may lead to
quality of the dietary supplement and (Comment 151) Some comments state
proposed § 111.35(k), which would adulteration (id.). Thus, the types of
that the dietary supplement is packaged contamination that we were referring to
and labeled as specified in the master require that you test or examine
components and dietary supplements in proposed § 111.35(k) are those that
manufacturing record.’’ are likely or certain to be present in or
(Comment 148) One comment for those types of contamination that
may adulterate or lead to adulteration, on components received, based on the
recommends proposed § 111.35(c) be
is more appropriate for, and should be nature of the product, its source,
revised to state ‘‘ensures that the * * *
incorporated into, proposed § 111.35(e) handling prior to receipt by the facility,
dietary supplement meets
which would require, in part, that you or other reason, and not due to poor
manufacturing specifications for
establish specifications for the identity, manufacturing practices that resulted in
identity, purity, quality, strength, and
purity, quality, strength, and their presence in the first instance.
composition.’’
(Response) We are not making this composition of components that you It is the responsibility of the
change because it is unnecessary in the receive and of dietary supplements that manufacturer to identify those
context of the provisions of final you manufacture. The comments note contaminants and to establish limits to
§ 111.65. this suggestion would help simplify and prevent adulteration under section
(Comment 149) One comment argues eliminate some redundancy in proposed 402(a)(1), (a)(2), (a)(3), and (a)(4) of the
that proposed § 111.35(c) is too wordy § 111.35. One comment would revise act. For example, if you manufacture a
and needs clarification. The comment proposed § 111.35(k) to state ‘‘Purity polysaccharide that derives from
recommends it be revised to state ‘‘You specifications for purchased or seaweed, it is likely that you would
must use a quality control unit to ensure manufactured components and dietary include a limit on cadmium, because
that the dietary supplement meets supplements must be established for cadmium is a common contaminant that
specifications for identity, purity, those types of contamination which can can be present in marine-derived
quality, strength, and composition.’’ reasonably be expected to affect the ingredients. If you manufacture a
(Response) We disagree with this component, ingredient, or supplement polysaccharide that has a composition
comment. The change requested by the in question * * *.’’ According to the similar to seaweed-derived
comment would emphasize a single comment not all ingredients or polysaccharide, but derives from a land-
responsibility of quality control supplements are subject to the same based plant, it is not likely that you
personnel (i.e., releasing final product) types of contamination, and it would be would include a limit on cadmium,
and would obscure the fact that quality unduly burdensome to require that all because cadmium is not a common
control personnel have a role in the ingredients and supplements be tested contaminant of land-based plants.
design and conduct of most of your for all possible contaminants (as Likewise, if you manufacture a mineral
operations. opposed to all likely contaminants). that contains phosphates, it is likely that
(Comment 150) One comment (Response) We agree that not all you would include a limit on arsenic,
recommends proposed § 111.35(c) be ingredients or dietary supplements are because phosphates are generally mined
revised to state ‘‘ensures that the * * * subject to the same types of and arsenic is a common contaminant
dietary supplement meets specifications contamination. It would not be that can be present in ingredients that
are mined. If you manufacture a mineral supplement, i.e., to ensure that the cattle, sheep, goats, elk, deer, cats, and
that does not include ingredients that dietary supplement has been mink), but primarily in ruminants
are mined, it is not likely that you manufactured, packaged, labeled, and (cattle, sheep, elk, deer) (69 FR 42256,
would include a limit on arsenic. held under conditions to prevent July 14, 2004). Most scientists believe
We agree that controlling adulteration under section 402(a)(1), that variant Creutzfeldt Jakob Disease
contamination is critical to the quality (a)(2), (a)(3), and (a)(4) of the act. (vCJD), a progressive neurological
of the dietary supplement. However, we Thus, in addition to the presence of disease in humans, is caused by
do not agree that the types of contaminants that may be in or on consumption of cattle products
contamination addressed by proposed components that you receive, there may contaminated with the agent that causes
§ 111.35(k) should be considered as a be sources of contamination that you BSE (69 FR 42256 at 42257).
purity specification. We have described need to control for in your facility. As In the 2003 CGMP Proposal (68 FR
purity in this final rule to mean discussed in this section, you must 12157 at 12180), we stated that we had
something that you intend to be present establish specifications under final communicated with the public and
in the final product. As explained in § 111.70(a) and (c) to prevent manufacturers of FDA-regulated
section VI of this document, purity adulteration from such sources. The products about appropriate steps to
means that portion or percentage of a specifications established under final increase product safety and minimize
dietary supplement that represents the § 111.70(a) and (c) may or may not the risk of products contaminated with
intended product. For example, you include limits on such contaminants. By the BSE agent. We referenced a notice
‘‘limits on those types of in the Federal Register of August 29,
may manufacture a dietary supplement
contamination’’ in final § 111.70, we do 1994 (59 FR 44591), entitled ‘‘Bovine-
that uses a natural product such as fish
not mean contamination from, for Derived Materials; Agency Letters to
oil to provide triglycerides that are a
example, the presence of rodent pellets Manufacturers of FDA-Regulated
source of the polyunsaturated fatty acids
or other filth that would constitute an Products.’’ We sent letters to dietary
DHA and EPA. The purity refers to the
insanitary condition under section supplements manufacturers to alert
percent of the fish oil that is
402(a)(3) or (a)(4) of the act, if such filth them to the developing concern about
triglycerides. (Note that if you are
was present in your facility. You are not TSEs in animals and Creutzfeldt-Jakob
manufacturing fish oil to provide the
allowed to establish specifications for Disease in humans. We recommended
fatty acids DHA and EPA in the dietary
limits on contaminants that would they investigate the source of any
supplement, the component otherwise adulterate your product under bovine and ovine material used in their
specifications for the fish oil must the act if such contaminants were products. We suggested that
include a strength specification for DHA present. manufacturers develop plans to ensure,
and EPA in whatever amount you Further, in proposed § 111.35(k), we with a high degree of certainty, that
determine is necessary to meet the included a listing of the types of bovine and ovine materials used in their
specification for strength of DHA and contamination we considered to be products were not from BSE countries
EPA in the dietary supplement.) If the applicable to dietary supplements (68 or from sheep flocks (foreign or
natural product also contains lead, or 12157 FR at 12258). We stated that the domestic) infected with scrapie. We
other unwanted ingredients that may types of contamination include: (1) stated that our Center for Biologics
adulterate or may lead to adulteration, Filth, insects, or other extraneous Evaluation and Research (CBER) had
you would have to establish limits for material; (2) microorganisms; and (3) developed guidances for industry that
such contaminants. Thus, to distinguish toxic substances. We have deleted the describe steps manufacturers should
the proposed requirement in § 111.35(k), listing of the types of contamination in take to ensure the safety and suitability
which relates to contaminants that may the final rule because the listing is for human use of animal-derived
be present on or in the components that simply informative and establishes no biologics. We also stated that we were
you receive, from the requirements independent requirement. We received considering whether the procedures that
related to specifications for desired several comments, discussed in the CBER recommends for a product with
characteristics of identity, purity, following paragraphs, on the types of animal-derived materials, substances, or
strength, and composition, we are contamination that may be present, tissues would be appropriate for dietary
including a separate requirement on some which were solicited by us in the ingredients and dietary supplements
establishing limits on such 2003 CGMP Proposal (68 FR 12157 at that contain animal-derived materials,
contaminants for components that you 12179 through 12181). substances, or tissues. We believed that
receive (final § 111.70(b)). We also In the 2003 CGMP Proposal, we the use of an animal-derived material,
include a requirement for establishing solicited comment on whether we substance, or tissue in a dietary
an in-process specification for any should include in the final rule specific supplement may raise many of the same
point, step, or stage in the master requirements for manufacturing, serious public health and safety issues
manufacturing record where control is packaging, or holding animal-derived as animal-derived materials, substances,
necessary to help ensure that dietary ingredients, because animal- or tissues, in a biologic. We invited
specifications are met, as necessary, for derived dietary ingredients present comment on whether there is a
limits on contamination. In addition, we important public health and safety scientific basis for us to treat animal-
are including a requirement for such issues. derived dietary ingredients in a manner
limits on contaminants in the finished In the 2003 CGMP Proposal, the different from, or that would offer less
batch of dietary supplement (or subset example we used was an animal-derived protection than, what is recommended
of finished batches) (final § 111.70(e)) to dietary ingredient potentially for animal-derived biologics when the
ensure that the manufacturing process contaminated with the agent that causes same public health and safety risks may
has not adversely affected such levels, bovine spongiform encephalopathy be present.
e.g., has not contributed an additional (BSE), which is a type of transmissible (Comment 152) Several comments
source of such contaminant or failed to spongiform encephalopathy (TSE). TSEs state there should not be specific
remove the contaminant, when are fatal, neurodegenerative disorders, requirements for manufacturing,
necessary. Such limits would need to which have been identified in humans packaging, or holding animal-derived
ensure the quality of the dietary and a number of animal species (e.g., dietary ingredients because BSE issues
are not specific to dietary supplements, derived biologics apply to dietary DALs for the types of contaminants for
and because other guidance and supplement products. One comment dietary ingredients because there are not
regulations, issued by FDA and by the includes a review of literature on BSE enough data available to identify an
U.S. Department of Agriculture (USDA), and claims the review justifies not appropriate DAL for most dietary
already address BSE and public health. applying the CBER guidances on BSE to ingredients. These comments do not
Other comments state it would be dietary supplement products under part provide data, or evidence that data are
appropriate to include specific CGMP 111. available, to enable us to issue guidance
requirements for BSE as long as the (Response) For cattle derived for DALs for specific contamination.
requirements reflect the thinking in materials, you must comply with the Therefore, we are not taking the action
currently existing regulations and requirements of the interim final rule on requested by these comments. We
guidance. BSE set forth in § 189.5 (see 70 FR discuss DALs in this section in response
Several comments do not support the 53063, September 7, 2005) and any to comment 156.
need for additional provisions regarding subsequent modifications. Under the (Comment 154) Some comments
the handling of imported animal- interim final rule, no human food, suggest the provisions in proposed
derived ingredients because the including dietary supplements, shall be § 111.35(k), testing for contamination
industry has already taken steps to manufactured from, processed with, or that could adulterate a product, would
comply with the requirements or otherwise contain, prohibited cattle be more appropriate to include in
recommendations issued by either materials as defined in the rule. In proposed § 111.35(e), which concerns
USDA or FDA. The comments state that addition, manufacturers and processors the establishment of specifications.
the regulations issued by USDA for meat of such food that is manufactured from, (Response) We agree with these
related products in the food industry processed with, or otherwise contains, comments and are including
provide adequate control over the use of cattle material must make existing requirements to include limits on
animal tissues that might contain records relevant to compliance available contamination in final § 111.70. The
microorganisms, specifically viruses, of to us for inspection and copying. For requirements set forth in final §§ 111.70
public health concern. both cattle-derived and other animal- and 111.75 are consistent with this
One comment argues that if purchases derived materials, you must comply comment. Under final § 111.70(b) you
of domestic raw tissues have been with all applicable provisions of this must establish limits on those types of
inspected by USDA, it is unfair to final rule. For example, under final contamination that may adulterate or
impose additional regulations simply § 111.70, you must establish may lead to adulteration of the finished
because these tissues are included in specifications for any point, step, or batch of the dietary supplement to
dietary supplements. This comment stage in the manufacturing process ensure the quality of the dietary
asserts it would be unfair to require where control is necessary to ensure the supplement. Under final § 111.70(c) you
testing of animal-derived products given quality of the dietary supplement. Thus, must establish in-process specifications
the fact that there are no tests for BSE you must establish specifications for for any point, step, or stage in the
available, and that reliance on USDA your animal-derived materials that are master manufacturing record where
and FDA is the best way to stop the necessary to ensure the quality of the control is necessary to help ensure that
spread of BSE. dietary supplement. Ensuring quality specifications are met for the identity,
Another comment states that industry includes preventing contamination that purity, strength, and composition of the
trade associations have been working may adulterate the product under dietary supplements, and as necessary,
actively with their member companies section 402(a)(1), (a)(2), (a)(3), or (a)(4) limits on contamination for those types
to ensure adherence to the requirements of the act. In addition, you must take of contamination that may adulterate or
set forth in our various letters regarding actions to determine whether the may lead to adulteration of the finished
the need to develop plans ‘‘that ensure, specifications are met (final § 111.73). batch of the dietary supplement. Under
with a high degree of certainty’’ that Therefore, if you used animal-derived final § 111.70(e), you must establish
animal-derived ingredients are used materials other than prohibited cattle product specifications for the identity,
only in accordance with FDA and USDA materials subject to the BSE interim purity, strength, and composition of the
policies designed to protect against BSE. final rule, you would need to establish finished batch of the dietary
The comment states that a summary of specifications necessary to ensure the supplement, and for limits on those
industry procurement and handling quality of the dietary supplement. types of contamination that may
practices regarding animal-derived The guidances issued by CBER are adulterate, or that may lead to
ingredients (submitted to us) contains still in effect for animal-derived adulteration of, the finished batch of the
lists of animal-derived ingredients used biologics, and we continue to dietary supplement to ensure the quality
by various companies, with examples of recommend that you use them as of the dietary supplement. As we
the certificates of origin and other appropriate for your products that explained in the response to comment
documentation required for import of contain animal-derived ingredients. 151, by ‘‘limits on those types of
any animal-derived materials. One (Comment 153) One comment agrees contamination’’ in final § 111.70, we do
comment states that industry members with the provisions of proposed not mean contamination from, for
who handle animal-derived ingredients § 111.35(k) but requests that we provide example, the presence of rodent pellets
already have implemented many of the guidance to the industry on allowable or other filth that would constitute an
controls that originated either from limits for the types of contamination insanitary condition under section
USDA or the dietary ingredient listed. Another comment asks us to 402(a)(3) or (a)(4) of the act, if such filth
suppliers in response to demands by develop specific defect action levels was present in your facility. You are not
various governments or consumers, and (DALs) for dietary supplements as more allowed to establish specifications for
that such matters should remain with information becomes available, rather limits on contaminants that would
USDA to avoid duplication of effort. than rely on existing DALs from the otherwise adulterate your product under
Some comments oppose any food industry. the act if such contaminants were
recommendation that guidance issued (Response) In the 2003 CGMP present.
by CBER for ensuring the safety and Proposal (68 FR 12157 at 12163), we (Comment 155) Several comments
suitability for human use of animal- stated that we were not identifying object to proposed § 111.35(k) because
the provision would be more stringent types of contamination that may monographs on many substances, such
than the food or drug CGMP adulterate the dietary supplement or as salts that are used as sources of
requirements. Some point out that the lead to adulteration for received minerals used in both dietary
consumption levels for food are higher components, we would not expect you supplements and conventional food.
than for dietary supplements. A few to set limits for every potential These monographs include limits on
comments argue that proposed contaminant or for every naturally common contaminants, such as lead or
§ 111.35(k) is too broad as it requires occurring constituent of a botanical. other heavy metals. In addition, the
testing or examination for those Rather, we agree with the comments regulations in 21 CFR part 109 provide
contaminants that ‘‘may’’ adulterate or that the substances you would consider information about certain contaminants.
‘‘may lead to’’ adulteration, which could when determining whether to set limits (Comment 157) One comment
be interpreted to mean testing for for particular types of contamination recommends that all finished products
unknown contaminants of every would vary depending on the source of be tested for microorganisms. Another
description. The comments suggest that a component, such as a plant source, an comment contends the manufacturer
this provision be revised to require animal source, a microbial source, or a should be allowed to restrict testing to
testing or examination for those types of marine source. the raw material if the facility and
contamination that ‘‘may be present in (Comment 156) Some comments point equipment are monitored for
an amount or at a level’’ that may out that some compounds, such as contamination. Some comments point
adulterate or lead to adulteration or that mycotoxins, that are toxic at higher out that contaminants may be detectable
‘‘may reasonably be expected’’ to levels are detectable in nearly all plant in raw materials but not in the finished
adulterate or lead to adulteration. Other ingredients and are found in the food product.
comments agree that to test for all supply. A few comments assert that (Response) We disagree that all
possible contaminants would be dietary ingredients should not contain finished products must, as a matter of
burdensome. levels of certain toxic compounds that course, be tested for contamination with
Several comments state that are higher than reasonable or higher microorganisms. Whether it is necessary
manufacturers should be allowed to rely than recognized maximum allowable to test the finished product for
on a supplier’s certificate of analysis limits as opposed to the zero tolerance microorganisms would depend, for
and that testing should not be required for toxic compounds contained in the example, on the characteristics of your
for every potential contaminant. One 2003 CGMP Proposal. product, the nature and source of your
comment recommends that CGMPs One comment requests clarification of components, the specifications you
should be specific to the source and that the term ‘‘toxic substances.’’ One establish for microbial contaminants in
testing should depend on the nature of comment points out that information for your components and whether these
the material. identifying potential adulterants is specifications are addressed in a
Some comments note that for provided in monographs. Another certificate of analysis, the in-process
botanicals it is sometimes nearly comment requests clarification on specifications you establish, and the
impossible to identify and analyze all whether dietary supplement nature of your manufacturing process.
naturally occurring substances. manufacturers will be required to test However, these comments raise an
(Response) The final rule does not for toxins while food manufacturers, important point—i.e., that microbial
include any specific requirements to test who may use some of the same contamination could occur at your
or examine components or dietary ingredients, will not. facility even if an incoming component
supplements for contamination. Rather, (Response) As the comments point
is free of microorganisms. Final subpart
under final § 111.70(b), (c), and (e), you out, the food supply does contain some
K discussed in section XVI of this
are required to establish specifications degree of contaminants such as
document, sets forth requirements for
for limits on those types of mycotoxins that can be found, for
contamination that may adulterate or example, in certain grain. We do not your manufacturing operations. Many of
may lead to adulteration of the finished have a ‘‘zero tolerance’’ policy for such these requirements are designed to limit
batch of the dietary supplement. Under unavoidable contaminants but we have the potential for contamination with
final § 111.73, you must determine issued some regulations and guidance to microorganisms.
whether the specifications established address certain common contaminants. (Comment 158) Some comments
under § 111.70 are met. Final § 111.75(a) We also have issued a booklet entitled would revise the requirements for
through (d) sets forth the criteria you ‘‘Action Levels For Poisonous Or establishment of specifications for in-
must use to determine whether the Deleterious Substances In Human Food process controls (proposed
specifications that you establish under And Animal Feed’’ (Ref. 30; available at § 111.35(e)(2)) and the finished batch of
final § 111.70(b), (c), and (e) are met. http://www.cfsan.fda.gov). The booklet dietary supplements (proposed
Consistent with these comments, under is a useful resource for manufacturers § 111.35(e)(3)), so that specifications for
final § 111.75(a) you may rely on a who seek information about common attributes of quality, strength, and
certificate of analysis (other than for the contaminants that may adulterate a composition are not required for a
identity of a dietary ingredient) from a dietary supplement product or lead to product that does not purport to possess
qualified supplier of components to adulteration. Another resource is the such attributes.
ensure that specifications that include (Response) We decline to reword the
Foods Chemical Codex,9 which includes
limits on contamination are met, provision as requested by these
provided you satisfy the criteria set 9The Food Chemicals Codex (FCC) project is an comments. The requirement to establish
forth in final § 111.75(a). This would activity of the Food and Nutrition Board of the specifications for strength and
include, for example, relying on a
Institute of Medicine. The FCC was intended to composition relate to the manufacturers’
provide standards for the purity of food chemicals responsibility to know what their
certificate of analysis to ensure that the and thus promote uniform quality and ensure safety
finished dietary supplement is
level of lead in each of your components in the use of such chemicals. The First Edition of
would not adulterate the dietary the resulting FCC, published in 1966, was limited
to chemicals added directly to foods to achieve a into contact with foods and some that are regarded
supplement. desired technological function. Succeeding editions as foods, rather than as additives. The FCC is
In determining compliance with the upgraded the specifications for these substances available for purchase at 1–800–624–6242 or at
requirements to set limits for those and added specifications for substances that come http://www.nap.edu.
composed of so that their products are step, or stage in the manufacturing have failed to establish a specification
consistently manufactured. Establishing process where control is necessary to required by final § 111.70(a) or (c)
specifications and following these ensure the quality of the dietary necessary to prevent a type of
CGMP requirements will help ensure supplement and that the dietary contamination that may lead to
the quality of the dietary supplement. supplement is packaged and labeled as adulteration under section 402(a)(4) of
The requirement to establish specified in the master manufacturing the act. We would consider it a failure
specifications is not limited to when a record. We require that you establish to follow CGMP requirements if a
manufacturer purports that its product specifications for components (final manufacturer allowed conditions in the
possesses attributes of strength and § 111.70(b)), in-process production manufacture of a dietary supplement
composition on the label. As discussed (final § 111.70(c)), labels and packaging that would not ensure the quality of the
in the 2003 CGMP Proposal (68 FR (final § 111.70(d)), the finished batch of dietary supplement.
12157 at 12162), the absence of dietary supplement (final § 111.70(e)), We have specified in final § 111.70(b)
minimum standards has contributed to product that you receive from a supplier that you must establish certain types of
the adulteration and misbranding of for packaging and labeling (final specifications that are critical to
dietary supplements because of § 111.70(f)), and the packaging and ensuring that you know what the
contaminants or because manufacturers labeling for the finished packaged and components are that you use in
do not set and meet specifications for labeled dietary supplement (final manufacturing a dietary supplement
their products, including specifications § 111.70(g)). The general requirement for and that are necessary to ensure that the
for identity, purity, strength, and establishing specifications in final dietary supplements you manufacture
composition and do not set and meet § 111.70(a) includes specifications, not meet their specifications for identity,
limits on contaminants, when otherwise required in final § 111.70(b) purity, strength, composition, and do
necessary. The comment does not through (g), that the manufacturer not exceed their limits for contaminants.
persuade us otherwise. We note, determines are necessary to achieve The identity, purity, strength, and
however, that the final rule’s quality, i.e., that are necessary to meet composition, and the limits that you
requirements to establish specifications the identity, purity, strength, or establish for contaminants, for a
for components do, in fact, provide composition of the dietary supplement finished batch of dietary supplement are
flexibility so that you are not required or that are necessary to prevent what we call ‘‘product specifications’’ in
to establish a component specification adulteration under section 402(a)(1), final § 111.70(e). These product
for certain attributes, such as the (a)(2), (a)(3), and (a)(4) of the act. specifications must be met in order for
strength of a tablet coating agent (see the Requirements to establish you to ensure the quality of your
discussion of final § 111.70(b) in this specifications to control for finished batch of dietary supplement. A
section). contamination are included in final specification may include a list of tests,
(Comment 159) One comment asks for § 111.70(a), (b), (c), and (e). As references to analytical procedures, and
guidance as to what constitutes an discussed earlier, the specifications for appropriate acceptance criteria that are
official or scientifically valid standard contaminants in final § 111.70(b) refer to numerical limits, ranges, or other
for specifications. those types of contamination of a criteria for the tests described. For
(Response) We are not aware of any component or dietary supplement that example, a specification for a
officially recognized standard for may adulterate or that may lead to component may include information
specifications. Specifications are critical adulteration that are due to about the test used to verify the identity
standards that are proposed and contaminants that may be present in or of the component and the range of test
justified by the manufacturer for each on the components that you receive, results that are acceptable. Under final
product that the manufacturer produces. based on the nature of the product, its § 111.70(c), a specification for an in-
The manufacturer establishes the set of source, its handling prior to receipt, or process control may include
criteria to which a product should other reason. Limits are established by information about the viscosity that
conform to be considered acceptable for the manufacturer for such contaminants must be achieved during a batch
its intended use. In general, a at receipt. production of a liquid product and
specification may include a list of tests, The requirement to establish information about the test or equipment
references to analytical procedures, and specifications to control for used to measure the viscosity. Under
appropriate acceptance criteria that are contamination under final § 111.70(a) final § 111.70(d), a specification for
numerical limits, ranges, or other and (c) include specifications necessary packaging may include the specific type
criteria for the tests described. to prevent adulteration under section or grade of plastic. Under final
(Comment 160) One comment asks 402(a)(1), (a)(2), (a)(3), and (a)(4) of the § 111.70(e), a specification for the
that we clarify whether every act as a result of what the manufacturer finished batch may include the
specification sheet must include may do or fail to do in its manufacturing quantitative amount of a dietary
separate, specific qualitative or operation, and not as a result of ingredient, such as vitamin C.
quantitative standards, and tests to be contaminants that are in or on the Under this final rule, the
established for each attribute, or components received. For example, it manufacturer has the flexibility—and
whether a specification sheet can be may be critical that a certain piece of the responsibility—to develop
modeled after a compendial monograph. equipment be cleaned and/or sanitized specifications that are appropriate to the
Some comments state that product after handling certain raw materials to circumstances, including whether
specification sheets should be modeled ensure that there is no microbial information in any particular
after pharmacopoeia monographs other contamination from microorganisms of monograph is an appropriate model for
than those listed in the preamble to the public health significance to a given dietary supplement.
2003 CGMP Proposal. components processed on the
1. Final § 111.70(a)
(Response) These CGMP requirements equipment. If the manufacturer failed to

do not establish any requirements to establish a specification for cleaning Final § 111.70(a) requires you to
have a ‘‘specification sheet.’’ Rather, the and/or sanitizing after handling those establish a specification for any point,
final rule (final § 111.70(a)) requires you raw materials before processing step, or stage in the manufacturing
to establish a specification for any point, components, the manufacturer would process where control is necessary to
ensure the quality of the dietary designed to ensure the quality of the § 111.70(b) derives from proposed
supplement and that the dietary dietary supplement that you § 111.35(e)(1) and (k). Final § 111.70(b)
supplement is packaged and labeled as manufacture. It is not meaningless to is consistent with comments, already
specified in the master manufacturing establish requirements that will ensure, discussed, that recommended the
record. Final § 111.70(a) derives from for example, the product meets the provisions of proposed § 111.35(k),
the opening statement in proposed established specifications for identity, regarding contaminants that could
§ 111.35(e). purity, strength, and composition, and adulterate a product, be incorporated
As we discussed in the preamble to is within specified limits on into proposed § 111.35(e). In addition,
the 2003 CGMP Proposal (68 FR 12157 contaminants to prevent adulteration. as discussed previously with respect to
at 12196), the points, steps, or stages (Comment 164) Some comments final § 111.55, final § 111.70(b) provides
where specifications must be express concern that the language of that the required component
established may include heating steps, proposed § 111.35(e) may require specifications you must establish for a
cooling steps, points where specific specifications beyond those already dietary supplement include identity,
sanitation procedures are needed, required in the master manufacturing purity, strength, and composition.
product formulation control steps, record, as stated in proposed (Comment 165) A few comments state
points where cross-contamination may § 111.45(a)(1), to identify specifications it is appropriate and acceptable to
occur, and steps where employee and for the points, steps, or stages in the establish a requirement for a
environmental hygiene are necessary to manufacturing process where control is specification for the identity and purity
ensure the quality of the dietary necessary to prevent adulteration, or of components, insofar as such
supplement. These specifications are may require specifications for attributes specifications are necessary to ensure
regulatory specifications addressed by that are not present at all stages. These that components are not contaminated
these CGMP regulations. The final rule comments urge us to be flexible during with substances having public health
does not prevent you from establishing inspections as to what specifications are significance. However, these comments
additional, nonregulatory specifications appropriate. argue that specifications for quality,
that are not at points, steps, or stages (Response) Final § 111.70(a) provides strength, and composition of
where control is necessary to ensure the the manufacturer with flexibility in components should only be required for
quality of the dietary supplement. For determining what specifications may be the quality, strength, and composition
example, you could establish necessary for its operation. Moreover, that a component is purported to
specifications that largely address the final § 111.70(a) through (g) provide the possess. One comment notes this would
appearance of the dietary supplement in manufacturer with flexibility to provide the same requirement that is
an aesthetic sense. Such nonregulatory determine what the specifications currently established for drug products
specifications are not addressed by the require in order to ensure the quality of and processing. Some comments
final rule. the dietary supplement. recommend that specifications should
(Comment 161) One comment notes 2. Final § 111.70(b) be established ‘‘as appropriate’’ or
that labelers would not be subject to ‘‘where control is necessary to assure
proposed § 111.35(e). Final § 111.70(b) requires you to production of a quality product.’’
(Response) Consistent with final establish component specifications for (Response) After considering the
§ 111.1, persons who perform labeling each component you use in the comments that questioned the need to
operations are, in fact, subject to the manufacture of a dietary supplement. establish specifications for the identity,
final rule, including the requirements to Under final § 111.70(b)(1), you must purity, quality, strength, and
establish specifications. As discussed in establish an identity specification for composition of components, as well as
this section, the final rule includes an each component that you use in the the general comments that led to the
explicit requirement that, if you receive manufacture of a dietary supplement. A overall approach that focuses on
a product from a supplier for packaging specification for identity may include building quality into a dietary
or labeling as a dietary supplement (and more than one attribute. For example, a supplement at every stage of the
for distribution rather than for return to specification for the identity of a salt production and process control system
the supplier), you must establish used in the manufacture of a vitamin (see discussion in section IV of this
specifications to ensure that the product and mineral supplement may include document), we are requiring in final
that you receive is adequately identified the physical characteristics of the solid § 111.70(b)(1) that you establish an
and is consistent with your purchase (e.g., as a crystal or as a powder), the identity specification for components
order (final § 111.70(f)). color, and the state of hydration (e.g., that you use. This identity specification
(Comment 162) One comment asks with two or three molecules of water). is necessary to ensure that the finished
whether the manufacturer determines A specification for the identity of a dietary supplement meets its
where control is ‘‘necessary’’ to prevent botanical may include the part of the specification for identity because you
adulteration. plant (e.g., roots or leaves), the color, could not know what your final product
(Response) In accordance with the and whether the part of the plant is in contains if you do not know what you
changes made to the section, the a native state or has been ground. Under put into it. In addition, final
manufacturer does determine where final § 111.70(b)(2), you must establish § 111.70(b)(2) requires you to establish
control is necessary to ensure the component specifications that are those component specifications for
quality of the dietary supplement. necessary to ensure that specifications purity, strength, and composition that
(Comment 163) Some comments for the purity, strength, and composition are necessary to ensure that
express concern that manufacturers who of dietary supplements manufactured specifications for the purity, strength,
must confirm the validity of subjective using the components are met. Under and composition of dietary supplements
criteria established as specifications final § 111.70(b)(3) you must establish manufactured using the components are
may set the specifications as low as limits on those types of contamination met.
possible or set meaningless that may adulterate or may lead to Final § 111.70(b)(2) provides
specifications. adulteration of the finished batch of the flexibility for you to determine which
(Response) The specifications you dietary supplement to ensure the quality component specifications other than
must establish under this final rule are of the dietary supplement. Final identity are, or are not, necessary to
ensure that the final dietary supplement composition. As explained in response are met. What criteria you must use in
meets its specifications. For example, it to comment 40, this final rule does not order to determine whether
is likely that you will need to establish require that you establish specifications specifications are met are set forth in
a specification for the strength of for the identity, purity, strength, or final § 111.75.
vitamin C added as a component, that composition of the various constituents
3. Final § 111.70(c)
you use to make a multivitamin that are inherently present in a natural
supplement, so that you will know how product such as a botanical. However, Final § 111.70(c)(1) requires you, for
much vitamin C to add to satisfy the as previously discussed in section VI of in-process production, to establish in-
specification for the strength of the this document, depending on what you process specifications for any point,
vitamin C in the final product. Thus, if are manufacturing, the product step, or stage in the master
you are manufacturing a vitamin C specifications for the finished batch of manufacturing record where control is
tablet with a strength of 50 milligrams a dietary supplement may include a necessary to help ensure that
(mg) per tablet, you must determine specification, for example, of the specifications are met for the identity,
how much vitamin C, of a given strength of a substance that is present in purity, strength, and composition of the
strength, you must add in order to the dietary supplement because it is a dietary supplements and, as necessary,
produce tablets that will contain 50 mg, constituent of a natural product that you for limits on those types of
after accounting for the theoretical yield add as a component. For example, you contamination that may adulterate or
at each step in the manufacturing may establish a specification for the may lead to adulteration of the finished
process. However, you may not need to amount of vitamin C in a dietary batch of the dietary supplement. Final
establish a specification for the strength supplement that you manufacture by § 111.70(c)(1) derives from proposed
of the tablet coating agent for that adding the component rose hips. If this § 111.35(e)(2). Final § 111.70(c)(1)
multivitamin supplement, if your final is the case, then the component includes a nonsubstantive, editorial
specifications include the amount of the specifications for the natural product change that we are making for
tablet coating agent as part of the must include a specification for the consistency with other regulations in
specifications for the composition, but strength of the constituent (e.g., vitamin part 111. This change is to refer to ‘‘in-
not the strength of the multivitamin C) in whatever amount you determine is process specifications for any point,
supplement. In most cases, a necessary to meet the specification for step, or stage in the master
specification for the composition of the the constituent (vitamin C) in the manufacturing record where control is
dietary supplement would be sufficient finished batch of dietary supplement. necessary’’ rather than ‘‘in-process
to ensure that the tablet coating agent is (Comment 167) One comment asserts controls in the master manufacturing
used within the established level. it would be more appropriate for record where control is necessary.’’
(Comment 166) A few comments proposed § 111.35(e)(1) to address We also have added that you must
express concern about how to determine components ‘‘that you purchase’’ than establish in-process specifications, as
certain specifications for botanicals, to address components ‘‘that you necessary, for limits on those types of
such as the strength of peppermint leaf. receive,’’ because customers sometimes contamination that may adulterate or
The comments explain that a provide the ingredient or product to be may lead to adulteration of the finished
specification for strength of peppermint processed and the customer, rather than batch of the dietary supplement. This
leaf could be based on a number of the manufacturer, establishes the clarifies that if it is necessary to
different attributes. One comment specifications. establish limits on contaminants in-
argues that establishing specifications (Response) Final § 111.70(b) (derived process, due to contamination that may
for all dietary ingredients may not from proposed § 111.35(e)(2)) requires occur in the facility you do so under
contribute to any assurance of product that component specifications be final § 111.70(c)(1). With a requirement
quality and will not protect public established for each component that you to set, as necessary, limits on
health. Some comments assert that use in the manufacture of a dietary contamination in-process, aspects of the
‘‘quality, strength, and composition’’ are supplement. Thus, the firm must production and process system from
subjective with respect to botanical establish specifications for the receipt to finished product are covered
ingredients for which no potency claim components it uses to manufacture a with respect to contamination. For
is made, and, thus, these attributes dietary supplement, regardless of example, under final § 111.70(e) you
should not be included in the rule. whether it manufactures the may determine that you need to
Another comment asserts proposed components itself or contracts with establish a microbiological specification
§ 111.35(e)(1) goes beyond either food or another firm to manufacture the that the aerobic plate count of your
drug CGMPs and that the composition components. The firm that conducts the finished batch of the dietary supplement
of approximately 1,200 botanicals used manufacturing operations, as explained will not exceed a certain number of
in the industry will be impossible to in section VI of this document, would colony forming units per gram of
determine in an economically feasible be responsible for complying with all product. Under the written instructions
manner. relevant CGMP requirements in this in your master manufacturing record
(Response) To the extent that these final rule related to its operations. (final § 111.210(h)) and your written
comments assert that this final rule (Comment 168) One comment asserts procedures for manufacturing
should not require you to establish that proposed § 111.35(e)(1) is operations (final § 111.353), you would
specifications for the strength and unnecessary because the requirements establish controls to prevent microbial
composition of botanical ingredients, for testing to meet the manufacturer’s contamination at each point, step, or
we disagree. As explained in response specifications are described elsewhere. stage in the manufacturing process
to comment 145, it is fundamental to (Response) We disagree. The where control is necessary to prevent
CGMPs that you know what requirements to establish specifications microbial contamination. To ensure that
components are used to manufacture are distinct from what you must do to you will meet the microbiological
your dietary supplement and to ensure determine whether specifications are specification that you set for the
that the finished batch of dietary met. Under the final rule (§ 111.73), you finished batch of the dietary
supplement contains the established have a responsibility to determine supplement, you may determine that it
identity, purity, strength, and whether the established specifications is necessary to establish a specification
for the aerobic plate count at an and, as necessary, for limits on specifications for the identity, purity,
intermediate stage of the in-process contamination, final § 111.70(c)(1) and strength, and composition of the
production. (c)(2) state ‘‘help ensure’’ rather then finished batch of the dietary
Final § 111.70(c)(2) requires you, for ‘‘ensure’’ the identity, purity, strength, supplement, and for limits on those
in-process production, to provide and composition of dietary supplements types of contamination that may
adequate documentation of your basis and for limits on contamination. adulterate or may lead to adulteration of
for why meeting the in-process (Comment 169) One comment asserts the finished batch of the dietary
specifications, in combination with monitoring and process controls are supplement, all to ensure the quality of
meeting component specifications, will more practical and effective than the the dietary supplement. Final
help ensure that the specifications are proposed requirements for in-process § 111.70(e) derives from proposed
met for identity, purity, strength, and testing, which the comment asserts are § 111.35(e)(3) and (k). Final § 111.70(e)
composition of the dietary supplements overly broad and could impose an is consistent with comments, already
and for limits on those types of undue burden on small businesses. discussed, recommending that the
contamination that may adulterate or (Response) The comment’s objection provisions of proposed § 111.35(k)
may lead to adulteration of the finished is unclear. The final rule requires that regarding contaminants that could
batch of the dietary supplement. Final you establish in-process specifications adulterate a product be incorporated
§ 111.70(c)(3) requires that quality for any point, step, or stage in the into proposed § 111.35(e).
control personnel review and approve master manufacturing record where
the documentation you provide under control is necessary in the 6. Final § 111.70(f)
final § 111.70(c)(2). Final § 111.70(c)(3) manufacturing process to help ensure Final § 111.70(f) requires you, if you
also derives in part from proposed that specifications are met for the receive a product from a supplier for
§ 111.37(b)(1) which would require the identity, purity, strength, and packaging or labeling as a dietary
quality control unit to approve or reject composition of the dietary supplement supplement (and for distribution rather
all processes that may affect the and, as necessary, for limits on than for return to the supplier), to
identity, purity, strength, or contamination. You must monitor the establish specifications to provide
composition of a dietary supplement. in-process points, steps, or stages, where sufficient assurance that the product
In final § 111.70(c)(2), we are control is necessary to ensure the you receive is adequately identified and
requiring documentation that includes quality of the finished batch of dietary is consistent with your purchase order.
the basis for why meeting the in-process supplement, to determine whether the Final § 111.70(f) derives from proposed
specifications, in combination with in-process specifications are met and to § 111.35(e)(1) which would, in part,
meeting the component specifications detect any deviation or unanticipated require you to establish specifications
will help ensure the specifications for occurrence that may result in a failure for dietary supplements that you
the identity, purity, strength, and to meet specifications (see final receive. Final § 111.70(f) includes
composition of the dietary supplement § 111.75(b)). The final rule does not changes we are making after considering
and limits on contamination are met. establish specific requirements for in- comments.
Meeting in-process specifications alone process monitoring. The manufacturer (Comment 170) One comment notes
may not ensure the identity, purity, must determine any in-process that labelers would not be subject to
strength, or composition of the dietary monitoring that is necessary to ensure proposed § 111.35(e). Other comments
supplement, but information about the that the specifications are met for the request we clarify the roles of the
component specification may be needed finished batch. Examples of such various parties in the ‘‘pre-consumer
in order to put the results from the in- monitoring include measuring pH or supply chain’’ for dietary supplements.
process specification in perspective. For viscosity. One comment suggests that
example, if the manufacturer establishes manufacturers and packagers be
a component specification for lead that 4. Final § 111.70(d) responsible for establishing
it not be greater than ‘‘x’’ mg and Final § 111.70(d) requires you to specifications only for the operations
establishes a specification that all establish specifications for dietary occurring in their own facility or for
piping that comes into contact with the supplement labels (label specifications) which they are otherwise responsible
component be lead free in the facility, and for packaging that may come in (e.g., subcontracted operations), not for
and there are no other components or contact with dietary supplements upstream or downstream operations
equipment that would be a source of (packaging specifications). Final over which they may not have any
lead, then there should be no added § 111.70(d) derives from proposed control. This comment states that we
lead from processing, provided that the § 111.35(e)(4). Further, § 111.70(d) intended to relieve packagers from
material only came in contact with the requires that packaging that may come establishing specifications for the
lead-free pipes and only the other lead- into contact with dietary supplements dietary supplements that they package,
free components and equipment are must be safe and suitable for its and also states that such requirements
used. Thus, we would not know by intended use and must not be reactive should not be in the CGMP regulations.
looking solely at the in-process or absorptive or otherwise affect the (Response) We have discussed, in
specification whether the lead in the safety or quality of the dietary section VI of this document, who is
final product is not greater than ‘‘x’’ mg. supplements, consistent with proposed subject to the final rule under § 111.1 in
We would need to evaluate the § 111.35(e)(4). We deleted the phrase what the comment describes as the
component specification, in addition to ‘‘comply with other statutory and ‘‘pre-consumer supply chain’’ and do
the in-process specification, to ensure regulatory provisions’’ from proposed not repeat that discussion. We agree that
that the final product contains no § 111.35(e)(4) because the requirement packagers and labelers must establish
greater than ‘‘x’’ mg lead. To emphasize was redundant to final § 111.5. specifications for the dietary
the interplay of the specifications and supplements that they package and did
component specifications in ensuring 5. Final § 111.70(e) not intend to relieve them of complying
the specifications are met for the Final § 111.70(e) requires you, for with relevant CGMP requirements. We
identity, purity, strength, and each dietary supplement that you recognize that a firm that only packages
composition of dietary supplements, manufacture, to establish product and labels a product may rely on
information about the content of the (Comment 171) Some comments applied the label specified in the master
product that it receives from the assert that ‘‘packaging’’ should be manufacturing record (proposed
manufacturer. The information may included with ‘‘manufacturing process,’’ § 111.37(b)(11)(iv)). Final § 111.70(g)
consist of an invoice, certificate, but that a firm involved only in includes the minimum standards that
guarantee, or other form of verification ‘‘holding’’ a product should not have to we proposed to establish for packaged
as to what the product consists of so set specifications. and labeled dietary supplements in
that the packager or labeler has adequate (Response) Under final § 111.70(a), a proposed § 111.37(b)(11)(iv).
information about the dietary person who holds packaged and labeled To make clear that the use of
supplement it receives to label the dietary supplements for distribution and packaging and labels for a final
product and to ensure that the product who does no manufacturing, packaging, packaged and labeled product must be
is consistent with its purchase order. or labeling, would be required to that which is specified in the master
Therefore, we are setting forth certain establish a specification for any point, manufacturing record, we have created
requirements that distinguish a product step, or stage in the manufacturing a separate provision (under final
you receive for packaging or labeling as process where control is necessary to § 111.70(g)) requiring you to create the
a dietary supplement (and for ensure the quality of the dietary relevant specifications to be met.
distribution rather than for return to the supplement. For example, a person may Final § 111.70(g) requires you to
supplier) from a product you need to establish a specification for the establish specifications that ensure you
manufacture. One such requirement is temperature at which the product will use the ‘‘specified packaging’’ and to
final § 111.70(f) which requires you to be held. However, a person who only apply the ‘‘specified label’’ as we
establish specifications for a product holds packaged and labeled dietary proposed under proposed
you receive for packaging or labeling as supplements for distribution is not § 111.37(b)(11)(iv). We removed the
a dietary supplement (and for required to establish component words ‘‘specified in the master
distribution rather than for return to the specifications (final § 111.70(b)), in- manufacturing record’’ as an editorial
supplier). process specifications (final § 111.70(c)), change that we are making to simplify
The inclusion of final § 111.70(f), or specifications for labels and for the language of the requirement.
any other provision that relates packaging (final § 111.70(d)), product As already explained (see discussion
explicitly to a product you receive for specifications (final § 111.70(e)), of final § 111.70(a)), the specifications
packaging or labeling as a dietary specifications for product received from you establish under final § 111.70 are
supplement, does not alter the fact that a supplier for packaging as a dietary regulatory specifications required by
such a product is no different from any supplement (and for distribution rather these final CGMP requirements. The
other dietary supplement as far as the than for return to the supplier) (final final rule would not prevent you from
applicability of these CGMP § 111.70(f)), or specifications for the establishing additional, nonregulatory
requirements. packaging and labeling of the finished specifications, such as specifications
Under final § 111.70(f), the packaged and labeled dietary that largely address the appearance of
specifications you establish for a supplements (final § 111.70(g)) because the dietary supplement in an aesthetic
product you receive for packaging or the person does not engage in any of sense.
labeling as a dietary supplement must those activities. This is consistent with H. What is Your Responsibility for
provide sufficient assurance that the the views expressed by the comments Determining Whether Established
received product is adequately regarding the applicability of proposed Specifications Are Met? (Final § 111.73)
identified and is consistent with your § 111.35(e) to persons who only hold
purchase order. For example, you may packaged and labeled dietary Final § 111.73 requires you to
be purchasing tablets that provide 500 supplements for distribution. determine whether all specifications
mg (strength) (quantitative amount per you establish under final § 111.70 are
serving) of vitamin C (identity). 7. Final § 111.70(g) met. The criteria for determining
Therefore, your purchase order would Final § 111.70(g) requires you to whether the specifications that you
need to include the identity and amount establish specifications for the establish under final § 111.70 are met
of vitamin C per tablet to distinguish it packaging and labeling of the finished are set forth in final § 111.75. The
from other tablets of vitamin C that may packaged and labeled dietary oversight by quality control personnel
contain only 60 mg, or from other supplements, including specifications for determining whether specifications
vitamin tablets of 500 mg that you may that ensure you used the specified established under final § 111.70 are met
also purchase. packaging and you applied the specified in accordance with the criteria
Final § 111.70(f) sets forth a label. established under final § 111.75 and
requirement for a product you receive Final § 111.70(g) is a new provision under what conditions quality control
for packaging or labeling as a dietary we are adding for clarity and personnel can approve deviations from
supplement that will be distributed by consistency. We had proposed to specifications are set forth in final
you, rather than returned to the firm require that you conduct a material § 111.77 and final subpart F. Although
from which you receive the product. review and make a disposition decision final § 111.73 requires you to determine
Thus, § 111.70(f) applies to product that of any packaged and labeled dietary whether specifications are met, it is the
has left the control of the person who supplements that do not meet responsibility of quality control
manufactured the batch. specifications (proposed § 111.70(c)). personnel to conduct a material review
If you are a packager or labeler who We proposed minimum standards for and make a disposition decision if a
packages and labels for the packaged and labeled dietary specification established in accordance
manufacturer and you will return the supplements—i.e., we would require with final § 111.70 is not met.
packaged and labeled dietary that the quality control unit collect Final § 111.73 derives, in part, from
supplement to the manufacturer, we representative samples of each batch of proposed § 111.35(f), (g), and (h). Final
would not consider that you are packaged and labeled dietary § 111.73 includes changes associated
‘‘receiving’’ product within the meaning supplements to determine whether you with reorganization, and other revisions
of final § 111.70(f). Thus, you would not used the packaging specified in the associated with final § 111.70. Final
be subject to final § 111.70(f). master manufacturing record and § 111.73 neither includes any finished
batch testing requirements that derive occurrence and severity), and control of supplement. The comments that assert
from proposed § 111.35(g)(3) nor the biological, chemical, and physical that the CGMP requirements should
specifies what you must do to determine hazards associated with a particular place greater emphasis on HACCP
whether all specifications are met food production process or practice. principles and, in so doing, reduce the
because the requirements for what HACCP is a preventive strategy. It is requirements to test product at the
means and methods you must use to based on development by the food finished batch stage, did not explain
determine whether specifications are producer of a plan that anticipates food how the preventive measures that are
met, including certain requirements for safety hazards and identifies the points associated with a HACCP plan would be
testing, are set forth in final § 111.75. in the production process where a effective at ensuring that a dietary
The comments relevant to final failure would likely result in a hazard supplement is what you established it to
§ 111.73 are the general comments that being created or allowed to persist; be in your specifications. Therefore, we
recommend an overall approach that these points are referred to as critical are not, as the comments request,
focuses on building quality into a control points (CCPs). including additional HACCP
dietary supplement throughout the Under HACCP, identified CCPs are requirements as part of the overall
production and process control system. systematically monitored, and records approach set forth in this final rule.
Because the primary focus of the kept of that monitoring. Corrective In the 2003 CGMP Proposal, we noted
relevant comments is on the proposed actions are taken when control of a CCP that you may voluntarily choose to
requirements for testing, we discuss is lost, including proper disposition of implement a HACCP plan that meets the
those comments when we describe the the food produced during that period, requirements of the National Advisory
derivation of the testing requirements in and these actions are documented. Committee on Microbiological Criteria
final § 111.75. Thus, the focus of a HACCP-based for Foods, but that proposed part 111
approach is to anticipate food safety would still apply to you (68 FR 12157
I. What Must You Do to Determine
hazards, take actions to prevent them, at 12174). We also noted that any
Whether Specifications Are Met? (Final
and keep records of both the actions HACCP plans that are intended to meet
§ 111.75)
taken to prevent problems and the the records requirements under
Final § 111.75 derives from proposed actions taken if a problem nonetheless proposed part 111 would be treated as
§§ 111.35(f), (g), (h), (k), and (l); occurs. records under the CGMP regulations.
111.37(b)(11); and 111.40(a) and (b). As discussed in the preamble to the (Comment 173) One comment states
Final § 111.75 describes the steps you 2003 CGMP Proposal (68 FR 12157 at that it supports a requirement that a
must take to determine whether 12174), most of the comments that we firm ensure that specifications have
specifications are met. received to the ANPRM opposed basing been met and asserts that the 2003
(Comment 172) Many comments a CGMP regulation for dietary CGMP Proposal failed to do so. This
assert that the CGMPs for dietary supplements on HACCP principles. comment asserts the specific testing
supplements should place greater Consistent with those comments, we requirements in proposed § 111.35(g)(1)
emphasis on in-process controls and proposed certain requirements that, and (g)(2) must be significantly
HACCP principles. The comments state although consistent with a HACCP- modified and suggests that a more
FDA’s narrow focus on finished product based approach, did not require a effective approach would be to establish
testing is not in line with the HACCP-based approach. For example, separate requirements for ensuring that
philosophy of HACCP, in which proposed § 111.65 would establish specifications are met in each of the four
manufacturing steps are controlled and requirements for manufacturing categories addressed by proposed
verified so as to result in end products operations, including several proposed § 111.35(e): Goods received
that are safe, with minimal finished requirements to prevent contamination (§ 111.35(e)(1)), in-process controls
product testing. One comment cites a of components or dietary supplements, (§ 111.35(e)(2)), manufactured goods
1997 document entitled ‘‘Hazard but would not require that you develop (§ 111.35(e)(3)), and labels and
Analysis and Critical Control Point a specific plan for the precautions that packaging (§ 111.35(e)(4)).
Principles and Application Guidelines’’ you would take, or that you keep (Response) The final rule is consistent
in which we state that ‘‘[A]n effective records of any monitoring that was with this comment. Final § 111.70
HACCP system requires little end- directed solely at preventing specific requires you to establish certain
product testing, since sufficient types of contamination. specifications (including specifications
validated safeguards are built-in early in In contrast to the specific focus of for components, in-process controls, the
the process.’’ (Ref. 31). HACCP to anticipate food safety finished batch and packaging and
(Response) In the 1997 ANPRM, we hazards, take actions to prevent them, labels), and final § 111.75 sets forth the
asked for comments on whether certain, and keep records of both the actions requirements for what you must do to
or all, of the requirements for taken to prevent problems and the determine whether those specifications
manufacturing and handling dietary actions taken if a problem nonetheless are met.
ingredients and dietary supplements occurs, CGMP requires that you take all
may be more effectively addressed by a necessary steps to both prevent hazards 1. Final § 111.75(a)
regulation based on the principles of and ensure that the product that you Final § 111.75(a)(1) requires you,
HACCP, rather than the system outlined manufacture is what you established in before you use a component that is a
in the industry submission (62 FR 5700 your specifications. The proposed dietary ingredient, to conduct at least
at 5708). HACCP is a science-based, testing requirements were directed at one appropriate test or examination to
systematic approach to preventing food ensuring that a dietary supplement verify the identity of the dietary
safety problems by anticipating how meets all of its established ingredient. We recognize, however, that
such problems are most likely to occur specifications, including specifications it may be possible for a manufacturer to
and by installing effective measures to for the identity, purity, strength, and demonstrate, through various methods
prevent them from occurring. The composition, rather than on ensuring and processes in use over time for its
HACCP concept is a systematic only that specific food safety hazards particular operation, that a system of
approach to the identification and the that you take steps to prevent are not, less than 100 percent identity testing
assessment of risk (likelihood of in fact, present in the dietary would provide no material diminution
of assurance of the identity of the (also, see comment 145 of this Some comments address the
dietary ingredient as compared to the document). requirement in proposed § 111.40(a)(2)
assurance provided by 100 percent Some comments recommend an to ‘‘Visually examine the suppliers
identity testing. To provide an appropriate vendor qualification invoice, guarantee, or certification
opportunity for a manufacturer to make program, including a combination of * * * and perform testing, as needed, to
such a showing and reduce the vendor audits and product testing, to determine whether specifications are
frequency of identity testing of alleviate the need for complete testing of met.’’ One comment agrees with this
components that are dietary ingredients every lot of incoming components. proposed requirement and asserts that
from 100 percent to some lower Several comments stress that a the supplier’s certification is not
frequency, we decided to provide, in an meaningful certificate of analysis must sufficient to ensure that appropriate
interim final rule published elsewhere be based on the results of actual standards are met. Other comments,
in this issue of the Federal Register, a analytical testing. One comment adds however, disagree with this aspect of
procedure that allows for submission to, that reliance on a supplier’s certificate the proposed requirement or ask for
and review by, FDA of an alternative to of analysis should be conditioned on a further clarification. A few comments
the required 100 percent identity testing qualification program whereby the assert that manufacturers should not
of components that are dietary recipient independently verifies the have to retest material already tested by
ingredients, provided certain conditions supplier’s ability to conduct tests and a supplier. Some comments note that a
are met. verifies test results through certificate of analysis can be used for
Final § 111.75(a)(2) requires you, confirmatory testing. ensuring received materials are
before you use a component, to confirm Many comments provide suggestions consistent with the purchase order, and
the identity of other components and for ways in which manufacturers could assert the certificate of analysis can be
determine whether other applicable demonstrate the reliability of a an appropriate way to ensure
component specifications established in certificate of analysis, which include the specifications are met without requiring
accordance with § 111.70(b) are met. To following: (1) Identity testing of testing. One comment suggests the
do so, final § 111.75(a)(2) requires you ingredients and components, (2) phrase ‘‘perform testing, as needed’’ be
to either conduct appropriate tests or maintenance of documentation of replaced with ‘‘perform testing, if
examinations (final § 111.75(a)(2)(i)); or appropriate test results, (3) appropriate necessary’’ and that the CGMP
rely on a certificate of analysis from the verification of the information provided regulations allow for the use of a
suppler of the component that you initially and at appropriate intervals, certificate of analysis that has been
receive (final § 111.75(a)(2)(ii)). Final and (4) documentation that any verified through a vendor certification
§ 111.75(a)(2)(ii) sets forth the criteria suppliers have adequate CGMP process. Another comment states that
that you must satisfy in order to rely on programs in place. the provisions requiring testing in
a certificate of analysis from a supplier: proposed § 111.40(a)(2) are more
Some comments recommend that
• You must first qualify the supplier burdensome than those required of food
vendor certification programs include
by establishing the reliability of the and pharmaceutical products and cites
plant visits and inspections, while other
supplier’s certificate of analysis through the drug CGMP provision that permits
comments do not believe manufacturers
confirmation of the results of the the use of certificates of analysis in lieu
should be required to conduct plant
supplier’s tests or examinations; of testing for conformity with written
inspections. Other comments
specifications. One comment supports
• The certificate of analysis must recommend that vendor certification the idea of testing upon receipt in the
include a description of the test or programs include CGMP audits or specific circumstance when testing
examination method(s) used, limits of process reviews at supplier facilities; cannot be performed on the finished
the test or examinations, and actual verification of laboratory test results product.
results of the tests or examinations; against a certificate of analysis; and 100 Several comments contend that there
• You must maintain documentation percent inspection and testing of is a conflict between the 2003 CGMP
of how you qualified the supplier; incoming materials for a specified Proposal and our position during our
• You must periodically re-confirm period of time while reliability is being stakeholder meetings. The comments
the supplier’s certificate of analysis; and assessed. assert that, at the meetings, FDA
• Quality control personnel must Some comments provide suggestions representatives recognized that a
review and approve the documentation for the types of information that should verified certificate of analysis is
setting forth the basis for qualification be included on an acceptable certificate acceptable, provided it is based on
(and re-qualification) of any supplier. of analysis, such as moisture, sieve appropriate testing from suppliers who
Final § 111.75(a)(1) and (a)(2) derive, analysis, identity, and results of tests are audited by their customers as to
in part, from proposed § 111.35(g) and against established raw material their testing and manufacturing
(h) and proposed § 111.40(a)(2) and specifications and specifications of any practices.
(a)(3). Final § 111.75(a)(1) and (a)(2) compendia referenced on the label. One A few comments say the 2003 CGMP
include changes that we are making comment suggests that a certificate of Proposal should allow more reliance on
after considering comments to proposed analysis could be converted into sworn strict chain of custody and
§§ 111.35 and 111.40(a). affidavits to guarantee their reliability. documentation requirements. Other
(Comment 174) Many comments Some comments suggest that a system of comments recommend that
assert that a certificate of analysis from testing one batch for agreement with the manufacturers not be required to retest
a properly certified supplier can be a certificate of analysis, and then relying previously tested incoming ingredients
key element of the manufacturing on this information for future purchases, if they arrive with the vendor’s seal
process, and reduce the need for testing would work well if the suppliers are intact. Rather, the purchaser should be
at the finished batch stage. Some required to provide reliable and valid able to rely on the vendor’s test results,
comments specifically recommend the certificate of analysis documents. One as presented in a verified certificate of
dietary supplement manufacturer comment suggests we issue guidelines analysis, unless there has been a breach
conduct identity tests to ensure that the as to what should be included in a in quality control during distribution
correct component has been received properly verified certificate of analysis. and subsequent manufacture. One
comment notes the Canadian in this issue of the Federal Register, a (Comment 175) One comment asks if
regulations for Natural Health Products procedure that allows for submission to, a raw material contains an unknown
allow periodic testing of ingredients if a and review by, FDA of an alternative to amount of excipients, is it necessary to
manufacturer has satisfactory evidence the required 100 percent identity testing quantify the excipients or can a
that the raw materials sold to him/her of components that are dietary company simply assess the active
are consistently manufactured in ingredients, provided certain conditions material and rely on a vendor’s
compliance with established are met. For components other than specification for the excipient content?
specifications. dietary ingredients you must confirm (Response) To the extent that this
(Response) We agree that CGMP the identity of the component and you comment is asking whether it is
requires that a person who have the flexibility of relying on a necessary to set a component
manufactures a dietary supplement certificate of analysis, in lieu of specification for the strength of
conduct at least one appropriate test or conducting a test or examination, to excipients that are present in a dietary
examination to verify the identity of confirm identity. The preamble to the supplement, the final rule does not
each dietary ingredient that will be used 2003 CGMP Proposal discussed why we require you to do so provided that such
in the manufacture of the dietary were not proposing that you could rely a component specification is not
supplement. For example, because some on a certificate of analysis, but did not necessary to ensure that the
botanicals require microscopic express a view as to whether the specifications for the purity, strength,
examination and comparison to a establishment of minimum criteria for composition, or contamination limit for
reference to be distinguished, and how you would qualify the supplier, the dietary supplement manufactured
because suppliers of such botanicals and for what must be included on the using the excipients are met (final
may manufacture several of these certificate of analysis, could alleviate § 111.70(b)(2)). If such a strength
botanicals, it is important to verify that our concerns about whether the specification for an excipient is
a botanical that you receive from a certificate of analysis could ensure necessary to ensure that the purity,
supplier is the correct botanical. In certain attributes of dietary strength, or composition specifications
some cases, a single test or examination supplements. are met, or that a contamination limit is
may be all that is needed to verify the After considering the comments, we met for the dietary supplement, you
identity of a dietary ingredient; in other also are persuaded that it is possible to could, as the comment suggested, rely
cases, it may be necessary to conduct rely on a certificate of analysis from the on a certificate of analysis for that
more than one test or examination. It is supplier, for attributes other than quantitative information provided that
the responsibility of the manufacturer to identity of the dietary ingredient,
you satisfy the criteria set forth in final
determine the appropriate test(s) or provided you satisfy certain minimum
§ 111.75(a).
examination(s) necessary to verify the criteria set forth in final
identity of a dietary ingredient. § 111.75(a)(2)(ii). These criteria include 2. Final § 111.75(b)
The comments discussed the qualifying the supplier, maintaining
importance of testing all components for Final § 111.75(b) requires that you
documentation of how you qualified the
identity and did not appear to limit monitor the in-process points, steps, or
supplier, periodically reconfirming the
their recommendation for conducting stages where control is necessary to
supplier’s certificate of analysis, and
identity tests to those components that ensure the quality of the finished batch
having quality control personnel review
are dietary ingredients. Based on the of dietary supplement, to determine
and approve the documentation setting
comments, we conclude that many firms forth the basis for qualifying the whether the in-process specifications
would conduct an identity test for most supplier. These criteria also require that are met, and to detect any deviation or
ingredients and other components the certificate of analysis, at a unanticipated occurrence that may
rather than limit identity testing to minimum, includes a description of the result in a failure to meet specifications.
dietary ingredients. However, because test or examination method(s) used, Final § 111.75(b) derives from proposed
dietary ingredients are the central limits of the tests or examinations, and § 111.35(f) with revisions associated
defining ingredient of a dietary the actual results of the tests or with final § 111.70(c)(1).
supplement, final § 111.75(a) only examinations. Under final (Comment 176) A few comments
requires you to conduct tests or § 111.75(a)(2)(ii)(A), to qualify the argue that it is not possible to monitor
examinations to verify the identity of supplier you must establish the in-process for those specifications
any component that is a dietary reliability of the supplier’s certificate of required under proposed § 111.35(e).
ingredient. As discussed previously in analysis through confirmation of the One comment states that a specification
this section, we recognize, however, that supplier’s tests or examinations. such as identity is no longer identifiable
it may be possible for a manufacturer to Certain comments request that we at an in-process stage. This comment
demonstrate, through various methods provide guidance on what should be also notes any such requirement in
and processes in use over time for its included in a certificate of analysis. As proposed § 111.35(e) would be
particular operation, that a system of stated earlier in this section, a certificate redundant, because proposed
less than 100 percent identity testing of analysis is a document, provided by § 111.35(h) requires a firm to ensure,
would provide no material diminution the supplier of a component prior to or through testing or examination, that all
of assurance of the identity of the upon receipt of the component, that established specifications are met.
dietary ingredient as compared to the documents certain characteristics and Another comment contends that some
assurance provided by 100 percent attributes of the component. Instead of specifications are not met until
identity testing. To provide an guidance, we are establishing, in final processing is complete, such as with
opportunity for a manufacturer to make § 111.75(a)(2)(ii)(B), minimum criteria liquid extracts. A few comments
such a showing and reduce the that a certificate of analysis must meet recommend that the requirement for
frequency of identity testing of to satisfy these CGMP requirements. As monitoring be limited to ensuring that
components that are dietary ingredients we gain experience in applying the specifications established for in-process
from 100 percent to some lower CGMP regulations, we will consider controls under proposed § 111.35(e)(2)
frequency, we decided to provide, in an whether it is appropriate to provide and finished product under proposed
interim final rule published elsewhere guidance on certificates of analysis. § 111.35(e)(3) are met.
One comment states it is not always would not need to conduct in-process and limits on those types of
possible for a manufacturer to monitor monitoring for identity. contamination that may adulterate or
for strength and purity of raw materials (Comment 177) One comment that may lead to adulteration of the
during in-process steps. The comment requests clarification on what would be finished batch of the dietary
suggests this proposed requirement be considered ‘‘in-process’’ for materials supplement. Final § 111.75(c) also sets
removed or revised. that are simply blended together to form forth the following verification
a final product. The comment asks how requirements:
(Response) The comments may have a firm would test the samples if a final • You must select one or more
misunderstood what we refer to as ‘‘in- material cannot be tested due to established specifications for identity,
process’’ specifications. Under final interferences or lack of an available purity, strength, composition, and limits
§ 111.75(b), you must monitor the in- method. on those types of contamination that
process points, steps, or stages where (Response) Examples of in-process may adulterate or that may lead to
control is necessary to ensure the specifications when materials are adulteration of the dietary supplement
quality of the finished batch of dietary simply blended together are the mixing that, if tested or examined on the
supplement, to determine whether the time and speed. finished batch of the dietary
in-process specifications are met, and to (Comment 178) One comment points supplement, would verify that the
detect any deviation or occurrence that out that in-process testing for production and process control system
may result in a failure to meet ‘‘unanticipated occurrences’’ required is producing a dietary supplement that
specifications. The in-process under proposed § 111.35(f) would be meets all product specifications (or only
specifications that you establish ensure difficult, because the manufacturer those product specifications not
that, for example, the specification for would not know what to test for. otherwise exempted from this provision
strength is achieved. If you must deliver (Response) This comment may have by quality control personnel under final
a certain amount of powdered vitamin misunderstood the provision, which did § 111.75(d));
C to a mixture at a certain point in the not propose to require that you test for • You must conduct appropriate tests
process in order to achieve a final an unanticipated occurrence. Rather, or examinations on the specifications
product that contains 60 mg of vitamin proposed § 111.35(i)(2) would require selected in final § 111.75(c)(1);
C, a critical point in the process is you to review the results of any • You must provide adequate
where ‘‘x’’ mg of vitamin C is added to monitoring, and conduct a material documentation of your basis for why
ensure that the final product contains 60 review and make a disposition decision, meeting the specification(s) selected
mg of vitamin C. You would monitor the if there is any unanticipated occurrence under final § 111.75(c)(1), through the
operation to ensure that ‘‘x’’ mg of that adulterates or could result in use of appropriate tests or examinations
vitamin C is added. Your strength adulteration of a component or dietary conducted under final § 111.75(c)(2),
specification may be tested at the end of supplement. An example of such an will ensure that your finished batch of
the process as a product specification, occurrence is leakage of extraneous the dietary supplement meets all
but your in-process specification to material from a pipe onto a component. product specifications for identity,
ensure the addition of ‘‘x’’ mg of Quality control personnel, under final purity, strength, composition, and the
§ 111.113(a)(3), must conduct a material limits on those types of contamination
vitamin C is a specification that is
review and make a disposition decision that may adulterate, or that may lead to
separate and distinct from the
if there is such an unanticipated the adulteration of, the dietary
specification that you establish for
occurrence during the manufacturing supplement; and
strength, i.e., 60 mg vitamin C. You may • Quality control personnel must
determine that in-process specifications operations.
(Comment 179) One comment review and approve the documentation
are met through a test or examination. that you provide under final
suggests that the provision is a HACCP
You could monitor for the vitamin C § 111.75(c)(3).
requirement and is unnecessary for
product by checking the equipment you Final § 111.75(c) requires you to
dietary supplements whose production
use to mix the vitamin C-containing verify that your finished batch of dietary
generally does not involve bacterial
product to ensure that the mixing supplement meets specifications for
contamination.
process was carried out during the time (Response) We disagree. It is not a identity, purity, strength, composition,
period specified in the master HACCP requirement because the and limits that you established for those
manufacturing record to ensure provisions deal with unanticipated types of contamination that may
uniformity in the finished batch. Other occurrences. Dietary supplement adulterate or that may lead to
examples could include a measurement, production can involve bacterial adulteration of the finished batch. You
such as checking pH during the course contamination as discussed in section V may verify this by either testing or
of a process, or removing samples of this document. The purpose of final examining: (1) Every finished batch for
during the course of a process to § 111.75(b) is to ensure that the product each of these specifications or (2) a
conduct a test for viscosity. There may meets all specifications, which include subset of finished batches for the dietary
be no need for certain in-process specifications associated with supplement. The subset of batches
specifications to ensure that contamination, and, therefore, is a tested must be identified using a sound
specifications for identity, purity, necessary provision. statistical sampling plan.
strength, and composition of the If you choose to test or examine a
finished batch of dietary supplement are 3. Final § 111.75(c) and (d) subset of finished batches of dietary
met. If there are no in-process points, Final § 111.75(c) requires you, for a supplement, you may test or examine
steps, or stages at which any test or subset of finished dietary supplement each subset of batches for identity,
examination is needed to ensure that the batches, which you identify through a purity, strength, composition, and limits
identity specification for the finished sound statistical sampling plan (or for on contamination that you established.
batch of dietary supplement is met, then every finished batch), to verify that your Alternatively, you may determine that
you would not need to establish an in- finished batch of the dietary supplement you can select one, two, or three, or
process specification to ensure identity meets product specifications for other number of these specifications
in the finished batch, and, therefore, identity, purity, strength, composition, that, if determined to be in compliance
with specifications, would be able to when testing the finished product is not (Response) As we explain in section
verify that the other untested possible. Other comments object to the XXIV of this document, we have made
specifications are met. For example, you proposed requirements for finished changes to reduce the testing burden on
may be able to substantiate that, if you product testing on the grounds that they companies while still requiring steps
determine compliance with the are overly burdensome, duplicative, and necessary to ensure the quality of
specification for the identity and unnecessary. dietary supplements. For example,
composition of a product for which no Some comments suggest that a more under final § 111.75(a), instead of
contamination limits are needed, the practical approach to finished product testing or examination (other than for
system is adequately controlling for the testing would be to conduct identity identity of the dietary ingredients),
purity and strength of the product, testing of each component, combined firms may rely upon supplier
without the need to test for compliance with certification of the vendor by a certificates of analysis in certain
with the specifications for purity and program of complete testing for circumstances. Also, we recognize,
strength. If so, you must document, conformance with a certificate of however, that it may be possible for a
under final § 111.75(c)(3) your basis for analysis, as is allowed under the drug manufacturer to demonstrate, through
why this is so. Quality control CGMP regulations. Some comments various methods and processes in use
personnel must review and approve suggest manufacturers that have written over time for its particular operation,
such documentation under final procedures for each stage of their that a system of less than 100 percent
§ 111.75(c)(4). process, including raw material identity testing would provide no
Under final § 111.75(d), you may certification, production, and finished material diminution of assurance of the
determine, in the previous example, that product analysis, and a written plan for identity of the dietary ingredient as
you could not verify, by testing for qualifying the process, should be compared to the assurance provided by
compliance with the specifications for exempt from the proposed requirements 100 percent identity testing. To provide
identity and composition, that the to test each finished batch. Some an opportunity for a manufacturer to
purity specification is met, and there comments urge us to give companies the make such a showing and reduce the
may be no scientifically valid method flexibility to devise testing procedures. frequency of identity testing of
for testing or examining the finished (Response) The approach in final components that are dietary ingredients
batch to evaluate the purity in the § 111.75(c) and (d) is consistent with from 100 percent to some lower
finished batch of dietary supplement. In these comments and is part of the frequency, we decided to provide, in an
that case, you could exempt the overall approach of this final rule, interim final rule published elsewhere
specification for purity from the in this issue of the Federal Register, a
which focuses on ensuring the quality of
requirement in final § 111.75(c)(1) if you procedure that allows for submission to,
the dietary supplement throughout the
can document why the purity and review by, FDA of an alternative to
production and process control system.
specification is met without such testing the required 100 percent identity testing
The concept behind final § 111.75(c)
or examination. You could do so of components that are dietary
through, for example, documentation and (d) is analogous to the overall
concept of proposed § 111.35(g). Under ingredients, provided certain conditions
that meeting component and are met. In addition, under final
specifications for strength is sufficient, proposed § 111.35(g) you could rely on
a combination of meeting component § 111.75(c), testing or examination for a
or through documentation that in- portion of the finished batches is an
process monitoring is sufficient. Quality specifications and in-process
specifications when you are unable to option, and exemptions are provided for
control personnel must review and
test for a specification, provided you in final § 111.75(d).
approve such documentation (final
§ 111.75(d)). satisfied certain criteria. Under the final (Comment 182) One comment points
Final § 111.75(c) and (d) derive from rule, you may rely on a combination of out that, if a product cannot be tested
proposed § 111.35(g) and (h) and meeting component specifications and for technical reasons at the final product
include changes that we are making in-process specifications to verify that stage, then it also cannot be tested at the
after considering comments. your product meets specifications, final blending stage in the process,
(Comment 180) Several comments rather than test every batch to determine because the nature and composition of
assert that a more appropriate balance is whether specifications are met, the product at both stages are virtually
needed between an effective process regardless of whether a test is available, the same. Another comment asks
control system and a reasonable testing provided you satisfy certain criteria. whether a verification of content in the
scheme calculated to confirm the Thus, the final rule provides flexibility final product will suffice if there is no
quality of dietary supplements. The that is needed to build adequate valid testing procedure.
comments stress it is important to build controls early in the process to reduce (Response) Under final § 111.75(c),
quality into a product throughout the the need for end product testing on you have flexibility to select one or
entire production process by relying on every batch of finished dietary more established specifications for
strong process controls rather than by supplement. identity, purity, strength, composition,
testing at the finished batch stage. One (Comment 181) One comment and limits on those types of
comment asserts that in an appropriate expresses concern that the requirement contamination that may adulterate or
process control system, testing is a to use appropriate tests to determine that may lead to adulteration of the
means to monitor and ensure that the compliance with specifications could be dietary supplement that, if tested or
control system is functioning as interpreted as requiring companies to examined on the finished batch of the
intended. Several comments make a test dietary supplements not only for dietary supplement, would verify that
specific recommendation that the final compliance with company the production and process control
rule include rigorous controls. specifications, but also for compliance system is producing a dietary
Some comments support the with any labeled specifications of the supplement that meets all product
requirement under proposed § 111.35(g) ingredient suppliers, such as for specifications. Under final § 111.75(d),
to test each batch of finished product contaminants. The comment believes you have flexibility to exempt one or
when possible, and to perform testing of this would be redundant and overly more product specifications from
components and in-process testing burdensome. verification requirements, provided that
you satisfy the criteria established under § 111.75(e) derives from proposed receive for * * * for distribution rather
final § 111.75(d). § 111.35(e)(1) and (g) and from proposed than for return to the supplier’’ and,
(Comment 183) Some comments § 111.40(a)(2). thus, applies to product that has left the
request that the rule include (Comment 185) Some comments control of the person who manufactured
requirements for dissolution, request we clarify the roles and testing the batch. If you are a packager or
disintegration, and bioavailability obligations of the various parties in the labeler who packages and labels a
testing for dietary supplements. These ‘‘pre-consumer supply chain’’ for dietary supplement for the
comments note that, although a product dietary supplements. Some comments manufacturer, and you will return the
may contain the labeled amount, it may argue that redundant tests should not be packaged and labeled dietary
not dissolve readily in the body or be required at every transaction point in supplement to the manufacturer, we
available for absorption. the pre-consumer supply chain. The would not consider that you are
(Response) We decline to revise the comments contend that any testing ‘‘receiving’’ product within the meaning
rule as suggested by the comments. As already performed by a supplier, of final § 111.75(e). Thus, you would not
discussed in the preamble to the 2003 manufacturer, or packager should be subject to final § 111.70(f).
CGMP Proposal (68 FR 12157 at 12163), suffice, so long as other CGMP
tests for dissolution, disintegration, and certification, and chain of custody 5. Final § 111.75(f)
bioavailability of dietary supplements standards, are met. Other comments Before you use packaging, final
are examples of areas where scientific urge us to give companies the flexibility § 111.75(f)(1) requires you, at a
study is still evolving; thus it is to devise testing procedures and point minimum, to conduct a visual
premature to impose requirements for out that different testing is needed for identification of the containers and
such tests. The comments provide no different roles in the supply chain. closures and review the supplier’s
specific information that would alter One comment requests clarification of invoice, guarantee, or certification to
this view or support the technical the testing requirements applicable to determine whether packaging
feasibility of conducting such tests for packagers/labelers. The comment states specifications are met. Before you use
all types of dietary supplement it is unclear how a packager or labeler/ labels, final § 111.75(f)(2) requires you,
products. However, nothing in this final distributor could conduct testing of at a minimum, to conduct a visual
rule would preclude a manufacturer component ingredients if all the firm examination of the label and review the
from establishing such requirements. A receives is a finished product for which supplier’s invoice, guarantee, or
manufacturer should have data to there is no scientifically valid testing certification to determine whether
support any specifications it establishes method. labeling specifications are met. Final
for parameters such as dissolution, (Response) As discussed in section VI § 111.75(f)(1) and (f)(2) derive from
disintegration, and bioavailability. of this document, you are responsible proposed § 111.40(b)(2) which, in part,
(Comment 184) One comment for the CGMP requirements that are would require you, for packaging and
questions the requirements in the 2003 applicable to your operations. We agree labels you receive, to conduct at least a
CGMP Proposal that all manufacturers that redundant tests should not be visual identification on the containers
quantify certain marker compounds in required. Further, we agree that it is the and closures. Proposed § 111.40(b)(2)
their products. The comment offers two responsibility of the manufacturer to do also would require you, in part, for
reasons why such testing should not be component testing. The packager or packaging and labels you receive, to
required for botanical products: Their labeler does not need to do any required quarantine the packaging and labels
food-like composition and legal status, component testing because the packager until your quality control unit tests or
and the assertion that scientifically or labeler does not receive components, examines a representative sample to
valid analytical methods may prove to rather it receives a finished dietary determine whether specifications are
be irrelevant or even hinder the supplement. Under final § 111.70(f) if met. Consistent with changes that we
development of superior products. you receive a product from a supplier are making to the requirements for
(Response) The final rule does not for packaging or labeling as a dietary packaging and labels that you receive
require any specific testing supplement (and for distribution rather (see discussion of final § 111.160 in
requirements, such as testing for marker than for return to the supplier), you section XII of this document), final
compounds. You would determine the must establish specifications to provide § 111.75(f)(1) and (f)(2) include a
specific testing requirements, and sufficient assurance that the product requirement analogous to proposed
whether to use a marker compound in you receive is adequately identified and § 111.40(a)(2) which would require you
those tests, depending on your product is consistent with your purchase order. to visually examine the supplier’s
and process. In the 2003 CGMP Proposal Under final § 111.75(e), before you invoice, guarantee, or certification to
(68 FR 12157 at 12172), we merely package or label such a product, you determine whether the components,
discussed how a marker compound must visually examine the product and dietary ingredients, or dietary
could help you identify whether you have documentation to determine supplements you receive are consistent
have a particular species of an herb to whether the specifications that you with your purchase order and to
differentiate, for example, between a established under final § 111.70(f) are perform testing, as needed, to determine
poisonous and nonpoisonous species. met. Your documentation may consist of whether specifications are met.
an invoice, certificate, guarantee, or
4. Final § 111.75(e) other documentation from the supplier 6. Final § 111.75(g)
Final § 111.75(e) requires you, before to ensure that the product is adequately Final § 111.75(g) requires you, at a
you package or label a product you identified and is the product that you minimum, to conduct a visual
receive for packaging or labeling as a ordered. Final § 111.75(e) does not examination of the packaging and
dietary supplement (and for distribution require that the documentation consist labeling of the finished packaged and
rather than for return to the supplier), to of the result of testing or examination by labeled dietary supplements to
visually examine the product and have the packager or labeler of such a determine whether you used the
documentation to determine whether product. specified packaging and applied the
the specifications that you established As with final § 111.70(f), final specified label. Final § 111.75(g) derives
under final § 111.70(f) are met. Final § 111.75(e) applies to ‘‘product that you from proposed § 111.37(b)(11)(iv) which
would require the quality control unit to morphological examination and requirement that you use scientifically
collect representative samples of each comparison with voucher specimens or valid methods apply only to
batch of packaged and labeled dietary photographs. Another comment requests quantitative methods, because we also
ingredients or dietary supplements to clarification of whether gross proposed that tests in accordance with
determine whether you used the organoleptic analysis alone can be a test proposed § 111.35 must include at least
packaging specified in the master for releasing finished products. Some one of the following: (1) Gross
manufacturing record and applied the comments assert that several organoleptic analysis, (2) microscopic
label specified in the master organizations have published relevant analysis, (3) chemical analysis, or (4)
manufacturing record. Final § 111.75(g) methods that include macroscopic other appropriate test. To clarify that the
is associated with final § 111.70(g) methods that can be used in identifying requirement that methods be
which requires you to establish herbal ingredients. scientifically valid applies to all the
specifications for the packaging and (Response) Organolpetic analysis tests and examinations you use, rather
labeling for the finished packaged and would be an acceptable method under than to quantitative tests alone, final
labeled dietary supplements, including the 2003 CGMP Proposal and remains § 111.75(h)(1) does not use the term
specifications that ensure you used the an acceptable method under the final ‘‘analytical.’’
specified packaging and applied the rule, which clarifies that the method (Comment 191) One comment states
specified label. you use, including organoleptic that the proposed definition of
analysis, must be appropriate. ‘‘appropriate test’’ (i.e., ‘‘a scientifically
7. Final § 111.75(h) Organoleptic analysis may not be an valid analytical method’’) is extremely
Final § 111.75(h)(1) requires you to appropriate method of testing for certain onerous and violates congressional
ensure that the tests and examinations substances. This is particularly true intent. The comment believes that
you use to determine whether the when the nature of the substance mandating specific methods is
specifications are met are appropriate decreases the reliability of organoleptic inappropriate, and dietary supplement
and scientifically valid methods. Final analysis. For example, while CGMPs should comply with Executive
§ 111.75(h)(1) derives from proposed organoleptic analysis may be an Order 12866 and not impose additional
§ 111.35(h). Final § 111.75(h)(1) appropriate identity test for whole or requirements on small businesses that
includes editorial changes associated coarsely-cut botanical parts, it may not are better left to normal business
with the reorganization and changes be an appropriate identity test for practices.
that we are making after considering powdered or extracted botanicals Several comments take issue with our
comments. because of decreased reliability, or in statement that we were not aware of a
Final § 111.75(h)(2) requires that the those instances where misidentification situation where an appropriate
tests and examinations you use include of botanicals is known to occur. scientifically valid method is not
at least one of the following: Gross Additionally, we recognize available when, in fact, valid test
organoleptic analysis, macroscopic ‘‘macroscopic analysis’’ is one of the methods are not always available for
analysis, microscopic analysis, chemical tests or examinations you may select to testing dietary ingredients or dietary
analysis, or other scientifically valid determine whether specifications are supplements. One comment contends
methods. Final § 111.75(h)(2) derives met. the 2003 CGMP Proposal contains
from proposed § 111.35(l). (Comment 189) One comment conflicting information about available
(Comment 186) Some comments remarks that the appropriateness of the test methods. For example, the preamble
suggest that the tests listed in proposed test depends on the material being to the 2003 CGMP Proposal states that
§ 111.35(l) be incorporated into tested, and the method selected by the we are ‘‘not aware of a situation where
proposed § 111.35(h), relating to manufacturer may be inappropriate. an appropriate scientifically valid
appropriate test methods. One comment believes the methods analytical method is not available,’’ and
(Response) We agree with the stated in proposed § 111.35(l) our cost analysis does not address costs
comment, and final § 111.75(h)(2) (organoleptic, microscopy, chemical) for of method development. At the same
combines these requirements as establishment of identity and purity time, however, we set out alternatives to
requested. would not be applicable to animal finished product testing in cases where
(Comment 187) One comment states products. This comment suggests that a adequate methods are unavailable, and
that the list of tests should be deleted separate list of test methods should be we decline to require expiration dating
because it is not sufficient to cover the identified for those materials. because there may not be adequate
types of testing that will be required for (Response) We agree that the methods available for assessing the
compliance with proposed § 111.35(g). appropriateness of the test depends on strength of a dietary ingredient. The
(Response) The comment does not the material being tested. However, we comment cites numerous ongoing efforts
identify the types of tests that would not are not revising the rule to identify in methods development by both
be covered. We believe that final methods that are, or are not, appropriate industry and government that illustrate
§ 111.75(h)(2)(v)’s ‘‘catch-all’’ provision, for specific circumstances (such as the the lack of existing methods necessary
which requires that one of the tests that case of animal-derived ingredients). to confirm compliance with all quality
you use be an ‘‘other scientifically valid There are so many distinct specifications.
method’’ is sufficient to cover all other circumstances that such a list would be (Response) These comments appear to
types of testing required under this final neither practical nor useful. Beyond take our statements out of context. In
rule. that, the manufacturer is responsible for the 2003 CGMP Proposal, we stated: ‘‘If
(Comment 188) One comment states choosing the appropriate test. an AOAC or FDA method is not
that the final rule should make clear (Comment 190) One comment asks us available, a scientifically valid
that organolepsis is an acceptable to clarify in the final rule the analytical method is one that is based
method for identity testing. The requirement that methods be on scientific data or results published
comment contends it is imperative for scientifically valid applies only to in, for example, scientific journals,
the survival of small businesses that quantitative methods. references, text books, or proprietary
organolepsis be allowed, coupled as (Response) In proposed § 111.35(h), research. Although there may not be an
necessary with macroscopic and we did not intend that the proposed Association of Official Analytical
Chemist (AOAC) or FDA method specification they have set. The chemical analysis, or (5) other
available, we are not aware of a comment adds that companies should scientifically valid methods.
situation where an appropriate then be required to ensure, through (Comment 193) One comment
scientifically valid analytical method is appropriate rationale and data, that the questions how a company would know
not available’’ (68 FR 12157 at 12198). method is indeed suitable and produces of all the available scientifically valid
We also stated: ‘‘We recognize that accurate and reproducible results. methods when it deals with hundreds of
certain tests for identity, purity, quality, (Response) We agree that companies items. The comment states it cannot be
strength, or composition for certain should have the flexibility to adopt the expected to have expertise in the assay
finished product may not be available method most suitable to the ingredient methodology for so many different
due to complex finished matrices that they are testing. As discussed in the ingredients.
would make such testing impracticable’’ preamble to the proposal (68 FR 12157 Several comments suggest we make
(68 FR 12157 at 12197). We disagree at 12163 and 12208), official methods, fuller use of available monographs and
that our statement acknowledging that such as AOAC International methods, other resources on test methods and
the available tests may not be are validated in collaborative studies method development. These sources
practicable in certain matrices is using several laboratories under include USP and AHP monographs,
inherently inconsistent with our identical conditions and the AOAC AOAC International, the European
statement that we are not aware of a International methods are often cited as Pharmacopoeia, and the WHO. The
situation where an appropriate ‘‘official validated methods.’’ Other comments urge us to disseminate
scientifically valid analytical method is method validations are conducted in a information on these additional
not available. One statement relates to single laboratory by repeating the same resources.
the availability of methods, the other test multiple times. In the case of Many comments assert that several
relates to the practicality of using an methods used to support specific organizations have published relevant
available method in particular regulatory applications to FDA, data and analytical methods, such as
circumstances. information about methods that are macroscopic, microscopic, and chemical
In any case, under final § 111.75(d)(1) developed and conducted in a single methods, that can be used in identifying
you may exempt a product specification laboratory by repeating the test multiple herbal ingredients. These comments
from the verification requirements of times are sent to us, together with suggest that we should acknowledge
final § 111.75(c)(1) if you show that: (1) appropriate samples and reference those methods and organizations as
The specifications selected to verify that materials so the test can be repeated in authoritative sources of quality
the product meets all product an agency laboratory. Typical validation standards.
specifications are not able to verify that characteristics include accuracy, (Response) In the preamble to the
the control system is producing a precision, specificity, detection limit, 2003 CGMP Proposal (68 FR 12157 at
dietary supplement that meets the quantitation limit, linearity, range, and 12209), we acknowledged that validated
exempted product specification and (2) robustness. methods exist in official compendia for
there is no scientifically valid method The process of method validation vitamins, minerals, and several
for testing or examining the exempted discussed in the previous paragraph is botanicals, and we recommended you
product specification at the finished a formal process for demonstrating that use validated methods whenever such
batch stage. Final § 111.75(c)(1) also procedures are suitable for their methods are available. We explicitly
requires you to document why other intended use. Although many methods stated that you may use validated
information, such as component and in- that are scientifically valid have been methods that can be found in official
process testing, will determine whether formally validated, other methods may references, such as AOAC International,
the exempted product specification is not have been subject to the formal USP, and others.
met without finished batch testing. validation process, e.g., by collaborative As discussed in this section (see
Although we agree that there may be studies using multiple laboratories, but response to comment 196), we believe
some circumstances where there is not nonetheless remain scientifically valid that it is sufficient to provide in this
a scientifically valid method available because they are, in fact, suitable for preamble general guidance on what we
for finished product testing, we believe their intended use. For this reason, we consider to be scientifically valid tests,
that there would be some scientifically stated that the 2003 CGMP Proposal such as those based on scientific data or
valid method available for component would permit tests using methods other results published in, for example,
or in-process testing. than those that are officially validated scientific journals, references, text
(Comment 192) One comment (68 FR 12157 at 12163). Consistent with books, or proprietary research, and leave
encourages flexibility toward the the view that we expressed in the 2003 it to the manufacturer to decide what
development of a quality system that is CGMP Proposal, we believe a scientifically valid tests or examinations
based on a balance of prevention, scientifically valid method is one that is to use in a given operation. In the
appraisal, and process verification accurate, precise, and specific for its future, we may consider issuing
activities. Another comment asks intended purpose. In other words, a guidance as to sources of appropriate
whether the industry should use scientifically valid test is one that tests or examinations, along with other
industry standards and tests now used. consistently does what it is intended to guidances that we may find useful that
A few comments request that we do. relate to certain dietary supplement
clarify proposed § 111.35(h) to make it Under final § 111.75(h)(1), you must CGMP.
clear whether the section recommends ensure the tests and examinations you (Comment 194) One comment states
or requires the use of available USP, use to determine whether the the act prohibits us from imposing
AOAC International (formerly specifications are met are appropriate, testing requirements for which
Association of Official Analytical scientifically valid methods. Under final scientifically valid methods are not
Chemists) or FDA methods. One § 111.75(h)(2) the tests and generally available, and other comments
comment recommends that the final examinations you use must include at believe that not all components have
rule give companies flexibility to use least one of the following: (1) Gross scientifically valid identification tests.
the method(s) most suitable to the organoleptic analysis, (2) macroscopic Given the substantial ongoing efforts
ingredient they are testing and the analysis, (3) microscopic analysis, (4) towards method development, the
comments believe that the proposed testing requirements due to the (Response) The requirement to
requirements for testing would impose bacteriostata properties of ethanol. One establish corrective action plans (final
standards on many products and comment lists some alternatives for § 111.75(i)) applies to components, in-
ingredients that cannot be met through testing naturally occurring ingredients. process specifications, and to the
current and generally available One comment requests clarification finished batch.
methods. on the testing requirements for bovine (Comment 198) One comment states
(Response) We disagree that the cartilage products. The comment states that corrective action plans would be
statute prohibits us from imposing there is no published method for difficult to prepare for a variety of
testing requirements. Section 402(g)(2) extracting chondroitin sulfate from situations, such as for complex
of the act states that dietary supplement bovine cartilage. As a result, the multivitamin and mineral formulas. One
CGMP regulations ‘‘may not impose comment assumes that testing for comment recommends this requirement
standards for which there is no current chondroitin sulfate would not be be deleted. Another comment asserts
and generally available analytical required for these products. that establishment of corrective action
methodology.’’ We are not imposing (Response) We believe that it is plans should be at the manufacturer’s
such standards. The manufacturer must sufficient to provide in this preamble discretion.
establish specifications for its product general guidance about testing, such as (Response) We disagree that the final
and components, and we have provided our discussion that scientifically valid rule should not require you to establish
flexibility for how the manufacturer can tests include official, validated methods corrective plans or that having such
determine whether those specifications as well as tests based on scientific data plans should be at the manufacturer’s
are met. The manufacturer can test, or results published in, for example, discretion. The purpose of having
examine, rely on a certificate of analysis scientific journals, references, text corrective action plans in place before a
(other than to verify the identity of books, or proprietary research. It is the problem occurs is to help you to deal
dietary ingredients), or, in the case of a manufacturer’s responsibility to choose quickly and efficiently with problems as
specification that is exempted from which scientifically valid tests or they arise.
periodic testing of a finished batch, rely examinations to use in a given You may have a corrective action plan
on other information that ensures that operation. Therefore, the final rule does to determine the steps to take if
such an exempted product specification not address the specific testing something goes wrong such as not
is met. circumstances described in these meeting a specification. Moreover, a
(Comment 195) One comment comments, such as testing requirements corrective action plan may include steps
requests clarification on the definition for an herbal product that contains 20 not only for dealing with an acute
of ‘‘examination’’ and asks whether it percent or more ethanol, or for bovine problem, but also for dealing with steps
includes monitoring of process cartilage products. The manufacturer is you would take to followup after the
parameters as established in the master responsible for establishing acute problem is resolved. For example,
manufacturing record. If so, the specifications and meeting such after you resolve an acute problem, such
comment questions whether this specifications, consistent with the as a failure to meet an in-process
practice would satisfy the requirement requirements in this final rule. In the specification, your corrective action
now in final § 111.75(h)(1). future, we may consider issuing detailed plan may include testing of every
(Response) Under final § 111.75(h), guidance as to specific tests or finished batch, rather than a subset of
scientifically valid tests and examinations, along with other finished batches, for some period of
examinations include techniques such guidances that may be useful that relate time to verify that the problem is
as gross organoleptic analysis, to certain dietary supplement CGMP. resolved.
macroscopic analysis, chemical With respect to the comments that We acknowledge that it may not be
analysis, and other scientifically valid discuss botanical identification, we note practical to establish a corrective action
methods. As discussed in the response that the 2003 CGMP Proposal referred to plan for all circumstances, because not
to comment 169, monitoring in-process the draft report of the Dietary all circumstances are foreseeable.
parameters could encompass tests such Supplement Working Group of FDA’s However, the comment asserting that it
as measuring pH or viscosity. Such tests Food Advisory Committee (68 FR 12157 would be difficult to establish corrective
would fall under ‘‘other scientifically at 12161) (Ref. 32). The draft report action plans for the variety of situations
valid methods.’’ discusses the selection of the most that could come up for complex
(Comment 196) One comment appropriate and reliable identity test multivitamin and mineral formulas
contends that botanical identification is and the general principles for provided no basis for why
largely ignored in the 2003 CGMP consideration in setting performance manufacturers of such formulas could
Proposal. The comment states that standards for such tests (Ref. 32). This not anticipate specific situations that
botanical identification forms the basic report may provide useful guidance. present potential problems.
foundation for botanical authenticity (Comment 199) Some comments
and that manufacturers have a legal 8. Final § 111.75(i) recommend that proposed § 111.35(i)(1)
responsibility to ensure the authenticity Final § 111.75(i) requires you to state ‘‘Establish procedures,’’ rather than
of claimed ingredients. The comment establish corrective action plans for use ‘‘Establish corrective action plans.’’
recommends that specific requirements when an established specification is not (Response) The comments did not
for authentication of botanical met. Final § 111.75(i) derives from explain what, if any, practical difference
ingredients be included in the final rule. proposed § 111.35(i)(1). would exist between ‘‘procedures’’ and
One comment points out the difficulty (Comment 197) One comment asks ‘‘corrective action plans.’’ A corrective
in identifying and analyzing all whether the proposed requirement to action plan is a procedure for which you
naturally occurring ingredients in herbs establish corrective action plans for use must have a record in the master
and plants and suggests several when an established specification is not manufacturing record (final
alternatives to testing for all such met (proposed § 111.35(i)(1)) would § 111.210(h)(5)). Because ‘‘corrective
ingredients. Another comment requests apply to specifications for raw materials action plans’’ is a term that is commonly
that an herbal product containing 20 and finished goods as well as to in- used in the industry, we have retained
percent or more ethanol have relaxed process specifications. it in the final rule.
J. What Must You Do if Established • Proposed § 111.50(d)(2), which component in the manufacture of the
Specifications Are Not Met? (Final would require the quality control unit dietary supplement. This component
§ 111.77) not to approve and release for specification must be met and quality
distribution any batch of dietary control personnel are restricted in what
1. Final § 111.77
supplement that does not meet all action must be taken if this specification
As we explain in section II of this specifications; is not met.
document, we reorganized the final rule • Proposed § 111.50(f), which would
require you to not reprocess a batch that 4. Final § 111.77(c)
to make it more ‘‘user-friendly’’ and to
clarify the rule’s applicability to certain deviates from the master manufacturing Final § 111.77(c) requires that if you
persons, items, or activities. Final record unless approved by the quality do not meet the specifications
§ 111.77 is a new provision that clarifies control unit. established under § 111.70(f), quality
your responsibilities and identifies • Proposed § 111.50(g), which would control personnel must reject the
those responsibilities in a more ‘‘user- require that a reprocessed batch of product and the product must not be
friendly’’ fashion. We have identified in dietary supplement meet all packaged or labeled for distribution as
final § 111.77 the consequences of not specifications and that the quality a dietary supplement. As with final
meeting the specifications you establish control unit approve its release for § 111.77(b), final § 111.77(c) limits the
under subpart E and when you can distribution. actions you can take to package and
consider a treatment, in-process • Proposed § 111.35(i)(4)(i), which
label product you receive for packaging
adjustment, or reprocessing to correct a would require you, for any deviation or
and labeling from a supplier for
failure to meet and established unanticipated occurrence which
packaging or labeling as a dietary
specification for a component, dietary resulted in or could lead to adulteration
supplement (and for distribution rather
supplement, packaging, or label. of the component, dietary supplement,
than for return to the supplier). Final
Subpart F does identify these packaging, or label, to reject the
§ 111.77(c) complements final
consequences in several provisions component, dietary supplement,
§ 111.70(f), which requires you to
packaging, or label, unless the quality
which deal with the responsibility of establish a specification for such
control unit determines that in-process
quality control personnel to review and received product and final § 111.75(e),
adjustments are possible to correct the
approve or reject components, dietary which requires you to visually examine
deviation or occurrence.
supplements, packaging, and labels. We • Proposed § 111.35(i)(4)(ii), which the product, before you package or label
determined it would add clarity to state would require you, for any deviation or it, and have documentation to
the consequences for not meeting a unanticipated occurrence which determine whether the specifications
specification in the same subpart in resulted in or could lead to adulteration that you established under § 111.70(f)
which the requirements to establish of the component, dietary supplement, are met. If you do not meet the
specifications are located. packaging, or label, to not reprocess a specifications under final § 111.70(f),
2. Final § 111.77(a) rejected component or dietary you must reject the product and not
supplement unless approved by the package or label the product for
Final § 111.77(a) requires that for quality control unit. distribution as a dietary supplement.
specifications established under
§ 111.70(a), (b)(2), (b)(3), (c), (d), (e), and 3. Final § 111.77(b) K. Comments on Shelf Life
(g) that you do not meet, quality control Final § 111.77(b) requires that for In the preamble to the 2003 CGMP
personnel, in accordance with the specifications established under final Proposal (68 FR 12157 at 12203), we
requirements in subpart F of this part, § 111.70(b)(1) that you do not meet, stated that we had considered whether
must reject the component, dietary quality control personnel must reject the to propose requirements for expiration
supplement, package, or label unless it component and the component must not dating, shelf life dating, or ‘‘best if used
approves a treatment, an in-process be used in manufacturing the dietary by’’ dating (referred to in this preamble
adjustment, or reprocessing that will supplement. Final § 111.77(b) as shelf life or expiration dating). We
ensure the quality of the finished complements final § 111.70(b)(1) which recognized that there are current and
dietary supplement and that the dietary requires you to establish an identity generally available methods to
supplement is packaged and labeled as specification for components; final determine the expiration date of some
specified in the master manufacturing § 111.75(a)(1) which requires you to dietary ingredients, such as vitamin C.
record. No finished batch of dietary conduct at least one appropriate test or However, we were uncertain whether
supplements may be released for examination to verify the identity of any there are current and generally available
distribution unless it complies with component that is a dietary ingredient; methods to determine the expiration
final § 111.123(b). and final § 111.75(a)(2) which requires dating of other dietary ingredients,
This provision identifies those you to confirm the identity of all other especially botanical dietary ingredients.
specifications, if not fully met, that may components. As discussed earlier in this We did not propose to require
be able to be corrected by treatment, in- section, many comments recommended expiration dating because we had
process adjustment, or reprocessing and the final rule include a requirement for insufficient scientific information to
approved by quality control personnel. an identity test of incoming components determine the biological activity of
We emphasize, however, that even if, to ensure quality and safety. We agree certain dietary ingredients used in
for example, corrections are approved, with these comments and earlier dietary supplements, and such
the finished batch of dietary supplement comments that point out it may not be information would be necessary to
can not be released for distribution possible to confirm the identity of some determine an expiration date. Further,
unless it is compliance with the components after they have been because official validated testing
requirements of final § 111.123(b) processed into the finished batch of the methods (e.g., AOAC International or
(discussed in section XI of this dietary supplement. For these reasons, FDA) for dietary supplements are
document). we have concluded that, if the evolving, especially for botanical dietary
Final § 111.77(a) derives from the component specification for identity is ingredients, such methods are not
following proposed provisions: not met, you may not use the always available to assess the strength of
a dietary ingredient in a dietary CGMP Proposal gives the impression to test components that you receive),
supplement. that the required level of supporting § 111.37(b)(11)(i) (requirement to collect
The preamble to the 2003 CGMP data is similar to the requirements for representative samples of components
Proposal emphasized that, if you use an drug labeling, rather than the that you receive), § 111.40(a)(4)
expiration date on a product, you requirements for food shelf life labeling. (requirements for components that you
should have data to support that date Another comment recommends that a receive), § 111.40(b)(5) (requirements for
(68 FR 12157 at 12204). We general maximum shelf life of 4 or 5 packaging and labels that you receive),
recommended that you have a written years should be included in the rule, and § 111.50(c)(5) (requirement to
testing program designed to assess the with shortened or lengthened shelf lives identify materials that you use in the
stability characteristics of the dietary for individual products as data become batch production record). Some of these
supplement, and that you use the results available. proposed requirements (e.g., those in
of the stability testing to determine (Response) These comments do not §§ 111.40(a)(4) and (b)(3) and
appropriate storage conditions and provide data or information that would 111.50(b)(5)) make clear that you must
expiration dates. reduce the uncertainty about the be able to trace each lot of materials you
In the 2003 CGMP Proposal (68 FR feasibility of conducting tests to support receive to each separate shipment that
12157 at 12204), we invited comment an expiration date and, thus, do not contains that lot. To clarify and
on whether any final rule should persuade us to alter our position not to emphasize this meaning of shipment lot,
contain provisions regarding expiration require that you establish an expiration we are revising proposed
dating and the feasibility of conducting date for your product. Indeed, the § 111.37(b)(11)(i) so that the
tests needed to support such dates. We comments generally concur with that representative samples you collect must
also invited comment on whether to position. Because the final rule does not come from ‘‘each unique shipment, and
require expiration dating on certain require that you establish an expiration of each unique lot within each unique
dietary ingredients and not others, for date, we decline to offer guidance on the shipment.’’ We make analogous
example, require expiration dating of type of data that are acceptable to revisions throughout the final rule as
vitamin, mineral, and amino acid, but support an expiration date, other than to necessary.
not of botanical dietary ingredients. repeat that any expiration date that you As discussed in this section, final
(Comment 200) Several comments place on a product label (including a § 111.70(b) sets forth the requirements
agree with our decision not to require ‘‘best if used by’’ date) should be to establish specifications for
expiration dating on labels for dietary supported by data. components, final § 111.73 requires you
supplements at this time, because of the to determine if the specifications
wide range of products and the need for L. What Representative Samples Must
established are met, and final
additional data. Most of these comments You Collect? (Final § 111.80)
§ 111.75(a) sets forth the criteria you use
state, however, that manufacturers Final § 111.80 sets forth requirements to determine whether these
should be allowed to include a ‘‘best if to collect representative samples of specifications are met. Likewise, final
used by’’ date. One comment suggests components, packaging, and labels § 111.70(f) sets forth the requirements to
addressing the issue in a separate (final § 111.80(a)); in-process materials establish specifications for product that
rulemaking. Other comments support an (final § 111.80(b)); the finished batch of you receive from a supplier for
expiration date because consumers and dietary supplement (final § 111.80(c)); packaging or labeling as a dietary
retailers expect one, and some markets product you receive for packaging or supplement (and for distribution rather
require one. Some comments state that labeling as a dietary supplement (and than for return to the supplier), final
the expiration date or statement of for distribution rather than for return to § 111.73 requires you to determine if
product shelf life will help ensure that the supplier) (final § 111.80(d)); and specifications established are met, and
the product meets its label claims and packaged and labeled dietary final § 111.75(e) sets forth the criteria to
potency. supplements (final § 111.80(e)). Final use to determine whether these
Many comments state an expiration § 111.80(a) through (e) derive from specifications are met.
date on a label must be supported by a proposed § 111.37(b)(11)(i) through For consistency with the regulations
rationale or data on stability testing. (b)(11)(iv). in final §§ 111.70 and 111.75, we are
Some of those comments suggest that separating the requirement to collect
manufacturers should have flexibility in 1. Final § 111.80(a)
representative samples of components
the type of supporting data used. Final § 111.80(a) requires you to (final § 111.80(a)) from the requirement
Although label claims should be collect representative samples of each to collect representative samples of
confirmed by shelf life testing when unique lot of components, packaging, product that you receive from a supplier
analytical methods exist, data could and labels that you use to determine for packaging or labeling as a dietary
come from a manufacturer’s experience whether the components, packaging, supplement (and for distribution rather
with the product or accelerated stability and labels meet specifications than for return to the supplier) (final
testing on similar products with the established in accordance with § 111.(80)(d)).
same storage container. One comment § 111.70(b) and (d), and as applicable, We did not receive comments specific
points out that some manufacturers final § 111.70(a) (and, when you receive to proposed § 111.37(b).
already use stability testing. Another components, packaging, or labels from a
comment recommends that we provide supplier, representative samples of each 2. Final 111.80(b)
a guidance document on supporting unique shipment, and of each unique lot Final § 111.80(b) requires you to
data. within each unique shipment). Final collect representative samples of in-
One comment suggests stringent § 111.80(a) derives from proposed process materials for each manufactured
supporting data are not needed for a § 111.37(b)(11)(i). Final § 111.80(a) batch at points, steps, or stages, in the
‘‘best if used by’’ date, because that date includes changes related to our review manufacturing process as specified in
provides a recommended time frame to of the proposed requirements for clarity. the master manufacturing record, where
ensure the best quality. Another We had used the term ‘‘shipment lot’’ in control is necessary to ensure the
comment asserts that the discussion several proposed requirements, identity, purity, strength, and
about expiration dates in the 2003 including § 111.35(g)(1)(i) (requirement composition of dietary supplements, to
determine whether the materials meet § 111.70(g), which requires you to 1. Final § 111.83(a)
specifications established under final establish specifications for the Final § 111.83(a) requires you to
§ 111.70(c), and, as applicable, final packaging and labeling of the finished collect and hold reserve samples of each
§ 111.70(a). Final § 111.80(b) derives packaged and labeled dietary lot of packaged and labeled dietary
from proposed § 111.37(b)(11)(ii). supplements. Final § 111.70(g) includes supplements that you distribute. Final
We did not receive comments specific specifications that determine whether § 111.83(a) derives, in part, from
to proposed § 111.37(b)(11)(ii). you used the packaging specified in the proposed § 111.37(b)(12), which would
3. Final 111.80(c) master manufacturing record and you require the quality control unit to keep
applied the label specified in the master the reserve samples and, in part, from
Final § 111.80(c) requires you to manufacturing record. Under final
collect representative samples of a proposed § 111.50(h), which would
§ 111.70(a) and (g) the parameters that require you to collect representative
subset of finished batches of each we proposed to specify under proposed
dietary supplement you manufacture, reserve samples from each batch of
§ 111.37(b)(11)(iv) are the required dietary supplement.
which you identify through a sound specifications for packaged and labeled
statistical sampling plan (or otherwise (Comment 201) Several comments ask
dietary supplements. for clarification of the requirements for
every finished batch), before releasing
for distribution, to verify that the Final § 111.80(e) includes a change to representative and reserve samples as
finished batch of dietary supplement clarify the exact specifications by citing proposed in § 111.37(b)(11) and (b)(12).
meets product specifications established the relevant sections. Final § 111.80(e) One comment notes that proposed
in accordance with final § 111.70(e), also includes an editorial change in that § 111.37(b)(11) does not indicate
and, as applicable, final § 111.70(a). you are required to ‘‘determine whether representative samples are also
Final § 111.80(c) derives from proposed whether’’ specifications are met rather collected to serve as the reserve samples
§ 111.37(b)(11)(iii). Final § 111.80(c) than to ‘‘determine that’’ specifications described in proposed § 111.37(b)(12)
includes changes associated with final are met. We are making this change and asks whether the items in proposed
§ 111.75(c) which provides flexibility because ‘‘determine that specifications § 111.37(b)(11)(i) through (b)(11)(iv) are
for you to test or examine a subset of are met’’ may be interpreted as a to be kept as reserve samples.
finished batches you select through a predetermined outcome, i.e., that (Response) As discussed in section VI
sound statistical sampling plan rather specifications will, in fact, be met. of this document, we are adding a
than to test or examine all finished We did not receive comments specific definition of ‘‘reserve sample’’ to reduce
batches. Under final § 111.75(c) the tests to proposed § 111.37(b)(11)(iv). the potential for confusion between
or examinations you conduct at the requirements for reserve samples and
M. What Are the Requirements for requirements for representative samples.
finished batch stage verify that your Reserve Samples? (Final § 111.83)
process is in control. A reserve sample is a representative
We did not receive comments specific Final § 111.83 sets forth requirements sample that is held for a designated
to proposed § 111.37(b)(11)(iii). to collect and hold reserve samples of period of time.
4. Final § 111.80(d) dietary supplements. Final § 111.83 2. Final § 111.83(b)(1)
derives from proposed §§ 111.37(b)(12),
Final § 111.80(d) requires you to 111.50, and 111.83(b)(2). Final § 111.83(b)(1) requires the
collect representative samples of each reserve samples to be held using the
Under proposed § 111.37(b)(12) we same container-closure system in which
unique shipment, and of each unique lot
would require holding reserve samples the packaged and labeled dietary
within each unique shipment, of
as an operation performed by the quality supplement is distributed, or if
product you receive for packaging or
control unit. Under proposed distributing dietary supplements to be
labeling as a dietary supplement (and
§ 111.50(h), we proposed that you packaged and labeled, using a container-
for distribution rather than for return to
collect representative reserve samples of closure system that provides essentially
the supplier) to determine whether the
each batch of dietary supplement. the same characteristics to protect
received product meets the
Consistent with the changes that we are against contamination or deterioration
specifications established under final
making to final § 111.80, final § 111.83 as the one in which it is distributed for
§ 111.70(f), and, as applicable, final
does not specify who must collect and packaging and labeling elsewhere. Final
§ 111.70(a). Final § 111.80(d) derives
hold the required reserve samples. § 111.83(b)(1) derives from proposed
from proposed § 111.37(b)(11)(i). We did
However, under final § 111.105(g), § 111.83(b)(2) which we proposed to
not receive comments specific to this
quality control personnel retain include with the requirements for
proposed requirement. However, we are
oversight of the collection and holding holding and distributing. The final
making changes to final § 111.80(d)
of the required reserve samples. Because sections that derive from proposed
consistent with those described for final
the requirement to collect and hold § 111.83(b)(2) are in subpart M (final
§ 111.80(a).
reserve samples is not an operation that § 111.465). However, we are duplicating
5. Final § 111.80(e) must be performed by quality control these requirements in final
Final § 111.80(e) requires you to personnel, we are including the § 111.83(b)(1) for clarity and ease of use,
collect representative samples of each requirement to collect reserve samples so that you have information about the
lot of packaged and labeled dietary in subpart E as part of the elements of requirements for the container-closure
supplements to determine whether the a production and process control system system for holding reserve samples of
packaging and labeling of the packaged rather than in subpart F as part of the packaged and labeled dietary
and labeled dietary supplements meet requirements for quality control supplements in the same section as the
specifications established in accordance personnel. requirements to collect the samples.
with final §111.70(g), and, as applicable, For consistency with terms used
final § 111.70(a). Final § 111.80(e) elsewhere in the final rule, final 3. Final § 111.83(b)(2)
derives from proposed § 111.83 requires that you ‘‘hold’’ Final § 111.83(b)(2) requires that
§ 111.37(b)(11)(iv). Final § 111.80(e) reserve samples rather than ‘‘keep’’ reserve samples be identified with the
includes revisions associated with final them. batch, lot, or control number. Final
§ 111.83(b)(2) derives from proposed made by the comments. The final rule manufacturing. The comment asserts
§ 111.37(b)(12)(i) with editorial changes provides flexibility to hold reserve that the quality control unit should not
associated with the reorganization. We samples for 1 year past the shelf life be expected to make decisions
have added ‘‘control number’’ to the date, when such dating is used. Any concerning manufacturing operations;
provision for consistency with other shelf life date that you include on the however, it should be informed of
provisions of the final rule which refer label of the product should be changes so it can evaluate the results of
to a ‘‘control number’’ in addition to a supported by data. reprocessing on the finished product.
‘‘batch or lot number.’’ (Response) We agree, in part, with the
We did not receive comments specific 5. Final § 111.83(b)(4) comments and the final rule simplifies
to proposed § 111.37(b)(12)(i). Final § 111.83(b)(4) requires that the provisions regarding a material
reserve samples consist of at least twice review and disposition decision.
4. Final § 111.83(b)(3) the quantity necessary for all tests or Quality control personnel can conduct
Final § 111.83(b)(3) requires that examinations to determine whether or the material review and disposition
reserve samples be retained for 1 year not the dietary supplement meets decision by reviewing the underlying
past the shelf life date (if shelf life product specifications. Final information gathered or obtained by
dating is used), or for 2 years from the § 111.83(b)(4) derives from proposed other qualified personnel and then
date of distribution of the last batch of § 111.37(b)(12)(ii) which would require making the final decision. Under the
dietary supplements associated with that the reserve samples consist of at final rule, we retain the principle that
those reserve samples, for use in least twice the quantity necessary for qualified individuals other than quality
appropriate investigations. Final tests. control personnel can contribute to the
§ 111.83(b)(3) derives from proposed Final § 111.83(b)(4) provides that the quality control personnel’s material
§ 111.37(b)(12) which would require the reserve samples may be used for review and disposition decision. The
quality control unit to keep the reserve examinations or tests and to determine final rule sets forth the following
samples for 3 years from the date of whether or not the dietary supplement requirements:
manufacture for use in appropriate meets product specifications, as a • Under final § 111.87, quality control
investigations including, but not limited revision associated with final § 111.75. personnel must conduct all required
to, consumer complaint investigations (Comment 203) One comment agrees material reviews and make all required
to determine, for example, whether the that twice the quantity necessary for disposition decisions;
dietary supplement associated with a testing should be collected and held. • Under final § 111.103, you must
consumer complaint failed to meet any (Response) The final rule is consistent establish and follow written procedures
of its specifications for identity, purity, with this comment. for conducting a material review and
quality, strength, and composition, as making a disposition decision; and
N. Who Conducts a Material Review and • Under final § 111.140(b)(3)(vii),
well as from proposed § 111.50(h) Makes a Disposition Decision? (Final
which would require reserve samples to documentation of a material review and
§ 111.87) disposition decision and followup must
be kept for 3 years from the date of
manufacture. We discuss the change Final § 111.87 requires quality control include the signature of the
from 3 years to 2 years and the change personnel to conduct all required individual(s) designated to perform the
from ‘‘date of manufacture’’ to ‘‘the date material reviews and make all required quality control operations, who
of distribution’’ in connection with the disposition decisions. Final § 111.87 conducted the material review and
recordkeeping requirements in subpart derives from a number of proposed made the disposition decision, and of
P, in section XXI of this document. requirements for conducting a material any qualified individual who provided
Final § 111.83(b)(3) thus provides review and making a disposition information relevant to that material
flexibility in determining how long you (§§ 111.35(i) and (n), 111.37(b)(5) and review and disposition decision.
must hold reserve samples of packaged (b)(14), 111.40(a)(3), 111.50(d)(1), and Taken in total, the final rule
and labeled dietary supplements. 111.85(a) and (c)). Under each of these establishes a system in which you have
Final § 111.83(b)(3) does not include provisions, the quality control unit flexibility to develop procedures that
the proposed examples of investigations would have an oversight role and would suit your organization, including having
that may require the use of reserve review and approve all material reviews qualified individuals, other than the
samples because these examples are not and all disposition decisions. Under designated quality control personnel,
requirements. some of these provisions (i.e., provide information relevant to the
(Comment 202) Many comments §§ 111.50(d)(1) and 111.85(a) and 85(c)) material review and disposition
address the requirement to keep the the quality control unit would conduct decision. For example, under final
reserve samples after manufacture and the material review itself and make the § 111.140(b)(3), you could have a
recommend that expiration dates be a disposition decision. qualified individual in the production
factor when determining the amount of (Comment 204) One comment department prepare a report that
time reserve samples should be kept and disagrees that the quality control unit includes all the required documentation
maintained. Most of the comments must conduct the material review and and information and provide a signed
recommend holding reserve samples of make the disposition decision. The copy of that report to designated quality
packaged and labeled dietary comment argues that manufacturing control personnel. An individual
supplements for 3 years from the date of personnel are better qualified to conduct designated to perform quality control
manufacture or, when an expiration the review and make disposition operations would then read that report,
date has been established by the decisions because they are often add to it if necessary, conduct any
manufacturer, for 1 year after the engineers and have the relevant additional investigations if necessary,
expiration date. Other comments expertise regarding the use of machinery and if he or she agrees with the report,
recommend holding reserve samples for and people to produce a product. In co-sign the report or an amended report
time periods ranging from 6 months to contrast, the comment asserts that that includes additional documentation
2 years after the expiration date. quality control unit personnel generally or information, thus completing a
(Response) The final rule contains are chemists with expertise only in material review and disposition
requirements similar to the suggestions testing and little expertise in decision.
The final rule provides for the (Comment 205) One comment do not intend to limit those who may
participation of qualified individuals, recommends deletion of proposed participate in a material review and
other than those designated to perform § 111.35(i)(4) and (i)(4)(i), arguing that disposition decision to only those
quality control operations, in the principles of those sections are persons acting in their capacity as
conducting the material review. In covered under proposed § 111.35(i)(2) designated quality control personnel.
addition, as already discussed, under and (i)(3). Others may assist quality control
final § 111.12(b) you may assign a (Response) We disagree with the personnel in gathering and considering
qualified individual who has comment’s assertion. The requirements information relevant to the review and
responsibilities for operations other of proposed § 111.35(i)(4) and (i)(4)(i) decision, however the quality control
than quality control to perform quality are not covered by proposed personnel have the responsibility to
control operations, provided that the § 111.35(i)(2) and (i)(3). All the sections conduct a material review and make
individual has distinct and separate are related, but deal with different disposition decisions. Thus, we are
responsibilities related to performing aspects of corrective action. Proposed retaining in final § 111.90(a) the
quality control operations. § 111.35(i)(2) and (i)(3) would require requirements in proposed
the firm to conduct a material review §§ 111.25(i)(4)(ii) and 111.50(d)(1).
O. What Requirements Apply to and make a disposition decision, while
Treatments, In-Process Adjustments, 3. Final § 111.90(b)
proposed § 111.35(i)(4) would prohibit
and Reprocessing When There is a Final § 111.90(b) requires that you
the use of rejected ingredients unless
Deviation or Unanticipated Occurrence must not reprocess any dietary
the quality control unit determines that
or When a Specification Established in supplement or treat or provide an in-
in-process adjustments are possible to
Accordance with § 111.70 Is Not Met? process adjustment to a component to
correct the deviations or occurrence. We
(Final § 111.90) make it suitable for use in the
are making no changes as suggested by
1. Final § 111.90 this comment and the primary elements manufacture of a dietary supplement,
of proposed § 111.35(i)(4) are retained in unless: (1) Quality control personnel
Final § 111.90 is a unified provision
final § 111.90. conduct a material review and make a
that clarifies your responsibilities
(Comment 206) A few comments state disposition decision based on a
regarding treatment or in-process
their support for the requirement that scientifically valid reason and approve
adjustments to a component, and in-
the quality control unit have the the reprocessing, treatment, or in-
process adjustments or reprocessing of a
authority to determine whether process adjustment and (2) the
dietary supplement, in a more ‘‘user-
adjustments are possible to correct a reprocessing, treatment or in-process
friendly’’ fashion. We have identified in
deviation. adjustment is permitted by § 111.77.
one provision the restrictions that apply
(Response) We are retaining the Final § 111.90(b) derives from proposed
to these operations. Final § 111.90
proposed requirement for quality §§ 111.35(i)(4)(iii), 111.50(f), and
derives from proposed §§ 111.35(i)(4)(i),
control personnel in final § 111.90. 111.65(d). We revised this provision to
(i)(4)(ii), and (i)(4)(iii); 111.50(d)(1), (f),
be consistent with the changes in final
and (g); and 111.65(d). 2. Final § 111.90(a)
Final § 111.90 includes the following § 111.77.
Final § 111.90(a) requires that you (Comment 208) As discussed in
changes we are making to the proposed
must not reprocess a rejected dietary section VI of this document (discussion
provisions for consistency and clarity:
• We are making revisions to make supplement or treat or provide an in- of the definition of ‘‘reprocessing’’),
the section consistent with the process adjustment to a component, some comments object to the
definition of ‘‘reprocessing’’ in final packaging, or label to make it suitable restrictions in the definition of
§ 111.3, which refers only to for use in the manufacture of a dietary reprocessing in proposed § 111.3
‘‘components or dietary supplements supplement, unless: (1) Quality control because the definition would not permit
that have been previously removed from personnel conduct a material review the reprocessing of ingredients that may
manufacturing.’’ and make a disposition decision to have been removed because of
• We are adding ‘‘treatments’’ as a approve the reprocessing, treatment, or insanitary conditions even if there are
step that quality control personnel in-process adjustment and (2) the processes available that are safe and
could approve, because that term better reprocessing, treatment, or in-process effective in removing foreign matter,
describes actions that could be taken to adjustment is permitted by § 111.77. microorganisms, or chemicals that may
correct a deviation or unanticipated Final § 111.90(a) derives from have rendered the ingredient
occurrence with a component, proposed §§ 111.35(i)(4)(ii) and ‘‘insanitary.’’ These comments also
packaging, or label. 111.50(d)(1). We revised this provision object to proposed § 111.35(i)(4)(iii) for
• We are clarifying that it is quality to be consistent with the changes in the same reasons. A few comments
control personnel who reject final § 111.77. argue that a manufacturer should be
components, packaging, or labels. (Comment 207) Several comments able to reprocess a component or dietary
• We are clarifying that quality state their support for proposed supplement if it has been rejected
control personnel approve the § 111.35(i)(4)(ii), which would require because of contamination with
treatment, in-process adjustment, or the quality control unit to approve the microorganisms or types of
reprocessing rather than determine reprocessing of any rejected component, contamination, such as heavy metals, if
whether the treatment, in-process dietary ingredient, or dietary the quality control unit approves the
adjustment, or reprocessing is possible. supplement. However, not all comments reprocessing. These comments indicate
• We are clarifying that, with respect agree that the quality control unit this is the industry practice, one based
to labels, the provision applies to the should have to conduct (under proposed on a scientific rationale for doing the
potential that a label not specified in the § 111.50(d)(1)), rather than review and reprocessing and that ensures other
master manufacturing record could be approve, a material review and quality attributes of the product are not
used. disposition decision. affected.
• We are making changes to be (Response) As discussed in this Some comments state that the
consistent with the new provision, final section, by ‘‘conduct a material review requirement is more strict than the food
§ 111.77. and make a disposition decision,’’ we or drug CGMP requirements, noting that
reprocessing is widely accepted and section 201(s) of the act, irradiation P. Under This Subpart, What Records
allowed in the food CGMPs. Other intended for use in producing, Must You Make and Keep? (Final
comments believe that the prohibition manufacturing, packing, processing, § 111.95)
in proposed § 111.35(i)(4)(iii) against preparing, treating, packaging,
1. Final § 111.95(a)
reprocessing materials contaminated transporting, or holding food is a food
with microorganisms should be limited additive that requires premarket review Final § 111.95(a) requires you to make
to materials contaminated with health- and approval before it can be used in and keep records required under this
hazardous microorganisms. food. Our Office of Food Additive Safety subpart in accordance with subpart P.
(Response) As we discussed in the is currently reviewing a food additive Final § 111.95(a) derives from proposed
response to comment 53 for the petition for the use of irradiation on § 111.35(o). Some of the records
definition of ‘‘reprocessing,’’ we agree dietary ingredients and dietary required under subpart E are set forth as
with the comments that state that in- supplements. Until that review process recordkeeping requirements in other
process materials can be reprocessed is completed and we have authorized subparts of this final rule, such as those
when there are suitable processes this use of irradiation through a final related to receiving records for
available. However, as noted by the rule codified in part 179, irradiation of components, packaging, and labels in
comments, it is critical that there be dietary ingredients and dietary subpart G, and the results of testing or
appropriate oversight of the supplements as a means to reduce or examination in subpart J. The record
reprocessing so the quality of the dietary eliminate microbial loads is not requirements not specifically required
supplement is not compromised. Final permitted. However, you may use an in other related subparts are listed in
§ 111.90(b) provides for the flexibility irradiated component (such as a spice subpart E.
requested by the comments, provided that is used to flavor a dietary (Comment 212) One comment
that there is oversight by quality control supplement) when the irradiation of supports the recordkeeping
personnel. that component is allowed under requirements, states that the records
(Comment 209) Proposed § 179.26. provide a valuable paper trail that will
§ 111.35(i)(4)(iii) mentions allow manufacturers to identify and fix
‘‘microorganism or other contaminants, 4. Final § 111.90(c) problems in the process, and suggests
such as heavy metals.’’ One comment the requirements protect consumers
proposes that other contaminants, such Final § 111.90(c) requires that any
from adulterated and misbranded
as pesticides and aflatoxin, should be batch of dietary supplement that is
products.
mentioned. Another comment suggests reprocessed, that contains components (Response) We agree. Under final
that the final rule should specify limits that you have treated, or to which you § 111.95(a), a firm must make and keep
for heavy metals in dietary have made in-process adjustments to records required by subpart E in
supplements. make them suitable for use in the accordance with subpart P. As
(Response) We decline to revise the manufacture of the dietary supplement discussed in this section, firms are
final rule as suggested by the comments. must be approved by quality control required to keep the records necessary
It is impractical to provide an personnel and comply with final for determining whether their products
exhaustive list of relevant types of § 111.123(b) before releasing for are made in accordance with
contamination, and a list that is longer, distribution. Final § 111.90(c) derives specifications. This will help them
but not exhaustive, is more likely to be from proposed § 111.50(g). identify and correct any problems. In
misunderstood as suggesting that the Final § 111.90(c) also includes addition, under subpart P, the records
only types of contamination that are conforming revisions to clarify that a must be kept for 1 year past the shelf life
significant are the types of dietary supplement that contains a date (if shelf life dating is used) or 2
contamination in the list. For that component treated before use or years beyond the date of distribution of
reason, we have eliminated the adjusted in-process, or that has had in- the last batch of dietary supplements
reference to contamination to clarify process adjustments to make it suitable associated with those records.
that in any instance where it is for use in the manufacture of a dietary Moreover, firms must make their
appropriate quality control personnel supplement, must be approved by records available to us for inspection
must ensure that the disposition quality control personnel and comply and copying, which will permit us to
decision is based on a scientifically with final § 111.123(b) before releasing determine whether firms are
valid reason and also approve the for distribution. We revised this manufacturing, packaging, labeling, and
reprocessing. provision to be consistent with the holding dietary supplements in
(Comment 210) One comment notes changes in final §§ 111.77 and accordance with the requirements of
that in the May 9, 2003, satellite 111.123(b). this rule.
broadcast concerning the 2003 CGMP Final § 111.90(c) also includes
Proposal, we indicated that treating a 2. Final § 111.95(b)
revisions to reflect the final provisions
component or dietary supplement with that relate to reprocessing and in- Final § 111.95(b) specifies the records
irradiation as a means to reduce or process adjustments (see final you must make and keep under subpart
eliminate the microbial load was §§ 111.113, 111.120, and 111.155). E. Under the reorganization several
acceptable as long as the treatment was recordkeeping requirements of proposed
part of the process for producing that (Comment 211) One comment asserts § 111.35 are set forth in other subparts.
material. The comment asks for that a reprocessed product should be Final § 111.95(b)(1) requires you to
confirmation that irradiation of retested to confirm that it meets product make and keep records of the
components or dietary supplements is specifications. specifications established. Final
allowed under part 179 (21 CFR part (Response) Under final § 111.75(c) § 111.95(b)(1) derives from proposed
179), even though such treatments are and (d) quality control personnel have § 111.35(o)(1).
not listed in the table provided in flexibility to determine whether tests or Final § 111.95(b)(2) requires you to
§ 179.26(b). examinations are necessary to ensure make and keep records of your
(Response) We are unable to provide that a reprocessed product meets qualification of a supplier for the
the requested confirmation. Under product specifications. purpose of relying on the supplier’s
certificate of analysis. Final appropriate test methods because these TABLE 7.—DERIVATION OF SECTIONS
§ 111.95(b)(2) is a record that is required requirements are related and probably IN FINAL SUBPART F—Continued
under final § 111.75(a)(2)(B). best understood without intervening
Final § 111.95(b)(3) requires you to information. 2003 CGMP
make and keep documentation for why Final Rule Proposal
meeting in-process specifications, in (Response) Consistent with this
combination with meeting component comment, the recordkeeping § 111.113 What quality § 111.35(i)(2),
specifications, helps ensure that the requirements of proposed § 111.35(m) control operations are (i)(3), (i)(4)(i),
are set forth in final subpart J instead of required for a material (i)(4)(ii), (j),
dietary supplement meets the
subpart E. review and disposition and (n)
specifications for identity, purity, decision? § 111.37(b)(3)
strength, and composition and for limits XI. Comments on Requirements for § 111.37(c)
on those types of contamination that Quality Control (Final Subpart F) § 111.40(a)(3)
may adulterate or may lead to and (b)(2)
adulteration of the finished batch of the A. Organization of Final Subpart F § 111.50(d)(1)
dietary supplement. Final § 111.95(b)(3) § 111.65(d)
refers to records required under final Proposed § 111.37 set forth § 111.70(c)
§ 111.70(c)(2). requirements for quality control
Final § 111.95(b)(4) requires you to operations. Other proposed § 111.117 What quality § 111.30(b)(4),
requirements related to quality control control operations are (b)(6), (b)(7),
make and keep documentation for why
required for equip- and (b)(8)
the results of appropriate tests or operations were set forth in other ment, instruments, and
examinations for the product sections. For example, proposed controls?
specifications selected under final § 111.40(a) would require the quality
§ 111.75(c)(1) ensures that the dietary control unit to perform operations § 111.120 What quality § 111.35(i)(4)(i)
supplement meets all product associated with components that you control operations are and (i)(4)(ii)
specifications. Final § 111.95(b)(4) is a use in the manufacturing process. required for compo- § 111.37(b)(2)
record that is required under final nents, packaging, and and (b)(10)
Proposed § 111.45 would establish labels before use in § 111.40(a)(3)
§ 111.75(c)(3). requirements for the master
Final § 111.95(b)(5) requires you to the manufacture of a and (b)(2)
manufacturing record and would have dietary supplement? § 111.50(e)(1)
make and keep documentation for why
the quality control unit review and
any component and in-process testing, § 111.123 What quality § 111.35(e)(2),
examination, or monitoring, and any approve each master manufacturing
record. Proposed § 111.50 would have control operations are (f), (i)(2), and
other information, will ensure that a required for the master (o)(2)
product specification that is exempted the quality control unit review batch manufacturing record, § 111.37(b)(2),
under final § 111.75(d) is met without production records. the batch production (b)(4), (b)(5),
verification through periodic testing of As shown in table 7 of this document, record, and manufac- and (b)(11)(iii)
the finished batch, including the final rule reorganizes the turing operations? § 111.45(c)
documentation that the selected § 111.50(d)(1)
requirements related to quality control and (d)(2)
specifications tested or examined under operations into a distinct subpart (final § 111.50(g)
final § 111.75(c)(1) are not able to verify Subpart F—Production and Process
that the production and process control Control System: Requirements for § 111.127 What quality § 111.37(b)(2)
system is producing a dietary Quality Control Operations). Table 7 control operations are and (b)(10)
supplement that meets the exempted lists the sections in final subpart F and required for packaging § 111.40(a)(2)
product specification and there is no and labeling oper- and (a)(3)
identifies the proposed sections that
scientifically valid method for testing or ations? § 111.70(c), (d),
form the basis for the sections in the and (e)
examining such exempted product
specification at the finished batch stage. final rule.
Final § 111.95(b)(5) refers to a record § 111.130 What quality § 111.37(b)(2)
TABLE 7.—DERIVATION OF SECTIONS control operations are and (b)(15)
required under final § 111.75(d)(1). As required for returned § 111.85(a)
previously discussed in this section, we IN FINAL SUBPART F
dietary supplements?
are issuing an interim final rule,
published elsewhere in this issue of the 2003 CGMP § 111.135 What quality § 111.95
Final Rule Proposal
Federal Register, that sets forth a control operations are
procedure for requesting an exemption required for product
§ 111.103 What are the N/A complaints?
from the requirement that the requirements under
manufacturer conduct at least one this subpart F for writ- § 111.140 Under this § 111.35(j)
appropriate test or examination to verify ten procedures? subpart F, what § 111.37(c) and
the identity of any component that is a records must you (d)
dietary ingredient. Included in the § 111.105 What must § 111.37(a), make and keep?
interim final rule is an amendment to quality control per- (b)(1), (b)(11),
final § 111.95(b) adding a new sonnel do? and (b)(12)
paragraph (b)(6) requiring the retention Proposed Requirements for Quality
§ 111.110 What quality § 111.37(b)(9)
of FDA’s response to a petition control operations are and (b)(13) Control Operations
submitted under § 111.75(a)(1)(ii) that required for laboratory
provides for an exemption from the operations associated
1. Revisions
provision of § 111.75(a)(1)(i). with the production

(Comment 213) One comment The final rule:
and process control
recommends the recordkeeping system? • Reflects that the rule applies to
requirements of proposed § 111.35(m) persons who manufacture, package,
be moved to follow the requirements for label, or hold dietary supplements
unless subject to an exclusion under of instruments, and for calibrations, require that quality control personnel
§ 111.1; inspections, and checks of automatic, conduct the tests or examinations. Thus,
• Changes the requirement for a mechanical, or electronic equipment to you would not need to consider that an
quality control unit to a requirement for be performed on a periodic basis rather individual who conducts tests or
quality control operations performed by than at the time the record is made. examinations at a laboratory under
quality control personnel; contract to your organization is
• Requires quality control personnel performing a quality control operation
§ 111.37 (Final Subpart F)
to review and approve documentation that must be performed by quality
for why meeting in-process (Comment 214) Some comments control personnel. However, you may
specifications will ensure the support the use of a quality control unit choose to designate that individual as
specifications for identity, purity, and recognize it as an important need in part of your quality control personnel
strength, and composition of a dietary manufacturing operations. Some and require that the tests or
supplement are met; comments assert the quality control unit examinations conducted by that
• Requires quality control personnel may not have all the responsibilities individual be quality control operations.
to review and approve documentation listed in proposed § 111.37 because Importantly, however, for the purposes
setting forth the basis for qualifying a there may be some duties contracted out of this final rule, we consider that a
supplier of a component; to someone else, such as testing that quality control operation performed by
• Requires quality control personnel could be sent to a contract laboratory, or an individual under contract to you or
to review and approve documentation of some duties that may be better suited for by another third party is no different
your basis for why meeting certain employees in other organizational units. than a quality control operation
selected specifications in a subset of As an example, a few comments note performed by your employees who are
finished batches will ensure your that the instrument and equipment designated to perform such operation. If,
finished batch of the dietary supplement calibration functions in proposed during the course of an inspection, we
meets all product specifications for § 111.37 may be better performed by find the requirements of this final rule
identity, purity, strength, and individuals responsible for the were not followed, we will hold you,
composition and limits on those types equipment in their particular rather than the contractor or other third
of contamination that may adulterate, or operational area, by those in a unit party, responsible. The applicability of
that may lead to the adulteration of, the dedicated to equipment maintenance this final rule to contractors is discussed
dietary supplement; and and calibration, or possibly by a third in detail in section VI of this document.
• Requires quality control personnel party, who is qualified by training and/ (Comment 215) Several comments
to review and approve documentation or experience, to do these functions. request that the quality control unit
for why a product specification Similarly, other comments note that focus on reviewing tasks performed by
exempted from the verification other groups with the appropriate others rather than on performing the
requirements in final subpart E is met expertise may be assigned or required to tasks itself.
without verification through periodic review and approve proposed changes (Response) We agree with these
testing of the finished batch. or procedures in manufacturing comments and have revised several
operations or to conduct material provisions accordingly. For example, in
2. Changes Associated With the reviews and make disposition decisions. the 2003 CGMP Proposal we would
Reorganization These comments assert the quality require the quality control unit to
The final rule: control unit should have overall perform appropriate tests and
• Reduces redundant provisions and responsibility and oversight for quality examinations of incoming materials, in-
• Combines parts of various proposed control functions but also should be process materials, each finished batch of
requirements that were scattered able to rely on the expertise of other dietary supplements, and each batch of
throughout the 2003 CGMP Proposal. persons in the organization to packaged and labeled dietary
accomplish the tasks. supplements (proposed § 111.37(b)(13)).
3. Changes After Considering Comments (Response) As already discussed with Under the final rule, quality control
The final rule: respect to the definition of quality operations include ensuring appropriate
• Incorporates a new requirement to control personnel in section VI of this tests and examinations are conducted
establish, and keep as a record, written document, these comments may have (final § 111.110(b)) but do not include
procedures for quality control misunderstood the quality control unit’s conducting these tests and
operations; role under the proposed rule. examinations.
• Simplifies the requirements Consequently, we have added final (Comment 216) One comment asks
associated with conducting a material § 111.12(b) in subpart B, discussed in whether we expect the quality control
review and making a disposition section VII of this document, to state unit to approve operational activities as
decision; you must identify who is responsible for soon as they occur or collectively at the
• Requires quality control personnel your quality control operations. Each end of the process. This and other
to ensure that representative samples person who is designated to perform comments argue the quality control
are collected rather than collecting these quality control operations must be function is usually accomplished by a
samples; qualified to do so and have distinct and team of qualified persons with the
• Requires quality control personnel separate responsibilities related to quality control unit having the overall
to ensure that reserve samples are held performing such operations from those responsibility and authority to perform
rather than quality control personnel responsibilities that the person a collective, post-processing, final
holding these samples; otherwise has when not performing approval.
• Requires quality control personnel such operations. (Response) The time at which quality
to ensure tests or examinations are The final rule requires quality control control personnel conduct assigned
appropriate rather than conduct these personnel to ensure all appropriate tests duties will vary by the specific
tests or examinations; and and examinations are conducted, and operation, the size and complexity of
• Requires review by quality control review and approve the results of all the operation, and how quality control
personnel of all records for calibration tests and examinations, but does not functions are assigned to qualified
persons. For example, the final rule identity, purity, quality, strength, and (Comment 217) One comment
requires quality control personnel to composition. recommends revising proposed
determine whether components This final rule focuses on ensuring § 111.37(b)(1) by replacing ‘‘* * *
conform to specifications, and to release that the manufacturer establishes identity, purity, quality, strength, and
components from quarantine before you specifications for its dietary composition’’ with ‘‘* * * identity,
use them in the manufacture of a dietary supplements; includes those purity, quality, strength, or
supplement (final § 111.120). However, specifications in the master composition.’’ The comment asserts the
this final rule does not require, for manufacturing record; meets those quality control unit must be responsible
example, that quality control personnel specifications and manufactures, for approving or rejecting anything that
determine whether components packages, labels, and holds the product may affect one of these attributes.
conform to specifications as soon as you in a manner that will ensure the quality (Response) We agree with this
receive them, although it may be of the dietary supplement; and that the comment. Under proposed
common business practice to do so. dietary supplement is packaged and § 111.37(b)(1) we had intended that the
Regardless of when quality control labeled as specified in the master quality control unit be responsible, for
personnel perform their operations, manufacturing record. Because of that example, for approving a test that would
quality control personnel have the focus, the labeling requirements of the establish the identity of a component
ultimate responsibility for ensuring final rule address the operation of even if that test did not also establish
manufacturing, packaging, labeling, and putting the label that is specified in the the strength of that component. Final
holding operations are performed in a master manufacturing record on the § 111.105(a) changes ‘‘and’’ to ‘‘or’’ as
manner that will ensure the quality of product rather than the content of a requested by this comment.
the dietary supplement and that the product label that meets all of the (Comment 218) One comment
dietary supplement is packaged and labeling requirements of the act and our recommends the quality control unit be
labeled as specified in the master implementing regulations. The failure to responsible for maintaining the master
manufacturing record. put the label identified in the master copies of all current and approved
manufacturing record on the finished written procedures, for distributing
D. What Are the Requirements Under copies of approved written procedures
product would be a violation of this
This Subpart for Written Procedures? to relevant personnel, and for collecting
final rule. In addition, if the label on the
(Final § 111.103) and destroying outdated Standard
product does not correctly reflect the
We received many comments that ingredients, the label would misbrand Operating Procedures (SOPs) (except
recommend written procedures for the product under section 403 of the act. designated historical SOP files).
various provisions. We address the need For purposes of this final rule, the (Response) This comment is
for written procedures generally in labeling operations are CGMP consistent with the underlying principle
section IV of this document. We also requirements and relate to the label that quality control personnel oversee
respond to comments on specific identified in the master manufacturing the design and conduct of the
provisions in the same section. record. Therefore, we are deleting operations associated with the
Final § 111.103 requires that you ‘‘misbranding’’ from proposed production of a dietary supplement.
establish and follow written procedures § 111.37(a) (final § 111.105) since the act After considering these comments, final
for the responsibilities of the quality of misbranding other than applying a § 111.105(a) requires quality control
control operations. Final § 111.103 label different from the one identified in personnel to approve all written
specifically identifies two of the written the master manufacturing record is not procedures that may affect the identity,
procedures you must establish and considered a CGMP violation in the purity, strength, or composition of a
follow, i.e., written procedures for context of this final rule. Any dietary supplement. With respect to the
conducting a material review and misbranding is still a violation of the other suggested duties of quality control
making a disposition decision and for act, however, and manufacturers must personnel, we are leaving the decision
approving or rejecting any reprocessing. comply with all applicable statutory and as to who performs them, up to the
regulatory requirements in addition to individual firm to best suit its overall
E. What Must Quality Control Personnel
the requirements of this final rule. operations.
Do? (Final § 111.105)
This series of changes emphasizes the
Final § 111.105 broadly captures the 2. Final § 111.105(b), (c), d), and (e)
need to ensure the quality of a dietary
responsibility of quality control supplement and that the dietary Final § 111.105(b) requires quality
personnel to provide oversight for supplement is packaged and labeled as control personnel to review and approve
manufacturing, packaging, labeling, and specified in the master manufacturing the documentation setting forth the
holding operations. It requires quality record. As discussed in detail in the rest basis for qualification of any supplier.
control personnel to ensure that your of this section, final § 111.105 also Final § 111.105(c) requires quality
manufacturing, packaging, labeling, and requires that quality control personnel control personnel to review and approve
holding operations ensure the quality of perform certain operations and groups the documentation setting forth the
the dietary supplement and that the of operations. basis for why meeting in-process
dietary supplement is packaged and specifications, in combination with
labeled as specified in the master 1. Final § 111.105(a) meeting component specifications, will
manufacturing record. Final § 111.105 Final § 111.105(a) requires that help ensure that specifications for the
derives from proposed § 111.37(a) quality control personnel approve or identity, purity, strength, and
which would require you to use a reject all processes, specifications, composition of the dietary supplement
quality control unit to ensure your written procedures, controls, tests, and are met. Final § 111.105(d) requires
manufacturing, packaging, labeling, and examinations, and deviations from or quality control personnel to review and
holding operations in the production of modifications to them, that may affect approve the documentation setting forth
dietary supplements are performed in a the identity, purity, strength, or the basis for why the results of
manner that prevents adulteration and composition of a dietary supplement. appropriate tests or examinations for
misbranding, including ensuring dietary Final § 111.105(a) derives from each product specification selected
supplements meet specifications for proposed § 111.37(b)(1). under final § 111.75(c)(1) will ensure
that the finished batch of the dietary operations include determining whether production and process control system.
supplement meets product all specifications established in Final § 111.110(a) derives, in part, from
specifications. Final § 111.105(e) accordance with final § 111.70(a) are proposed § 111.37(b)(9) which would
requires quality control personnel to met. Final § 111.105(h) derives from require that the quality control unit
review and approve the basis and proposed § 111.37(b)(2) which would review and approve all laboratory
documentation for why any product require that the quality control unit control processes. For clarity, we are
specification is exempted from the determine whether all components, adding that the laboratory operations
verification requirements in final dietary supplements, packaging, and covered by final § 111.110 are those
§ 111.75(c)(1), and for why any labels conform to specifications. Under associated with the production and
component and in-process testing, the final rule, we are identifying each of process control system. We want to
examination, or monitoring, or other the specifications subject to review by make clear that laboratory operations
methods will ensure that such exempted quality control personnel under final such as those in your research and
product specification is met without § 111.77. The requirement for quality development department are not subject
verification through periodic testing of control personnel to determine whether to final § 111.110.
the finished batch. specifications established under final We did not receive comments specific
Final § 111.105(b), (c), (d), and (e) are § 111.70(a) are met is included for to quality control operations under
requirements associated with the consistency. This requirement is also proposed § 111.37(b)(9).
requirements established in final consistent with final § 111.73 which 2. Final § 111.110(b)
§§ 111.70(c)(3) and 111.75(a)(ii)(2)(E), requires that the production and process
(c)(4), (d)(1) and (d)(2). control system must include a Final § 111.110(b) requires that
determination of whether all of the quality control operations for laboratory
3. Final § 111.105(f) established specifications under final operations associated with the
Final § 111.105(f) requires quality § 111.70(a) are met. production and process control system
control personnel to ensure that include ensuring all tests and
6. Final § 111.105(i) examinations required under final
required representative samples are
collected. Final § 111.105(f) differs Final § 111.105(i) requires quality § 111.75 are conducted. Final
slightly from proposed § 111.37(b)(11)(i) control personnel to perform other § 111.110(b) derives, in part, from
through (b)(11)(iv) which would require operations required under subpart F. proposed § 111.37(b)(13) which would
the quality control unit to collect Final § 111.105(i) is associated with the require the quality control unit to
representative samples of incoming reorganization. Under the 2003 CGMP perform appropriate tests and
materials, in-process materials, each Proposal, proposed § 111.37(a) broadly examinations of incoming materials, in-
finished batch of dietary supplements, captured the responsibility of the process materials, each finished batch of
and each batch of packaged and labeled quality control unit to provide oversight dietary supplements, and each batch of
dietary supplements. for your manufacturing, packaging, packaged and labeled dietary
After considering comments labeling, and holding operations. supplements.
requesting the quality control unit focus Proposed § 111.37(b) listed specific Proposed § 111.37(b)(13) would list
on reviewing tasks performed by others operations that we would require the the types of materials that must be
rather than on performing the tasks quality control unit to perform. Final tested, including components,
themselves, the final rule does not § 111.105 now captures the packaging, labels, dietary ingredients,
specify that quality control personnel responsibility of quality control and dietary supplements that you
must collect representative samples. personnel to provide oversight for your receive; the batch production at the in-
Under final § 111.105(f), however, manufacturing, packaging, labeling, and process and finished batch stages; and
quality control personnel retain holding operations. The specific packaged and labeled dietary
oversight of sample collection. operations that quality control supplements. This list would include
personnel must perform to provide that materials that, at a minimum, would be
4. Final § 111.105(g) tested under the 2003 CGMP Proposal.
oversight are set forth in final
Final § 111.105(g) requires quality § 111.105(a) through (h) and in final Under the final rule, the minimum
control personnel to ensure that §§ 111.110, 111.113, 111.117, 111.120, requirements for testing or examination
required reserve samples are collected 111.123, 111.127, 111.130, 111.135, and of the materials listed in proposed
and held. Final § 111.105(g) derives 111.140. § 111.37(b)(13) are set forth in final
from proposed § 111.37(b)(12) which § 111.75. To simplify and clarify
would require the quality control unit to F. What Quality Control Operations Are proposed § 111.37(b)(13), final
keep reserve samples. Required for Laboratory Operations § 111.110(b) replaces this list with ‘‘all
After considering comments Associated With the Production and tests and examinations required under
requesting the quality control unit focus Process Control System? (Final § 111.75.’’
on reviewing tasks performed by others § 111.110)
3. Final § 111.110(c)
rather than on performing the tasks Final § 111.110 sets forth the
themselves, the final rule does not minimum required operations that Final § 111.110(c) requires that
specify that quality control personnel quality control personnel must perform quality control operations for laboratory
must keep reserve samples. Under final with respect to laboratory operations operations associated with the
§ 111.105(g), however, quality control associated with the production and production and process control system
personnel retain oversight of sample process control system. include reviewing and approving the
collection and holding. results of all tests and examinations
1. Final § 111.110(a) required under final § 111.75. Final
5. Final § 111.105(h)
Final § 111.110(a) requires that § 111.110(c) derives from proposed

Final § 111.105(h) requires that quality control operations for laboratory § 111.37(b)(9), which would require, in
quality control operations for the master operations include reviewing and part, that the quality control unit review
manufacturing record, the batch approving all laboratory control and approve all testing results. Final
production record, and manufacturing processes associated with the § 111.110(c) requires that quality control
personnel review and approve the The final rule establishes a system in • If calibration of an instrument or
results of examinations as well as tests. which you have the flexibility to control suggests a problem that may
This revision reflects the flexibility develop procedures that suit your have caused batches of a dietary
provided in the final rule to use either organization, including having qualified supplement to become adulterated; or
tests or examinations to determine individuals, who are not designated to • If a dietary supplement is returned.
whether specifications are met, perform the quality control operation, Final § 111.113(a) also incorporates
provided that the test or examination is provide information relevant to the elements from other proposed sections
an appropriate, scientifically valid material review and disposition regarding the circumstances that require
method. decision. For example, under final a material review and disposition
As with final § 111.110(b), we provide § 111.140(b)(3), you could have a decision as follows:
in final § 111.110(c) that the tests and qualified individual in the production • Proposed § 111.35(n), which would
examinations are those required under department assist quality control require you, for any specification that is
final § 111.75. personnel in conducting a material not met, to conduct a material review
We did not receive comments specific review by preparing a report that and disposition decision under
to quality control operations under includes all the required documentation proposed § 111.35(i);
proposed § 111.37(b)(9). and information and providing a signed • Proposed § 111.40(a)(3), which
copy of that report to quality control would require you, for components,
G. What Quality Control Operations Are
personnel. An individual who is dietary ingredients, or dietary
Required for a Material Review and
designated to perform the quality supplements you receive, to conduct a
Disposition Decision? (Final § 111.113)
control operation could then use that material review and make a disposition
Final § 111.113 derives from several decision if specifications are not met;
report as part of the material review,
proposed provisions, including
conduct any further investigations, as • Proposed § 111.40(b)(2), which
§§ 111.35(i), (j), and (n); 111.37(b)(3); would require that for packaging and
necessary, and decide to accept, amend,
111.40(a)(3) and (b)(2); 111.50(d)(1); labels you receive, you must conduct a
or reject the report.
111.65(d); and 111.70(c). All these material review and make a disposition
proposed requirements are related to 1. Final § 111.113(a) decision if specifications are not met;
one or more aspects associated with a
Under final § 111.113(a) quality • Proposed § 111.50(d)(1), which
material review and disposition, would require that if a batch deviates
control personnel must conduct a
including the circumstances that require from the master manufacturing record,
material review and make a disposition
a material review and disposition including any deviation from
decision if:
decision, the documentation that must specifications, the quality control unit
• A specification established in
be included in a material review and must conduct a material review and
accordance with § 111.70 is not met;
disposition decision, any restrictions on make a disposition decision and record
• A batch deviates from the master
who must conduct the material review any decision in the batch production
manufacturing record, including when
and make the disposition decision, and record;
any step established in the master • Proposed § 111.65(d), which would
the need for oversight by the quality
manufacturing record is not completed require you to conduct a material review
control unit. As discussed in section X
and including any deviation from and make a disposition decision in
of this document, we simplified the
specifications; accordance with proposed § 111.35(i)
provisions regarding a material review
and disposition decision (final • There is any unanticipated for any component, dietary ingredient,
§ 111.87), emphasizing the importance occurrence during the manufacturing or dietary supplement that fails to meet
of oversight by quality control personnel operations that adulterates or may lead specifications or that is or may be
and retaining the principle that to adulteration of the component, adulterated; and
qualified individuals other than those dietary supplement, or packaging, or • Proposed § 111.70(c), which would
who are designated quality control could lead to the use of a label not require you to conduct a material review
personnel can contribute to the material specified in the master manufacturing and make a disposition decision of any
review and disposition decision. The record; packaged and labeled dietary
final rule sets forth the following • Calibration of an instrument or supplements that do not meet
requirements for quality control control suggests a problem that may specifications.
personnel that relate to final § 111.113: have resulted in a failure to ensure the In final § 111.113(a) we are
• Under final § 111.87, quality quality of a batch or batches of a dietary incorporating, into a single unified
control personnel must conduct all supplement; or provision, the various proposed
required material reviews and make all • A dietary supplement is returned. circumstances that would require a
required disposition decisions; Final § 111.113(a) is substantially material review and disposition
• Under final § 111.103, you must similar to proposed § 111.35(i)(3), which decision under the 2003 CGMP
establish and follow written procedures would require, in part, that you make a Proposal. We included revisions
for conducting a material review and material disposition decision for any associated with final § 111.87 which
making a disposition decision; and component, dietary supplement, requires quality control personnel to
• Under final § 111.140(b)(3)(vii), packaging, or label: conduct any required material review
documentation of a material review and • If a component, dietary supplement, and make any required disposition
disposition decision and followup must packaging, or label fails to meet decision. We also included revisions
include the signature of the individual, established specifications; associated with final § 111.90 that relate
designated to perform the quality • If any step established in the master to the impact on labeling operations due
control operation, who conducted the manufacturing record is not completed; to deviations and unanticipated
material review and made the • If there is any unanticipated occurrences.

disposition decision and of any occurrence during the manufacturing In establishing final § 111.113(a)(1),
qualified individual who provided operations that adulterates or may lead we are deleting the specific reference to
information relevant to that material to adulteration of the component, the articles (components, dietary
review and disposition decision. dietary supplement, packaging, or label; supplements, packaging, and labels)
required to undergo a material review. Final § 111.113(b)(2) requires that • Reviewing and approving all
We are deleting these references, in part, when a specification established in processes for calibrating instruments
to simplify the provision. Under final accordance with § 111.70 is not met, and controls;
§ 111.113(a) quality control personnel quality control personnel must reject the • Periodically reviewing all records
must conduct a material review and component, dietary supplement, for calibration of instruments and
make a disposition decision if any package, or label, unless quality control controls; and
specification established in accordance personnel approve a treatment, an in- • Periodically reviewing all records
with final § 111.70 is not met. It is not process adjustment, or reprocessing, as for calibrations, inspections, and checks
necessary to repeat, in final § 111.113, permitted in final § 111.77. This of automated, mechanical, or electronic
the list of specifications that is clearly provision has been added as a result of equipment.
set forth in final § 111.70. the new provision, final § 111.77 which Final § 111.117(a), (b), and (c) derive
We did not receive comments specific provides for what happens when certain from proposed § 111.37(b)(6), (b)(7), and
to quality control operations under specifications are not met, the (b)(8) which would require the quality
proposed §§ 111.35(i)(3) and (n), responsibilities of quality control control unit to:
111.40(a)(3) and (b)(2), 111.50(d)(1), personnel, and the changes made to • Review and approve all processes
111.65(d), or 111.70(c). final § 111.90. for calibrating instruments or controls;
• Review all records for calibration of
2. Final § 111.113(b) (Comment 219) Several comments instruments, apparatus, gauges, and
Final § 111.113(b)(1) requires that, request that the quality control unit recording devices; and
when there is a deviation or focus on reviewing tasks performed by • Review all records for equipment
unanticipated occurrence during the others rather than on performing the calibrations, inspections, and checks.
production and in-process control tasks itself. Final § 111.117 includes the following
system that results in or could lead to (Response) We agree, and final changes we are making for consistency
adulteration of a component, dietary § 111.113(b) provides that quality with the requirements, set forth in
supplement, or packaging, or could lead control personnel ‘‘approve’’ an in- subpart D, for equipment and utensils:
to the use of a label not specified in the process adjustment rather than • We have deleted the terms
master manufacturing record, quality ‘‘determine whether’’ the in-process ‘‘apparatus,’’ ‘‘gauges,’’ and ‘‘recording
control personnel must reject the adjustment is possible. devices’’ from proposed § 111.37(b)(7)
component, dietary supplement, or as they would fall under the terms
3. Final § 111.113(c)
packaging, or label unless it approves a ‘‘instruments and controls’’ in final
treatment, an in-process adjustment, or Final § 111.113(c) requires the person § 111.117, and because subpart D does
reprocessing to correct the applicable who conducts a material review and not use the terms ‘‘apparatus,’’
deviation or occurrence. makes the disposition decision, at the ‘‘gauges,’’ or ‘‘recording devices.’’
Final § 111.113(b)(1) derives from the time of performance, to document that • We are characterizing the records
following proposed provisions: material review and disposition for equipment calibrations, inspections,
• Proposed § 111.35(i)(4)(i) which, in decision. Final § 111.113(c) derives from and checks as records for calibrations,
part, would require that, for any proposed § 111.35(j) which, in part, inspections, and checks of ‘‘automated,
deviation or unanticipated occurrence would require that the person who mechanical, or electronic equipment,’’
which resulted in or could lead to conducts the material review and makes because final § 111.30(c) requires you to
adulteration of the component, dietary the disposition decision must, at the calibrate, inspect, or check ‘‘automated,
ingredient, dietary supplement, time of performance, document every mechanical, or electronic equipment.’’
packaging, or label, you reject the material review and disposition (Comment 220) One comment argues
component, dietary ingredient, dietary decision in proposed § 111.35(i). the requirements for oversight by the
supplement, packaging, or label, unless quality control unit in proposed
As an editorial revision, final
the quality control unit determines that § 111.37(b)(7) and (b)(8) are excessive
§ 111.113(c) requires documentation of
in-process adjustments are possible to and go beyond requirements for both the
‘‘that’’ decision rather than ‘‘every’’
correct the deviation or occurrence; drug CGMPs and food CGMPs. The
decision. As a practical matter, under
• Proposed § 111.35(i)(4)(ii) which, in final § 111.113(c) every material review
comment recommends revising
part, would require that, for any proposed § 111.37(b)(7) and (b)(8) to
and disposition decision is documented.
deviation or unanticipated occurrence require a review of all records when
which resulted in or could lead to We did not receive comments specific there is a negative impact on the
adulteration of the component, dietary to quality control operations under product due to a calibration failure.
ingredient, dietary supplement, proposed § 111.35(j). Other comments refer to the related
packaging, or label, you not reprocess a H. What Quality Control Operations Are requirements in proposed § 111.30(b)(1)
rejected component or dietary Required for Equipment, Instruments, that the quality control unit approve
supplement unless approved by the and Controls? (Final § 111.117) calibrations, inspections, or checks of
quality control unit; and automatic, mechanical, or electronic
• Proposed § 111.37(b)(3) which, in Final § 111.117 (proposed equipment. These comments assert the
part, would require the quality control § 111.37(b)(6) through (b)(8)) sets forth requirement for the quality control unit
unit to approve or reject all dietary the minimum required operations that to approve such calibrations,
ingredients, dietary supplements, quality control personnel must perform inspections, and checks of equipment is
components, packaging, and labels. with respect to equipment, instruments, too prescriptive and that qualified
For consistency with other provisions and controls. persons outside of the quality control
in final subpart F, final § 111.113(b)(1) 1. Final § 111.117(a) through (c) unit should be able to approve these
requires that quality control personnel calibrations, inspections, or checks.

‘‘reject’’ a component, dietary Final § 111.117(a) through (c) requires These comments also assert the quality
supplement, packaging, or label. We the quality control operations for control unit should perform audits of
also included revisions that are equipment, instruments, and controls to the records generated to ensure the
associated with final § 111.90. include: appropriate calibrations, inspections,
and checks are being adequately responsibilities that the person shipment you receive to the product
performed at the required intervals. otherwise has when not performing that you manufacture and distribute.
(Response) As already discussed with such operations. Thus, in the situation The final rule separates these and other
respect to proposed § 111.30(b)(1) (final described by these comments, you could requirements for quality control
§ 111.30(c)), we disagree that the review identify a qualified person in a operations for ‘‘product that you receive
by quality control personnel should be department dedicated to equipment from a supplier’’ for packaging or
limited to circumstances when there has maintenance and calibration to perform labeling as a dietary supplement from
been a calibration failure. One of the quality control operations for equipment the analogous requirements for
oversight functions of quality control calibration. Neither the definition of components. Thus, the requirements for
personnel is to prevent problems with ‘‘quality control personnel,’’ nor the quality control operations for product
the product you distribute by finding requirements of final § 111.12(b), would you receive for packaging and labeling
any problems with the equipment you preclude a person who performs as a dietary supplement (and for
use to produce the product rather than ‘‘Operation X’’ from being identified as distribution rather than for return to the
to investigate the cause of a problem the person who performs quality control supplier) are found in final § 111.127
with a product that you already operations for ‘‘Operation X.’’ However, rather than final § 111.120.
distributed. However, we agree it is we strongly recommend that the person
sufficient to review the records of 1. Final § 111.120(a)
you identify to perform a given quality
calibrations, inspections, and checks of control operation be a different person Final § 111.120(a) requires that
automated, mechanical, or electronic than the person who performed the quality control operations for
equipment periodically, for example, on operation that is subject to quality components, packaging, and labels
an annual basis, rather than to approve control oversight. include reviewing all receiving records
each record when it is made. A periodic for components, packaging, and labels
review can uncover trends in the 2. Final § 111.117(d) before use. Final § 111.120(a) derives
performance of the equipment that have Final § 111.117(d) requires that from the following proposed provisions:
the potential to adversely affect the quality control operations for • Proposed § 111.37(b)(10) which, in
quality of the dietary supplement and equipment, instruments, and controls part, would require the quality control
that may not be obvious by merely include reviewing and approving unit to review and approve all
approving each record when it is made. controls to ensure automated, packaging and label records which
Seeing such trends would enable quality mechanical, or electronic equipment include, but are not limited to, cross-
control personnel to recommend actions functions in accordance with its referencing receiving and batch
to correct the trend. Therefore, we have intended use. Final § 111.117(d) derives, production records;
revised the proposed requirement so in part, from proposed § 111.30(b)(4) • Proposed § 111.40(a)(3) which, in
that under final § 111.117(c) quality (final § 111.30(e)) which would require part, would require that you quarantine
control personnel must review all that, for any automated, mechanical, or dietary supplements until your quality
records of calibrations, inspections, and electronic equipment you use, you must control unit reviews the supplier’s
checks of automatic, mechanical, or establish and use appropriate controls invoice, guarantee, or certification; and
electronic equipment on a periodic and the controls are approved by your • Proposed § 111.50(e)(1) which, in
basis. Likewise, we have revised the quality control unit to ensure that the part, would require the quality control
rule so that the quality control equipment functions in accordance with unit to document its review of
personnel’s review of all records of its intended use. We are clarifying the component receiving records.
equipment calibrations also is on a proposed requirement related to quality (Comment 222) One comment asserts
periodic basis. control personnel in final § 111.117(d). that the proposed requirement that the
(Comment 221) A few comments We did not receive comments specific review of the batch record by the quality
argue the review of calibration records to this responsibility of the quality control unit include cross-referencing of
may be conducted by a qualified person control unit in proposed § 111.30(b)(4). receiving records with the batch
other than the quality control unit, such production record is redundant and
I. What Quality Control Operations Are should be mandatory only in cases
as by a supervisor or by a separate
Required for Components, Packaging, where a specification has not been met.
department dedicated to equipment
and Labels Before Use in the This comment asserts the quality
maintenance and calibration. These
Manufacture of a Dietary Supplement? control unit has already reviewed and
comments assert the quality control unit
(Final § 111.120) approved components, packaging, and
should approve calibration processes,
but review of completed calibration Final § 111.120 sets forth the labels prior to their release and has used
records by the dedicated department is minimum required operations that unique identifiers for these raw
sufficient to assure compliance with the quality control personnel must perform materials as they are recorded on related
approved process. with respect to components, packaging, documentation and records, which
(Response) As already discussed, and labels before use in the manufacture allow traceability back to this
many comments about the quality of a dietary supplement. Some of the documentation for review when
control unit may have misunderstood proposed provisions that form the basis necessary. This comment also asserts all
the proposed definition of ‘‘quality for final § 111.120 included material review and disposition
control unit’’ (now replaced by ‘‘quality requirements for ‘‘dietary supplements decisions must be documented and
control personnel’’). Under final that you receive.’’ For example, these will include the unique identifiers
§ 111.12(b), you must identify who is proposed § 111.40(a) would require you, that tie them to particular raw or in-
responsible for your quality control for components or dietary supplements process materials.
operations. Each person who is you receive, to visually examine Another comment asserts that the
identified to perform quality control containers and documentation provided quality control unit should only need to
operations must be qualified to do so by the supplier, quarantine the materials repeat a review of the receiving records
and have distinct and separate until they are released by the quality as a result of conducting an
responsibilities related to performing control unit, and identify the materials investigation or a material review, as is
such operations from those in a manner that allows you to trace the required for drugs, and to require
otherwise would be redundant. This include conducting any required dietary supplement to fail to meet
comment also states requiring the material review and making any product specifications.
quality control unit to repeat its review required disposition decision before
4. Final § 111.120(d)
of the receiving records places a fairly use. Final § 111.120(c) derives from the
large burden on the quality control unit following proposed provisions: Final § 111.120(d) requires that
because this re-review must be • Proposed § 111.40(a)(3) which, in quality control operations for
performed for each and every batch part, would require you to conduct a components, packaging, and labels
production record. The comments assert material review and make a disposition include approving, or rejecting, any
the requirement should be completed decision if specifications are not met for treatment and in-process adjustments of
properly and only once. components; and components, packaging, or labels to
(Response) In the preamble to the • Proposed § 111.40(b)(2) which, in make them suitable for use in the
2003 CGMP Proposal (68 FR 12157 at part, would require you to conduct a manufacture of a dietary supplement.
12200), we stated that cross-referencing material review and make a disposition Final § 111.120(d) derives from the
receiving and batch production records decision if specifications are not met for following proposed provisions:
means the quality control unit must packaging and labels. • Proposed § 111.35(i)(4)(i) which, in
verify that the batch record includes Final § 111.120(c) includes revisions part, would require that you reject the
certain documentation of the receiving associated with final § 111.87 which component, packaging, or label, unless
records for the components such as the requires quality control personnel to the quality control unit determines that
unique identifier assigned to the conduct any required material review in-process adjustments are possible to
shipment lot of components, testing and make any required disposition correct the deviation or occurrence and
results, a material review and decision. • Proposed § 111.35(i)(4)(ii) which
disposition decision, if conducted, and (Comment 223) One comment would have prohibited you from
approval for use by the quality control recommends the quality control unit reprocessing a rejected component
unit. We agree with the comments that have authority to allow usage of unless approved by the quality control
the review of records such as receiving material that has failed to meet unit.
records (including proper specifications if the defect will not Final § 111.120(d) includes a revision
documentation of a unique identifier for significantly affect the overall quality of associated with final § 111.90(c), and
components, packaging, and labels), if the finished product even if refers to ‘‘treatment and in-process
done properly the first time it is reprocessing is not an option. The adjustments to make them suitable for
performed, need not be repeated. comment gives an example of a material use in the manufacture of a dietary
Therefore, the final rule does not that fails to meet particle size supplement’’ (see discussion of final
include any requirement for cross- specifications designed to maximize the § 111.90(c) in section X of this
referencing receiving records with the efficiency of processing of the material, document).
batch production record as we would but ultimately does not impair strength, (Comment 224) Several comments
require under proposed § 111.37(b)(10). and asserts the quality unit should have request the quality control unit focus on
As noted, we have changed ‘‘quality the authority to release the material for reviewing tasks performed by others
control unit’’ to ‘‘quality control use. rather than on performing the tasks
personnel.’’ We agree that cross- (Response) The final rule provides for itself.
referencing receiving and batch a process in which quality control (Response) Final § 111.120(d)
production records is an appropriate personnel determine whether a includes a revision that quality control
step to take when conducting a material component meets specifications and personnel ‘‘approve’’ a treatment rather
review and making a disposition when, conduct a material review and make a than ‘‘determine that’’ the treatment is
disposition decision if a component possible.
for example, a specification is not met.
does not meet one or more (Comment 225) A few comments
We encourage firms to include this
specifications. The final rule does not support the proposed requirement that
activity in the written procedures for
prohibit the use of a component that the quality control unit have the
conducting a material review and
does not meet all component authority to approve reprocessing
making a disposition decision.
specifications other than the identity measures.
2. Final § 111.120(b) specification. For example, under final (Response) These comments are
Final § 111.120(b) requires that § 111.120(d) quality control personnel consistent with proposed § 111.35(i) and
quality control operations for may approve an in-process adjustment (i)(4)(ii) and final § 111.120(d), as
components, packaging, and labels of a component to make it suitable for applicable to quality control personnel.
include determining whether all use in the manufacture of a dietary (Comment 226) One comment states
components, packaging, and labels supplement (see discussion of final that the decision to reprocess a material
conform to specifications established § 111.120(d) in the following belongs within the particular
under § 111.70(b) and (d) before use. paragraphs). Under final § 111.123(b) operational unit, and that the role of the
Final § 111.120(b) derives from quality control personnel must not quality control unit should be to
proposed § 111.37(b)(2). approve and release for distribution any approve the results of the reprocessing.
We did not receive comments specific batch of dietary supplement, including (Response) We disagree that the role
to quality control operations under any reprocessed batch, that does not of quality control personnel should be
proposed § 111.37(b)(2). For clarity, we meet all product specifications or is not limited to approving the results of
have identified the specifications as a quality product. Thus, although a reprocessing or, in this case, of the
those required under final § 111.70(b) disposition decision could be made treatment or in-process adjustments of
and (d). under final § 111.120(c) to use a components, packaging, or labels. An
component even if it does not meet underlying principle of these CGMP

3. Final § 111.120(c) certain specifications, that decision requirements is that quality control
Final § 111.120(c) requires that should take into account whether the personnel oversee the design and
quality control operations for failure for the component to meet conduct of manufacturing, packaging,
components, packaging, and labels specifications will ultimately cause the labeling, and holding operations. A
decision about when reprocessing is, or but have combined them as final performed, need not be repeated.
is not, appropriate requires oversight. § 111.123(a)(1). Therefore, the final rule does not
As already discussed, under final include any requirements for cross-
2. Final § 111.123(a)(2)
§ 111.12(b) you must identify who is referencing receiving records with the
responsible for your quality control Final § 111.123(a)(2) requires that batch production record as we would
operations. Each person who is quality control operations for the master require under proposed § 111.37(b)(5).
identified to perform quality control manufacturing record, the batch
production record, and manufacturing 3. Final § 111.123(a)(3)
operations must be qualified to do so
and have distinct and separate operations include reviewing and Final § 111.123(a)(3) requires that
responsibilities related to performing approving all batch production-related quality control operations for the master
such operations from those records. Final § 111.123(a)(2) derives manufacturing record, the batch
responsibilities that the person from proposed § 111.37(b)(5), which production record, and manufacturing
otherwise has when not performing would require, in part, the quality operations include reviewing all
such operations. control unit to review and approve all monitoring required under subpart E.
batch production-related records. Final § 111.123(a)(3) derives from the
5. Final § 111.120(e) Proposed § 111.37(b)(5) explicitly following proposed provisions:
Final § 111.120(e) requires that stated, in part, that the batch record • Proposed § 111.35(f) which would
quality control operations for would include, but not be limited to, require you to monitor the in-process
components, packaging, and labels cross-referencing receiving and batch control points, steps, or stages to ensure
include approving and releasing from production records. that specifications established under
quarantine all components, packaging, (Comment 227) One comment proposed § 111.35(e) are met and to
and labels before they are used. Final expresses concern that proposed detect any unanticipated occurrence
§ 111.120(e) derives from the following § 111.37(b) does not state specifically that may result in adulteration;
proposed provisions: that the complete batch history, • Proposed § 111.35(e)(2) which
• Proposed § 111.40(a)(3) which, in including batch record, analytical would require you to establish a
part, would require that you quarantine records, quality control records, yields, specification for any point, step, or stage
components until your quality control and packaging records should be in the manufacturing process where
unit approves the components and reviewed and approved by the quality control is necessary to prevent
releases them from quarantine and control unit before the batch is shipped. adulteration, including the in-process
• Proposed § 111.40(b)(2) which, in The comment believes these are controls in the master manufacturing
part, would require that you quarantine important requirements that should be record where control is necessary to
packaging and labels until your quality clearly stated. ensure the identity, purity, quality,
control unit approves the packaging and (Response) Proposed § 111.37(b)(5) strength, and composition of dietary
labels and releases them from would require that the quality control supplements;
quarantine. unit ‘‘review and approve all batch • Proposed § 111.35(i)(2) which
We did not receive comments specific production-related records, including would require you to review the results
to quality control operations under but not limited to * * *’’ We disagree of the monitoring required under
proposed § 111.40(a)(3) or (b)(2). with the comment that this proposed proposed § 111.35(f) and conduct a
provision would not include what the material review if an established
J. What Quality Control Operations Are comment describes. To the extent that specification is not met or if there is any
Required for the Master Manufacturing the comments interpreted the list of unanticipated occurrence that
Record, the Batch Production Record, records to mean that only the partial adulterates or could result in
and Manufacturing Operations? (Final listing of records was required, we have adulteration;
§ 111.123) modified final § 111.123(a)(2) to require • Proposed § 111.35(o)(2) which
Final § 111.123 sets forth the quality control personnel to review all would require you to make and retain
minimum required operations that batch production-related records. We do records to ensure you follow the
quality control personnel must perform not emphasize any particular aspect of requirements of proposed § 111.35,
with respect to the master the batch production record. This including the actual results obtained
manufacturing record, the batch reduces the potential to misinterpret the during the monitoring operation; and
production record, and manufacturing requirement as being limited to the • Proposed § 111.37(b)(5) which
operations. specific items cited. would require the quality control unit to
(Comment 228) As already discussed review and approve all batch
1. Final § 111.123(a)(1) in detail with respect to final production-related records.
Final § 111.123(a)(1) requires that § 111.120(a), some comments assert the Under the final rule, the results of the
quality control operations for the master proposed requirement that the review of monitoring required under proposed
manufacturing record, the batch the batch record by the quality control § 111.35(f) must be kept in the batch
production record, and manufacturing unit include cross-referencing of record (see the discussion of the batch
operations include reviewing and receiving records with the batch record in section XIV of this document).
approving all master manufacturing production record is redundant to other Quality control personnel must review
records and all modifications to the requirements that the quality control the results of the required monitoring.
master manufacturing records. Final unit review receiving records for (Comment 229) One comment
§ 111.123(a)(1) derives from duplicate components, packaging, and labels. In suggests the phrase ‘‘review the results
proposed requirements, in proposed general, these comments assert the of the monitoring required by this
§§ 111.37(b)(4) and 111.45(c), with no requirement should be completed section’’ be deleted from proposed
changes other than the editorial changes properly and only once. § 111.35(i)(2) because it is unnecessary
associated with the reorganization. (Response) We agree with the and can be read as narrowing any final
We did not receive comments specific comments that the review of records, rule. This comments points out the only
to quality control operations under such as receiving records, if done required monitoring in the proposal
proposed §§ 111.37(b)(4) or 111.45(c), properly the first time that it is appears in § 111.35(f) related to
monitoring of in-process control points, personnel must approve—or reject—any reprocessed finished batch. Final
steps, or stages, and that such reprocessing. § 111.123(a)(8) derives from the
monitoring would not necessarily find We did not receive comments specific following proposed provisions:
all failures in specifications, for to quality control operations under • Proposed § 111.37(b)(5) which, in
example, specifications related to raw proposed § 111.37(b)(5). part, would require the quality control
materials or labels. unit to approve batch production
(Response) We disagree with the 6. Final § 111.123(a)(6)
records for releasing finished batches for
comment that the quoted language Final § 111.123(a)(6) requires that distribution;
narrows the final rule. Monitoring that quality control operations for the master • Proposed § 111.50(d)(2) which
relates to in-process control points, manufacturing record, the batch would require the quality control unit to
steps, or stages would be required under production record, and manufacturing not approve and release for distribution
proposed § 111.35(f) and is now operations include determining whether any batch that does not meet all
required in final § 111.123(a)(3). all in-process specifications established specifications; and
However, in practice, a manufacturer in accordance with § 111.70(c) are met. • Proposed § 111.50(g) which would
must monitor its entire operation to Final § 111.123(a)(6) derives from the require the quality control unit to not
ensure that the requirements of the final following proposed provisions: approve and release for distribution any
rule are met. For example, under final • Proposed § 111.35(f) which would reprocessed batch of dietary supplement
§ 111.73, a manufacturer must require you to monitor the in-process that does not meet all specifications.
determine whether specifications control points, steps, or stages to ensure We did not receive comments specific
established under final § 111.70 are met specifications are met (including the in- to the proposed provisions cited above.
and under final § 111.75(a) and (f) a process specifications required under
9. Final § 111.123(b)
manufacturer must use certain criteria proposed § 111.35(e)(2)) and
to determine whether specifications for • Proposed § 111.37(a) which, in part, Final § 111.123(b) requires that
components and labels, respectively, are would require the quality control unit to quality control personnel must not
met. Thus, there are sufficient controls ensure your manufacturing, packaging, approve and release for distribution:
in other requirements to ensure the labeling, and holding operations are • any batch of dietary supplement for
entire production and process controls performed in a manner that prevents which any component in the batch does
are functioning as intended. adulteration, including that such not meet its identity specification;
operations ensure the dietary • any batch of dietary supplement,
4. Final § 111.123(a)(4) supplement meets its specifications for including any reprocessed batch, that
Final § 111.123(a)(4) requires that identity, purity, quality, strength, and does not meet all product specifications
quality control operations for the master composition. established in accordance with
manufacturing record, the batch Final § 111.123(a)(6) is consistent § 111.70(e);
production record, and manufacturing with the overall approach, set forth in • any batch of dietary supplement,
operations include conducting any final §§ 111.70, 111.73, and 111.75, that including any reprocessed batch, that
required material review and making focuses on ensuring the quality of the has not been manufactured, packaged,
any required disposition decision. Final dietary supplement throughout the labeled, and held under conditions to
§ 111.123(a)(4) derives from the production and process control system. prevent adulteration under section
following proposed provisions: We did not receive comments specific 402(a)(1), (a)(2), (a)(3), and (a)(4) of the
• Proposed § 111.37(b)(5) which, in to quality control operations under act; and
part, would require the quality control proposed §§ 111.35(e)(2) or (f), or • any product received from a
unit to approve a material review and 111.37(a). supplier for packaging or labeling as a
disposition decision related to batch dietary supplement (and for distribution
7. Final § 111.123(a)(7) rather than for return to the supplier) for
production records; and
• Proposed § 111.50(d)(1) which, in Final § 111.123(a)(7) requires that which sufficient assurance is not
part, would require, if a batch deviates quality control operations for the master provided to adequately identify the
from the master manufacturing record, manufacturing record, the batch product and to determine that the
including any deviation from production record, and manufacturing product is consistent with your
specifications, the quality control unit operations include determining whether purchase order.
to conduct a material review and make each finished batch conforms to product Final § 111.123(b) derives from the
a disposition decision. specifications established in accordance following proposed provisions:
We did not receive comments specific with final § 111.70(e). Final • Proposed § 111.50(d)(2) which
to quality control operations under § 111.123(a)(7) derives from proposed would require the quality control unit to
proposed §§ 111.37(b)(5) or 111.50(d)(1). § 111.37(b)(2) which, in part, would not approve and release for distribution
require the quality control unit to any batch of dietary supplement that
5. Final § 111.123(a)(5) does not meet all specifications;
determine whether all dietary
Final § 111.123(a)(5) requires that supplements conform to specifications. • Proposed § 111.50(g) which would
quality control operations for the master We did not receive comments specific require that a reprocessed batch of
manufacturing record, the batch to quality control operations under dietary supplement meet all
production record, and manufacturing proposed § 111.37(b)(2). specifications and that the quality
operations include approving or control unit approve its release for
rejecting any reprocessing. Final 8. Final § 111.123(a)(8) distribution; and
§ 111.123(a)(5) derives from proposed Final § 111.123(a)(8) requires that • Proposed § 111.37(b)(11)(iii) which
§ 111.37(b)(5) which would require the quality control operations for the master would require the quality control unit to
quality control unit to approve any manufacturing record, the batch collect representative samples of each
reprocessing. For consistency with other production record, and manufacturing batch of dietary supplement
provisions in this final rule (such as operations include approving and manufactured to determine, before
final § 111.90), final § 111.123(a)(5) releasing, or rejecting, each finished releasing for distribution, whether the
includes a revision that quality control batch for distribution, including any dietary supplement meets its
specifications for identity, purity, decision. The comments argue the final rule and its applicability to
quality, strength, and composition. quality control unit should have the contractors.
The final provision clarifies all of the authority to release products with minor a. Final § 111.127(a). Final
responsibilities of quality control deviations. § 111.127(a) requires that quality control
personnel and includes provisions (Response) As discussed previously operations for packaging and labeling
consistent with changes made to final (see discussion of final § 111.90 in operations include reviewing the results
§§ 111.73, 111.77, and 111.90. subpart E in section X of this of any visual examination and
We did not receive comments specific document), we acknowledge that some documentation to ensure that
to those aspects of proposed specifications, such as component, other specifications established under final
§§ 111.50(g) and 111.37(b)(11)(iii) that than for identity, and in-process § 111.70(f) are met for product you
are relevant to final § 111.123(b). We specifications, that are not met may be receive for packaging or labeling as a
discuss in the following paragraphs able to be corrected by a treatment or an
comments we received to proposed dietary supplement (and for distribution
in-process adjustment. Quality control rather than for return to the supplier).
§ 111.50(d)(2). personnel would need to conduct a
(Comment 230) Several comments Final § 111.127(a) derives from the
material review and disposition following proposed provisions:
object to proposed § 111.50(d)(2) decision for any such specification not
because it would prohibit the release of • Proposed § 111.40(a)(2) which
met. If there are specifications for any
any batch that does not meet all would require you to visually examine
point, step, or stage in the
specifications. Other comments suggest the supplier’s invoice, guarantee, or
manufacturing process where control is
the prohibition should apply to meeting certification to ensure that dietary
necessary to ensure the quality of the
‘‘release specifications’’ or ‘‘essential supplements you receive are consistent
dietary supplement and that the dietary
manufacturer specifications’’ rather than with your purchase order and perform
supplement is packaged and labeled as
‘‘all specifications’’ because in-process testing, as needed, to determine whether
specified in the master manufacturing
deviations and minor deviations may specifications are met and
record (final § 111.70(a)), you must
not affect product quality. • Proposed § 111.40(a)(3) which
(Response) A finished dietary determine whether these specifications
are met (final § 111.73). would, in part, require you to
supplement that is ready for release for quarantine dietary supplements you
distribution must meet component Final § 111.123(b) does not preclude
you, for example, from releasing a receive until your quality control unit
specifications for identity established
product that was the subject of a reviews the supplier’s invoice,
under final § 111.70(b) and all product
material review because sampling guarantee, or certification and performs
specifications established for the batch
procedures had not been followed if, as testing, as needed, of a representative
under final § 111.70(e) and must be
a corrective action, the appropriate sample to determine that specifications
manufactured in a manner to prevent
samples were collected and subjected to are met.
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act. The appropriate tests and examinations. Final § 111.127(a) includes revisions
final rule does not prevent you from associated with final §§ 111.70(f) and
K. What Quality Control Operations Are
establishing additional specifications 111.75(e) which set forth requirements
Required for Packaging and Labeling
that do not affect the identity, purity, for all products you receive from a
Operations? (Final § 111.127)
strength, composition, or contaminant supplier for packaging or labeling as
levels of your finished dietary Final § 111.127 sets forth the required dietary supplements (and for
supplement. Such a specification is not operations that quality control distribution rather than for return to the
a component specification for identity personnel must perform with respect to supplier). As discussed in section X of
or a product specification that is packaging and labeling operations. this document, under final § 111.70(f) if
required under the final rule. Final 1. Final § 111.127(a) and (b) you receive such product, you must
§ 111.123(b) would not preclude you establish specifications to provide
from releasing a product that fails to Final § 111.127(a) and (b) set forth sufficient assurance that the product
meet a specification that is not a requirements for product you receive for you receive is adequately identified and
component specification for identity or packaging or labeling as a dietary is consistent with your purchase order.
a product specification established supplement (and for distribution rather In addition, under final § 111.75(e)
under final § 111.70 provided quality than for return to the supplier). before you package or label such
control personnel approve such release. Final § 111.127(a) and (b) apply to products, you must visually examine
Final § 111.123(b) would not preclude product that has left the control of the the products and have documentation to
you from releasing a product that you person who manufactured the batch; for determine whether the specifications
are permitted to release under final example, the purchase of dietary that you established under final
§ 111.77. supplements in bulk for packaging or § 111.70(f) are met. The documentation
(Comment 231) Some comments note labeling by a person who will distribute you have to satisfy the requirements of
that proposed § 111.50(d)(2) would not the packaged and labeled dietary final § 111.75(e) is not limited to a
allow the quality control unit to conduct supplements under a private label. If supplier’s invoice, guarantee, or
an investigation, and make a disposition you are a packager or labeler who certification and, thus, final § 111.127(a)
decision, of the failure of a batch to operates under contract to the incorporates the standard set by final
meet specifications. These comments manufacturer, and you will return the § 111.75(e) (i.e., documentation) rather
assert proposed § 111.50(d)(2) therefore dietary supplement to the manufacturer, than the proposed standard of the
restricts the provision in proposed we would not consider that you are supplier’s invoice, guarantee, or
§ 111.50(d)(1) which would require that, ‘‘receiving’’ product within the meaning certification. In addition, consistent
if a batch deviates from the master of final § 111.127(a) and (b). We would with final § 111.75(e), final § 111.127(a)
manufacturing record, including any consider you to be no different than an requires quality control personnel to
deviation from specifications, the operating unit of the manufacturer. In review the results of the visual
quality control unit must conduct a section VI of this document (subpart A), examination but not otherwise review
material review and make a disposition we discuss in detail the scope of this the results of tests or examinations.
We did not receive comments specific specified in the master manufacturing We did not receive comments specific
to quality control operations under record and applied the label specified in to quality control operations under
proposed § 111.40(a)(2) or (a)(3). the master manufacturing record. proposed §§ 111.37(b)(10) or 111.70(d).
b. Final § 111.127(b). Final For clarity, final § 111.127(d)
§ 111.127(b) requires that quality control identifies the specifications as those 6. Final § 111.127(h)
operations for packaging and labeling established in final § 111.70(g). Final § 111.127(h) requires that
operations include approving, and We did not receive comments specific quality control operations for packaging
releasing from quarantine, all products to quality control operations under and labeling operations include
you receive for packaging and labeling proposed § 111.37(b)(2) or (b)(11)(iv). approving for release, or rejecting, any
as a dietary supplement (and for packaged and labeled dietary
4. Final § 111.127(e) supplement (including a repackaged or
distribution rather than for return to the
supplier) before the products are used Final § 111.127(e) requires that relabeled dietary supplement) for
for packaging and labeling. Final quality control operations for packaging distribution. Final § 111.127(h) derives
§ 111.127(b) derives from proposed and labeling operations include from the following proposed provisions:
§ 111.40(a)(3) which, in part, would conducting any required material • Proposed § 111.37(b)(10) which, in
require you to quarantine dietary review and making any required part, would require the quality control
supplements that you receive until your disposition decision. Final § 111.127(e) unit to approve the release of packaged
quality control unit reviews the derives from the following proposed and labeled dietary supplements for
supplier’s invoice, guarantee, or provisions: distribution; and
certification and performs testing, as • Proposed § 111.70(c) which would • Proposed § 111.70(e) which, in part,
needed, of a representative sample to require you to conduct a material review would require the quality control unit to
determine that specifications are met, and make a disposition decision of any approve or reject the release of any
and approves and releases the dietary packaged and labeled dietary repackaged or relabeled dietary
supplements from quarantine before you supplement that does not meet supplement.
use them. specifications and We did not receive comments specific
As with final § 111.127(a), final • Proposed § 111.40(a)(3) which, in to quality control operations under
§ 111.127(b) includes revisions part, would require you, if proposed §§ 111.37(b)(10) or 111.70(e).
associated with changes made in final specifications are not met for a received
L. What Quality Control Operations Are
§§ 111.70(f) and 111.75(e). dietary supplement, to conduct a
Required for Returned Dietary
We did not receive comments specific material review and make a disposition
Supplements? (Final § 111.130)
to quality control operations under decision.
proposed § 111.40(a)(3). Final § 111.127(e) includes revisions Final § 111.130 sets forth the
associated with final § 111.87 which minimum required operations quality
2. Final § 111.127(c) requires quality control personnel to control personnel must perform with
Final § 111.127(c) requires that conduct any required material review respect to returned dietary supplements.
quality control operations for packaging and make any required disposition Final § 111.130 modifies proposed
and labeling operations include decision. § 111.85 which set forth requirements
reviewing and approving all records for We did not receive comments specific for returned dietary ingredients and
packaging and label operations. Final to quality control operations under dietary supplements, including
§ 111.127(c) derives from proposed proposed §§ 111.70(c) or 111.40(a)(3). requirements for quality control
§ 111.37(b)(10) which, in part, would operations for returned dietary
5. Final § 111.127(f) and (g) supplements. We did not explicitly
require the quality control unit to
review and approve all packaging and Final § 111.127(f) requires that quality include quality control operations with
label records. control operations for packaging and respect to returned dietary supplements
We did not receive comments specific labeling operations include approving under proposed § 111.37 but did
to quality control operations under or rejecting any repackaging of a include quality control operations in
proposed § 111.37(b)(10). packaged dietary supplement. Final proposed § 111.85 for returned dietary
§ 111.127(g) requires that quality control supplements. The provisions of the final
3. Final § 111.127(d) operations for returned dietary rule that pertain to returned dietary
Final § 111.127(d) requires that supplements include approving or supplements are set forth in final
quality control operations for packaging rejecting any relabeling of a packaged subpart N. However, we are duplicating
and labeling operations include and labeled dietary supplement. Final these requirements in subpart F to make
determining whether the finished § 111.127(f) and (g) derive from the clear that once returned products are
packaged and labeled dietary following proposed provisions: back within your control, quality
supplement conforms to specifications • Proposed § 111.37(b)(10) which, in control personnel must perform
established in accordance with final part, would require the quality control appropriate operations before the
§ 111.70(g). Final § 111.127(d) derives unit to approve any repackaging and products are redistributed, if they are
from the following proposed provisions: relabeling and approved for redistribution. Any
• Proposed § 111.37(b)(2) which, in • Proposed § 111.70(d) which would returned dietary supplements that are
part, would require the quality control require the quality control unit to reprocessed must be returned to your
unit to determine whether all dietary approve and document any repackaging production and process control system,
supplements conform to specifications or relabeling of a dietary supplement. and, therefore, must be properly
and For consistency with other provisions reviewed by quality control personnel.
• Proposed § 111.37(b)(11)(iv) which, in this final rule (such as final § 111.90),
1. Final § 111.130(a)
in part, would require the quality final § 111.127(f) and (g) provide that
control unit to collect representative quality control personnel must clearly Final § 111.130(a) requires that
samples of each batch of packaged and choose between approving—or quality control operations for returned
labeled dietary supplements to rejecting—any repackaged or relabeled dietary supplements include conducting
determine that you used the packaging dietary supplements. any required material review and
making any required disposition 4. Final § 111.130(c) M. What Quality Control Operations Are
decision. Final § 111.130(a) differs Required for Product Complaints? (Final
slightly from proposed § 111.85(a) Final § 111.130(c) requires that § 111.135)
which, in part, would require the quality control operations for returned
dietary supplements include approving Final § 111.135 requires that quality
quality control unit to conduct a control operations for product
material review and make a disposition or rejecting any reprocessing of any
returned dietary supplement. Final complaints include reviewing and
decision for any returned dietary approving decisions about whether to
supplement. § 111.130(c) derives from proposed
§ 111.37(b)(15) which, in part, would investigate a product complaint and
(Comment 232–233) Some comments reviewing and approving the findings
support the proposed requirement to require the quality control unit to
approve the reprocessing of returned and followup action of any investigation
specify that it is the quality control unit performed.
that conducts the material review and dietary supplements. For consistency
Final § 111.135 derives from proposed
makes the disposition decision with other provisions of this final rule
§ 111.95 which would set forth
regarding returned dietary supplement (such as final § 111.90), final
requirements for consumer complaints
products. § 111.130(c) provides that quality
(now ‘‘product complaints’’), including
control personnel must clearly choose
(Response) These comments are requirements for quality control
between approving—or rejecting—any
consistent with proposed § 111.85(a) operations for consumer complaints. We
reprocessing. did not explicitly include quality
which is being incorporated into final
§ 111.130(a). (Comment 235) One comment argues control operations with respect to
that the responsibility to decide whether consumer complaints under proposed
2. Final § 111.130(a)(1) and (a)(2) a returned dietary supplement is § 111.37 but did include quality control
Final § 111.130(a)(1) requires that reprocessed belongs with qualified operations in proposed § 111.95 for
quality control operations for returned persons in manufacturing operations, review and investigation of consumer
dietary supplements include and the only responsibility of the complaints. The final rule’s product
determining whether tests or quality control unit is to approve the complaint requirements are now set
examination are necessary to determine reprocessed product for distribution. forth in final subpart O. However, we
compliance with product specifications (Response) We disagree with the have duplicated the requirements for
established in accordance with final comment. An underlying principle of quality control operations for product
§ 111.70(e). these CGMP requirements is that quality complaints in subpart F to make clear
Final § 111.130(a)(2) requires that the control personnel oversee the design that your investigation of the product
review and disposition decision for and conduct of manufacturing, complaint has the potential to uncover
returned dietary supplements include packaging, labeling, and holding a problem with your production and
review of the results of any tests or operations. A decision about when process control system and, therefore,
examinations that are conducted to reprocessing is, or is not, appropriate quality control personnel must exercise
determine compliance with product requires oversight. appropriate oversight of your
specifications established in accordance investigation of any product complaint.
5. Final § 111.130(d)
with final § 111.70(e). N. What Records Must You Make and
3. Final § 111.130(b) Final § 111.130(d) requires that Keep? (Final § 111.140)
quality control operations for returned Final § 111.140 sets forth the
Final § 111.130(b) requires that dietary supplements include
quality control operations for returned requirements for records that quality
determining whether the reprocessed control personnel must make and keep.
dietary supplements include approving dietary supplement meets product
or rejecting any salvage and specifications and either approving for 1. Final § 111.140(a)
redistribution of any returned dietary release, or rejecting, any returned Final § 111.140(a) requires quality
supplement. Final § 111.130(b) derives dietary supplement that is reprocessed. control personnel to make and keep
from proposed § 111.37(b)(15) which, in Final § 111.130(d) derives from the records required under subpart F in
part, would require the quality control following proposed provisions: accordance with subpart P. Final
unit to approve the distribution of • Proposed § 111.37(b)(2) which, in § 111.140(a) derives from proposed
returned dietary supplements. As part, would require the quality control § 111.37(d) with editorial revisions
discussed in the preamble to the 2003 unit to determine whether all dietary associated with the reorganization.
CGMP Proposal, ‘‘salvage’’ means to supplements conform to specifications; Other than comments that generally
return to distribution without and opposed the requirements to make and
reprocessing (68 FR 12157 at 12215).
For consistency with other regulations • Proposed § 111.65(d) which, in part, keep records, and to have records
would require you, if a material review available for inspection and copying by
in this final rule (such as final § 111.90), FDA when requested (see the discussion
final § 111.130(e) provides that quality and disposition decision allows you to
reprocess a dietary supplement, to in section V of this document), we did
control personnel must clearly choose not receive comments specific to
between approving—or rejecting—any ensure it meets specifications and is
approved by the quality control unit. proposed § 111.37(d).
salvage and redistribution.
(Comment 234) Some comments For consistency with other regulations 2. Final § 111.140(b)(1)
support the proposed requirement to in this final rule (such as final § 111.90), The final rule (final § 111.103)
specify that it is the quality control unit final § 111.130(d) provides that quality requires you to establish and follow
who approves, or rejects, a returned control personnel must clearly choose written procedures for the
dietary supplement for redistribution. between approving—or rejecting—a responsibilities of the quality control
(Response) These comments are reprocessed dietary supplement. operations, including written
consistent with proposed § 111.37(b)(15) We did not receive comments specific procedures for conducting a material
which is being incorporated into final to quality control operations under review and making a disposition
§ 111.130(b). proposed §§ 111.37(b)(2) or 111.65(d). decision and for approving or rejecting
reprocessing. The written procedures • Section 111.140(b)(3)(i)— G and identifies the sections in the 2003
are records. Therefore, final Identification of the specific deviation CGMP Proposal that form the basis of
§ 111.140(b)(1) requires you to make and or the unanticipated occurrence; the final rule.
keep a record of the written procedures • Section 111.140(b)(3)(ii)—A
for the responsibilities of the quality description of your investigation into TABLE 8.—DERIVATION OF SECTIONS
control operations. the cause of the deviation from the IN FINAL SUBPART G
specification or the unanticipated
3. Final § 111.140(b)(2)
occurrence; Final Rule 2003 CGMP
Final § 111.140(b)(2) requires written • Section 111.140(b)(3)(iii)—An Proposal
documentation, at the time of evaluation of whether the deviation or
§ 111.153 What Are the N/A
performance, that quality control unanticipated occurrence has resulted
requirements under
personnel performed the review, in or could lead to a failure to ensure this subpart G for writ-
approval, or rejection requirements the quality of the dietary supplement or ten procedures?
under subpart F. Final § 111.140(b)(2)(i) a failure to package and label the dietary
requires quality control personnel to supplement as specified in the master § 111.155 What require- § 111.40(a)(1)
record the date that the review, manufacturing record; ments apply to compo- through (a)(5)
approval, or rejection was performed. • Section 111.140(b)(3)(iv)— nents of dietary sup- § 111.35(d)(1)
Final § 111.140(b)(2)(ii) requires quality Identification of the action(s) taken to plements? throug (d)(5)
control personnel to record the correct, and prevent a recurrence of, the
§ 111.160 What require- § 111.35(e)(4)
signature of the person performing the deviation or the unanticipated ments apply to pack- § 111.40(a)(2)
review, approval, or rejection. Final occurrence; aging and labels re- and (b)
§ 111.140(b)(2) derives from proposed • Section 111.140(b)(3)(v)—An ceived?
§ 111.37(c) with revisions associated explanation of what you did with the
with the reorganization. component, dietary supplement, § 111.165 What require- § 111.40(a)
We did not receive comments specific packaging, or label; ments apply to a prod-
to proposed § 111.37(c). • Section 111.140(b)(3)(vi)—A uct received for pack-
scientifically valid reason for any aging or labeling as a
4. Final § 111.140(b)(3) dietary supplement
reprocessing of a dietary supplement
(and for distribution
Final § 111.140(b)(3) requires quality that is rejected, or the treatment or in- rather than for return
control personnel to document any process adjustment of a component that to the supplier)?
material review and disposition is rejected; and
decision and followup and include the • Section 111.140(b)(3)(vii)—The § 111.170 What require- § 111.74
documentation in the batch record. signature of the individual(s) designated ments apply to re-
Final § 111.140(b)(3) derives from to perform the quality control operation, jected components,
who conducted the material review and packaging, and labels,
proposed § 111.35(j) with revisions and to rejected prod-
associated with the reorganization and a made the disposition decision, and of
ucts that are received
revision, associated with final § 111.87 each qualified individual who provided for packaging or label-
which requires quality control information relevant to that material ing as a dietary sup-
personnel to conduct the material review and disposition decision. plement?
review and make the disposition We did not receive comments specific
decision. to proposed § 111.35(j). § 111.180 Under this § 111.40(c)(1)(i)
subpart G, what through
Final § 111.140(b)(3) details the type XII. Comments on the Production and records must you (c)(1)(iv) and
of information that must be included as Process Control System: Requirements make and keep? (c)(2)
part of this documentation. Five for Components, Packaging, and Labels, § 111.35(d)(4)
paragraphs derive from proposed and for Product that You Receive for
§ 111.35(j)(1) through (j)(5), with Packaging or Labeling as a Dietary B. Highlights of Changes to the
editorial changes associated with the Supplement (Final Subpart G) Proposed Requirements for
reorganization. One paragraph is Components, Packaging, and Labels,
associated with final § 111.90(b) which A. Organization of Final Subpart G
and Product That You Receive for
requires that you not reprocess any In the 2003 CGMP Proposal, the Packaging or Labeling as a Dietary
component or dietary supplement that requirements for production and Supplement
is rejected or treat a component or make process controls related to components,
an in-process adjustment to make it packaging, dietary ingredients, labels, 1. Revisions
suitable for use in the manufacture of a and dietary supplements that you The final rule:
dietary supplement, unless quality receive were set forth in proposed • Applies to persons who
control personnel conduct a material § 111.40. As shown in table 8 of this manufacture, package, label, or hold a
review and make a disposition decision document, we are reorganizing the dietary supplement unless subject to an
that is based on a scientifically valid requirements related to components, exclusion in § 111.1.
reason and approve the reprocessing, packaging, labels, and product that you • Includes requirements that apply to
treatment, or in-process adjustment. receive for packaging and labeling as a components, including components that
Another paragraph derives, in part, from dietary supplement, into a distinct are dietary ingredients, regardless of
proposed § 111.37(c)(2) which would subpart (final Subpart G—Production whether you receive the components or
require the signature of the quality and Process Control System: manufacture them yourself (final
control unit person performing the Requirements for Components, §§ 111.70(b) and 111.75(a)).
requirement. Packaging, and Labels, and for Product • Separates the requirements for
The documentation that must be that You Receive for Packaging or product you receive from a supplier for
included under final § 111.140(b)(3) is Labeling as a Dietary Supplement). packaging or labeling as a dietary
as follows: Table 8 lists the sections in final subpart supplement (and for distribution rather
than for return to the supplier) (final E. What Requirements Apply to all other applicable statutory and
§ 111.165) from the requirements for Components of Dietary Supplements? regulatory requirements under the act,
components (final § 111.155). (Final § 111.155) and therefore, there is no need to refer
The final rule applies only to persons to food additive, color additive, and
2. Changes After Considering Comments
who manufacture, package, label, or GRAS requirements. Some comments
The final rule incorporates a new hold dietary supplements unless subject assert that proposed § 111.35(d) is
requirement to establish and follow to an exclusion under final § 111.1. The unnecessary because there is no such
written procedures for fulfilling the requirement in the food CGMPs. Other
effect of this revision is that the
requirements for components, comments assert this proposed
requirements that derive from proposed
packaging, labels, and product you requirement should be deleted because
§ 111.40(a) for components you receive
receive from a supplier for packaging or it is only tangentially related to the
now apply to all components, whether
labeling as a dietary supplement for manufacturing process, and CGMP
you receive them or manufacture them
distribution rather than for return to the should be focused on setting minimum
yourself.
supplier. standards for manufacturing systems
The final rule separates the
and steps in the production and
C. General Comments on Proposed requirements for product you receive
distribution of dietary supplements that
§ 111.40 (Final Subpart G) from a supplier for packaging or labeling
are required to produce safe and
as a dietary supplement (and for
accurately labeled products. Other
(Comment 236) One comment states distribution rather than for return to the
comments assert that because the drug
that many companies use an electronic supplier) (final § 111.165) from the CGMPs do not have such a requirement,
material resource planning system to analogous requirements for components, dietary supplement CGMPs should not
control the status of inventory, and packaging, and labels (final § 111.155). have such a requirement.
assert this type of system provides Other comments did not object to the
1. Proposed § 111.35(d)
suitable controls to ensure only principle underlying proposed
materials that are approved by the In proposed § 111.35(d), we would § 111.35(d), i.e., that we need to ensure
quality control unit are used. The require that any substance, other than a GRAS substances used in dietary
comment notes only the quality control ‘‘dietary ingredient’’ within the meaning supplements are GRAS under the
unit has the authority to release any of section 201(ff) of the act, that is manufacturer’s specified use. However
material in quarantine and asks whether subject to section 409 of the act, be: (1) many comments disagreed, for various
such a system would comply with the Authorized for use as a food additive reasons, with the proposed requirement
requirements of the proposed under section 409 of the act; or (2) in § 111.35(d)(4) that a claim that a
regulation. authorized by a prior sanction substance is GRAS must be supported
consistent with § 170.3(l) (21 CFR by a citation to our regulations or by an
(Response) Based on the limited
170.3(l)); or (3) if used as a color explanation for why there is general
information provided by the comment,
additive, subject to a listing that, by the recognition of safety of the use of the
it appears the electronic inventory
terms of that listing (including a listing substance in a dietary supplement.
system that the comment describes
for use in coloring foods generally), (Response) We agree that proposed
would comply with the requirements of
includes the use in a dietary § 111.35(d) is unnecessary because there
final § 111.155(c)(3) to quarantine
supplement; or (4) GRAS for use in a are already existing statutory and
components until quality control
dietary supplement. We also proposed regulatory requirements related to the
personnel release them for use in
that any claim that a substance is GRAS lawful use of ingredients used in dietary
manufacture, provided that appropriate
must be supported by a citation to the supplements. We do not have to repeat
controls are established and used to
agency’s regulations or by an those requirements in this final rule.
ensure the system functions in
explanation for why there is general Ensuring the ingredients you use to
accordance with its intended use as
recognition of safety of the use of the manufacture a dietary supplement are
required by final § 111.30(e). We are
substance in a dietary supplement. lawful under the applicable statutory
making no changes based on this
Further, under § 111.35(d)(5), we and regulatory requirements is the
comment.
proposed to require that you comply responsibility of the dietary supplement
D. What Are the Requirements Under with all other applicable statutory and manufacturer.
This Subpart for Written Procedures? regulatory requirements under the act. For the reasons set forth in the
(Final § 111.153) We received several comments previous paragraphs, we are deleting
objecting to one or more of the proposed § 111.35(d)(4) from the final
We received many comments that provisions of proposed § 111.35(d) and rule. Because we are deleting this
recommended written procedures for to our statement in the preamble to the provision, it is unnecessary to respond
various provisions. We address the need 2003 CGMP Proposal regarding how we to the various comments related to the
for written procedures generally in would apply the provisions of proposed documentation that proposed
section IV of this document. We also § 111.35(d)(4). After considering these § 111.35(d)(4) would have required, or
respond to individual comments on comments, we have deleted the whether we could not have included
specific provisions in the same section. requirements in § 111.35(d) in this final such requirements in the dietary
Final § 111.153 requires you to rule. supplement CGMP final rule because
establish and follow written procedures (Comment 237) Several comments the requirements are not in food or drug
for fulfilling the requirements of subpart recommend proposed § 111.35(d) be CGMP regulations.
G. Under final § 111.180(b)(1), as a deleted because the statute already We also agree that proposed
conforming requirement, we require you requires that ingredients, other than § 111.35(d)(5) is redundant to proposed
to make and keep records of such ‘‘dietary ingredients,’’ be approved as a § 111.5 and final § 111.5 and are
written procedures. Such records would food additive or a color additive, or be therefore not repeating proposed
be available to us under the GRAS. Some comments assert that § 111.35(d)(5) in final § 111.35.
requirements in Subpart P—Records proposed § 111.35(d) and proposed Although we are deleting § 111.35(d)
and Recordkeeping. § 111.5 already require compliance with from the final rule, there were several
comments that we received, and becoming a component or otherwise more critical. We advise persons who
respond to in the following paragraphs, affecting the characteristics of any food’’ need more information about the basis
that seemed to question whether if the use of such substance is not GRAS for concluding that a use of a substance
existing statutory and regulatory (section 201(s) of the act).11 We have is GRAS to consult § 170.30 and our
requirements apply to the use of discretion to determine whether an GRAS Proposal to establish a
ingredients in a dietary supplement. ingredient is one where the agency notification program for the use of
(Comment 238) One comment would find the presence to be ‘‘de GRAS substances (62 FR 18938, April
suggests components not found in minimis’’ (Monsanto v. Kennedy, 613 17, 1997).
finished goods in a material amount F.2d 947, 956 (D.C. Cir. 1979)). (Comment 240) Some comments
should not be subject to the same GRAS However, whether the agency would assert it is not feasible to require that
requirements as those found in a find it appropriate to exercise such starting materials used by bulk
material amount. Another comment discretion with respect to the use of a ingredient manufacturers be GRAS or
states dietary supplements are excluded particular ingredient is beyond the approved food additives. The comments
from the food additive definition in scope of this final rule. state many ingredients are not food
section 201(s) of the act, and that (Comment 239) Several comments grade substances or approved for use in
components that constitute the dietary questioned whether certain ingredients food until after processing. One
supplement are also excluded from the would be considered GRAS. One comment states raw materials may
food additive definition. The comment comment stated excipients regularly become dietary ingredients after
suggests that, under proposed used in pharmaceuticals for many years processing, but the materials from
§ 111.35(d), we are erroneously trying to and safely used in dietary supplements which the dietary ingredient is derived
maintain food additive authority for may not be considered GRAS for use in are not considered to be a GRAS
dietary supplements. foods, approved for use as a food ingredient, a dietary ingredient, or a
(Response) The assertion that dietary additive, or considered a dietary dietary supplement. The comment gives
supplements and all of their ingredient. An example provided was examples of Ginkgo biloba leaves or
components are not subject to the food ‘‘croscarmellose sodium’’ used for Saw palmetto or cartilage. The comment
additive provisions of the act’s disintegration. The comment asks asks us to consider natural products
definition is incorrect. We do maintain permission to use any recognized (from animal, mineral, or vegetable
authority over the use of certain excipient, an excipient that is origin) to be included in the rule as
substances, as color additives, food monographed in a recognized potential raw materials for nutritional
additives,10 or GRAS substances that compendium, used in drug products, or supplements. Another comment
may be used in manufacturing dietary shown to be in use prior to the expresses concern that a soy isolate,
supplements. implementation of the final rule. Other from which natural vitamin E is
The food additive definition in comments stated proposed § 111.35(d) derived, would not be considered a
section 201(s) of the act excludes ‘‘an would be overly burdensome since GRAS substance.
ingredient described in paragraph (ff) in, many ingredients are GRAS for broad (Response) These comments seem to
or intended for use in, a dietary food use, have been used in dietary be concerned about the regulatory status
supplement.’’ Thus, a ‘‘dietary supplements without specific of substances used as raw materials in
ingredient’’ described in section recognition as a GRAS use, and should the manufacture of a dietary ingredient
201(ff)(1) of the act is not a ‘‘food be permitted. Other comments state or dietary supplement. An important
additive.’’ Nor can the use of a dietary substances listed in the USP National consideration, however, is whether such
ingredient be considered to be GRAS, Formulary, Food Chemical Codex, the materials become a component of the
since the GRAS status itself is an American Pharmaceutical Associations dietary ingredient or dietary
exception to the definition of a food Handbook of Pharmaceutical Excipients, supplement.
and FDA’s inactive ingredient guide are Dietary ingredient manufacturers who
additive. However, ingredients that may
considered GRAS based on a history of manufacture dietary ingredients for
be used in a dietary supplement, other
common use even though there is no further processing by another person
than those excepted in section 201(s),
listing of these substances as GRAS. into a dietary supplement are outside
are subject to our regulatory authority as the scope of this final rule. However,
(Response) The GRAS status of
a food additive, unless their use is such manufacturers are still subject to
specific uses of excipients cannot be
GRAS or authorized by a prior sanction. other applicable statutory and
treated as a general class and is beyond
Thus, it is incorrect to say, as the regulatory provisions. For example, if
the scope of this final rule. It is possible
comment asserts, that dietary you are a dietary ingredient
that the data needed to support safe uses
supplements and all of their manufacturer that uses a material in the
as an excipient in a drug may be widely
components are not subject to the food manufacture of a dietary ingredient, and
known among experts and form a basis
additive definition. for a consensus that use in a dietary the material becomes part of the dietary
We also disagree that components not ingredient, we would consider it to be
supplement is safe. However, use of
found in finished goods in a material part of the dietary ingredient and
drugs containing the excipient may be
amount should not be subject to the short term or may be intermittent, subject to the exception to the food
same GRAS requirements as those found leading to far less exposure than routine additive definition in section 201(s)(6)
in a material amount. It is not clear what use in some dietary supplements. As of the act. However, because the
the comment meant by ‘‘material human exposure increases, not only material becomes a component of the
amount.’’ A food additive means ‘‘any does the safety profile of the intended dietary ingredient, you are subject to the
substance the intended use of which excipient become more important, but applicable statutory and regulatory
results or may reasonably be expected to the purity specifications also become requirements that would apply to the
result, directly or indirectly, in its
dietary ingredient, including the safety

11It is important to note that it is the use of the
10Although
of the dietary ingredient.
we refer to the term ‘‘food additive’’ substance, not the substance itself, that must be
in the preamble, the reader should also consider GRAS. The amount of a substance in the food is a
If you use a material, other than a
color additives and substances prior-sanctioned for critical factor in determining whether the use dietary ingredient, in the manufacture of
such use as being relevant to the discussion. would be GRAS. a dietary supplement, that becomes a
part of the dietary supplement, you are coloring foods generally’’) mean we saw (Response) The provisions of final
subject to the applicable statutory and no need for restriction of the use of the § 111.155(a) are requirements, not
regulatory requirements that apply to color additive when FDA approved the guidelines, as stated by the comment.
the use of such material, including its listing of that color additive. Thus, a
3. Final § 111.155(b)
safety for such use. In this case, the use color additive listed for use in food
of the material would be subject to generally may be used in a dietary Final § 111.155(b) (proposed
regulation as a food additive (unless it supplement. § 111.40(a)(2)) requires you to visually
is GRAS or prior-sanctioned). Although most listings of color examine the supplier’s invoice,
Alternatively, if you use material in additives provide for the use of the color guarantee, or certification in a shipment
the manufacture of a dietary ingredient additive in food generally, some listings you receive to ensure that the
or a dietary supplement that does not for color additives restrict the use of the components are consistent with your
become part of the dietary ingredient or color additive in terms of the food purchase order. Final § 111.155(b) is
dietary supplement, then we would not category in which it may be used. For substantially similar to proposed
consider the material to be a food. example, under 21 CFR 73.125 sodium § 111.40(a)(2) which would require you
(Comment 241) Several comments copper chlorophyllin may be safely to visually examine the supplier’s
state the color additive provision would used to color citrus-based dry beverage invoice, guarantee, or certification to
be too restrictive if it only allowed mixes in an amount not exceeding 0.2 ensure the components are consistent
colors listed for use in a dietary percent in the dry mix, and the terms of with your purchase order and perform
supplement, rather than colors listed for this listing would not include the use in testing, as needed, to determine whether
use in foods generally. Some comments a dietary supplement. We list a color specifications are met. As with final
note none of the color additives additive with restrictions such as these § 111.155(a), final § 111.155(b) clarifies
currently approved generally for ‘‘food’’ when for example, the person who that the invoice, guarantee, or
use is approved specifically for dietary submits a petition for us to approve the certification comes in the shipment you
supplements within the food category. listing of a color additive only requests receive.
Another comment argues we gave no a specific use, or when the available Final § 111.155(b) does not include
rationale for requiring a categorical data and information only support the any requirements related to testing
listing under specific color additives for safety of a limited consumption of the components. Final § 111.75(a) sets forth
dietary supplements. The comment color additive. the requirements to test or examine
states color additives are not used in components; final §§ 111.110 and
any greater amount in supplements than 2. Final § 111.155(a)
111.120 set forth requirements for
in foods and, if anything, are probably Final § 111.155(a) (proposed quality control personnel to ensure that
used less because supplements are § 111.40(a)(1)) requires you to visually appropriate tests or examinations are
consumed in smaller amounts than examine each immediate container or conducted, review the results of any
foods and less color additive must be grouping of immediate containers in a tests or examination, determine whether
used to achieve the desired effect. One shipment you receive for appropriate components conform to specifications,
comment notes it was not familiar with content label, container damage, or and approve the components before
any evidence to indicate that a color broken seals to determine whether the they are used in the manufacture of a
additive (whether it is certified or container condition may have resulted dietary supplement. Given this set of
exempt) found by us to be safe for use in contamination or deterioration of the requirements, it would be redundant to
in foods is not safe in dietary components. Final § 111.155(a) is set forth requirements regarding testing
supplements. substantially similar to proposed for components in final subpart G.
(Response) We acknowledge that the § 111.40(a)(1) which would require you, We did not receive comments specific
combination of proposed § 111.35(d)(3) for components you receive, to visually to the requirements of proposed
and several color additive listings is examine each container or grouping of § 111.40(a)(2).
confusing and could lead to incorrect containers in a shipment for appropriate
conclusions about whether specific content label, container damage, or 4. Final § 111.155(c)
color additives may lawfully be used in broken seals to determine whether the Final § 111.155(c) (proposed
a dietary supplement. As the comments container condition has resulted in § 111.40(a)(3)) requires you to
point out, some listings for color contamination or deterioration of the quarantine components before you use
additives (such as for the certified colors components. Because you do not receive them in the manufacture of a dietary
FD&C Blue No. 1 (21 CFR 74.101) and shipments for components you make, supplement until:
FD&C Red No. 40 (21 CFR 74.340)) list we are revising proposed § 111.40(a) so • You collect representative samples
the color additive ‘‘for coloring foods that it applies only to shipments of of each unique lot of components (and,
(including dietary supplements) components you receive. We have for components that you receive, of each
generally’’ (i.e., the listings specifically added the word ‘‘immediate’’ to identify unique shipment, and of each unique lot
identify dietary supplements as a food the container as the one in contact with within each unique shipment);
category in which the color additive the dietary supplement or component. • Quality control personnel review
may be used). In contrast, some listings We also have changed ‘‘has resulted’’ to and approve the results of any test or
for color additives (such as for annatto ‘‘may have resulted’’ since in some examinations conducted on
extract (21 CFR 73.30) and for beta- cases you may not be able to make a components; and
carotene (21 CFR 73.95)) list the color final determination from a visual • Quality control personnel approve
additive ‘‘for coloring foods generally’’ inspection alone whether the container the components for use in the
(i.e., without specifically identifying condition has resulted in contamination manufacture of a dietary supplement,
dietary supplements as a food category or deterioration of the components. including approval of any treatment
in which the color additive may be (Comment 242) One comment (including in-process adjustments) of
used). In general, the terms of either of supports the proposed requirements of components to make them suitable for
these two kinds of listings (i.e., ‘‘for proposed § 111.40(a) as an effective use in the manufacture of a dietary
coloring foods (including dietary guideline for the inspection of supplement, and release them from
supplements) generally’’ and ‘‘for purchased ingredients. quarantine.
Final § 111.155 modifies proposed (Response) We decline to revise Final § 111.155(d)(1) and (d)(2) are
§ 111.40(a)(3) which would require: proposed § 111.40(a)(3) as suggested by substantially similar to proposed
• You to quarantine components until the comments. The comment describes § 111.40(a)(4) which would require you
your quality control unit reviews the a situation where a manufacturer of a to identify each lot of components in a
supplier’s invoice, guarantee, or dietary supplement is also shipment in a manner that allows you
certification; manufacturing a dietary ingredient or to trace the shipment to the supplier,
• The quality control unit to perform other component but only provides the date received, the name of the
testing, as needed, of a representative limited information. It appears that, component, and the status (e.g.,
sample to determine that specifications however, the procedures described for quarantined, approved, or rejected), and
are met; quarantine of the isolated, stable matrix, to trace the shipment lot to the dietary
• You to conduct a material review with subsequent evaluation by quality supplement you manufactured and
and make a disposition decision if control personnel before release for use distributed. Proposed § 111.40(a)(4) also
specifications are not met; and in the manufacture of the dietary would require you to use this unique
• The quality control unit to approve supplement, would satisfy the identifier whenever you record the
and release the components from requirements of final § 111.155(c), disposition of each shipment lot
quarantine before you use them. provided quality control personnel are received.
Final § 111.155(c) includes revisions able to determine that all specifications Final § 111.155(d)(1) and (d)(2)
related to the following changes to other for the component are met. include revisions associated with final
provisions already discussed. (Comment 244) One comment states § 111.80(a).
• Under final § 111.110, quality that plant personnel who are not We did not receive comments specific
control personnel ensure that all formally part of the manufacturer’s to proposed § 111.40(a)(4).
appropriate tests and examinations are quality control unit can conduct the
quality control functions required for 6. Final § 111.155(e)
conducted, and review and approve the
results of tests and examinations the release of materials from quarantine Final § 111.155(e) (proposed
conducted on components, but quality before use. § 111.40(a)(5)) requires you to hold
(Response) As already discussed with components under conditions that will
control personnel are not required to
respect to the definition of quality protect against contamination and
conduct the tests or examinations;
control personnel (see section VI of this deterioration and avoid mixups.
• Under final § 111.80(a), we document), these comments may have
establish the convention in this final We did not receive comments specific
misunderstood the role of the quality to proposed § 111.40(a)(5).
rule of referring to ‘‘each unique lot control unit (now quality control
within each unique shipment’’ rather personnel). To clarify that role, final F. What Requirements Apply to
than ‘‘each shipment lot;’’ § 111.12(b) states you must identify a Packaging and Labels Received? (Final
• The requirements to conduct a qualified person who is responsible for § 111.160)
material review and make a disposition your quality control operations.
decision are already set forth in final 1. Final § 111.160(a)
(Comment 245) One comment
§§ 111.87, 111.113, and 111.120 and, suggests components that cannot be Final § 111.160(a) (proposed
therefore, are not repeated in final used in a short time should be retested § 111.40(b)(1)) requires you to visually
§ 111.155; and at least yearly. examine each immediate container or
• Under final § 111.90(c), any batch of (Response) We are making no changes grouping of immediate containers in a
dietary supplement that is reprocessed, to the provision after considering this shipment for appropriate content label,
that contains components that you have comment. Whether any tests or container damage, or broken seals to
treated, or to which you have made in- examinations must be repeated over determine whether the container
process adjustments to make them time, or whether the information in a condition may have resulted in
suitable for use in the manufacture of certificate of analysis remains valid over contamination or deterioration of the
the dietary supplement, must meet all time, is a matter to be decided by the packaging and labels. Final § 111.160(a)
product specifications for the dietary manufacturer based on the established is similar to proposed § 111.40(b)(1)
supplement and be approved by quality characteristics and shelf life of the with the addition of the word
control personnel before being released component. ‘‘immediate’’ to identify the container as
for distribution. the container that is in contact with the
(Comment 243) Some comments 5. Final § 111.155(d) packaging or labels and substituting
address the requirement to quarantine Final § 111.155(d)(1) (proposed ‘‘may have’’ for ‘‘has’’ before the word
components before you use them and § 111.40(a)(4)) requires you to identify ‘‘resulted’’ as discussed in this section.
assert that it is not feasible to quarantine each unique lot within each unique We did not receive comments specific
incoming materials in a continuous shipment of components you receive to proposed § 111.40(b)(1).
extraction and purification operation, and any lot of components that you
such as one built adjacent to a soy produce in a manner that allows you to 2. Final § 111.160(b)
crushing or vegetable oil refinery to trace the lot to the supplier, the date Final § 111.160(b) requires you to
receive a continuous side stream flow received, the name of the component, visually examine the supplier’s invoice,
from that operation. One comment the status of the component (e.g., guarantee, or certification in a shipment
explains that in such operations, quarantined, approved, or rejected), and to ensure the packaging or labels are
quarantine and quality control approval to the dietary supplement you consistent with your purchase order.
occurs later in the process after the manufactured and distributed. Final Final § 111.160(b) is a new requirement
material has been isolated and § 111.155(d)(2) requires you to use this that is analogous to proposed
concentrated in a stable matrix suitable unique identifier whenever you record § 111.40(a)(2). We are requiring in final
for holding. One comment suggests the disposition of each unique lot § 111.160(b), that, as part of your visual
proposed § 111.40(a)(3) state within each unique shipment of identification, you compare what was
‘‘quarantine components or dietary components that you receive and any lot received, based on the supplier’s
supplements as applicable * * *’’. of components that you produce. invoice, guarantee, or certification, with
your purchase order so you can ensure labels in a manner that allows you to (Response) This comment may have
your specifications for packaging and trace the lot to the supplier, the date misinterpreted proposed § 111.40(b)(3).
labels are met. This is consistent with received, the name of the packaging and Under proposed § 111.40(b)(3) (final
what you would do with respect to label, the status of the packaging and § 111.160(d)) you must assign the
components and dietary supplements label (e.g., quarantined, approved, or identifier to each unique lot within each
you receive. Without final § 111.160(b), rejected), and to the dietary supplement unique shipment of packaging and
the review by quality control personnel you distributed. Final § 111.160(d)(2) labels when you receive them rather
under final § 111.120(a) would be a requires you to use this unique than each time that you use them. This
matter of performing receiving identifier whenever you record the number would stay the same for each of
operations rather than performing disposition of each unique lot within the short runs described by the
quality control operations; as already each unique shipment of packaging and comment. We are making no changes to
discussed in this section, some labels. Final § 111.160(d) derives from the requirement.
comments asserted the quality control proposed § 111.40(b)(3) which would
5. Final § 111.160(e)
unit should focus on reviewing the work require you to identify each shipment
of others rather than conducting the lot of packaging and labels in a manner Final § 111.160(e) requires you to
operations themselves. Thus, final that allows you to trace the shipment lot hold packaging and labels under
§ 111.160 is consistent with these to the supplier, the date received, the conditions that will protect against
comments. name of the packaging and label and the contamination and deterioration, and
status (e.g., quarantined, approved, or avoid mixups. Final § 111.160(e) is
3. Final § 111.160(c) identical to proposed § 111.40(b)(4).
rejected) and to trace the shipment lot
Final § 111.160(c) requires you to to the dietary supplement manufactured We did not receive comments specific
quarantine packaging and labels before and distributed. Proposed § 111.40(b)(3) to proposed § 111.40(b)(4).
you use them in the manufacture of a also would require that you use this G. What Requirements Apply to a
dietary supplement until: unique identifier whenever you record Product Received for Packaging or
• You collect representative samples the disposition of each shipment lot Labeling as a Dietary Supplement (and
of each unique shipment, and of each received. for distribution rather than for return to
unique lot within each unique Final § 111.160(d) includes revisions the supplier)? (Final § 111.165)
shipment, of packaging and labels and, that reflect the following changes
at a minimum, conduct a visual Final § 111.165 (proposed § 111.40(a))
already discussed in this final rule:
identification of the immediate sets out actions you must take when you
• Reference to ‘‘each unique lot receive a product for packaging and
containers and closures; within each unique shipment’’ rather
• Quality control personnel review labeling and for distribution. Final
than ‘‘each shipment lot.’’ § 111.165 includes editorial changes
and approve the results of any tests or • As a clarification, final
examinations conducted on the associated with the reorganization and
§ 111.160(d)(2) refers to the ‘‘dietary revisions that reflect changes we are
packaging and labels; and supplement that you distributed’’ rather
• Quality control personnel approve than to the ‘‘dietary supplement
making to other sections of the final
the packaging and labels for use in the rule.
manufactured and distributed’’ to avoid Final § 111.165 sets forth
manufacture of a dietary supplement a narrow—and incorrect—interpretation
and release them from quarantine. requirements for ‘‘product that you
of ‘‘manufactured.’’ Under proposed receive from a supplier for packaging or
Final § 111.160(c) is similar to
§ 111.40(b)(3), we used the term labeling as a dietary supplement (and
proposed § 111.40(b)(2) which would
‘‘manufactured’’ in a broad sense that for distribution rather than for return to
require that:
includes any aspect of the
• You quarantine packaging and the supplier)’’ rather than for ‘‘dietary
manufacturing process rather than a supplements that you receive.’’
labels until your quality control unit
narrow sense that applied to The final rule separates the
tests or examines a representative
manufacturing operations for producing requirements in proposed § 111.40(a) for
sample to determine that specifications
a batch of dietary supplement. Both product that you receive from a supplier
are met;
• You conduct at least a visual proposed § 111.40(b)(3) and final for packaging or labeling as a dietary
identification of the containers and § 111.160(e) address the need to trace supplement (and for distribution rather
closures; the packaging and labels that you use to than for return to the supplier) (final
• If specifications are not met, you the product that you distribute, § 111.165) from the analogous
conduct a material review and make a regardless of whether your role in the requirements for components,
disposition decision; and manufacturing process includes the packaging, and labels (final § 111.155).
• Your quality control unit approve production of the batch or includes only
packaging a dietary supplement you 1. Final § 111.165(a)
and release packaging and labels from
quarantine before you use them. receive from a supplier. Final § 111.165(a) requires you to
Final § 111.160(c) includes revisions (Comment 246) One comment visually examine each immediate
that reflect the following change already believes packaging and labels are rarely container or grouping of immediate
discussed in this final rule: the source of quality problems. This containers in a shipment of product you
• Refers to ‘‘each unique lot within comment suggests proposed receive for packaging or labeling as a
each unique shipment’’ rather than § 111.40(b)(3) allow the use of packaging dietary supplement (and for distribution
‘‘each shipment lot’’. approved by the quality control unit rather than for return to the supplier) for
We did not receive comments specific without the need to use a specific lot appropriate content label, container
to proposed § 111.40(b)(2). identification number. The comment damage, or broken seals to determine
explains that this type of flexibility is whether the container condition may
4. Final § 111.160(d) needed when they have dozens of short have resulted in contamination or
Final § 111.160(d)(1) requires you to run lots each day and use less than a deterioration of the received product.
identify each unique lot within each carton of packaging supplies for each Final § 111.165(a) is substantially
unique shipment of packaging and run. similar to proposed § 111.40(a)(1)
which, in part, would impose this 4. Final § 111.165(d) dietary supplement, packaging, and
requirement for dietary supplements Final § 111.165(d)(1) requires that you label that is rejected and unsuitable for
you receive. We have added the word identify each unique lot within each use in manufacturing, packaging, or
‘‘immediate’’ to identify the container as unique shipment of received product in labeling operations.
the container that is in contact with the We did not receive comments specific
a manner that allows you to trace the lot
product you receive for packaging or to proposed § 111.74. Final § 111.170
to the supplier, the date received, the
labeling as a dietary supplement and includes revisions associated with the
name of the received product, the status
substituted ‘‘may have’’ for ‘‘has’’ before series of provisions that distinguish a
of the received product (e.g.,
the word ‘‘resulted’’ as explained in this product you receive for packaging or
quarantined, approved, or rejected), and
section. labeling as a dietary supplement (and
to the product you packaged or labeled
for distribution rather than for return to
2. Final § 111.165(b) and distributed as a dietary supplement.
the supplier) from a dietary supplement
Final § 111.165(b) requires you to Final § 111.165(d)(2) requires you to use
you manufacture.
visually examine the supplier’s invoice, this unique identifier whenever you
guarantee, or certification in a shipment record the disposition of each unique lot I. Under This Subpart, What Records
of the received product to ensure the within each unique shipment of the Must You Make and Keep? (Final
received product is consistent with your received product. Final § 111.165(d) § 111.180)
purchase order. Final § 111.165(b) is derives from proposed § 111.40(a)(4) Final § 111.180 sets forth the
substantially similar to proposed which would require you, in part, to requirements to make and keep records
§ 111.40(a)(2) which, in part, would identify each lot of dietary supplements associated with components, packaging,
establish a similar requirement for in a shipment in a manner that allows labels, and product you receive for
dietary supplements that you receive. you to trace the shipment to the packaging and labeling as a dietary
supplier, the date received, the name of supplement. Final § 111.180 derives
3. Final § 111.165(c) the dietary supplement, and the status from proposed § 111.40(c).
Final § 111.165(c) requires you to (e.g., quarantined, approved, or
quarantine the received product until: rejected), and to trace the shipment lot 1. Final § 111.180(a)
• You collect representative samples to the dietary supplement manufactured Final § 111.180(a) requires you to
of each unique shipment, and of each and distributed. Proposed § 111.40(a)(4) make and keep records required under
unique lot within each unique also would require you to use this subpart G in accordance with subpart P.
shipment, of received product; identifier whenever you record the Final § 111.180(a) derives from
• Quality control personnel review disposition of each shipment lot proposed § 111.40(c)(2), with editorial
and approve the documentation to received. changes associated with the
determine whether the received product Final § 111.165(d) includes a revision reorganization.
meets the specifications that you associated with final § 111.80 referring We did not receive comments specific
established under § 111.70(f); and to ‘‘each unique lot within each unique to the requirements set forth in final
• Quality control personnel approve shipment’’ rather than ‘‘each shipment § 111.180(a).
the received product for packaging or lot.’’
2. Final § 111.180(b)(1)
labeling as a dietary supplement and 5. Final § 111.165(e)
release the received product from Final § 111.153 requires you to
quarantine. Final § 111.165(e) requires you to establish and follow written procedures
Final § 111.165(c) is similar to hold the received product under to fulfill the requirements of subpart G.
proposed § 111.40(a)(3) which, in part, conditions that will protect against These written procedures are records.
would require that: contamination and deterioration, and Therefore, final § 111.180(b)(1) requires
• You quarantine dietary avoid mixups. Final § 111.165(e) derives you to make and keep a record of the
supplements that you receive until your from proposed § 111.40(a)(5) with written procedures for fulfilling the
quality control unit reviews the editorial changes associated with the requirements of subpart G.
suppliers invoice, guarantee, or reorganization.
3. Final § 111.180(b)(2)
certification; H. What Requirements Apply to
• The quality control unit performs Rejected Components, Packaging, and
Final § 111.180(b)(2) requires you to
testing, as needed, of a representative make and keep receiving records
Labels, and to Rejected Products That (including records such as certificates of
sample to determine that specifications Are Received for Packaging or Labeling
are met; analysis, suppliers’ invoices, and
as a Dietary Supplement? (Final
• You conduct a material review and suppliers’ guarantees) for components,
§ 111.170) packaging, and labels, and for products
make a disposition decision if
specifications are not met; and Final § 111.170 requires you to clearly you receive for packaging or labeling as
• The quality control unit approves identify, hold, and control under a dietary supplements (and for
and releases the dietary supplements quarantine system for appropriate distribution rather than for return to the
that you receive from quarantine before disposition any component, packaging, supplier). Final § 111.180(b)(2) derives
you use them. and label, and any product you receive from proposed § 111.40(c)(2) with
Final § 111.165(c) includes revisions for packaging or labeling as a dietary editorial changes associated with the
that reflect that under final § 111.75(e) supplement (and for distribution rather reorganization. Final § 111.180(b)(2)
before you package or label a product than for return to the supplier), that is also includes revisions associated with
you received for packaging or labeling rejected and unsuitable for use in the series of provisions that distinguish
as a dietary supplement, you must manufacturing, packaging, or labeling a product you receive for packaging or
visually examine the product and have operations. Final § 111.170 is labeling as a dietary supplement (and
documentation to determine whether substantially similar to proposed for distribution rather than for return to
the specifications you established under § 111.74 which would require you to the supplier) from a dietary supplement
§ 111.70(f) are met, but not otherwise clearly identify, hold, and control under you manufacture. Because the final rule
examine or conduct tests. a quarantine system any component, provides that you may rely, under
certain circumstances, on a certificate of Additionally as a conforming revision sections in final subpart H and
analysis to ensure that some component associated with final § 111.75(a) which identifies the proposed provisions that
specifications are met (final requires appropriate tests and form the basis for the final rule.
§ 111.75(a)(2)(ii)) and that you may rely, examinations, final § 111.180(b)(3)
in part, on documentation to determine requires you to include in the TABLE 9.—DERIVATION OF SECTIONS
whether specifications for received documentation the results of any IN FINAL SUBPART H
products are met, we specifically examinations as well as tests. Final
identify a certificate of analysis and § 111.180(b)(3) also includes revisions Final Rule 2003 CGMP
common forms of documentation as associated with the series of changes Proposal
being ‘‘receiving records’’ for purposes that distinguish a product that you § 111.205 What is the § 111.45(a)(1),
of this rule. receive for packaging or labeling as a requirement to estab- (a)(2), and (d)
(Comment 247) One comment on dietary supplement (and for distribution lish a master manufac-
proposed § 111.40(c)(2) points out the rather than for return to the supplier) turing record?
recordkeeping requirements of any final from a dietary supplement that you
rule will be a costly burden for a manufacture. § 111.210 What must the § 111.45(b)
company that produces multiple (Comment 248) A few comments note master manufacturing
ingredient products in several packaging proposed § 111.40(c) requires the record include?
configurations and will be much greater signature of the person performing the
than the burden for a company that requirement, whereas other sections of The requirements in final subpart H
produces batches of single ingredient the 2003 CGMP Proposal, such as are set forth from the perspective of the
products in one packaging proposed § 111.50(c)(2), only require the manufacture of a batch of a dietary
configuration. initials of the person performing the supplement. You must comply with all
(Response) We acknowledge that requirement. One comment requests the requirements that pertain to your
companies that produce multiple format for the requirement to document activity. However, you must comply
ingredient products in several packaging with the requirement to prepare and
the person performing the step be made
configurations will have more records to follow a ‘‘master manufacturing record’’
consistent throughout the regulations.
keep than companies that produce (Response) We agree that the identity regardless of whether you manufacture
single ingredient products in one of the person performing a requirement a batch, or whether you package or label
packaging configuration. However, these should be required throughout the final product you receive from a supplier for
records are necessary to be able to rule and that this can be accomplished packaging or labeling as a dietary
determine the source of the component, through initials except for operations supplement (and for distribution rather
packaging, and labels, so that if than for return to the supplier). If you
that are performed by quality control
adulteration of the dietary supplement are a packager or labeler, you only need
personnel. Therefore, we are revising
occurs, the records will show the source to include those parts relevant to your
the requirements so that a signature
of the material so that its use can be process. For example, if you are a
(and not initials) is required for any
stopped. labeler, under final § 111.210(c) you
operation performed by quality control
would not need to include an accurate
4. Final § 111.180(b)(3) personnel (see final § 111.140). Because
statement of the weight or measure of
§ 111.40(c)(1)(ii) is not a quality control
Final § 111.180(b)(3) requires you to each component to be used because you
operation, we also revised proposed
make and keep documentation that the would be starting from packages already
§ 111.40(c)(1)(ii) (final § 111.180(b)(3))
requirements of subpart G were met. filled.
to require the initials, rather than the
Under final § 111.180(b)(3)(i), the signature, of the person performing the B. Highlights of Changes to the
person who performs the required required operation. Initials are required Proposed Requirements for the Master
activity must document, at the time of for other circumstances that do not Manufacturing Record
performance, that the required operation involve quality control operations,
was performed. Under final 1. Revisions
including final § 111.180(b)(3).
§ 111.180(b)(3)(ii), the documentation However, whenever this final rule The final rule:
must include: requires initials, a signature is also • Includes revisions that reflect that
• The date that the components, acceptable, because a signature would the final rule applies to persons who
packaging, labels, or products you achieve the goal of identifying the manufacture, package, label, or hold
receive for packaging or labeling as a person who performed the requirement. dietary supplements unless subject to an
dietary supplement were received; exclusion in § 111.1;
• The initials of the person XIII. Comments on the Production and • Includes revisions so the
performing the required operation; Process Control System: Requirements requirements for the master
• The results of any tests or for the Master Manufacturing Record manufacturing record are consistent
examinations conducted on (Final Subpart H) with final § 111.70(a) which requires
components, packaging, or labels, and of you to establish a specification for any
A. Organization of Final Subpart H
any visual examination of product you point, step, or stage in the
receive for packaging or labeling as a In the 2003 CGMP Proposal, the manufacturing process where control is
dietary supplement; and requirements for the master necessary to ensure the quality of the
• Any material review and manufacturing record were set forth in dietary supplement and that the dietary
disposition decision conducted on proposed § 111.45. As shown in table 9 supplement is packaged and labeled as
components, packaging, labels, or of this document, we are setting forth specified in the master manufacturing
products that you receive for packaging the requirements for the master record; and
or labeling as a dietary supplement. manufacturing record in a distinct • Includes a revision associated with
Final § 111.180(b)(3) differs from subpart (final Subpart H—Production final § 111.75(h), which provides for the
proposed § 111.40(c)(1)(i) through and Process Control System: use of either tests or examinations for
(c)(1)(iv), by referring to ‘‘required Requirements for the Master complying with the requirements of part
operation’’ rather than ‘‘requirement.’’ Manufacturing Record). Table 9 lists the 111.
2. Changes Associated With the (Response) We agree the master specifications will be. We are making no
Reorganization manufacturing record requirements in changes to the requirement.
the 2003 CGMP Proposal are important (Comment 251) Some comments
The proposed requirement assert that the proposed requirement to
for reasons that include those expressed
(§ 111.45(c)) that the quality control unit prepare a separate record ‘‘for each
in the comments. Establishing a master
approve each master manufacturing batch size’’ is burdensome, particularly
manufacturing record will help to
record and any modifications to a for smaller firms who specialize in
ensure the quality of the dietary
master manufacturing record is set forth custom blended products. These
supplement. The proposed requirements
as final § 111.123(a) in subpart F, rather comments would revise the rule so the
for the master manufacturing record
than in final subpart H, with the master manufacturing record includes a
have been codified as subpart H in this
changes we made to the definition of master formula with instructions for
final rule.
‘‘quality control unit’’ to ‘‘quality how to adjust the amount of ingredients
control personnel’’ as explained in D. What Is the Requirement to Establish to add depending on the batch size,
section VI of this document (subpart A). a Master Manufacturing Record? (Final with the actual amounts included in the
§ 111.205) applicable batch record.
3. Changes After Considering Comments
Final § 111.205 (proposed § 111.45(a) (Response) We disagree with these
The final rule: comments. Requiring a separate master
and (d)) sets forth the requirement to
• Retains a requirement to state any prepare and follow a written master manufacturing record for each batch
intentional overage of a dietary manufacturing record. size will lessen the likelihood of
ingredient but does not require an mistakes that can happen when a
explanation for such an overage; 1. Final § 111.205(a) formula is ‘‘multiplied up’’ or ‘‘divided
• Provides flexibility to include either Final § 111.205(a) requires you to down,’’ particularly in light of the
a representative label, or a cross- prepare and follow a written master requirement that quality control
reference to the physical location of the manufacturing record for each unique personnel review and approve each
actual or representative label if an actual formulation of dietary supplement that master manufacturing record (final
label is not provided; and you manufacture, and for each batch § 111.123(a)). Moreover, it is not clear
• Provides flexibility for what must size, to ensure uniformity in the that the scenario described in the
be included in written instructions finished batch from batch to batch. Final comments would lessen any burden,
when operations are not conducted § 111.205(a) is similar to proposed because a new ‘‘formula,’’ based on the
manually. § 111.45(a) which would require you to master formula, would still need to be
prepare and follow a written master prepared for each batch.
C. General Comments on Proposed In essence, these comments suggest
§ 111.45 (Final Subpart H) manufacturing record for each type of
shifting the burden from a requirement
dietary supplement you manufacture
1. Comments on Written Procedures to prepare a master manufacturing
and for each batch size to ensure
record to a requirement to prepare a
We received many comments that uniformity from batch to batch.
batch record. Under final § 111.123,
recommended written procedures for (Comment 250) Some comments quality control personnel review the
various provisions. We address the need suggest the phrase ‘‘to ensure uniformity master manufacturing record before that
for written procedures generally in from batch to batch’’ be changed to ‘‘to record is used, but review the batch
section IV of this document. We also ensure that specifications are met from record only after the batch is prepared.
respond to individual comments on batch to batch.’’ One comment states the Shifting the requirement in the manner
specific provisions in the same section. term ‘‘uniformity’’ could be interpreted suggested by these comments would
As discussed in section IV of this to mean that two batches would be defeat the purpose of having quality
document, we do not require you to exactly the same, down to the minutest control personnel review and approve
establish and follow written procedures detail. The comment expresses concern each ‘‘formula.’’ We are not making the
for preparing a master manufacturing about how batches of herbal products suggested changes to proposed
record. will meet this standard of ‘‘uniformity’’ § 111.45(a).
from batch to batch. We are changing the word ‘‘type’’ to
2. Comments That Support Proposed
(Response) These comments may have ‘‘unique formulation’’ to clarify that the
§ 111.45
misinterpreted the term ‘‘uniformity’’ as requirement for a master manufacturing
(Comment 249) A few comments we used it in proposed § 111.45(a). record applies to each different dietary
support the proposed requirements for Uniformity means that the supplement whether it is a different
the master manufacturing record. One specifications you establish for identity, strength, includes any different
comment states that properly recorded purity, strength, and composition of the ingredients, is a capsule or tablet, or
quality control measures, such as the finished batch must be the same includes minor variations.
batch production and master throughout a given batch, e.g., at the
manufacturing records, will aid beginning, middle, and end of a 2. Final § 111.205(b)(1)
manufacturers in producing dietary production run. To emphasize this, we Final § 111.205(b)(1) requires that the
supplements in a consistent and have revised the requirement so it is master manufacturing record identify
uniform manner, as well as serve as clear that the uniformity relates to ‘‘the specifications for each point, step, or
tools to assess possible sources of finished batch.’’ Whether two batches stage in the manufacturing process
contamination and flaws in the must be exactly the same, down to the where control is necessary to ensure the
production process. Another comment minutest level, would depend on the quality of the dietary supplement and
asserts the master manufacturing and specifications the manufacturer that the dietary supplement is packaged
batch production records probably have establishes for the finished batch under and labeled as specified in the master
the second greatest impact on overall final § 111.70(e). Although a finished manufacturing record. Final
product quality, surpassed only by the batch must meet those specifications § 111.205(b)(1) derives from proposed
quality of the ‘‘people’’ manufacturing ‘‘from batch to batch,’’ it is up to the § 111.45(a)(1). We received no
the product. manufacturer to determine what those comments specific to proposed
§ 111.45(a)(1). We revised this section to that dietary ingredient is and how much unit of weight or measure of the
include changes that we made to is to be used in a given batch, the product, for each batch size.
§ 111.70(a). manufacturer could use weight or (Response) The final rule does not
measure. To the extent that a prescribe the units you must use. Thus,
3. Final § 111.205(b)(2) firms have the flexibility to include this
manufacturer determines, for a
Final § 111.205(b)(2) requires that the particular dietary ingredient, strength, information in the way that best suits
master manufacturing record establish or concentration would best describe their product.
controls and procedures to ensure that what is to be used in a given batch, the
each batch of dietary supplement you 2. Final § 111.210(b)
manufacturer could use those instead.
manufacture meets the specifications We are giving firms the flexibility to use Final § 111.210(b) requires that the
identified in accordance with the measure that they determine best master manufacturing record include a
§ 111.205(b)(1). Final § 111.205(b)(2) describes the amount of dietary complete list of components to be used.
derives from proposed § 111.45(a)(2) ingredient to use in their batch. For Final § 111.210(b) is identical to
with grammatical changes and changes example, assume you are manufacturing proposed § 111.45(b)(2). We did not
associated with the reorganization. We a million tablets of a vitamin C product receive comments specific to proposed
did not receive comments specific to in 250 mg tablets and the only other § 111.45(b)(2).
proposed § 111.45(a)(2). ingredients in your product are starch, 3. Final § 111.210(c)
microcrystalline cellulose, and
4. Final § 111.205(c) Final § 111.210(c) requires that the
dicalcium phosphate. Under proposed
Final § 111.205(c) requires you to § 111.45(b)(1) (final § 111.210(a)) your master manufacturing record include an
make and keep master manufacturing master manufacturing record would accurate statement of the weight or
records in accordance with subpart P. state: ‘‘Vitamin C 250 mg, 1,000,000 measure of each component to be used.
Final § 111.205(c) derives from tablets.’’ As another example, if you are Final § 111.210(c) is identical to
proposed § 111.45(a) and (d), and manufacturing 100 liters of a liquid proposed § 111.45(b)(3). We did not
clarifies that you must prepare and keep dietary supplement that provides tuna receive comments specific to proposed
the master manufacturing records. We oil as a dietary ingredient, and the only § 111.45(b)(3).
did not receive comments specific to other ingredients are alpha-tocopherols 4. Final § 111.210(d)
proposed § 111.45(d), and comments for use as an antioxidant, then your
relevant to § 111.45(a) are discussed in master manufacturing record would Final § 111.210(d) requires that the
the response to comment 250. state: ‘‘Tuna oil, 100 liters.’’ master manufacturing record include
The unique identifier comment states the identity and weight or measure of
E. What Must the Master Manufacturing each dietary ingredient that will be
‘‘the identity of each dietary ingredient
Record Include? (Final § 111.210) can be controlled instead with the use declared on the Supplement Facts label
Final § 111.210 sets forth the of a unique item identifier, along with and the identity of each ingredient that
requirements for what the master a brief description of the ingredient.’’ It will be declared on the ingredients list
manufacturing record must include. is not clear what the comment meant by of the dietary supplement. Final
Final § 111.210 derives from proposed ‘‘a brief description of the ingredient.’’ § 111.210(d) is similar to proposed
§ 111.45(b). If the ‘‘brief description of the § 111.45(b)(4). We have removed the
ingredient’’ includes the identity, then it phrase ‘‘in compliance with section
1. Final § 111.210(a)
would comply with the final rule. Firms 403(s) of the act’’ as it is unnecessary in
Final § 111.210(a) requires that the are free to use unique identifiers in the context of compliance with the
master manufacturing record include addition to the identity. If, however, the dietary supplement CGMP
the name of the dietary supplement to comment means something other than requirements. The manufacturer must
be manufactured and the strength, identity, the comment fails to explain still comply with section 403(s) and
concentration, weight, or measure of how the identity will be controlled to failure to do so will result in a
each dietary ingredient for each batch prevent manufacturing errors. In the misbranding violation, not a CGMP
size. Final § 111.210(a) derives from absence of such an explanation, we have violation under this final rule.
proposed § 111.45(b)(1). no basis to make the requested change. (Comment 254) One comment
(Comment 252) One comment Moreover, under final § 111.205(c) the supports having the identity and weight
supports listing the weight or measure master manufacturing record is a record or measure of each dietary ingredient as
for each ingredient but believes that you must make and keep in accordance required by proposed § 111.45(b)(4), but
including the strength and with final § 111.610 in final subpart P. asserts it is unnecessary for the verbiage
concentration is unnecessary. This Under final § 111.610, the master to identically match the corresponding
comment also suggests that the identity manufacturing record must be available label statements. This comment also
of each ingredient can be controlled during the record retention period for asserts that the ingredients can be
using a unique item number identifier, inspection and copying by us when we controlled in the master manufacturing
along with a brief description of the request that you do so. A master record by use of a unique identifier,
ingredient. manufacturing record that does not instead of the ingredient name, along
(Response) Proposed § 111.45(b)(1) identify the dietary ingredient and the with a brief description of the
would require the master manufacturing weight or measure of the dietary ingredient.
record to include strength, ingredient would not allow an FDA (Response) We disagree for the
concentration, weight, or measure of investigator to determine, for example, reasons stated in response to comment
each dietary ingredient for each batch how your master manufacturing record 252 and decline to revise the provision
size. We did not intend that all would relates to the finished dietary in this manner.
be required. The purpose of this supplement and to the product label of

requirement is to ensure the correct that dietary supplement. 5. Final § 111.210(e)
dietary ingredient and amount are used (Comment 253) One comment Final § 111.210(e) requires that the
in a given batch. To the extent that recommends the weight or measure be master manufacturing record include a
weight or measure best describes what expressed per unit or portion, or per statement of any intentional overage
amount of a dietary ingredient. Final § 111.45(b)(6) be replaced with the term the manufacturer has established in its
§ 111.210(e) derives from proposed ‘‘normal range.’’ specifications and its master
§ 111.45(b)(5) which would require you Another comment recommends manufacturing record. The
to explain any intentional excess proposed § 111.45(b)(6) be replaced manufacturer must establish
amount of a dietary ingredient. with: ‘‘A statement of theoretical yield specifications for the identity, purity,
(Comment 255) Some comments of a manufactured dietary ingredient or strength, and composition and limits on
request us to modify this requirement. dietary supplement expected at contamination and other specifications
Several comments note that a appropriate phases of manufacturing.’’ the manufacturer decides are necessary
manufacturer may design products with This comment states the detail in this to ensure the quality of the dietary
overage levels adjusted so the product proposed requirement should be supplements that it makes, and design
always tests at least 100 percent of the eliminated because the manufacturer and implement a production and
amount claimed on the label throughout should decide where and when to process control system that will ensure
the declared shelf life. One comment include a statement about theoretical those specifications are met. In the
states it should be sufficient to identify yield. situation described by the comment, it
any overage amount, rather than having (Response) Final § 111.210(f) clearly is the manufacturer’s responsibility to
to explain it. communicates when it is necessary to design and implement a production and
(Response) We understand that some conduct a material review and make a process control system that will ensure
firms design products using an disposition decision. The comment’s the quality of the dietary supplement
additional amount of certain ingredients suggestions do not improve the regardless of the problems presented by
to ensure the product meets its communication or clarify this point. the nature of the ingredients.
specifications for the amount of the Final § 111.210(f) gives firms the
ingredient during the expected shelf life flexibility to decide what steps, in the 7. Final § 111.210(g)
of the product. We agree it is not manufacturing process, are points,
Final § 111.210(g) requires that the
necessary to include the reason for steps, or stages where control is needed
master manufacturing record include a
adding the intentional excess amount. to ensure the quality of the dietary
description of packaging and a
We also understand it would be more supplement. A statement about
representative label, or a cross-reference
appropriate to refer to the additional theoretical yield is necessary at each
to the physical location of the actual or
amount as an ‘‘overage’’ amount rather such point, step, or stage including at
representative label. Final § 111.210(g)
than an ‘‘excess’’ amount, because the finished batch stage so that you will
derives from proposed § 111.45(b)(7),
‘‘overage’’ is commonly used in the know, when you manufacture a batch,
industry to convey the practice that is whether the process is proceeding as which would require a description of
now the subject of final § 111.260(e). expected or whether something is packaging and a copy of the label to be
Therefore, we have revised proposed wrong. For example, your master used.
§ 111.45(b)(1) to use the term ‘‘overage’’ manufacturing record could state the (Comment 258) One comment
rather than ‘‘excess’’ and to delete the theoretical yield after mixing a series of supports the proposed requirement that
proposed requirement to include the components is 100 percent, because the master manufacturing record
reason for the intended overage. As nothing about the additional step would contain a copy of the dietary
discussed in the preamble to the 2003 remove any material from the supplement label. Other comments
CGMP Proposal (68 FR 12157 at 12203), production system. When contend that the proposed requirement
the amount of overage should be limited manufacturing the batch, a yield of less to include a copy of the label is neither
to the amount needed to meet the than 100 percent would tell you appropriate nor necessary. Some
amounts listed in accordance with final something was wrong, for example, if comments state that companies often do
§ 111.210(d). there was an obstruction that prevented not have a label available to include in
a component that was being delivered the master manufacturing record and
6. Final § 111.210(f) by automated equipment from actually believe that a description of the
Final § 111.210(f) requires that the entering the production vessel. For a packaging or label in the master
master manufacturing record include a process such as recrystallization, manufacturing record should be
statement of theoretical yield of a knowing the theoretical yield is critical, sufficient. Another comment, by a
manufactured dietary supplement because if the expected yield is not company that produces many different
expected at each point, step, or stage of achieved at a given step it may mean brands for each bulk product, asserts
the manufacturing process where that the process did not proceed as that updating labels in the record would
control is needed to ensure the quality intended. be burdensome and suggests wording
of the dietary supplement, and the (Comment 257) One comment argues similar to that used by USP, for which
expected yield when you finish it is not possible for the majority of a positive identification of all labeling
manufacturing the dietary supplement, supplement products, especially used is permitted. One comment asks
including the maximum and minimum botanicals, to provide 100 percent of the whether the packaging and label copy
percentages of theoretical yield beyond claimed amount of the botanical, requirements can be in separate
which a deviation investigation of a because botanicals are inherently of documents cross-referenced in the
batch is necessary and material review uneven consistency, density, and master manufacturing record, because
is conducted and disposition decision is particle size. This comment some companies treat tablet
made. Final § 111.210(f) derives from recommends that we allow for manufacturing and packaging as two
proposed § 111.45(b)(6). We revised the variability in yield, especially for separate and distinct operational
section to state ‘‘beyond which a botanicals. elements. This comment explains that
deviation investigation of a batch is (Response) Final § 111.210(f) does not the master manufacturing record
necessary’’ rather than ‘‘beyond which a specify what the yield must be, so no includes the specifics required to
deviation is performed’’ for clarity. revision is necessary. It is the manufacture the tablets, but the actual
(Comment 256) One comment manufacturer’s responsibility to description of packaging and label copy
suggests the term ‘‘maximum and manufacture the product in a way that requirements are contained in separate
minimum percentages’’ in proposed will ensure that a product contains what documents cross-referenced to the
master manufacturing record by a We did not receive comments specific record. Final § 111.210(h)(3) derives
product part number. to proposed § 111.45(b)(8)(i). from proposed § 111.45(b)(8)(iii) which
(Response) We understand there may would require that the master
9. Final § 111.210(h)(2)
be some circumstances where it would manufacturing record include written
be impractical to have actual copies of Final § 111.210(h)(2) requires that the instructions for specific actions
labels in the master manufacturing master manufacturing record include necessary to perform and verify each
record. If an actual label is not available, written instructions for procedures for point, step, or stage necessary to meet
you may include a representative label sampling, and a cross-reference to specifications and otherwise prevent
in the master manufacturing record. A procedures for tests or examinations. adulteration. Final § 111.210(h)(3)
representative label could be a graphic Final § 111.210(h)(2) derives from includes changes for consistency with
representation of the label, including proposed § 111.45(b)(8)(ii), which final § 111.70(a).
the exact statements that would be on would require that the master Final § 111.210(h)(3)(i) requires that
the product label, or a detailed manufacturing record include written the specific actions include verifying
description of the statements and other instructions for sampling and testing. the weight or measure of any
information (such as pictures or (Comment 260) A few comments component and verifying the addition of
object to including certain written any component. Final § 111.210(h)(3)(ii)
graphics) that will be on the actual
instructions for sampling and testing requires that, for manual operations, the
label. The representative label must be
procedures in the master manufacturing specific actions include: (1) One person
an accurate representation of the label
record. One comment states that this weighing or measuring a component
that will be affixed to the dietary
documentation, such as laboratory and another person verifying the weight
supplement distributed. We also agree
testing procedures, would be a or measure and (2) one person adding a
that it would be acceptable to cross-
burdensome task and should be component and another person
reference the physical location of the
maintained separate from the master verifying the addition. Final
actual or representative label.
manufacturing record and be retrievable § 111.210(h)(3)(i) and (h)(3)(ii) derive
Finally, because the actual or by appropriate cross-referencing
representative label is a record that you from proposed § 111.45(b)(8))(iii).
information. (Comment 261) Some comments
must make and keep in accordance with (Response) As we discussed in the suggest the requirement to have more
final § 111.610 in final subpart P, it preamble to the 2003 CGMP Proposal than one person involved in performing
must be readily available during the (68 FR 12157 at 12204), the written and verifying each point, step, or stage
retention period for inspection or instructions are similar to a recipe. As in the manufacturing process is overly
copying by FDA. Thus, we are revising such, the written instructions must prescriptive and that alternative,
proposed § 111.45(b)(6) (final include instructions related to reliable methods for verifying the
§ 111.210(g)) as discussed above. procedures for sampling plans so you weighing and addition of components
(Comment 259) One comment states can collect appropriate samples for tests should be permitted. One comment
that a company that manufactures a or examinations. We agree, however, explains many manufacturers use bar
dietary supplement under contract to that it is not necessary for the master code systems to identify the weight and
another company would not have access manufacturing record to include written identity of components both before and
to the product label. instructions for tests or examinations. after weighing. In such cases, a
(Response) Under final § 111.210(g) a Accordingly, we have revised the computer generated weight record and
company that manufactures a dietary provision to permit the master corresponding bar code can be created
supplement under contract could manufacturing record to include a cross- and affixed to the container by one
comply with the requirement by, for reference to the procedures for tests or individual as reliable verification of the
example, providing the name and examinations. The final rule includes a material’s contents and weight.
address of the company who contracted requirement that you establish and Likewise, the addition of components to
for the manufacture of the batch as the follow written procedures for laboratory a blender can be adequately controlled
cross-reference to the physical location operations, including for tests and and verified by one person through
of the label. examinations that you conduct to scanning technology that allows reliable
8. Final § 111.210(h)(1) determine whether specifications are verification of the identity and weight of
met (final § 111.303). In essence, these components added to a blender without
Final § 111.210(h)(1) requires that the written procedures for tests and the need for a second person.
master manufacturing record include examinations would constitute the (Response) These comments describe
written instructions for specifications written instructions that we proposed a system partially under the control of
for each point, step, or stage in the under § 111.45(b)(8)(ii) for testing automated equipment. Final § 111.30
manufacturing process where control is procedures. This requirement for establishes a series of requirements for
necessary to ensure the quality of the written procedures is generally automated equipment. We agree that,
dietary supplement and that the dietary described in section IV of this with such requirements in place for an
supplement is packaged and labeled as document. automated system such as that
specified in the master manufacturing described by the comments, the
record. Final § 111.210(h)(1) is similar 10. Final § 111.210(h)(3) requirement to verify the weight or
to proposed § 111.45(b)(8)(i) which Final § 111.210(h)(3) requires that the measure of a component, or to verify the
would require that the master master manufacturing record include addition of a component, can be
manufacturing record include written written instructions for specific actions achieved without requiring that one
instructions for specifications for each necessary to perform and verify each person do the weighing or measuring
point, step, or stage in manufacturing point, step, or stage in the and another person verify the weighing
the dietary supplement necessary to manufacturing process where control is or measuring and without requiring that
prevent adulteration. Final necessary to ensure the quality of the one person add the component and
§ 111.210(h)(1) includes changes that we dietary supplement and that the dietary another person verify the addition.
are making for consistency with final supplement is packaged and labeled as Therefore, final § 111.210(h)(3) provides
§ 111.70(a). specified in the master manufacturing both that the written instructions must
include verifying the weight or measure presents itself. Therefore, for any The requirements in final subpart I
of any component and verifying the circumstance you can predict, final are set forth from the perspective of the
addition of any component and that, for § 111.210(h)(5) requires that you manufacture of a batch of a dietary
manual operations, the written establish corrective action plan. supplement. However, you must comply
instructions must include: (1) One with the requirement to prepare and
F. Quality Control Responsibility
person weighing or measuring a follow a ‘‘batch production record’’ or a
(Proposed § 111.45(c))
component and another person ‘‘batch record’’ regardless of whether
verifying the weight or measure and (2) In proposed § 111.45(c) we would you manufacture a batch or whether you
one person adding a component and require the quality control unit to package or label product you receive
another person verifying the addition. review and approve each master from a supplier for packaging or labeling
The final rule makes clear that there manufacturing record and any as a dietary supplement (and for
must be a verification step and gives modifications to a master manufacturing distribution rather than for return to the
firms flexibility, when the weighing or record. As part of the reorganization, supplier). As discussed in section VI of
addition is not done manually, to this requirement is set forth under final this document, if you are a packager or
determine how they would accomplish § 111.123(a) in subpart F for quality labeler, you only need to include those
the verification. control personnel. There is no reason to parts relevant to your process. For
repeat the requirement in final subpart example, if you are a labeler under final
11. Final § 111.210(h)(4)
H and, thus, it does not appear in final § 111.260(e) you would not need to
Final § 111.210(h)(4) requires that the subpart H. include the identity and weight or
master manufacturing record include measure of each component used,
written instructions for special XIV. Comments on the Production and
Process Control System: Requirements because you would be starting from
notations and precautions to be packages that already had been filled.
followed. Final § 111.210(h)(4) derives for the Batch Production Record (Final
from proposed § 111.45(b)(8)(iv). We did Subpart I) B. Highlights of Changes to the
not receive comments specific to A. Organization of Final Subpart I Proposed Requirements for the Batch
proposed § 111.45(b)(8)(iv). Production Record
In the 2003 CGMP Proposal, the
12. Final § 111.210(h)(5) proposed requirements for the batch 1. Revisions
Final § 111.210(h)(5) requires that the production record were set forth in The final rule:
master manufacturing record include § 111.50. As shown in table 10 of this • Includes revisions that reflect that
written instructions for corrective action document, we are setting forth the the final rule applies to persons who
plans for use when a specification is not requirements for the batch production manufacture, package, label, or hold
met. Final § 111.210(h)(5) derives from record in a distinct subpart (final dietary supplements unless subject to an
proposed § 111.45(b)(8)(v). Subpart I—Production and Process exclusion in § 111.1.
(Comment 262) Several comments Control System: Requirements for the • Does not use the term ‘‘shipment
argue pre-established corrective action Batch Production Record) that contains lot’’ when referring to components.
plans are not useful for complex failure the requirements that derive from 2. Changes Associated With the
scenarios, and that the quality control proposed § 111.50. In addition, we are Reorganization
unit should instead approve corrective moving some proposed requirements
from §§ 111.35 and 111.37 into final • Several provisions derive in whole
action procedures on a case-by-case
subpart I. Table 10 lists the sections in or in part from proposed §§ 111.35,
basis. One comment suggests the rule
final subpart I and identifies the 111.37, or 111.70.
should refer to ‘‘procedures’’ rather than • Several requirements in proposed
specifying ‘‘corrective action plans.’’ provisions that form the basis for the
final rule. § 111.50 are redundant to requirements
(Response) We acknowledge that
set forth in other subparts and are not
corrective action plans would be
TABLE 10.—DERIVATION OF SECTIONS repeated in subpart I.
focused on each point, step, or stage • Several proposed requirements for
where control is necessary to ensure the IN FINAL SUBPART I
reprocessing are moved to final § 111.90
quality of the dietary supplement. We in final subpart E.
also acknowledge that it may not be 2003 CGMP
Final Rule Proposal • The proposed requirement to
practical to establish a corrective action collect reserve samples of each batch of
plan for all foreseeable circumstances. § 111.255 What is the § 111.50(a), (b), dietary supplement is moved to final
In circumstances such as the complex requirement to estab- and (i) § 111.83 in subpart E, where we clarify
failure scenario described by the lish a batch production that the requirement relates to each lot
comments, the documentation of the record? of packaged and labeled dietary
material review and disposition supplement rather than to a finished
decision (rather than the corrective § 111.260 What must the § 111.35(i)(2),
batch record include? (j), (m), and batch awaiting packaging and labeling.
action plan) would identify the action
(o)(2) 3. Changes After Considering Comments
taken to correct, and prevent a
§ 111.37(b)(3),
recurrence of, the deviation and discuss (b)(5), and The final rule:
what you did with the batch (final (b)(9) • Provides flexibility for firms to
§ 111.140(b)(3)(iv) and (b)(3)(v)). § 111.50(c)(1) document information about the
However, we disagree that the fact that through maintenance, cleaning, and sanitizing of
it may not be practical to establish a (c)(11), equipment used in producing the batch
corrective action plan for all foreseeable (c)(13), in either the batch production record or
circumstances means you could not (c)(14), (d)(2), in individual equipment logs that it
establish a corrective action plan at each (e), and (g) cross-references in the batch production
§ 111.70(b)(6),
point, step, or stage where you can, in record.
(e), and (g)
fact, predict a scenario and provide a • Provides flexibility for firms to
plan for action when that scenario include in the batch production record
either the results of any testing or labeled dietary supplement from all we agree with these comments.
examination performed, or a cross- stages of manufacturing through Consistent with final § 111.35(b)(2),
reference to the results of any testing or distribution, and to be consistent with final § 111.260(c) provides flexibility to
examination. other provisions of this final rule. In the retain the records of maintenance,
discussion of subpart L (section XVII of cleaning, and sanitizing equipment and
C. What Is the Requirement to Establish this document), we explain in detail processing lines in either the batch
a Batch Production Record? (Final final § 111.410(d), which requires you to production record or another record you
§ 111.255) be able to determine the complete cross-reference in the batch production
Final § 111.255(a) requires you to manufacturing history and control of the record.
prepare a batch production record every packaged and labeled dietary
4. Final § 111.260(d)
time you manufacture a batch of a supplement through distribution. In that
dietary supplement. Final § 111.255(b) same section, we explain final Final § 111.260(d) requires that the
requires that the batch production § 111.415(f) which requires you to batch production record include the
record include complete information assign a batch, lot, or control number to unique identifier you assigned to each
relating to the production and control of each lot of packaged and labeled dietary component (or, when applicable, to a
each batch. Final § 111.255(a) and (b) supplement from a finished batch and product you receive from a supplier for
derive from proposed § 111.50(a), with a each lot of dietary supplement from a packaging or labeling as a dietary
nonsubstantive revision that divides the finished batch that you distribute to supplement), packaging, and label used.
proposed requirements into two another person for packaging and Final § 111.260(d) derives from
separate paragraphs. labeling. In that way, these batch, lot, or proposed § 111.50(c)(5), which would
Final § 111.255(c) requires your batch control numbers can be used to require that the batch record include the
production record to accurately follow determine the manufacturing history shipment lot unique identifier of each
the appropriate master manufacturing and control of the batch. However, you component, dietary supplement,
record and you to perform each step in can determine how you track the batch, packaging, and label used. Consistent
the production of the batch. Final lot, or control number of the packaged with the convention we are establishing
§ 111.255(c) derives from proposed and labeled dietary supplement, or under final §§ 111.80(a), 111.155, and
§111.50(b). dietary supplement you send to another 111.160, final § 111.260(d) does not use
Final § 111.255(d) requires you to person for packaging and labeling, to a the term ‘‘shipment lot.’’
make and keep batch production distributed dietary supplement. We did not receive comments specific
records in accordance with subpart P. We did not receive comments specific to proposed § 111.50(c)(5).
Final § 111.255(d) derives from to proposed § 111.50(c)(1). We respond 5. Final § 111.260(e) and (f)
proposed § 111.50(i) with editorial to comments relevant to final subpart L
changes associated with the in section XVII of this document. Final § 111.260(e) requires that the
reorganization. batch production record include the
2. Final § 111.260(b) identity and weight or measure of each
We did not receive comments specific
to proposed § 111.50(a), (b), or (i). Final § 111.260(b) requires that the component used and derives from
batch production record include the proposed § 111.50(c)(6).
D. What Must the Batch Record Include? identity of equipment and processing Final § 111.260(f) requires that the
(Final § 111.260) lines used in producing the batch and batch record include a statement of the
derives from proposed § 111.50(c)(3). actual yield and a statement of the
1. Final § 111.260(a)
We did not receive comments specific percentage of theoretical yield at
Final § 111.260(a) requires the batch to proposed § 111.50(c)(3). appropriate phases of processing. Final
production record to include the batch, § 111.260(f) derives from proposed
lot, or control number: (1) Of the 3. Final § 111.260(c) § 111.50(c)(9).
finished batch of dietary supplement Final § 111.260(c) requires that the (Comment 264) A few comments
and (2) that you assign in accordance batch production record include the argue that the requirements in proposed
with § 111.415(f) for each lot of date and time of the maintenance, § 111.50(c)(6) are not applicable to
packaged and labeled dietary cleaning, and sanitizing of the continuous operations and that yield
supplement from the finished batch of equipment and processing lines used in information required in proposed
dietary supplement, and for each lot of producing the batch, or a cross-reference § 111.50(c)(9) is irrelevant for quality
dietary supplement, from the finished to records, such as individual control in continuous operations used
batch of dietary supplement, that you equipment logs, where this information for producing dietary ingredients. One
distribute to another person for is retained. Final § 111.260(c) derives of these comments also discusses
packaging or labeling. from proposed § 111.50(c)(4). ‘‘continuous operations,’’ such as a
Final § 111.260(a) derives, in part, (Comment 263) Many comments continuous operation built adjacent to a
from proposed § 111.50(c)(1), which argue that it is not necessary or soy crushing or vegetable oil refinery to
would require the batch, lot, or control appropriate to retain the records of receive a continuous side stream flow
number in the batch production record. maintenance, cleaning, and sanitizing from that operation (see the discussion
Consistent with comments that equipment and processing lines in the of final § 111.155(c) in section XII of this
requested that we clarify responsibilities batch production record. These document). This comment explains that
when more than one party is involved comments request that the final rule in such operations, quarantine and
with the manufacturing, packaging, provide flexibility to retain such records quality control approval occurs after the
labeling, or holding of a dietary in individual equipment files or log material has been isolated and
supplement (see section VI of this books for easy access. One comment concentrated in a stable matrix suitable
document), we have added the recommends the requirement to retain for holding.
requirements of final § 111.260(a)(1), such records be set forth within subpart (Response) Based on the limited
(a)(2)(i), and (a)(2)(ii) to ensure that you D. information provided by these
are able to determine the manufacturing (Response) As discussed in section IX comments, it appears that they are
history and control of the packaged and of this document (final § 111.35(b)(2)), describing the manufacture of a ‘‘dietary
ingredient’’ or other component that include these in your batch production production and quality control
will subsequently be used in the record or in another appropriate record management systems that utilize
manufacture of a dietary supplement. that you can cross-reference and make password-protected (or otherwise
Therefore, in this scenario, the identity readily available for inspection. secure) means of entering data at key
and weight or measure of the stable quality control steps.
8. Final § 111.260(i)
matrix must be taken. The statement of (Response) The use of electronic
the actual yield and the theoretical yield Final § 111.260(i) requires that the signatures is governed by our
refers to the batch in which the stable batch production record include regulations in part 11, which control
matrix is added as a component. documentation that the finished dietary whether electronic signatures are
supplement meets specifications permitted. Our guidance entitled
6. Final § 111.260(g) established in accordance with ‘‘Guidance for Industry Part 11,
Final § 111.260(g) requires that the § 111.70(e) and (g). Final § 111.260(i) Electronic Records; Electronic
batch production record include the derives from proposed § 111.50(c)(11). Signatures—Scope and Application,’’
actual results obtained during any We have made a change to identify available at http://www.fda.gov/cder/
monitoring operation. Final § 111.260(g) which required specifications the guidance/5667fnl.htm, discusses the use
derives from proposed § 111.35(o)(2) dietary supplement must meet. of electronic signatures (Ref. 33).
which would require you to make and We did not receive comments specific c. Final § 111.260(j)(2)(i) through
retain records of the actual results to proposed § 111.50(c)(11). § 111.260(j)(2)(iv). Final
obtained during monitoring of the in- § 111.260(j)(2)(i) requires you to
process production. Consistent with the 9. Final § 111.260(j)
document at the time of performance
reorganization we are specifying that the Final § 111.260(j) sets forth the
the initials of the person responsible for
records of monitoring be located in the requirements for documentation you
weighing or measuring each component
batch production record, because the must make and include in the batch
used in the batch, and final
monitoring is associated with the batch production record, at the time of
§ 111.260(j)(2)(ii) requires you to
production. performance, of the manufacture of the
document at the time of performance
We did not receive comments specific batch. Final § 111.260(j) derives from
the initials of the person responsible for
to proposed § 111.35(o)(2). proposed § 111.50(c)(2) and (c)(7).
a. Final §111.260(j)(1). Final verifying the weight or measure of each
7. Final § 111.260(h) § 111.260(j)(1) requires documentation, component used in the batch. Final
Final § 111.260(h) requires that the at the time of performance, of the date § 111.260(j)(2)(i) and (j)(2)(ii) derive
batch production record include the on which each step of the master from proposed § 111.50(c)(2)(i) and
results of any testing or examination manufacturing record was performed. (c)(7), respectively.
performed during the batch production, Final §111.260(j)(1) derives from Final § 111.260(j)(2)(iii) requires you
or a cross-reference to such results. proposed § 111.50(c)(2). We did not to document, at the time of
Final § 111.260(h) derives from receive comments specific to proposed performance, the initials of the person
proposed § 111.50(c)(10) which would § 111.50(c)(2). responsible for adding the component to
require you to record the actual results b. Final §111.260(j)(2). Final the batch; and final § 111.260(j)(2)(iv)
of any testing performed during § 111.260(j)(2) requires documentation, requires you to document, at the time of
production of the batch. at the time of performance, of the performance, the initials of the person
(Comment 265) A few comments initials of the persons performing each responsible for verifying the addition of
object to the requirement in proposed step in the master manufacturing record. components to the batch. Final
§ 111.50(c)(10) that actual test results be Final § 111.260(j)(2) derives from the § 111.260(j)(2)(iii) derives from
included in the batch production second part of proposed proposed § 111.50(c)(2)(ii) and final
record. These comments state test § 111.50(c)(2),(c)(7) and (c)(8). § 111.260(j)(2)(iv) derives from proposed
results are typically retained in other (Comment 266) One comment asks § 111.50(c)(8).
records, such as laboratory records, and whether the persons responsible for We did not receive comments specific
that it would be duplicative to include batch production must be identified by to proposed § 111.50(c)(2)(i) and
such results in the batch production name or by position. (c)(2)(ii) or § 111.50(c)(7) and (c)(8).
record. One comment states the ‘‘actual’’ (Response) The requirement is for the 10. Final § 111.260(k)
(original record of) test results may not initials of the name of the person rather
be available to the manufacturer when than for identification of the position. Final § 111.260(k) sets forth the
the testing is performed electronically or Requiring that the record include the requirements for documentation you
an outside laboratory does the testing. initials of the person(s) performing each must make and include in the batch
This comment adds for test results step in the master manufacturing record production record, at the time of
obtained in-house, original records are means that the person performing the performance, of the packaging and
typically kept as part of the master step is the person who physically labeling operations. Final § 111.260(k)
laboratory records and cross-referenced initials the batch record at the time the derives from proposed § 111.70(g)
in batch records. person performs the step. The intent is which we discuss in the following
(Response) After considering these for the person to acknowledge that he or paragraphs.
comments, we are providing flexibility she performed the requirement rather In final § 111.260(k)(3), we are
to either include the results of tests or than to merely provide information that eliminating proposed § 111.70(g)(4)
examinations in the batch production would identify that person. which would require that the
record, or provide a cross-reference to (Comment 267) One comment asks documentation include any material
such results. We note that final whether we will allow electronic reviews and disposition decisions for
§ 111.260(h) does not require that you signatures for batch production records, packaging and labels, because it would
have the original documentation of the laboratory test results, and quality be redundant to final
test results. If an outside laboratory has control unit documentation. The § 111.180(b)(4)(ii)(D).
performed testing for you, you must comment notes that many companies a. General comments on proposed
obtain a copy of the test results and have fully computerized, automated § 111.70(g).
(Comment 268) Some comments drug products, which are generally referring to finished product labels, bulk
assert that the requirement of proposed identical or similar in nature to labeling material labels, or in-process container
§ 111.70(g) that all packaging releases be operations for dietary supplements. As labels. One comment asserts proposed
placed in the batch production record is such, the comments assert the same § 111.50(c)(12) is unnecessary for
unnecessary. According to the flexibility should be afforded to dietary ensuring the dosage form of dietary
comments, most packaging material lots supplement manufacturers. Some supplements meets specifications.
are used in multiple batches. The comments specifically suggest changing One comment finds proposed
comments assert that a requirement for the language of proposed § 111.70(g)(1) § 111.50(c)(12) confusing, because it
this disposition information to be to read ‘‘The identity and quantity of the does not specify what is meant by ‘‘label
copied into each batch production packaging and labels used and either operation.’’ This comment notes that
record is unnecessary as long as lot reconciliation of any discrepancies during the course of manufacturing
traceability exists and this information between issuance and use or use of operations, containers holding in-
is kept in a central file. appropriate electronic or process materials are often labeled but
(Response) These comments may have electromechanical equipment to the comment assumes that proposed
misinterpreted proposed § 111.70(g). It conduct a 100-percent examination for § 111.50(c)(12) does not require the
would require that the documentation labeling during or after completion of retention of copies of in-process
in the batch production record for finishing operations.’’ container labels, which would not add
packaging and label operations include: (Response) We agree that label significant value toward the assurance
(1) The identity and quantity of the reconciliation need not be required for of a quality product.
packaging and labels used and cut or rolled labels if a 100-percent In general, these comments ask for
reconciliation of any discrepancies examination for correct labels is clarification of proposed § 111.50(c)(12),
between issuance and use, (2) the performed by appropriate electronic or and suggest it be deleted.
examination conducted in accordance electromechanical equipment during or (Response) Proposed § 111.50(c)(12)
with proposed § 111.70(b)(7), (3) the after completion of finishing operations. referred to the product label that would
conclusions reached from retests Thus we have made two changes in this be affixed to the containers that hold the
conducted in accordance with proposed final rule in addition to the changes in packaged and labeled dietary
§ 111.70(e), and (4) any material reviews final § 111.260(k)(1) that provide there supplement. We did not receive any
and disposition decisions for packaging must be label reconciliation when such comments that a related requirement (in
and labels. None of these proposed reconciliation is required either to proposed § 111.45(b)(7) in the master
requirements would require that account for discrepancies or to ensure manufacturing record) was confusing or
‘‘packaging releases’’ be included in the the use of the label that is specified in needed clarification. We therefore
batch record. the master manufacturing record. First, believe that the requirement that the
The requirements for documentation we have revised the final rule in subpart batch production record include a label
for packaging you receive are set forth L (for packaging and labeling will be clearer if we state the
in final § 111.180(b) in subpart G. operations) to provide that you need not requirement in a way that is similar to
b. Final § 111.260(k)(1). Final conduct label reconciliation if a 100- the requirement in proposed
§ 111.260(k)(1) requires the percent examination for correct labels is § 111.45(b)(7). However, because
documentation of packaging and performed by appropriate electronic or comments to proposed § 111.45(b)(7)
labeling operations to include the electromechanical equipment during or persuaded us to provide flexibility for
unique identifier you assigned to after completion of finishing operations (1) having a representative label rather
packaging and labels used, the quantity (see discussion of final § 111.410(b) in than an actual label and (2) cross-
of the packaging and labels used, and, subpart L in section XVI of this referencing the physical location of the
when label reconciliation is required, document). Second, final actual or representative label that is
reconciliation of any discrepancies § 111.260(k)(1), requires you to include specified in the master manufacturing
between issuance and use of labels. documentation in the batch production record, we are providing the same
Final § 111.260(k)(1) derives from of reconciliation of any discrepancies flexibility for having a label in the batch
proposed § 111.70(g)(1) which would between issuance and use of labels only production record. Therefore, we are
require that the documentation include when label reconciliation is required. revising the proposed requirement that
the identity and quantity of the c. Final § 111.260(k)(2). Final the batch production record include
packaging and labels used and § 111.260(k)(2) requires the ‘‘copies of all container labels used’’ so
reconciliation of any discrepancies documentation of packaging and that, under final § 111.260(k)(2), the
between issuance and use. For labeling operations to include an actual batch production record must include
consistency with other provisions of or representative label, or a cross- an actual or representative label, or a
this final rule, such as final reference to the physical location of the cross-reference to the physical location
§ 111.160(e)(1), final § 111.260(k)(1) actual or representative label specified for the actual or representative label that
requires ‘‘the unique identifier you in the master manufacturing record. is specified in the master manufacturing
assigned to packaging and labels used,’’ Final § 111.260(k)(2) derives from record.
rather than ‘‘the identity of packaging proposed § 111.50(c)(12) which would However, we are not requiring in final
and labels used.’’ Final § 111.260(k)(1) require that the batch production record § 111.260(k)(2) that the batch
also includes changes we are making include copies of all container labels production record include the results of
after considering comments. used and the results of examinations examinations conducted during the
(Comment 269) Some comments conducted during the label operation to label operation to ensure that the
assert comprehensive label ensure that the containers have the containers have the correct label that is
reconciliation should not be required if correct label. specified in the master manufacturing
appropriate electronic controls are (Comment 270) A few comments ask record, because this would be
instituted to ensure that correct labels that we clarify the container labels that redundant to final § 111.260(k)(3).
are used during labeling operations. The proposed § 111.50(c)(12) is referring to. d. Final § 111.260(k)(3). Final
comments state this alternative is Specifically, these comments ask § 111.260(k)(3) requires that the
permitted for labeling operations for whether proposed § 111.50(c)(12) is documentation of packaging and
labeling operations include the results monitoring operation required under documentation by quality control
of any tests or examinations conducted subpart E. Final § 111.260(l)(1)(i) personnel include that quality control
on packaged and labeled dietary derives from proposed § 111.35(i)(2) personnel approved or rejected any
supplements (including repackaged or which would require that you review, reprocessing or repackaging. Final
relabeled dietary supplements), or a among other things, the results of the § 111.260(l)(2) derives from proposed
cross-reference to such results. Final monitoring of the in-process control § 111.50(c)(14) which would require
§ 111.260(k)(3) combines the proposed points, steps, or stages to ensure that the batch production record include
requirements of proposed § 111.70(g)(2) specifications are met. As discussed in the signature of the quality control unit
which would require that the section XI of this document (final to document its review of the batch
documentation include the results of § 111.123(a)(3)), the final rule requires production record and any approval for
examinations conducted in accordance quality control personnel to review the reprocessing or repackaging. For
with proposed § 111.70(b)(7), and required monitoring. consistency with other provisions in
proposed § 111.70(g)(3) which would We did not receive comments specific this final rule (such as final § 111.90),
require that the documentation include to proposed § 111.35(i)(2). final § 111.260(l)(2) includes a revision
the conclusions from retests conducted c. Final § 111.260(l)(1)(ii). Final that quality control personnel must
in accordance with proposed § 111.70. § 111.260(l)(1)(ii) requires the clearly choose between approving—or
For consistency with other requirements documentation by quality control rejecting—any reprocessing or
for documentation that must be in the personnel to include the review by repackaging.
batch record, final § 111.260(k)(3) quality control personnel of the results We did not receive comments specific
requires you to include ‘‘the results of of any tests or examinations, including to proposed § 111.50(c)(14).
any tests or examinations,’’ rather than tests or examinations conducted on e. Final § 111.260(l)(3). Final
‘‘the examination’’ (proposed components, in-process materials, § 111.260(l)(3) requires the
§ 111.70(g)(2)) and ‘‘conclusions’’ finished batches of dietary supplements, documentation by quality control
(proposed § 111.70(g)(3)). Final and packaged and labeled dietary personnel to include that it approved
§ 111.260(k)(3) also includes editorial supplements. Final § 111.260(l)(1)(ii) and released, or rejected, the batch for
revisions associated with combining derives from the following proposed distribution, including any reprocessed
proposed § 111.70(g)(2) and (g)(3). provisions:
batch. Final § 111.260(l)(3) derives from
We did not receive comments specific • Proposed § 111.50(e)(1) which
the following proposed regulations:
to proposed § 111.70(g)(2) or (g)(3). would require that the documentation
by the quality control unit include • Proposed § 111.37(b)(5) which
11. Final § 111.260(l) review of component, dietary would require, in part, the quality
ingredient, and dietary supplement control unit to review the batch
Final § 111.260(l) sets forth the
receiving records, including review of production record to approve the batch
requirements for documentation quality
testing and examination results and for release for distribution;
control personnel must make at the time
• Proposed § 111.37(b)(9) which • Proposed § 111.50(d)(2) which
of performance and that must be
would require, in part, the quality would require the quality control unit
included in the batch production
control unit to review all testing results. not to approve and release for
record. Final § 111.260(l) derives from
(Comment 271) A few comments distribution any batch of dietary
proposed §§ 111.35(i)(2), (j), (m), (o)(2);
assert that the proposed requirement ingredients or dietary supplement that
111.37(b)(3), (b)(5), and (b)(9);
that the quality control unit review does not meet all specifications; and
111.50(c)(1) through (c)(11), (c)(13),
receiving records as part of its review of • Proposed § 111.50(g) which would
(c)(14), (d)(2), (e), and (g); 111.70(b)(6);
the batch record is redundant and require, in part, the results of the
and 111.70(g).
a. Final § 111.260(l)(1). Final should be eliminated. One comment reevaluation by the quality control unit
§ 111.260(l)(1) requires quality control argues that it is unnecessarily to be documented in the batch
personnel to document at the time of burdensome to require the quality production record.
performance the review of the batch control unit to re-review and cross- For consistency with other provisions
production record. Final § 111.260(l)(1) reference all receiving records, noting of this final rule (such as final § 111.90),
derives from the following proposed that the quality control unit already has final § 111.260(l)(3) requires that quality
regulations: performed a review of these records control personnel must clearly choose
• § 111.50(d), which would require when the components or dietary between approving—or rejecting—the
that the quality control unit review in supplements were received, approved, batch for distribution. We did not
accordance with § 111.37(b)(5) the batch and released for use. The comment receive comments specific to those parts
production record established in asserts the quality control unit should of proposed §§ 111.37(b)(5) or
§ 111.50(c); and only have to repeat this review if it is 111.50(d)(2) that we are setting forth in
• § 111.50(e), which would require conducting an investigation or a final § 111.260(l)(3).
that the quality control unit document material review. f. Final § 111.260(l)(4). Final
at the time of performance in (Response) We agree with the § 111.260(l)(4) requires the batch
accordance with § 111.37(c), the review comments. Therefore, final production record to include
performed in accordance with § 111.260(l)(1)(ii) retains the documentation, at the time of
§ 111.50(d). requirements of proposed performance, that quality control
Final § 111.260(l)(1) includes editorial §§ 111.37(b)(9) and 111.50(e)(1) to personnel approved and released, or
changes associated with the review the results of testing and rejected, the packaged and labeled
reorganization. We did not receive examination, but does not require dietary supplement, including any
comments specific to proposed quality control personnel to document, repackaged or relabeled dietary
§ 111.50(d) or (e). as part of the review of the batch record, supplement. Final § 111.260(l)(4)
b. Final § 111.260(l)(1)(i). Final receiving records for components and derives from the following proposed
§ 111.260(l)(1)(i) requires the dietary supplements. regulations:
documentation by quality control d. Final § 111.260(l)(2). Final • Proposed § 111.37(b)(3) which
personnel to include review of any § 111.260(l)(2) requires that the would require, in part, that the quality
control unit approve or reject all dietary be redundant to include proposed TABLE 11.—DERIVATION OF SECTIONS
supplements and § 111.50(d)(1) in final subpart I. IN FINAL SUBPART J
• Proposed § 111.70(e) which would Proposed § 111.50(e)(2) would require
require, in part, that any repackaged or 2003 CGMP
that the review of the batch production Final Rule
relabeled dietary supplement meet all Proposal
record and documentation by the
specifications and that the quality
quality control unit include § 111.303 What are the N/A
control unit must approve or reject their
release for distribution. identification of any deviation from the requirements under
We did not receive comments specific master manufacturing record that may this subpart J for writ-
to those parts of proposed have caused a batch or any of its ten procedures?
§§ 111.37(b)(3) or 111.70(e) that we are components to fail to meet
specifications identified in the master § 111.310 What are the § 111.60(a)
setting forth in final § 111.260(l)(4). requirements for the
production record. Proposed laboratory facilities
12. Final § 111.260(m) § 111.50(e)(3) would require that the that you use?
Final § 111.260(m) requires the batch review of the batch production record
production record to include and documentation by the quality § 111.315 What are the § 111.60(b)(1)
documentation, at the time of control unit include records of requirements for lab-
performance, of any required material investigations, conclusions, and oratory control proc-
review and disposition decision. Final esses?
corrective actions performed in
§ 111.260(m) derives from the following accordance with proposed § 111.50(d).
proposed provisions: § 111.320 What require- § 111.60(c) and
Proposed § 111.50(e)(4) would require ments apply to labora- (d)
• Proposed § 111.50(c)(13) which that the review of the batch production tory methods for test-
would require that the batch production ing and examination?
record and documentation by the
record include any documented review
quality control unit include the identity
and disposition decision and § 111.325 Under this § 111.60(b)(2)
• Proposed § 111.35(j) which would of the person qualified by training and
subpart J, what and (b)(3)
require that the person who conducts experience who performed the records must you
the material review and makes the investigation in accordance with make and keep?
disposition decision document that § 111.50(d).
activity, at the time of performance, in Each of these requirements is already B. Highlights of the Changes to the
the batch production record. included in final § 111.140(b)(3) which Proposed Requirements for Laboratory
We did not receive comments specific sets forth the requirements for the Operations
to proposed §§ 111.35(j) or documentation that quality control
111.50(c)(13). 1. Revisions
personnel must include for any required
13. Final § 111.260(n) material review and disposition The final rule applies to persons who
decision. In addition, under final manufacture, package, label, or hold
Final § 111.260(n) requires that the
batch production record include § 111.260(m), the batch production dietary supplements unless subject to an
documentation, at the time of record must include documentation of exclusion in § 111.1.
performance, of any reprocessing. We any required material review and
disposition decision. Given the 2. Changes Associated With the
have added this requirement in Reorganization
conjunction with the requirement for requirements of final §§ 111.140(b)(3)
written procedures for the quality and 111.260(m), it would be redundant This subpart contains fewer details,
control operations for approving or to include proposed § 111.50(e)(2), compared to the 2003 CGMP Proposal,
rejecting any reprocessing, discussed (e)(3), and (e)(4) in final subpart I, and regarding the requirements for
generally in section IV of this document. we are not including them. collecting representative samples and
E. Review of Batch Production Record XV. Comments on Production and for testing, because these details are set
Deviations (Proposed § 111.50(d)(1), Process Control System: Requirements forth elsewhere in this final rule (i.e., in
(e)(2), (e)(3), and (e)(4)) for Laboratory Operations (Final final §§ 111.75 and 111.80) and would
Proposed §111.50(d)(1) would Subpart J) be redundant in final subpart J.
require, if a batch deviates from the A. Organization of Final Subpart J 3. Changes After Considering Comments
master manufacturing record, including
any deviation from specifications, the In the 2003 CGMP Proposal, the The final rule:
quality control unit to conduct a proposed requirements for production • Includes a new requirement to
material review and make a disposition and process controls for laboratory establish and follow written procedures
decision and record any decision in the operations were set forth in proposed for laboratory operations, including
batch production record. Under final § 111.60(a) through (d). As shown in written procedures for the tests and
§ 111.87 quality control personnel must table 11 of this document, we are examinations you conduct to determine
conduct any required material review reorganizing the requirements for whether or not specifications are met.
and make any required disposition laboratory operations into a distinct
decision; under final § 111.113(a)(2) • Requires you to identify and use the
subpart (final Subpart J—Production appropriate ‘‘scientifically valid
quality control personnel must conduct and Process Control System:
a material review and make a method,’’ rather than an appropriate
Requirements for Laboratory
disposition decision if a batch deviates ‘‘validated testing method,’’ for each

Operations). Table 11 lists the sections established specification for which
from the master manufacturing record,
in final subpart J and identifies the testing or examination is required to
including any deviation from
specifications. Given the requirements proposed sections that form the basis of determine whether the specification is
of final §§ 111.87 and 111.113, it would the final rule. met.
C. What Are the Requirements Under for specifications other than the identity is more appropriately described as a
This Subpart for Written Procedures? of a dietary ingredient. quality control function rather than as a
(Final § 111.303) laboratory function.
E. What Are the Requirements for (Response) We disagree that the
We received many comments that Laboratory Control Processes? (Final proposed requirement to use a sampling
recommended written procedures for § 111.315) plan is more appropriately described as
various provisions. We address the need Final § 111.315 sets forth the a quality control function than as a
for written procedures generally in minimum laboratory control processes laboratory function. Under both the
section IV of this document. We also that you must establish and follow. proposed and the final rule, the
respond to individual comments on These laboratory control processes must sampling plans that are part of the
specific provisions in the same section. be reviewed and approved by quality laboratory control operations are subject
Final § 111.303 requires you to control personnel. to approval by quality control personnel
establish and follow written procedures (‘‘unit’’ in the proposed rule) but are not
1. Final § 111.315(a)
for laboratory operations, including developed by quality control personnel.
written procedures for the tests and Final § 111.315(a) requires the We are making no changes based on this
examinations you conduct to determine laboratory control processes you comment.
whether specifications are met. establish and follow to include the use (Comment 274) One comment asserts
of criteria for establishing appropriate sampling can be better accomplished at
D. What Are the Requirements for the specifications. Final § 111.315(a) is
Laboratory Facilities That You Use? the point of packaging rather than at a
identical to proposed § 111.60(b)(1)(ii). laboratory remote from the packaging
(Final § 111.310) We did not receive comments specific operation.
Final § 111.310 requires you to use to proposed § 111.60(b)(1)(ii). (Response) This comment
adequate laboratory facilities to perform 2. Final § 111.315(b) misinterprets proposed
whatever testing and examinations are § 111.60(b)(1)(iii) which proposed to
Final § 111.315(b) requires you to establish a process (i.e., the use of a
necessary to determine whether: (1)
establish and follow laboratory control sampling plan) rather than to direct that
Components that you use meet
processes that are reviewed and a particular operating unit (such as a
specifications; (2) in-process
approved by quality control personnel, laboratory) collect samples. We are
specifications are met as specified in the
including the use of sampling plans for making no changes based on this
master manufacturing record; and (3)
obtaining representative samples, in comment.
dietary supplements that you
accordance with subpart E, of: (1)
manufacture meet specifications. Final 3. Final § 111.315(c)
Components, packaging, and labels; (2)
§ 111.310(a) is substantially similar to
in-process materials; (3) finished Final § 111.315(c) requires the
proposed § 111.60(a). The requirement
batches of dietary supplements; (4) laboratory control processes you
for ‘‘adequate laboratory facilities’’ is to
product you receive for packaging or establish and follow include use of
ensure that the facilities used are
labeling as a dietary supplement (and criteria for selecting appropriate
designed and suitable for carrying out
for distribution rather than for return to examination and testing methods. Final
the necessary tests and examinations.
the supplier); and (5) packaged and § 111.315(c) is identical to proposed
Other CGMP requirements of this final
labeled dietary supplements. Final § 111.60(b)(1)(i).
rule would apply to the manufacturer’s
§ 111.315(b) derives from proposed (Comment 275) One comment
laboratory facilities, such as Subpart C—
§ 111.60(b)(1)(iii)(A) through recommends that a contract laboratory
Physical Plant and Grounds, and
(b)(1)(iii)(E). hired by a person who is subject to the
Subpart D—Equipment and Utensils, Final § 111.315(b) combines the
and should be considered in assessing final rule be able to determine the
proposed requirements of specific type of test that is most
the adequacy of the laboratory facilities. § 111.60(b)(1)(iii)(A) and (b)(1)(iii)(D) for
If the tests and examinations are carried appropriate.
consistency with final § 111.80(a) which (Response) Nothing in the final rule
out by an outside laboratory, you will be combines the requirements to collect
responsible for ensuring that the test would preclude you from relying on the
representative samples of components, recommendation of the contract
and examinations are adequately packaging, and labels. However, for
performed. laboratory in selecting an appropriate
consistency with other requirements test or examination. However, the
(Comment 272) One comment states established by this final rule, we are manufacturer of the dietary supplement
that proposed § 111.60(a) would be separating the requirements to collect has the responsibility to comply with
highly disruptive to the dietary representative samples of ‘‘dietary these CGMP requirements, including the
supplement industry and would impose supplements received’’ (which the final requirement to select appropriate tests,
a great burden on companies that rule refers to as ‘‘product that you regardless of who conducts the tests.
traditionally rely on certification of receive for packaging or labeling as a
ingredient suppliers. Some comments dietary supplement (and for distribution 4. Final § 111.315(d)
assert it would be redundant to require rather than for return to the supplier,’’ Final § 111.315(d) requires the
testing by companies who are suppliers or ‘‘received product’’)) from the laboratory control processes you
of dietary ingredients, as well as by requirements to collect representative establish and follow to include use of
companies who receive the dietary samples of components. criteria for selecting standard reference
supplements, to determine whether the (Comment 273) Some comments note materials used in performing tests and
dietary ingredients meet specifications. that proposed § 111.60(b)(1)(iii) restates examinations. Final § 111.315(d) derives
(Response) The final rule already the requirements, already contained in from proposed § 111.60(b)(1)(iv).
includes changes that address the proposed § 111.37(b)(11)(i) through (Comment 276) Several comments
concerns raised by these comments. As (b)(11)(iv), that the quality control unit support the use of standard reference
discussed in section X of this document collect representative samples. These materials. Some comments distinguish
regarding final § 111.75(a), the final rule comments request proposed between a reference standard (which
permits the use of certificates of analysis § 111.60(b)(1)(iii) be deleted, because it they describe as a highly purified
compound that is well characterized reference standards be established has the responsibility to comply with
and is used in quantitative assays for appropriate to the assay procedure for these CGMP requirements, including the
single chemical entities) and a reference which they are used. requirement to select appropriate tests,
material (which they describe as similar (Response) Reference materials regardless of who conducts the tests.
to a reference standard but with less should be appropriate to the assay (Comment 281) One comment
specificity). These comments urge us to procedure for which they are used. suggests modifying proposed § 111.60(c)
recognize the difference between (Comment 278) Several comments to add ‘‘reference materials and/or
reference standards and reference recommend we acknowledge certain reference standards’’ to the list of
materials and to require the use of both reference materials as authoritative elements that must be verified to be
in the final rule. sources for botanical ingredients, such appropriate for their intended use.
(Response) The comments that as American Herbal Pharmacopoeia, (Response) If reference materials and
request we recognize a difference European Pharmacopoeia, and the reference standards are used as part of
between certain types of reference World Health Organization, in part the test or examination method, then
materials are consistent with proposed because other sources include only a such materials and standards are
§ 111.60(b)(1)(iv) and with statements limited number of botanicals as already required to be verified under the
that we made in the preamble to the supplements. In the comments’ view, language in proposed § 111.60(c). Thus,
2003 CGMP Proposal. We distinguished explicit acknowledgment by FDA would there is no need for the modification
two general types of reference materials: encourage manufacturers to use and we decline to modify the language
(1) Compendia reference standards that independent standards, increase CGMP of final § 111.320(a).
do not require characterization and (2) compliance, and show that validation is 2. Final § 111.320(b)
noncompendia standards that should be not limited to quantitative chemical
of the highest purity that can be Final § 111.320(b) requires you to
methods.
obtained by reasonable effort and that identify and use the appropriate
(Response) We decline to
should be thoroughly characterized to scientifically valid method for each
acknowledge certain reference materials
ensure their identity, purity, quality, established specification for which
as authoritative sources for botanical
and strength. We recommended you use testing or examination is required to
ingredients. Such a request is outside
compendia reference standards determine whether the specification is
the scope of this final rule. met. Final § 111.320(b) derives from
whenever possible, and that you (Comment 279) One comment
establish appropriately characterized in- proposed § 111.60(d) which would
believes we should designate USP to require you to identify and use an
house materials prepared from develop appropriate standards.
representative lots if no compendia appropriate validated testing method for
(Response) This comment is outside each established specification for which
reference standard exists. the scope of this final rule.
We also discussed reference materials testing is required to determine whether
from the perspective of the type of test 5. Final § 111.315(e) the specification is met. Final
or examination. For organoleptic § 111.320(b) includes a provision
Final § 111.315(e) requires that the
examinations, we described an associated with final § 111.75(h) which
laboratory control processes you must
authenticated plant reference material provides flexibility to use examinations
establish and follow include use of test
as material that has been authenticated as well as tests to determine whether
methods and examinations in
as the correct plant species and correct specifications are met.
accordance with established criteria. (Comment 282) Many comments
plant part(s) by a qualified plant Final § 111.315(e) derives from
taxonomist. For microscopic and express concern about the amount of
proposed § 111.60(b)(1)(vi). testing required for the validation of the
chemical tests (including calibration We did not receive comments specific
tests), we described a reference material appropriate test method. Several
to proposed § 111.60(b)(1)(vi). comments object to the use of the terms
as a highly purified compound that is
well characterized. F. What Requirements Apply to ‘‘validations’’ and ‘‘validated’’ which
To the extent that the comments are Laboratory Methods for Testing and they assert have a specific meaning in
recommending that both compendia Examination? (Final § 111.320) a pharmaceutical context and would be
reference standards and noncompendia overly burdensome in this rule. Other
1. Final § 111.320(a) comments assert that methods already
reference standards comply with any
final rule, this final rule would allow for Final § 111.320(a) requires you to recognized as official standards do not
the use of both compendia reference verify that laboratory examination and need to be ‘‘validated,’’ but simply
standards and noncompendia reference testing methodologies are appropriate ‘‘verified’’ as to suitability. Some
standards. However, to the extent that for their intended use. Final § 111.320(a) comments suggest substituting
the comments are requesting this final is identical to proposed § 111.60(c). ‘‘scientifically valid testing method’’ for
rule require that both types of reference (Comment 280) One comment states ‘‘appropriate validated testing method.’’
materials be used, we disagree. We see that this decision should be made by a One comment suggests ‘‘qualifications’’
no reason to require, for example, that qualified person, whether in-house or at replace ‘‘validations.’’ Another
a firm with access to compendia a contract laboratory. comment suggests test methods need
standards be required to develop (Response) We agree. Nothing in the not be validated if they are ‘‘proven to
noncompendia standards. Likewise, final rule would preclude you from be suitable under actual conditions of
given that we have acknowledged that relying on the judgment of a qualified use.’’ Another comment suggests adding
noncompendia standards may be used, person at a contract laboratory to satisfy ‘‘established by the manufacturer’’ after
we see no reason to require the use of the requirements of final § 111.320(a). ‘‘appropriate validated test method.’’
compendia standards in all We would not consider that a One comment recommends the final
circumstances. recommendation from a contract rule give companies the flexibility to

(Comment 277) One comment laboratory is any different from a adopt the method most suitable to the
expresses confusion about the preamble recommendation from an operating unit ingredient they are testing, regardless of
discussion of proposed § 111.60(b)(1)(iv) of the manufacturer. However, the whether the method is, or is not, an
and suggests the preamble specify that manufacturer of the dietary supplement ‘‘official method’’ such as those
established by AOAC International or already have been validated when such § 111.325 are not limited to laboratory
FDA. tests are available. examination and testing records, but
(Response) In the preamble to the (Comment 283) One comment also include the written procedures.
2003 CGMP Proposal (68 FR 12157 at specifically asks how much Final § 111.325(a) also includes editorial
12208), we stated that test method modification of a validated method is revisions associated with the
validation determines whether a newly- allowed before the method must be re- reorganization and editorial revisions
developed or existing test method is validated by the laboratory. The for consistency with the recordkeeping
accurate, precise, and specific for its comment cites an example of moisture requirements in subparts P.
intended purpose and involves testing in which the testing method We did not receive comments specific
evaluating the test method on multiple needs to be modified to provide a more to proposed § 111.60(b)(3).
occasions or in multiple test facilities. valid moisture reading.
(Response) In the preamble to the 2. Final § 111.325(b)(1)
We explained that official methods,
such as AOAC International methods, 2003 CGMP proposal (68 FR 12157 at The final rule includes a new
are validated in collaborative studies 12209), we recommended that, if you requirement (final § 111.303) that you
using several laboratories under modify an officially validated method, establish and follow written procedures
identical conditions and that the AOAC you document the reason for the for laboratory operations, including
International methods are often cited as modification and have data to show that written procedures for the tests and
‘‘official validated methods.’’ We also the modified method produces results examinations you conduct to determine
explained that other method validations that are at least as accurate and reliable whether specifications are met. Those
are conducted in a single laboratory by as the established method for the written procedures are records.
repeating the same test multiple times. material being tested. We also Therefore, final § 111.325(b)(1) requires
Typical validation characteristics recommended that you have complete you to make and keep a record of the
include accuracy, precision, specificity, records of any testing and written procedures for laboratory
detection limit, quantitation limit, standardization of laboratory reference operations, including written
linearity, range, and robustness. standards, reagents, and standard procedures for the tests and
The process of method validation solutions that you use in your laboratory examinations that you conduct to
discussed above is a formal process for operations. We are making no changes determine whether specifications are
demonstrating that procedures are to these recommendations in this final met.
suitable for their intended use. rule.
(Comment 284) Several comments 3. Final § 111.325(b)(2)
Although all methods that are formally
validated are considered ‘‘scientifically request the final rule incorporate by Final § 111.325(b)(2) sets forth
valid,’’ other methods that are based on reference authoritative sources of requirements for documenting that you
scientific data or results published in, compendial methods. followed the laboratory methodology
for example, scientific journals, (Response) We decline this request for established in accordance with this
references, text books, or proprietary the reasons discussed in response to subpart. Final § 111.325(b)(2)(i) requires
research can be scientifically valid even comments 193 and 196. that the person who conducts the testing
if they are not formally ‘‘validated’’ in G. Appropriate Test Method Validation and examination document, at the time
collaborative studies (68 FR 12157 at (Proposed § 111.60(b)(1)(v)) of performance, that laboratory
12198). methodology established in accordance
Proposed § 111.60(b)(1)(v) would with this subpart is followed. Final
We agree that companies should have require the laboratory control processes
flexibility to adopt the method most § 111.325(b)(2)(ii) requires that the
you establish and follow to include the documentation include the results of the
suitable to the ingredient they are use of appropriate test method
testing. Consistent with the view that testing and examination. Final
validations. Because the final rule does § 111.325(b)(2) derives from proposed
we expressed in the preamble to 2003 not require that you use a validated
CGMP Proposal (68 FR 12157 at 12198), § 111.60(b)(2) with revisions associated
method for any tests or examinations with the reorganization.
we believe that a scientifically valid that you conduct, we are removing
method is one that is accurate, precise, (Comment 285) One comment states
proposed § 111.60(b)(1)(v). that, without appropriate
and specific for its intended purpose. In
other words, a scientifically valid H. Under This Subpart, What Records documentation, there would be no
method is one that consistently does Must You Make and Keep? (Final assurance that the appropriate testing
what it is intended to do. § 111.325) was indeed performed and that the
Because we acknowledge that product’s identity, purity, quality,
Final § 111.325 sets forth the strength, and composition are what they
methods that are based on scientific requirements for records that quality
data or results published in, for are represented to be.
control personnel must make and keep. (Response) We agree and have
example, scientific journals, references,
text books, or proprietary research can 1. Final § 111.325(a) retained the requirement in this final
be scientifically valid even if they are Final § 111.325(a) requires you to provision.
not formally ‘‘validated,’’ we are make and keep records required under XVI. Comments on the Production and
revising proposed § 111.60(d). Under subpart J in accordance with subpart P. Process Control System: Requirements
final § 111.320(b) you must identify and Final § 111.325(a) derives from for Manufacturing Operations (Final
use an appropriate ‘‘scientifically valid proposed § 111.60(b)(3), which would Subpart K)
method’’ (rather than a ‘‘validated require you to keep laboratory
method’’) for each established examination and testing records in A. Organization of Final Subpart K
specification for which testing or accordance with proposed § 111.125. In the 2003 CGMP Proposal, the
examination is required to determine Because final § 111.303 requires you to requirements for manufacturing
whether the specification is met. establish and follow written procedures operations were set forth in § 111.65. As
However, we continue to recommend for laboratory operations, the records shown in table 12 of this document, we
that you use tests and examinations that you must make and keep under final are establishing the requirements for
manufacturing operations in a distinct 3. Revisions Associated With the G. What Precautions Must You Take to
subpart (final Subpart K—Production Reorganization Prevent Contamination? (Final
and Process Control System: The final rule sets forth in final § 111.365)
Requirements for Manufacturing § 111.90, rather than in subpart K, the
Operations). In addition, we are Final § 111.365 requires you to take
requirements for in-process adjustments all necessary precautions during the
incorporating some requirements from or reprocessing. manufacture of a dietary supplement to
proposed § 111.74 relating to rejected
C. General Comments on Manufacturing prevent contamination of components
components, dietary supplements, and
Operations or dietary supplements. Final § 111.365
packaging and labels into final subpart
derives from proposed § 111.65(c)(1)
K. Table 12 lists the sections in final (Comment 286) Some comments through (c)(11).
subpart K and identifies the proposed support proposed § 111.65 as a ‘‘good
sections that form the basis of the final model’’ for an appropriate level of 1. Final § 111.365(a)
rule. flexibility, noting that proposed § 111.65
clearly states the requirements and Final § 111.365(a) requires that the
TABLE 12.—DERIVATION OF SECTIONS presents relevant factors that must be necessary precautions include
considered when determining how to performing manufacturing operations
IN FINAL SUBPART K
best meet the requirements of the rule. under conditions and controls that
(Response) We acknowledge these protect against the potential for growth
2003 CGMP
Final Rule comments and utilize many elements of of microorganisms and the potential for
Proposal
proposed § 111.65 in final § 111.355. contamination. Final § 111.365(a)
§ 111.353 What are the N/A derives from proposed § 111.65(c)(1).
requirements under D. What Are the Requirements Under
This Subpart for Written Procedures? (Comment 287) One comment
this subpart K for writ-
ten procedures? (Final § 111.353) contends that the requirement in
proposed § 111.65(c)(1) to protect
§ 111.355 What are the § 111.65(a)
We received many comments that ‘‘against the potential for growth of
design requirements recommended written procedures for microorganisms,’’ does not take into
for manufacturing op- various provisions. We address the need account processes that have a kill step.
erations? for written procedures generally in The comment recommends that
section IV of this document. We also proposed § 111.65(c)(1) be revised to be
§ 111.360 What are the § 111.65(b) respond to individual comments on more consistent with § 110.80(b)(2) and
requirements for sani- specific provisions in the same section. state, ‘‘performing manufacturing
tation? We are including a new provision, operations under such conditions and
final § 111.353, to require that you controls as are necessary to minimize
§ 111.365 What pre- § 111.65(c)
cautions must you
establish and follow written procedures the potential for the growth of
take to prevent con- for manufacturing operations. undesirable microorganisms, or for the
tamination? E. What Are the Design Requirements contamination of the product.’’
for Manufacturing Operations? (Final (Response) We decline to modify final
§ 111.370 What require- § 111.74
ments apply to re-
§ 111.355) § 111.365(a) as requested by the
jected dietary supple- Final § 111.355 requires you to design comment because the provision
ments? or select manufacturing processes to accomplishes what is requested by the
ensure that product specifications are comment. We defined ‘‘microorganism’’
§ 111.375 Under this N/A consistently met. Final § 111.355 in the 2003 CGMP Proposal similar to
subpart K, what
derives from proposed § 111.65(a) how we describe ‘‘undesirable
records must you microorganisms’’ in § 110.3(i). Further,
make and keep? which would require you to design or
select manufacturing processes to we decline to use the words ‘‘minimize
ensure that dietary supplement the potential for growth’’ instead of
B. Highlights of Changes to the ‘‘protect against the potential for
specifications are consistently achieved.
Proposed Requirements for growth’’ because the word ‘‘minimize’’
Final § 111.355 refers to ‘‘product
Manufacturing Operations suggests a lesser standard than ‘‘protect
specifications’’ rather than ‘‘dietary
supplement specifications’’ to conform against’’ the potential for growth of
1. Revisions
with final § 111.70(e). We have microorganisms.
The final rule: substituted the word ‘‘met’’ for We would consider that you are not
• Applies to persons who ‘‘achieved’’ to comply with plain complying with the final rule if you do
manufacture, package, label, or hold language initiatives and to be consistent not perform manufacturing operations
dietary supplements unless subject to an with other provisions. under conditions and controls that
exclusion in § 111.1 and We did not receive comments specific protect against the potential for growth
to proposed § 111.65(a). of microorganisms and the potential for
• Reflects changes relevant to this contamination, regardless of whether
subpart that we are making to final F. What Are the Requirements for you use a kill step. Although a kill step
subpart C concerning water standards. Sanitation? (Final § 111.360) may be necessary in some
2. Changes Made After Considering Final § 111.360 requires you to circumstances, it is not a substitute for
Comments conduct all manufacturing operations in conditions and controls that protect
accordance with adequate sanitation against the potential for growth of

The final rule requires written principles. Final § 111.360 derives from microorganisms and the potential for
procedures for manufacturing proposed § 111.65(b). We did not contamination. Therefore, we decline to
operations. receive comments specific to proposed make the change requested by this
§ 111.65(b). comment.
2. Final § 111.365(b) manufactured in a foreign country contamination of the dietary

Final § 111.365(b) requires that would be subject to the requirements of supplement. The standard ‘‘safe and
necessary precautions include washing this final rule. Although the sanitary’’ in final § 111.15(e)(1) allows
or cleaning components that contain Environmental Protection Agency some flexibility for the manufacturer in
soil or other contaminants. Final NPDW regulations would not apply to a deciding what water it can use in
§ 111.365(b) is identical to proposed foreign manufacturer, the foreign various operations for which no other
§ 111.65(c)(2). We did not receive manufacturer would need to use water requirements in this final rule apply.
that is of a standard required in this The requirements of final § 111.365(c)
comments specific to proposed
final rule and that achieves the same are consistent with the changes in final
§ 111.65(c)(2).
level of performance required of § 111.15(e).
3. Final 111.365(c) domestic manufacturers. The water used
4. Final § 111.365(d)
Final § 111.365(c) requires that the by the foreign facility must not
contaminate the dietary supplement that Final § 111.365(d) requires that the
necessary precautions include using necessary precautions you take during
water that, at a minimum, complies is manufactured. We decline to add ‘‘or
equivalent water quality’’ because that the manufacture of a dietary supplement
with the applicable Federal, State, and to prevent contamination of components
local requirements and does not would suggest domestic firms would not
need to follow whatever Federal, State, or dietary supplements include
contaminate the dietary supplement performing chemical, microbiological,
when the water may become a and local requirements are applicable.
(Comment 289) One comment or other testing, as necessary to prevent
component of the finished batch of the use of contaminated components.
recommends that proposed
dietary supplement. Final § 111.365(d) derives from
§ 111.65(c)(3) be revised to be consistent
The proposed requirements would set proposed § 111.65(c)(4).
with proposed § 111.15(d)(1), which
forth parallel requirements for water (Comment 290) One comment asserts
would require you to provide water that
that is used in the manufacture of a that requirements for testing belong in
is safe and of adequate sanitary quality,
dietary supplement for both your at suitable temperatures, and under proposed § 111.25 (proposed
physical plant (proposed § 111.15(d)(2)) pressure as needed, in all areas where requirements for equipment and
and for manufacturing operations water is necessary for: (1) utensils) rather than in proposed
(proposed § 111.65(c)(3)). Thus, Manufacturing dietary ingredients or § 111.65 (proposed requirements for
proposed § 111.15(d)(2) would require dietary supplements; (2) making ice that manufacturing operations).
that water that contacts components, comes in contact with components, (Response) In our discussion of
dietary ingredients, dietary dietary ingredients, dietary proposed § 111.65(c)(4) in the 2003
supplements, or any contact surface supplements, or contact surfaces; (3) CGMP Proposal (68 FR 12157 at 12210),
must, at a minimum, comply with the cleaning any surface; and (4) employee we stated that you consider identifying
NPDW regulations prescribed by the bathrooms and hand-washing facilities. those areas in the processing and
Environmental Protection Agency under (Response) We do not agree with the production areas where chemical,
40 CFR part 141 and any State and local comment that we should be consistent microbial, or other forms of
requirements. in the water requirement related to contamination are most likely to occur.
As discussed in section VIII of this proposed § 111.15(d)(1) and the We also stated that chemical, microbial,
document (final § 111.15(e)(2) in requirement in proposed § 111.65(c)(3). or other testing is necessary to identify
subpart C), we are revising proposed The requirement in proposed areas where sanitation measures have
§ 111.15(d)(2) to require in the final rule § 111.15(d)(1) describes a variety of not been adequate or where products
that water, used in the manufacture of manufacturing operations where water may become adulterated. These remarks
a dietary supplement in a manner such is used. For example, water that is safe reflect that the proposed requirement in
that the water may become a component and of adequate sanitary quality, as proposed § 111.65(c)(4) is directed to
of the dietary supplement, i.e., when described in the proposed rule, for facilities rather than to equipment and
such water contacts components, purposes of manufacturing dietary utensils. For example, under proposed
dietary supplements, or any contact supplements or that comes into contact § 111.65(c)(4), we encouraged you to
surface, must, at a minimum, comply with a dietary supplement would be establish a testing program that
with applicable Federal, State, and local water that would have been required to monitors levels of microorganisms at
requirements and not contaminate the comply with the requirement in key places in your physical plant where
dietary supplement. Given the parallel proposed § 111.15(d)(2). Under the you process and produce your products.
nature of proposed § 111.65(c)(3) and proposed rule and under the final rule, Thus, we disagree with the comment
proposed § 111.15(d)(2), we are revising if such water is subject to that the testing requirements belong in
proposed § 111.65(c) to be consistent Environmental Protection Agency proposed § 111.25 and are not making
with the revisions we are making to NPDW, then the water must meet any changes in final § 111.365(d).
proposed § 111.15(d)(2) (final Environmental Protection Agency
§ 111.15(e)(2)). NPDW requirements at point of use. 5. Final § 111.365(e)
Final § 111.365(c) also includes Proposed § 111.15(d)(1) has been Final § 111.365(e) requires that the
grammatical changes consistent with the revised and simplified in final necessary precautions you take during
structure of final § 111.365. § 111.15(e)(1) to require you to provide the manufacture of a dietary supplement
(Comment 288) One comment asks water that is safe and sanitary, at to prevent contamination of components
that the words ‘‘or equivalent quality suitable temperatures, and under or dietary supplements include
water’’ be added to ‘‘water that meets pressure as needed, for all uses where sterilizing, pasteurizing, freezing,
the National Primary Drinking Water water does not become a component of refrigerating, controlling hydrogen-ion
regulations’’ in proposed § 111.65(c)(3) the dietary supplement. Water that is concentration (pH), controlling
to allow for ingredients manufactured in safe and sanitary for cleaning the floor humidity, controlling water activity
facilities outside the United States. in a facility would not need to meet (aw), or using any other effective means
(Response) As stated in response to standards for drinking water, but such to remove, destroy, or prevent the
comment 91, dietary supplements water could not be a source of growth of microorganisms, and prevent
decomposition. Final § 111.365(e) could then use irradiation in implement them if they are necessary to
derives from proposed § 111.65(c)(5). compliance with that rule to comply prevent contamination of components
(Comment 291) One comment asserts with final § 111.365(e) as an ‘‘other or dietary supplements. Final
that only sanitary practices are needed effective means.’’ § 111.65(h) retains this same language.
to prevent microbial contamination or
decomposition, and, therefore, requests 6. Final § 111.365(f) 9. Final § 111.365(i)
that we clarify the processes listed in Final § 111.365(f) requires that the Final § 111.365(i) requires that the
proposed § 111.65(c)(5) are optional. necessary precautions you take during necessary precautions you take during
(Response) We disagree with this the manufacture of a dietary supplement the manufacture of a dietary supplement
comment. Good sanitary practices are to prevent contamination of components to prevent contamination of components
important, but they are not the only or dietary supplements include holding or dietary supplements include using
precaution to take to prevent a components and dietary supplements effective measures to protect against the
component or dietary supplement from that can support the rapid growth of inclusion of metal or other foreign
contamination with microorganisms. In microorganisms of public health material in components or dietary
the preamble to the 2003 CGMP significance in a manner that prevents supplements. Compliance with this
Proposal, we gave the example of bovine the components and dietary requirement must include consideration
colostrum, which is the lacteal secretion supplements from becoming of the use of: (1) Filters or strainers, (2)
that precedes milk after a cow gives adulterated. Final § 111.365(f) derives traps, (3) magnets, or (4) electronic
birth and is a substance that is used in from proposed § 111.65(c)(6). We did metal detectors. Final § 111.365(i)
dietary supplements. We also stated that not receive comments specific to derives from proposed § 111.65(c)(9).
we consider that bovine colostrum proposed § 111.65(c)(6). (Comment 294) One comment
likely presents the same potential health contends it is sufficient to require in
risks as bovine milk, which can contain 7. Final § 111.365(g) proposed § 111.65(c)(9) that
pathogenic organisms capable of Final § 111.365(g) requires that the manufacturers inspect their equipment
causing diseases in man such as necessary precautions you take during before and after use to determine if any
tuberculosis, undulant fever, or the manufacture of a dietary supplement piece is missing, and if so, the entire
gastrointestinal disease and, thus, must to prevent contamination of components batch should be disposed of. The
be pasteurized (21 CFR 1240.61). Under or dietary supplements include comment states metal detection devices
final § 111.365(e) you must sterilize or identifying and holding any are not 100 percent effective and that
pasteurize bovine colostrums, or take components or dietary supplements, for inspection of equipment before and after
other steps, to remove or destroy which a material review and disposition use would be preferable.
microorganisms that could be present in decision is required, in a manner that (Response) We disagree with the
bovine colostrum. Under final protects components or dietary comment. As discussed in the 2003
§ 111.365(e) we list various ways that, supplements that are not under a CGMP Proposal, the purpose behind
depending upon the particular situation, material review against contamination proposed § 111.65(c)(9) is to ensure that
would be effective in removing, and mixups with those under a material no metal or foreign material becomes a
destroying, or preventing the growth of review. Final § 111.365(g) is source of possible contamination and
microorganisms and preventing substantially similar to proposed not to establish mechanisms to be used
decomposition. You must decide for § 111.65(c)(7). We did not receive after contamination has or is suspected
your given operation what means to use comments specific to proposed to have occurred (68 FR 12157 at
to remove, destroy, or prevent the § 111.65(c)(7). 12211). The source of metal
growth of microorganisms and prevent contamination is not limited to
deterioration of your components and 8. Final § 111.365(h)
manufacturing equipment. For example,
dietary supplements so that you ensure Final § 111.365(h) requires that the metal contamination could occur
the quality of the dietary supplement. necessary precautions you take during through using utensils such as metal
(Comment 292) Some comments the manufacture of a dietary supplement brushes during processing of natural
recommend adding ‘‘irradiating’’ to the to prevent contamination of components products. It would be impractical to
list of practices to prevent the growth of or dietary supplements include determine whether contamination has
microorganisms in proposed performing mechanical manufacturing occurred by examining the brush.
§ 111.65(c)(5) similar to the industry steps (such as cutting, sorting,
CGMP provision, ‘‘Production and inspecting, shredding, drying, grinding, 10. Final § 111.365(j)
Process Controls,’’ section (d)(5), blending, and sifting) by any effective Final § 111.365(j) requires that the
published in the 1997 ANPRM. means to protect the dietary necessary precautions you take during
(Response) We decline to revise the supplements against contamination. the manufacture of a dietary supplement
provision as suggested by these Final § 111.365(h) derives from to prevent contamination of components
comments. We are not adding proposed § 111.65(c)(8). Such steps or dietary supplements include
‘‘irradiating’’ to the list of practices must include consideration of: (1) segregating and identifying all
because, at this time, irradiation of Cleaning and sanitizing contact containers for a specific batch of dietary
dietary ingredients and dietary surfaces, (2) using temperature controls, supplements to identify their contents
supplements, as a means to reduce or and (3) using time controls. and, when necessary, the phase of
eliminate microbial loads, is not (Comment 293) One comment manufacturing. Final § 111.365(j)
permitted. CFSAN is currently suggests that the time controls required derives from proposed § 111.65(c)(10).
reviewing the use of irradiation for the in proposed § 111.65(c)(8)(iii) are not We did not receive comments specific to
control of microbial contamination on always necessary. proposed § 111.65(c)(10).
dietary supplements and ingredients (Response) As written, proposed

(including dietary ingredients) used in § 111.65(c)(8) acknowledges that time 11. Final § 111.365(k)
the manufacture of dietary supplements controls are not always necessary, Final § 111.365(k) requires that the
(68 FR 25048, May 9, 2003). If we because the provision requires that you necessary precautions you take during
authorize this use of irradiation you consider using time controls, and the manufacture of a dietary supplement
to prevent contamination of components These written procedures are required operation of putting the label specified
or dietary supplements include under final § 111.353. in the master manufacturing record on
identifying all processing lines and the final product.
XVII. Comments on the Production and
major equipment used during • Clarifies the applicability of the rule
Process Control System: Requirements
manufacturing to indicate their to labeling operations.
for Packaging and Labeling Operations
contents, including the name of the 2. Changes Associated With the
(Final Subpart L)
dietary supplement and the specific Reorganization
batch or lot number and, when A. Organization of Final Subpart L
necessary, the phase of manufacturing. We are moving to final § 111.260(k) in
In the 2003 CGMP Proposal, the
Final § 111.365(k) derives from subpart I the requirements for the
requirements for packaging and labeling
proposed § 111.65(c)(11). documentation, in the batch production
operations were set forth in § 111.70. As
(Comment 295) One comment record, of packaging and labeling
shown in table 13 of this document, the
suggests continuous processes should be operations (proposed § 111.70(g)).
final rule reorganizes the requirements
excluded from the requirement in related to quality control operations into 3. Changes After Considering Comments
proposed § 111.65(c)(11) to identify a distinct subpart (final Subpart L— The final rule:
specific batch or lot numbers. The Production and Process Control System: • Requires you to establish and
comment explains that in continuous Requirements for Packaging and follow written procedures for packaging
bulk operations for manufacturing Labeling Operations). Table 13 lists the and labeling operations.
dietary ingredients, the batch or lot sections in final subpart L and identifies • Provides for an exception to the
number often is not identified until after the proposed sections that form the requirements for label reconciliation for
the materials have been blended and basis of the final rule. cut or rolled labels if a 100-percent
moved into a storage bin. examination for correct labels is
(Response) We are making no changes TABLE 13.—DERIVATION OF SECTIONS performed by appropriate electronic or
to proposed § 111.65(c)(11) in final IN FINAL SUBPART L electromechanical equipment during or
§ 111.365(k) because the comment after completion of finishing operations.
describes a situation where the 2003 CGMP • Clarifies the requirement for
Final Rule
manufacturer is manufacturing a dietary Proposal
‘‘retesting or re-examining’’ any
ingredient, and the final rule does not repackaged or relabeled dietary
§ 111.403 What are the N/A
apply to the manufacture of a ‘‘dietary supplements, i.e., consistent with final
requirements under
ingredient’’ within the meaning of this subpart L for writ- § 111.75(g) you must examine a
section 201(ff) of the act. ten procedures? representative sample of each batch of
H. What Requirements Apply to repackaged or relabeled dietary
§111.410 What require- § 111.70(a), supplements to determine whether
Rejected Dietary Supplements? (Final ments apply to pack- (b)(6), and (f)
§ 111.370) repackaged or relabeled dietary
aging and labels?
supplements meet all specifications
Final § 111.370 requires you to clearly established in accordance with
§ 111.415 What require- § 111.70(b)
identify, hold, and control under a ments apply to filling, § 111.70(g).
quarantine system for appropriate assembling, pack-
disposition any dietary supplement that aging, labeling, and
is rejected and unsuitable for use in related operations? Requirements for Packaging and
manufacturing, packaging, or label Labeling Operations
operations. Final § 111.370 derives from §111.420 What require- § 111.70(d) and (Comment 296) Some comments
proposed § 111.74 which would require ments apply to repack- (e)
assert that the proposed packaging and
that you clearly identify, hold, and aging and relabeling?
labeling requirements are unnecessarily
control under a quarantine system any §111.425 What require- § 111.74 stringent for dietary ingredients,
component, dietary ingredient, dietary ments apply to a pack- because the potential for abuse is
supplement, packaging, and label that is aged and labeled die- primarily at the final product stage.
rejected and unsuitable for use in tary supplement that is (Response) To the extent that the
manufacturing, packaging, or label rejected for distribu- comment is saying that a dietary
operations. Because the requirements tion? ingredient manufacturer who
regarding components, packaging, and manufactures, packages, labels, and
§ 111.430 Under this § 111.70(g) and
labels that are rejected and unsuitable holds a dietary ingredient that is further
subpart L, what (h)
for use are already set forth in final records must you processed and incorporated into a
§ 111.170, final § 111.370 addresses only make and keep? dietary supplement by another person
the requirements for dietary should not have to comply with the
supplements. B. Highlights of Changes to the packaging and labeling requirements in
We did not receive comments specific Proposed Requirements for Packaging subpart L, we agree. We are modifying
to proposed § 111.74. and Labeling Operations the scope of the rule as to who is subject
to the CGMP requirements, as discussed
I. Under This Subpart, What Records 1. Revisions in section VI of this document (subpart
Must You Make and Keep? (Final
The final rule: A). The final rule applies to persons
§ 111.375)
• Reflects that the final rule applies to who manufacture, package, label, or
In order to ensure that records are persons who manufacture, package, hold dietary supplements unless subject
maintained as required under subpart P, label, or hold dietary supplements to an exclusion in § 111.1.
we are adding a new § 111.375. This unless subject to an exclusion in (Comment 297) Several comments
section requires that you make and keep § 111.1. assert that it is imperative that a dietary
records of the written procedures you • Reflects that the labeling supplement contain what it purports on
establish for manufacturing operations. requirements of the rule address the its label. Some comments state that the
amounts of ingredients listed on the Department of Health and Human safety information, label format, use of
label must accurately reflect what is in Services (HHS), Office of the Inspector label space, and directions and product
the package. General (OIG) ‘‘Dietary Supplement information are outside the scope of this
(Response) To the extent that the Labels: Key Elements,’’ March 2003, final rule. Further, with respect to
comments are suggesting that there need publication no. OEI–01–01–00120, requiring specific statements about
to be requirements for labeling available at http://oig.hhs.gov/oei/ dietary supplement product, such as,
operations as part of CGMP to ensure reports/oei–01–01–00120.pdf) (Ref. 34). ‘‘This product has not been reviewed for
that the label applied to the dietary The comment endorses the HHS/OIG safety and efficacy by the FDA,’’ or
supplement is the label specified in the recommendations, with the addition of ‘‘This product has been produced using
master manufacturing record for the batch or lot number on the label. The good manufacturing practice,’’ we have
finished product, we agree. To the comment also endorses the OIG’s stated previously that the manufacturer
extent that the comments suggest that proposed label presentation which calls is responsible for ensuring that any
CGMP requirements should ensure the for: (1) A standardized format with voluntary labeling statements on its
quality of the dietary supplement similar types of information in a similar dietary supplement products are
manufactured, we also agree. If order across supplements; (2) distinct truthful and not misleading (68 FR
consumers believe that dietary product features to assist consumers in 12157 at 12164). We would review the
supplements contain the ingredients as distinguishing supplements from other lawfulness of such statements under
labeled, as with any other product they health care products; (3) readability, sections 403(a)(1) and 201(n) of the act.
purchase, then CGMP requirements with language and visual cues that are We did not propose to require any
should help to ensure that dietary easily understood by consumers; (4) specific statements. We stated that an
supplements are manufactured balance to present information in a fair unqualified statement such as
consistently to ensure the quality of the and balanced format that omits ‘‘produced in compliance with dietary
dietary supplement and to help ensure marketing and sales pitches; and (5) supplement current good manufacturing
the proper identity and amount of constructive use of space whereby practice requirements,’’ without more,
ingredients identified on the label. innovative packaging is employed to could suggest a product may be safe and
expand label space. effective or somehow superior to other
D. General Comments on Requirements
Several comments address whether dietary supplement products that are
for What Must Be on the Product Label
we should permit manufacturers to state subject to the same CGMP requirements
Rather Than for Labeling Operations
on their products that the manufacturer (id.). Further, we stated that such a
(Comment 298) Some comments of the product is in compliance with statement would likely be considered
express disappointment that the 2003 FDA CGMP requirements. Several misleading by us under sections
CGMP Proposal does not address comments assert that a CGMP statement 403(a)(1) and 201(n) of the act, but that
product claims included on product on labels should not be allowed. These including language clarifying to
labels. These comments state that, if comments assert that the proposed consumers that all dietary supplements
FDA is not going to review label claims, ‘‘made in a CGMP facility’’ language is must be manufactured in compliance
it should, at a minimum, require the fraught with potential misuse, and that with CGMP requirements and that such
following statement be placed on the potential for confusion is compliance does not mean that the
dietary supplement products: ‘‘This overwhelming. These comments state dietary supplement is safe or effective
product has not been reviewed for safety that the rule also should be modified to may be a way to cure that unqualified
and efficacy by the FDA.’’ These exclude other similar statements such as statement (id.). Thus, we are not
comments assert that such a statement ‘‘produced using good laboratory prohibiting voluntary statements on the
should be included on all dietary practices,’’ ‘‘produced using good dietary supplement label, provided that
supplement products, regardless of practices,’’ or ‘‘produced in compliance such statements are truthful and not
whether the product makes structure/ with USP good manufacturing misleading.
function claims. These comments also practices.’’ According to these (Comment 299) Some comments
recommend that dietary supplement comments, similar statements currently assert that the labeling standards found
labeling encourage consumers to share appear on dietary supplement labels in the 2003 CGMP Proposal should be
information about their use of the and also may be misleading. These uniformly applied across manufacturers,
dietary supplements with their comments assert that CGMP regardless of size, because consumers
pharmacists and physicians and requirements are not voluntary and are unlikely to differentiate between
encourage consumers to seek the input should not be marketed as such. small companies and large ones when
of a health care provider if symptoms Some comments state that a voluntary selecting dietary supplements. These
that prompted use of the dietary label statement that a dietary comments assert that we should,
supplement are not resolved. supplement complies with CGMP therefore, only allow 1 year for labeling
One comment requests we establish should be allowed. According to these compliance for all manufacturers
specific label content to include on comments, there are several third party regardless of their size.
dietary supplement labels. The organizations such as USP and National Some comments assert that small
comment asserts that the technology Nutritional Foods Association (NNFA) manufacturers are more likely to suffer
and mechanical tools exist to produce that have proposed or established CGMP competitively if their labels lack
expanded labeling for dietary requirements as rigorous as, or more important ingredient and other
supplements efficiently and cost- rigorous than, those proposed by FDA. information relative to labeling
effectively. The comment asserts that These comments assert that a voluntary employed by their larger competitors.
the content should include a complete statement that characterizes the nature These comments argue that enhanced
listing of ingredients, relative of the GMP compliance should be labeling is a cost-effective packaging
percentages, batch or lot number, allowed. feature and should not represent a
intended use, safety information, (Response) The comments related to significant cost burden when
directions, and product information. requests about specific label content, outsourced to a qualified print-
Specifically, the comment supports the such as ingredient listing, relative packaging vendor. Moreover, labels
labeling recommendations of the U.S. percentage of ingredients, intended use, already represent a budgeted cost item
for dietary supplement producers. or cause them to deteriorate. We have specifications for packaging. Other
Labels with additional content would made changes to be consistent with final factors to consider include whether your
add little to manufacturer overhead. § 111.70 and the definition of ‘‘quality’’ product is sensitive to moisture or could
(Response) These comments may have by substituting the phrase ‘‘ensure the interact with certain kinds of packaging.
misinterpreted the 2003 CGMP quality of your dietary supplement’’ (For other requirements related to
Proposal. The CGMP requirements do instead of using the words packaging, see final §§ 111.70(d), (f), (g),
not impose any requirements for the ‘‘contamination’’ and ‘‘deterioration’’ and 111.160.)
specific content of the label. We discuss which would be encompassed in the
2. Final § 111.410(b)
the requirements necessary to determine definition of ‘‘quality.’’ We are deleting
the complete manufacturing history and the words ‘‘container’’ and ‘‘holding’’ Final § 111.410(b) requires you to
control of a packaged and labeled from final § 111.410(a) to emphasize control the issuance and use of
dietary supplement through distribution that all packaging must meet packaging and labels and reconciliation
in this subpart in our discussion on specifications and ensure the quality of of any issuance and use discrepancies,
final § 111.410(d). To the extent that the dietary supplement. except that label reconciliation is not
businesses with fewer than 500 (Comment 300) One comment required for cut or rolled labels if a 100-
employees want to comply with the requests the removal of the word ‘‘each’’ percent examination for correct labels is
CGMP requirements for labeling from proposed § 111.70(a) because the performed by appropriate electronic or
operations in a shorter timeframe than inclusion of the word mandates that electromechanical equipment during or
what we are allowing in this final rule, each and every container, rather than a after completion of finishing operations.
such businesses may do so. However, to representative sample, be inspected. Final § 111.410(b) derives from
assist businesses with fewer than 500 (Response) Because the final rule only proposed § 111.70(f)(1) which would
employees in complying with dietary requires the use of representative require you to control the issuance and
supplement CGMPs, we are giving samples to ensure compliance, as use of packaging and labels and
businesses with fewer than 500 but 20 provided in final § 111.80, to reduce the reconciliation of any issuance and use
or more employees a compliance date of potential for confusion, we are deleting discrepancies.
24 months after the date of publication the word ‘‘each’’ and making associated (Comment 302) Some comments
of this final rule, and we are giving grammatical revisions. assert that comprehensive label
(Comment 301) Some comments reconciliation should not be required if
businesses with fewer than 20
request we clarify our expectations appropriate electronic controls are
employees a compliance date of 36
under proposed § 111.70(a) with respect instituted to ensure that correct labels
months after the date of publication of
to substantiating that packaging are used during labeling operations. The
this final rule.
containers meet specifications and will comments state this alternative is
E. What Are the Requirements Under not contaminate dietary supplements. permitted for labeling operations for
This Subpart for Written Procedures? The comments assert that it is not drug products, which are generally
(Final § 111.403) necessary for a manufacturer to test identical or similar in nature to labeling
We received many comments that these types of products proactively, and operations for dietary supplements. As
recommended written procedures for that a continuing product guarantee such, the comments assert that the same
various provisions. We address the need combined with a statement of intended flexibility should be afforded to dietary
for written procedures generally in use from the manufacturer of the supplement manufacturers.
section IV of this document. We also packaging material should suffice to (Response) We agree with these
meet the proposed requirements. The comments and the revisions are
respond to individual comments on
comments assert this is consistent with reflected in final § 111.410(b) (proposed
specific provisions in the same section.
expected practice in other industries § 111.70(f)(1)).
Final § 111.403 requires you to
that FDA regulates.
establish and follow written procedures 3. Final § 111.410(c)
(Response) Final § 111.410(a)
for packaging and labeling operations.
reiterates the requirement of final Final § 111.410(c) requires you to
Under final 111.430(b), relating to
§ 111.70(d) to establish packaging examine, before packaging and labeling
records you must make and keep, we
specifications and the requirement of operations, packaging and labels for
require that you make and keep records
final § 111.75(f)(1) to determine whether each batch of dietary supplement to
of such written procedures.
packaging specifications are met. Under determine whether the packaging and
F. What Requirements Apply to final § 111.75(f)(1), to determine labels conform to the master
Packaging and Labels? (Final § 111.410) whether packaging meets its manufacturing record. Final § 111.410(c)
specifications, you must conduct a derives from proposed § 111.70(f)(2). We
1. Final § 111.410(a)
visual identification of the containers did not receive comments specific to
Final § 111.410(a) requires that you and closures and review the supplier’s proposed § 111.70(f)(2).
take necessary actions to determine invoice, guarantee, or certification.
whether the packaging for dietary Thus, the final rule does not require that 4. Final § 111.410(d)
supplements meets specifications so you test packaging proactively, and does Final § 111.410(d) requires you to be
that the condition of the packaging will allow you to rely on documentation able to determine the complete
ensure the quality of your dietary such as a continuing product guarantee manufacturing history and control of the
supplements. Final § 111.410(a) is combined with a statement of intended packaged and labeled dietary
similar to proposed § 111.70(a) which use from the manufacturer of the supplement through distribution. We
would require you to take necessary packaging. are revising the language of proposed
actions to ensure that each packaging As we discussed in the preamble to § 111.70(b)(6) and including in final
container for holding dietary ingredients 2003 CGMP Proposal (68 FR 12157 at § 111.410 the similar requirement stated
or dietary supplements meets 12212), proposed § 111.70(a) would in proposed § 111.70(b)(6). Section
specifications so that the condition of require you to take into account factors 111.410 is where we chose to place this
the packaging container will not such as whether your product is requirement because it is likely that you
contaminate your dietary supplements sensitive to light when setting will affix the batch, lot, or control
number that you used for the finished § 111.50(c)(1) we provided that the These requirements relate to the
batch of dietary supplement on the batch production record must include a tracking of a component, packaging,
immediate container or on the product batch, lot, or control number, and in labeling, or dietary supplement
label as the means to trace the product proposed § 111.50(c)(5) we provided throughout the manufacturing process.
through distribution, although this is that the batch production record must The use of a batch, lot, or control
not required. Other means are include the shipment lot unique number or other unique identifier, as
acceptable besides the use of a batch, identifier of each component, dietary required, for product in the
lot, or control number. ingredient, dietary supplement, manufacturing process is needed for
(Comment 303) Some comments packaging, and label used. Further, in tracking components, packaging, and
assert that we do not propose in the proposed § 111.85(d), we required that labels used to manufacture, package, or
2003 CGMP Proposal the affixing of a lot you conduct an investigation if a label a dietary supplement so that once
number to the container of product returned dietary supplement implicates a batch is identified, the components,
marketed to the consumer. These associated batches. Thus, we proposed packaging, and labels used in a batch
comments assert that all the to require that you be able to trace a will also be known. But by contrast,
recordkeeping in the 2003 CGMP dietary supplement through when the distribution of a final product
Proposal is of little value unless issues distribution. However, we did not may be distributed to a few select
can be traced back from the individual require you to use a specific customers, or where every unique batch
container, perhaps received from a mechanism, such as affixing a batch, lot, is placed in a different type of container,
customer complaint, to a specific batch. or control number to the immediate there may not be a need to use batch,
These comments state that such labeling container or product label. Under the lot, or control numbers affixed to the
should be a requirement. 2003 CGMP Proposal, the manufacturer immediate container or product labels
(Response) We agree that it is would have flexibility to determine the to be able to trace the product.
necessary to be able to trace a dietary method to trace its product in
supplement in distribution to a specific This final rule will enhance the
distribution to the batch, lot, or control benefits of the new statutory
batch or lot of product. We disagree that number assigned to the finished batch
we did not provide any requirements in requirement for mandatory reporting to
or lot of dietary supplement. FDA of serious adverse events as the
the 2003 CGMP Proposal that would In final § 111.415(f), we require you to
require you to be able to trace a result of the enactment of the ‘‘Dietary
assign a batch, lot, or control number to:
distributed dietary supplement to a Supplement and Non-Prescription Drug
(1) Each lot of packaged and labeled
specific batch or lot. dietary supplement from a finished Consumer Protection Act’’ (Public Law
In proposed § 111.70(b)(6) we stated batch of dietary supplement and (2) 109–462), signed into law on December
that a batch, lot, or control number is each lot of dietary supplement, from a 22, 2006. This final rule will facilitate
necessary for you to trace the finished batch of dietary supplement, the additional traceback activities taking
manufacturing history for a particular that you distribute to another person for place as a result of the additional
batch, which will help you investigate packaging or labeling. We do not require serious adverse events discovered
and correct any safety problems for a you to affix this batch, lot, or control through mandatory reporting. We will
batch or to recall a dietary supplement. number to the immediate container or evaluate such mandatory reports for
We discussed the fact that, without such the product label. Instead, we provide patterns or ‘‘signals’’ of problems with
a batch, lot, or control number, flexibility for you to determine how you particular products so that further harm
consumers would be unable to track the batch, lot, or control number to consumers may be prevented by
determine which product was the you assign to each lot of packaged and removing the products and, in some
subject of a recall and they would not labeled dietary supplement from a cases, related products from the
know which product to stop using, or finished batch of dietary supplement, marketplace. This cannot be done
there would be a need to recall more and each lot of dietary supplement from without first quickly and accurately
product than otherwise may be a finished batch of dietary supplement identifying the products of interest. To
necessary (68 FR 12157 at 12212). you distribute to another person for efficiently determine which specific
We also proposed several other packaging or labeling, to distributed products or group of products are
requirements related to the need to be dietary supplements. To clarify that we associated with the serious (or non-
able to trace the components, packaging, do not require you to affix a batch, lot, serious) adverse event report, traceback
and labeling used in the manufacture of or control number on the immediate ability is crucial. This final rule
a dietary supplement with the container or product label, final includes requirements that will provide
distributed dietary supplement. Under § 111.410(d) provides that you must be the information needed to quickly and
proposed § 111.40(a) (with respect to able to determine the complete accurately conduct a sufficient
components and dietary supplements) manufacturing history and control of the traceback. The provisions that require
and proposed § 111.40(b)(3) (with packaged and labeled dietary maintenance of records for production
respect to packaging and labeling) we supplement through distribution by a processes include records such as batch
would require you to identify each lot method of your choice. For example, a records, unique identifiers, and master
of product received in a shipment in a dietary supplement manufacturer may manufacturing records. The
manner to allow you to trace the make one type of product that it recordkeeping provisions of this final
shipment lot to the dietary supplement distributes to a select few customers and rule give us access to those records, so
manufactured and distributed. In the may be able to trace its dietary we will have an enhanced ability to
preamble to the 2003 CGMP Proposal supplement using dates on distribution investigate the serious adverse events
(68 FR 12157 at 12202), we stated that records to such customers, or may use reported to us, using records such as
using a unique identifier throughout the different containers or labeling, other information on ingredients, processing,
manufacturing process will make it than a batch, lot, or control number that storage, composition, and distribution.
possible to track and account for is affixed to the label. This enhanced ability to track
components and dietary supplements We are retaining the use of a unique information related to serious adverse
received to any necessary investigation identifier in final §§ 111.155(d), events will increase both the accuracy
of consumer complaints. In proposed 111.160(d), and 111.260(a), (d), and (k). and the speed of the response to such
events, which may in many cases proposed § 111.70(b)(7) is unwarranted record for a firm that only packages and
reduce the number of illnesses or deaths and unreasonable. labels the dietary supplement would
associated with unsafe dietary The comments assert that full product include specifications that are
supplements. testing should not be required for applicable to its operations and would
companies that merely package, label, not include specifications related to, for
G. What Requirements Apply to Filling, and store finished products. The
Assembling, Packaging, Labeling, and example, components.
comments assert that in-route
Related Operations? (Final § 111.415) contamination from the facility of a H. What Requirements Apply to
Final § 111.415 requires that you fill, supplier or manufacturer to the facility Repackaging and Relabeling? (Final
assemble, package, label, and perform of a packager, labeler, or distributor § 111.420)
other related operations in a way that facility is unlikely to occur if the proper 1. Final § 111.420(a)
ensures the quality of the dietary environmental conditions are
supplement and that the dietary Final § 111.420(a) provides that you
maintained as required by other
supplement is packaged and labeled as provisions of the 2003 CGMP Proposal. may repackage or relabel dietary
specified in the master manufacturing The comments assert that the supplements only after your quality
record. Final § 111.415 also requires that responsibility for raw material and control personnel have approved such
you do these functions using any finished product testing should lie repackaging or relabeling. Final
effective means you choose, including: solely with the companies that handle § 111.420(a) is similar to proposed
(1) Cleaning and sanitizing all filling the raw materials and dietary § 111.70(d) with a restructuring of the
and packaging equipment, utensils, and ingredients and that perform provision for clarity. We did not receive
dietary supplement packaging, as manufacturing duties. According to the comments specific to proposed
appropriate; (2) protecting comments, assuming the supplier/ § 111.70(d).
manufactured dietary supplements from manufacturer complies with the final 2. Final § 111.420(b) and (c)
contamination, particularly airborne rule and adequately performs the
contamination; (3) using sanitary Final § 111.420(b) requires you to
required testing, reasonable cost/benefit
handling procedures; (4) establishing examine a representative sample of each
analysis would dictate that redundant
physical or spatial separation of testing not be performed. Therefore, the batch of repackaged or relabeled dietary
packaging and label operations from comments assert that those who perform supplements to determine whether the
operations on other components and packaging and labeling operations repackaged or relabeled dietary
dietary supplements to prevent mixups; should only be required to test those supplements meet all specifications
(5) identifying, by any effective means, areas of contamination that are likely to established in accordance with
filled dietary supplement containers occur during the shipment, or in the § 111.70(g). Final § 111.420(c) requires
that are set aside and held in unlabeled receipt, identification, packaging, and that quality control personnel approve
condition for future label operations, to holding areas of production operations or reject each batch of repackaged or
prevent mixups; (6) assigning a batch, (e.g., surface contamination). relabeled dietary supplement prior to its
lot, or control number to each lot of The comments state it is our duty to release for distribution. Final
packaged and labeled dietary ensure that the industry is complying § 111.420(b) and (c) derive from
supplement from a finished batch of with any final rule, not the duty of proposed § 111.70(e) which would
dietary supplement and each lot of certain segments of the industry to require you to retest or re-examine any
dietary supplement from a finished ensure that other segments of the repackaged or relabeled dietary
batch of dietary supplement that you industry are complying. Since in-route supplements. Proposed § 111.70(e) also
distribute to another person for contamination is unlikely and rare, would require that any repackaged or
packaging or labeling; (7) examining a consumers would enjoy little or no relabeled dietary supplements meet all
representative sample of each batch of benefit from redundant testing at a specifications and that the quality
the packaged and labeled dietary tremendous cost to the industry, control unit approve or reject their
supplement to determine whether the particularly small businesses. release for distribution.
dietary supplement meets specifications (Response) The term ‘‘specifications’’ (Comment 305) Some comments
established in accordance with final in proposed § 111.70(b)(7) included any assert that the proposed requirement
§ 111.70(g); and (8) suitably disposing of specifications that you established for that directs companies to retest or re-
labels and packaging for dietary packaged and labeled dietary examine any repackaged or relabeled
supplements that are obsolete or supplements under proposed dietary supplement unnecessarily
incorrect to ensure that they are not § 111.35(e). In final § 111.415(g), we restricts the ability of the quality control
used in any future packaging and identify the specifications as those you unit to make an appropriate disposition
labeling operations. establish in accordance with final decision. These comments assert that
Final § 111.415 derives from proposed § 111.70(g). In final § 111.70(g), we testing would not be necessary, for
§ 111.70(b). We revised the section to be require you to establish specifications example, when a packager repackages a
consistent with other revisions. for the packaging and labeling for the multiple vitamin softgel from a 500-
(Comment 304) Some comments finished packaged and labeled dietary count bottle to a 60-count bottle. The
request clarification as to what supplements. We distinguish these comments also assert that it would be
specifications we are referring to in specifications (final § 111.70(g)) from costly to retest such product, and that
proposed § 111.70(b)(7). The comments product specifications you must such testing would not benefit
state that if we are referring to establish for a finished batch that you consumer health and safety. The
specifications required by proposed manufacture (final § 111.70(e)). The comments would revise proposed
§ 111.35(e), then we should indicate so specifications that you establish and § 111.70(e) to give the quality control
in any final rule. The comment asserts follow ensure that your product is what unit the authority to make an
that, if we intend this provision to mean you establish in your master appropriate disposition decision, e.g., to
that persons who simply package, label, manufacturing record. As discussed in assess the repackaged dietary
and store dietary supplements must sections VI and section XII of this supplement for conformity to
conduct full product testing, then document, a master manufacturing specifications.
(Response) We agree that there are procedures are records. Therefore, final 2. Changes Associated With the
circumstances, such as those described § 111.430(b) requires you to make and Reorganization
by these comments, when testing would keep records of the written procedures Final § 111.465 in subpart M
not be necessary. However, we disagree for packaging and labeling operations. duplicates the requirement of final
that it would not be necessary to § 111.83(b)(3) to retain reserve samples
‘‘examine’’ a representative sample of XVIII. Comments on Holding and
Distributing (Final Subpart M) of dietary supplements for 1 year past
the repackaged and relabeled dietary the shelf life date (if shelf life dating is
supplement to determine whether the A. Organization of Final Subpart M used) or for 2 years from the date of
required specifications are met, i.e., that distribution of the last batch of dietary
you used the specified packaging and In the 2003 CGMP Proposal, the
supplements associated with the reserve
applied the specified label. If no requirements for holding operations
samples. We are duplicating this
examination of a representative sample were set forth in §§ 111.80, 111.82, and
requirement in this subpart because we
took place, there would be no basis for 111.83 in subpart F; the requirements
believe that it will be useful to include
the determination. We believe that final for distribution operations were set forth
the length of time that you must hold
§ 111.420(b) makes this clear. in proposed § 111.90 in subpart F. As
reserve samples in each place of the
shown in table 14 of this document, the
I. What Requirements Apply to a codified where it is logical to look for
final rule moves the requirements
Packaged and Labeled Dietary this information.
related to holding and distributing
Supplement That Is Rejected for operations to a new subpart (final 3. Changes After Considering Comments
Distribution? (Final § 111.425) Subpart M—Holding and Distributing). The final rule:
Final § 111.425 requires you to clearly Table 14 lists the sections in the final • Does not require that you collect
identify, hold, and control under a rule and identifies the sections that form reserve samples of components;
quarantine system for appropriate the basis of the final rule. • Provides flexibility as to the
disposition any packaged and labeled container-closure system used to hold
dietary supplement that is rejected for TABLE 14.—DERIVATION OF SECTIONS reserve samples of dietary supplements;
distribution. Final § 111.425 derives IN FINAL SUBPART M • Includes a new requirement for
from proposed § 111.74 which would written procedures; and
require you to clearly identify, hold, and 2003 CGMP • Includes a new requirement to
Final Rule
control under a quarantine system any Proposal
make and keep records of product
component, dietary ingredient, dietary distribution and written procedures.
supplement, packaging, and label that is § 111.453 What are the N/A
requirements under C. General Comments on Proposed
rejected and unsuitable for use in
this subpart M for writ-
manufacturing, packaging, or label §§ 111.80, 111.82, 111.83, and 111.85
ten procedures?
operations. Under the final rule, the (Comment 306) One comment
requirements of proposed § 111.74 for § 111.455 What require- § 111.80 requests that factory sealed finished
components, packaging, and labels are ments apply to holding products, which have been specifically
being set forth in final § 111.170, and components, dietary manufactured to be held and
the requirements for a finished batch of supplements, pack-
transported in a variety of conditions, be
dietary supplement are set forth in final aging, and labels?
excluded from the requirements for
§ 111.370. Although the proposal did holding. Another comment states that
§ 111.460 What require- § 111.82
not include any packaged and labeled ments apply to holding there are many types of companies or
dietary supplement rejected for in-process material? individuals in the supply chain who
distribution, we are making this change may ‘‘hold’’ a dietary supplement after
to be consistent with the principle that § 111.465 What require- § 111.83(b)(1) final production, packaging, and
rejected components, dietary ments apply to holding and (b)(2) labeling is complete. This comment
supplements, packaging, or labels reserve samples of di- seeks clarification that brokers,
unsuitable for the distribution supply etary supplements?
distributors, or wholesalers would be
include finished product already subject only to the proposed
packaged and labeled. § 111.470 What require- § 111.90
ments apply to distrib- requirements for holding in proposed
J. Under This Subpart, What Records uting dietary supple- § 111.90.
Must You Make and Keep? (Final ments? (Response) If you hold a dietary
§ 111.430) supplement, you are subject to all
§ 111.475 Under this N/A applicable requirements of these CGMP
1. Final § 111.430(a) subpart M, what regulations related to your operation.
records must you For example, if you are a wholesaler,
Final § 111.430(a) requires you to make and keep?
make and keep records required under you would be subject to the
this subpart in accordance with subpart requirements in final § 111.470 for the
B. Highlights of Changes to the dietary supplements you are holding for
P. Final § 111.430(a) derives from
Proposed Requirements for Holding and distribution as well as other applicable
proposed § 111.70(h) with revisions
Distributing requirements, such as those related to
associated with the reorganization. We
did not receive comments specific to 1. Revisions personnel, physical plant and grounds,
proposed § 111.70(h). equipment and utensils, quality control,
The final rule includes changes that returned dietary supplements, and
2. Final § 111.430(b)
reflect that the scope of the final rule product complaints. We decline to list
As discussed in this section, final applies to persons who manufacture, all of the requirements that would be
§ 111.403 requires you to establish and package, label, or hold dietary applicable because individual
follow written procedures for packaging supplements, unless subject to an operations may vary. However, we
and labeling operations. The written exclusion in § 111.1. provide the following examples of
requirements that would, or would not, appropriate conditions so that the G. Proposed Requirement for Holding
apply in some specific circumstances. packaging and labels are not adversely Reserve Samples of Components
For example, if the dietary supplements affected. Final § 111.455(b) derives from (Proposed § 111.83(a))
that you hold require refrigeration, your proposed § 111.80(b) with modifications Proposed § 111.83(a) would require
refrigeration equipment must comply for consistency with other provisions you to hold any collected reserve
with the requirements to be fitted with addressing packaging and labels. samples of components or dietary
an indicating thermometer, temperature- We did not receive comments specific ingredients in a manner that protects
measuring device, or temperature- to proposed § 111.80(b).
against contamination and deterioration.
recording device that shows the 3. Final § 111.455(c) (Comment 308) One comment
temperature accurately within the requests the final rule not require that
compartment, and have an automated Final § 111.455(c) requires you to
hold components, dietary supplements, manufacturers of dietary supplements
device for regulating temperature or an collect and hold reserve samples of
automatic alarm system to indicate a packaging, and labels under conditions
that do not lead to the mixup, components. The comment asserts that
significant temperature change in a all components can be traced back to
manual operation. However, you would contamination, or deterioration of
components, dietary supplements, their source (i.e., the vendor or
not be required to establish manufacturer of the material) for a more
specifications for the finished batch of packaging, and labels. Final § 111.455(c)
derives from proposed § 111.80(c). in-depth investigation if a dietary
the dietary supplement, for product that supplement comes under investigation
is received for packaging or labeling, or We did not receive comments specific
to proposed § 111.80(c). due to a product complaint.
for packaged and labeled dietary (Response) We agree with this
supplements or to determine whether F. What Requirements Apply to Holding comment. Therefore, the final rule
such specifications are met if you only In-Process Material? (Final § 111.460) contains no requirement for holding
hold the product and do not perform reserve samples of components, only
any other functions. 1. Final § 111.460(a)
finished dietary supplements, and, thus,
Final § 111.460(a) requires you to proposed § 111.83(a) has no counterpart
D. What Are the Requirements Under
identify and hold in-process material in the final rule.
This Subpart for Written Procedures?
under conditions that protect against
(Final § 111.453) H. What Requirements Apply to Holding
mixups, contamination, and
We received many comments that deterioration. Final § 111.460(a) is Reserve Samples of Dietary
recommended written procedures for similar to proposed § 111.82(a) with a Supplements? (Final § 111.465)
various provisions. We address the need grammatical change (i.e., a change from
for written procedures generally in 1. Final § 111.465(a)
‘‘that will protect them’’ to ‘‘that
section IV of this document. We also protect’’). Final § 111.465(a) requires you to
respond to individual comments on We did not receive comments specific hold reserve samples of dietary
specific provisions in the same section. to proposed § 111.82(a). supplements in a manner that protects
We are including a new provision, against contamination and deterioration.
§ 111.453 ‘‘What are the requirements 2. Final § 111.460(b) Under final § 111.465(a)(1) this includes
under this subpart M for written Final § 111.460(b) requires you to holding the reserve sample under
procedures?’’ which requires you to hold in-process material under conditions consistent with product
establish and follow written procedures appropriate conditions of temperature, labels or, if no storage conditions are
for holding and distribution operations. humidity, and light. Final § 111.460(b) recommended on the label, under
is identical to proposed § 111.82(b). ordinary storage conditions. Final
E. What Requirements Apply to Holding (Comment 307) One comment asserts
Components, Dietary Supplements, § 111.465(a)(1) derives from proposed
it would be impractical, unnecessary, § 111.83(b)(1) which would require you
Packaging, and Labels? (Final § 111.455)
and extremely burdensome to maintain to hold reserve samples under
1. Final § 111.455(a) reserve samples of in-process materials. conditions of use recommended or
Final § 111.455(a) requires you to The comment asserts that collecting and suggested in the label of the dietary
hold components and dietary holding samples of in-process materials supplement and, if no conditions of use
supplements under appropriate would duplicate the requirement to are recommended or suggested in the
conditions of temperature, humidity, collect and hold reserve samples of label, then under ordinary conditions of
and light so that the identity, purity, finished dietary supplements and use.
strength, and composition of the require significant additional Final § 111.465(a)(1) refers to
components and dietary supplements documentation, time, and storage space. ‘‘conditions consistent with product
are not affected. Final § 111.455(a) (Response) This comment may have labels’’ rather than to ‘‘conditions of use
derives from proposed § 111.80(a) misinterpreted proposed § 111.37(b)(11) recommended or suggested in the label
which would require that you hold (final §111.80(g)) which included of the dietary supplement’’ and refers to
components, dietary ingredients, and requirements for collecting ‘‘storage conditions’’ rather than
dietary supplements under appropriate representative, rather than reserve, ‘‘conditions of use.’’ This change is to
conditions of temperature, humidity, samples of in-process materials. The reflect that the ‘‘conditions of use’’
and light so that the identity, purity, representative sample is used for those referenced in the 2003 CGMP Proposal
quality, strength, and composition of the tests or examinations conducted to referred to the typical storage of the
components, dietary ingredients, and determine whether the batch meets dietary supplement and not the
dietary supplements are not affected. specifications. A representative sample consumption of the product by the
We did not receive comments specific is held for only a short period of time, consumer.
to proposed § 111.80(a). i.e., the time between the collection and We did not receive comments specific
the test or examination. Neither the to proposed § 111.83(b)(1).
2. Final § 111.455(b) 2003 CGMP Proposal nor this final rule Under final § 111.465(a)(2) the
Final § 111.455(b) requires you to includes a requirement to maintain a manner in which you hold reserve
hold packaging and labels under reserve sample of in-process materials. samples of dietary supplements
includes using the same container- supplements associated with the reserve § 111.453 to ensure that records are
closure system in which the packaged samples, for use in appropriate maintained of the written procedures
and labeled dietary supplement is investigations. Final § 111.465(b) you establish for holding and
distributed, or if distributing dietary derives from proposed § 111.37(b)(12), distributing operations. As discussed,
supplements to be packaged and which proposed, in part, that you must comments stressed that such procedures
labeled, using a container-closure keep reserve samples for 3 years from must be available to us during the
system that provides essentially the the date of manufacture. Proposed course of an inspection.
same characteristics to protect against § 111.37(b)(12) is now final
contamination or deterioration as the § 111.83(b)(3) with a change to 2 years (Comment 311) One comment asserts
one in which you distribute the dietary for the retention period and with that the final rule should not include a
supplement for packaging and labeling changes that we are making consistent requirement for records of product
elsewhere. Final § 111.465(a)(2) derives with comments that requested that the distribution, because such records are
from proposed § 111.83(b)(2) which time frame for retaining reserve samples already common industry practice. This
would require that the manner in which be linked to a shelf life date (or other comment also points out that neither the
you hold reserve samples of dietary form of expiration dating) when such a food CGMPs in part 110 nor the
supplements include using the same date is established. We discuss the agency’s 1997 ANPRM have
container-closure system in which the reasons for the change from 3 years to requirements for records of product
dietary supplement is marketed or in 2 years and the change from ‘‘date of distribution.
one that provides the same level of manufacture’’ to ‘‘the date of (Response) To the extent that the
protection against contamination or distribution’’ in section XXI of this comment asserts that a practice that is
deterioration. document. In essence, final § 111.465(b)
(Comment 309) One comment states a a common industry practice should not
duplicates final § 111.83(b)(3) because
substantial amount of its product is be a requirement in the final rule, we
we believe it will be useful to include
shipped in bulk for packaging the length of time you must hold reserve disagree. CGMP includes those practices
elsewhere. As a result, one often does samples in each place in the codified that may be commonly used in industry.
not know the packaging being used to where it is logical to look for this In fact, the reason that such practices
market the dietary supplement or how information. may be common in industry is because
the packaged product is being stored. they are already considered to be CGMP.
This comment recommends we revise I. What Requirements Apply to As we noted in the preamble to the 2003
the proposed regulation to require using Distributing Dietary Supplements? CGMP Proposal (68 FR 12157 at 12221),
the same container-closure system in (Final § 111.470) however, not all dietary supplement
which the dietary supplement is Final § 111.470 requires you to establishments follow CGMP and,
marketed ‘‘if known and if not in a distribute dietary supplements under therefore, may not be keeping records of
typical market container-closure conditions that will protect the dietary product distribution. Thus, in this final
system.’’ supplements against contamination and rule we do not exclude practices we
(Response) We acknowledge that deterioration. Final § 111.470 derives consider to be CGMP and already may
some manufacturers of dietary from proposed § 111.90. be used by some in industry.
supplements will distribute product in We did not receive comments specific
bulk and will not know the packaging to proposed § 111.90. The industry outline we published in
used to market the dietary supplement. the 1997 ANPR suggested (under
In addition, if you ship products in J. Under This Subpart, What Records Warehousing, Distribution, and Post-
bulk, any commitment you make to your Must You Make and Keep? (Final Distribution Procedures) that the CGMP
customer about the quality of the § 111.475) rule require adequate distribution
product you shipped would relate to the In the 2003 CGMP Proposal, we records to be maintained and retained
container you used to ship the bulk invited comment on whether we should for at least 1 year beyond the expected
product. To address these points we require you to make and keep records product shelf life, whereby an effective
provide in final § 111.465(a)(2) that you on the distribution of dietary product recall can be achieved should
have the flexibility to use a container- supplements that you manufacture, one become necessary. Therefore, we
closure system that provides essentially package, or hold. disagree that the 1997 ANPRM did not
the same characteristics to protect (Comment 310) Some comments suggest a requirement to make and
against contamination or deterioration assert that written records of product retain records of product distribution.
as the one in which it is distributed for distribution would provide the ability to
packaging and labeling elsewhere. For trace the shipment of each finished XIX. Comments on Returned Dietary
example, if you distribute product in batch in the event of a product recall. Supplements (Final Subpart N)
bulk using a polyethylene bottle that One comment expresses the view that
the ability to quickly and efficiently A. Organization of Final Subpart N
can hold 50 kilograms of the product,
and there is an air space above the recall a product is an important In the 2003 CGMP Proposal, the
product, you would hold the reserve safeguard in ensuring public health in requirements for returned dietary
samples in a polyethylene bottle with an the event of a serious problem. Another supplements were set forth in proposed
air space. However, you would use a comment points out that the scope of
§ 111.85. As shown in table 15 of this
bottle that is sized to fit the amount that recall would likely be much broader if
document, we are reorganizing
you are holding in reserve. records of product distribution were not
available to pinpoint distribution. proposed § 111.85 into a distinct
2. Final § 111.465(b) (Response) We agree with these subpart (final Subpart N—Returned
Dietary Supplements). Table 15 lists the
Final § 111.465(b) requires you to comments. Therefore, final § 111.475

retain reserve samples for 1 year past requires you to make and keep records sections in final subpart N and
the shelf life date (if shelf life dating is of product distribution in accordance identifies the proposed sections that
used), or for 2 years from the date of with subpart P. In addition, we are form the basis of the final rule.
distribution of the last batch of dietary adding a provision to complement final
TABLE 15.—DERIVATION OF SECTIONS • Includes a new requirement to including requirements for any
IN FINAL SUBPART N establish and follow written procedures reprocessing of the returned dietary
to fulfill the requirements for returned supplements.
2003 CGMP dietary supplements;
Final Rule Proposal • Includes a revised description of D. What Are the Requirements Under
the conditions that preclude you from This Subpart for Written Procedures?
§ 111.503 What are the N/A salvaging a returned dietary (Final § 111.503)
requirements under supplement; and We received many comments that
this subpart N for writ- • Provides flexibility for firms to recommended written procedures for
ten procedures?
salvage a returned dietary supplement various provisions. We address the need
§ 111.510 What require- § 111.85(a) without conducting tests to demonstrate for written procedures generally in
ments apply when a that the dietary supplement meets all section IV of this document. We also
returned dietary sup- specifications, provided that quality respond to individual comments on
plement is received? control personnel conduct a material specific provisions in the same section.
review and make a disposition decision Final § 111.503 requires you to
§ 111.515 When must a § 111.85(b) and to approve the salvage. establish and follow written procedures
returned dietary sup- (c) to fulfill the requirements of subpart N.
plement be destroyed, C. General Comments on Proposed
or otherwise suitably § 111.85 Under final § 111.535(b)(1) we are
disposed of? requiring you to make and keep records
(Comment 312) Several comments of such written procedures. Such
§ 111.520 When may a § 111.37(b)(15) request we clarify the roles of the records would be available to us under
returned dietary sup- various parties in the ‘‘pre-consumer the requirements in subpart P.
plement be salvaged? supply chain’’ for dietary supplements.
(Response) We have discussed, in E. What Requirements Apply When a
§ 111.525 What require- § 111.50(g) section VI of this document, who is Returned Dietary Supplement is
ments apply to a re- subject to the final rule in what the Received? (Final § 111.510)
turned dietary supple- comment describes as the ‘‘pre- Final § 111.510 requires you to
ment that quality con- consumer supply chain’’ and do not
trol personnel approve identify and quarantine returned dietary
repeat that discussion here. The supplements until quality control
for reprocessing?
requirements for returned dietary personnel conduct a material review
§ 111.530 When must an § 111.85(d) supplements do not distinguish between and make a disposition decision. Final
investigation be con- those returned to a person who § 111.510 is similar to proposed
ducted of your manu- manufactures a finished batch and those § 111.85(a).
facturing processes returned to a person whose role in the We did not receive comments specific
and other batches? manufacturing process is limited to to proposed § 111.85(a).
operations such as packaging, labeling,
§ 111.535 Under this § 111.50(g) or holding. F. When Must a Returned Dietary
subpart N, what § 111.85(e) and Any reprocessing operations, other Supplement Be Destroyed, or Otherwise
records must you (f) Suitably Disposed Of? (Final § 111.515)
make and keep?
than repackaging or relabeling, by a
packager or labeler who receives a Final § 111.515(a) requires that you
product for packaging or labeling as a destroy, or otherwise suitably dispose
dietary supplement would make that of, any returned dietary supplement,
Proposed Requirements for Returned
packager or labeler subject to all unless the outcome of a material review
Dietary Supplements
relevant regulatory requirements under and disposition decision is that quality
1. Revisions this final rule, as explained in section VI control personnel either: (1) Approve
The final rule includes: of this document. A packager or labeler the salvage of the returned dietary
• Revisions that reflect that the final that only conducts repackaging or supplement for redistribution or (2)
rule applies to persons who relabeling operations may conclude that approve the returned dietary
manufacture, package, label, or hold a product was returned for reasons supplement for reprocessing. Final
dietary supplements unless subject to an related to a problem with the § 111.515(a) derives from the following
exclusion in § 111.1. manufacture of the product it received proposed sections:
• A provision (final § 111.520) that for packaging or labeling, and therefore • Proposed § 111.85(b) which would
we are adding for consistency, so that cannot be salvaged. In such a case, require that you not salvage returned
the final rule for returned dietary under final § 111.515 the packager or dietary supplements unless: (1)
supplements clearly sets forth the labeler would have to destroy or Evidence from their packaging (or, if
requirements for a positive outcome otherwise suitably dispose of the dietary possible, an inspection of the premises
(i.e., when you may salvage a returned supplement. Under final § 111.515, the where the dietary ingredients and
dietary supplement) as well as a packager or labeler may contact the dietary supplements were held)
negative outcome (i.e., when you must manufacturer to determine if the indicates that the dietary ingredients
destroy or otherwise suitably dispose of packager or labeler could suitably and dietary supplements were not
a returned dietary supplement); and dispose of the dietary supplement by subjected to improper storage
• A provision (final § 111.525) we are sending it back to the manufacturer for conditions and (2) tests demonstrate
adding for consistency, so that the final possible reprocessing (see discussion of that the dietary ingredients or dietary
rule for returned dietary supplements final § 111.515 in this section). A supplements meet all specifications for
clearly sets forth the requirements for manufacturer who receives a dietary identity, purity, quality, strength, and
reprocessed materials. supplement returned by a packager or composition; and
labeler would be required to comply • Proposed § 111.85(c) which would
2. Changes After Considering Comments with the requirements of final subpart N require that you destroy or suitably
The final rule: for returned dietary supplements, dispose of the returned dietary
ingredients or dietary supplements if appropriate standards of safety, identity, G. When May a Returned Dietary
such dietary ingredients and dietary strength, quality, or purity.’’ Supplement Be Salvaged? (Final
supplements do not meet specifications, These comments assert that § 111.520)
unless the quality control unit conducts inspection of the condition of the
a material review and makes a returned product could be used to Final § 111.520 permits the salvage of
disposition decision to allow determine that a product can be a returned dietary supplement only if
reprocessing. returned to inventory, and this quality control personnel conduct a
Final § 111.515(a) includes editorial inspection could be covered by internal material review and make a disposition
changes and other changes made after procedures and based on experience in decision to allow the salvage. Final
considering comments. testing product stored under conditions § 111.520 is a conforming provision we
(Comment 313) Several comments that include extremes in heat and are adding for consistency, so that the
assert it is unnecessary to conduct humidity without affecting the final requirement for returned dietary
testing for all specifications for every container or closure system. supplements clearly sets forth a positive
returned product because products may (Response) As already discussed in outcome (i.e., when you may salvage a
be returned for reasons unrelated to this section, the final rule includes a returned dietary supplement) as well as
product quality. For example, products new requirement that you establish and a negative outcome (i.e., when you must
may be returned due to overstocking, follow written procedures for handling destroy or otherwise suitably dispose of
ordering the wrong quantity, going out returned dietary supplements. The final a returned dietary supplement). Final
of business, or failing to pay for the rule also retains the requirement that § 111.520 is consistent with final
product on time. In addition, several quality control personnel (formerly § 111.130 (proposed § 111.37(b)(15))
comments assert that many returned ‘‘unit’’ in the proposed rule) conduct a which requires quality control
products are intact, show no signs of material review and make a disposition personnel to approve the distribution of
mishandling, and are within the time decision regarding all returned dietary returned dietary supplements.
limits for shelf life. These comments supplements (see discussion of final H. What Requirements Apply to a
assert that a material review and § 111.113(a)(5) in section XI of this Returned Dietary Supplement That
disposition decision by the quality document). We agree with the Quality Control Personnel Approve for
control unit to restock the material comments that it is not necessary to Reprocessing? (Final § 111.525)
without retesting may be acceptable in conduct testing for all specifications for
these types of situations. Some every returned product, because Final § 111.525(a) requires you to
comments assert that proposed products may be returned for reasons ensure that any returned dietary
§ 111.85(b) is more restrictive than unrelated to the quality of the dietary supplements that are reprocessed meet
CGMP requirements for drug products, supplement. Final § 111.130 provides all product specifications established in
and suggest that testing need be for quality control personnel to accordance with final § 111.70(e). Final
conducted only when some doubt has determine whether tests or § 111.525(b) requires quality control
been cast upon the identity, purity, examinations are necessary for returned personnel to approve or reject the
quality, strength, or composition of the dietary supplements to determine release for distribution of any returned
product, or if the product was returned compliance with product specifications. dietary supplement that is reprocessed.
for some other GMP-related problem. Therefore, final § 111.515 does not As with final § 111.520, final § 111.525
Some comments contend that include a testing requirement. We is a provision we are adding for
proposed §§ 111.35(i)(3)(v) and 111.85 believe the combination of written consistency. Final § 111.525 is
would make it difficult to salvage any procedures and oversight by quality consistent with final § 111.90(c).
returned product because companies control personnel is adequate to
receiving returns often cannot verify the determine the appropriate disposition of I. When Must an Investigation Be
conditions under which such products a returned dietary supplement, without Conducted of Your Manufacturing
were held. One comment refers to a requiring a test in every case to Processes and Other Batches? (Final
stakeholder meeting when we indicated demonstrate that the dietary supplement § 111.530)
that the extent of testing requirements meets specifications for identity, purity,
strength, and composition. Final § 111.530 requires that, if the
would depend upon the reason such
products were returned. The comments reason for a dietary supplement being
In final § 111.515(a) we generally
state that the rule should allow returned implicates other batches, you
accept the comments’ suggestions and
flexibility as to when returned products must conduct an investigation of your
reflect the approach of the USP for
must be tested. manufacturing processes and each of
returned products. Thus, you must
those other batches to determine
Some comments specifically suggest destroy or otherwise suitably dispose of
the approach used in the USP (revised the returned dietary supplement, unless compliance with specifications. Final
in 2nd supplement USP 26). These the outcome of the material review and § 111.530 derives from proposed
comments suggest that proposed disposition decision is that quality § 111.85(d) which would require that if
§ 111.85(b) be revised as follows: ‘‘If the control personnel approve the salvage of the reason for a dietary supplement
conditions under which returned the returned dietary supplement for being returned implicates associated
products have been held, stored, or redistribution or approve the batches, you must conduct an
shipped before or during their return, or reprocessing of the returned dietary investigation of your manufacturing
if the condition of the product, its supplement. We provide flexibility on processes and those other batches to
container, carton or labeling, as a result how quality control personnel may determine compliance with
of storage or shipping, cast doubt on the conduct a material review and make a specifications. Final § 111.530 includes
a nonsubstantive editorial change of
safety, identity, strength, quality, or disposition decision and do not require

purity of the product, the returned testing in every case. We respond in ‘‘associated’’ to ‘‘each of those other
product should be destroyed unless section V of this document to the batches’’ for clarity.
examination, testing or other comment asserting that the proposed We did not receive comments specific
investigations prove the product meets CGMPs exceed the drug CGMPs. to proposed § 111.85(d).
J. Under This Subpart, What Records determine whether specifications are dietary supplements unless subject to an
Must You Make and Keep? (Final met. exclusion in § 111.1.
§ 111.535) • Uses the term ‘‘product complaint’’
5. Final § 111.535(b)(4) rather than ‘‘consumer complaint,’’ and
Final § 111.535 sets forth the
Final § 111.535(b)(4) requires you to the definition of ‘‘product complaint’’
requirements to make and keep records
make and keep a record of does not include an explanation about
for returned dietary supplements. Final
documentation of the re-evaluation by the types of complaints that may or may
§ 111.180 derives from proposed
quality control personnel of any dietary not be covered by the CGMP
§ 111.85(e) and (f).
supplement that is reprocessed and the regulations. The definition does,
We did not receive comments specific
determination by quality control however, include examples of product
to proposed § 111.85(e) or (f).
personnel of whether the reprocessed complaints.
1. Final § 111.535(a) dietary supplement meets product 2. Changes After Considering Comments
Final § 111.535(a) requires you to specifications established in accordance
with § 111.70(e). Final § 111.535(b)(4) is The final rule modifies the process for
make and keep records required under handling product complaints as follows:
subpart N in accordance with subpart P. related to final § 111.525. Under final
• A qualified person investigates any
Final § 111.535(a) derives from § 111.525, you must ensure that any
product complaint that involves a
proposed §111.85(f) and includes returned dietary supplements that are
possible failure of a dietary supplement
changes associated with the reprocessed meet all product
to meet any requirements of part 111,
reorganization. specifications you established under
without an intermediate step of having
§ 111.70(e) and quality control
2. Final § 111.535(b)(1) quality control personnel first determine
personnel must approve or reject the
whether the complaint should be
As discussed in this section, the final release for distribution of any returned
investigated;
rule includes a new requirement (final dietary supplement that is reprocessed. • Quality control personnel review
§ 111.503) that you establish and follow XX. Comments on Product Complaints and approve all decisions made by a
written procedures to fulfill the (Final Subpart O) qualified person about whether to
requirements of subpart N. Those investigate a product complaint and the
written procedures are records. A. Organization of Final Subpart O findings and followup action of any
Therefore, final § 111.535(b)(1) requires In the 2003 CGMP Proposal, the investigation performed rather than
you to make and keep a record of the requirements for consumer complaints conduct the investigation and followup;
written procedures for fulfilling the were set forth in § 111.95. As shown in and
requirements of subpart N. table 16 of this document, we are • The review and investigation of the
3. Final § 111.535(b)(2) reorganizing proposed § 111.95 into product complaint extends to all
three provisions in a new subpart (final relevant batches and records, without
Final § 111.535(b)(2) requires you to identifying specific records, and specific
Subpart O—Product Complaints). Table
make and keep a record of any material batches, that must be included in the
16 lists the sections in final subpart O
review and disposition decision on a review and investigation.
and identifies the provisions that form
returned dietary supplement. Final
the basis for the final rule. C. General Comments on Proposed
§ 111.535(b) derives from proposed
§ 111.85(e), with revisions associated § 111.95 (Final Subpart O)
with the reorganization.
TABLE 16.—DERIVATION OF SECTIONS
(Comment 314) Some comments
IN FINAL SUBPART O
express general support for the
4. Final § 111.535(b)(3)
proposed procedures for consumer
2003 CGMP
Final § 111.535(b)(3) requires you to Final Rule Proposal complaints. Other comments request
make and keep a record of the results of proposed § 111.95 be deleted. Most of
any testing or examination conducted to § 111.553 What are the N/A these comments point out that we had
determine compliance with product requirements under announced the development of
specifications established under this subpart O for writ- CFSAN’s Adverse Event Reporting
§ 111.70(e). Final § 111.535(b) derives ten procedures? System (CAERS) for reporting to FDA
from proposed § 111.85(e) which would adverse events attributed to food
§ 111.560 What require- § 111.95(a), (b),
require you to establish and keep products and suggest that this new
ments apply to the re- (c), and (d)
records on any testing conducted to view and investigation system would be the appropriate
determine compliance with established of a product com- mechanism for handling complaints
specifications in the master plaint? about dietary supplements.
manufacturing record for the type of (Response) We disagree with these
dietary supplement that was returned. § 111.570 Under this § 111.95(e) and comments. Because the problem giving
Final § 111.535(b)(3) includes the subpart O, what (f) rise to the complaint may be associated
following revisions: records must you with a failure in manufacturing,
make and keep?
• Consistent with final § 111.70(e), packaging, labeling, or holding, it is
final § 111.535(b)(3) substitutes CGMP for a firm that receives a product
‘‘product specifications established B. Highlights of Changes to the complaint to review it and investigate,
under § 111.70(e)’’ for ‘‘established Proposed Requirements for Product if necessary, regardless of whether we
specifications in the master Complaints are notified about the complaint. An
manufacturing record for the type of 1. Revisions important goal of the firm’s review and
dietary ingredient or dietary supplement investigation is to determine whether

that was returned.’’ The final rule: there is a problem with the production
• Consistent with final § 111.75(c), • Includes changes that reflect the and process control system for the
final § 111.535(b)(3) provides flexibility final rule applies to persons who manufacture, packaging, labeling, or
to use either tests or examinations to manufacture, package, label, or hold holding of the dietary supplement. That
goal would not be achieved merely by to the proposed requirements regarding these comments. We responded in
notifying us. A firm subject to any of the consumer complaints. Some comments section V of this document to similar
requirements of this final rule, whether state the section should apply only to comments asserting that certain aspects
such firm is a manufacturer, packager, manufacturers of dietary supplements, of the proposed regulations are different
labeler, or holder, is responsible for the not to manufacturers of dietary from those for other food CGMP
requirements in subpart O for a product ingredients. Other comments are requirements.
complaint it receives. concerned that distributors who merely
(Comment 315) Some comments put their label on the finished product D. What Are the Requirements Under
assert that the proposed requirements may be held responsible for keeping This Subpart for Written Procedures?
for consumer complaints do not go far records of adverse events caused by (Final § 111.553)
enough and urge that any final rule failures to follow CGMPs during the We received many comments which
require any complaints that involve an manufacture of the supplements. recommended written procedures for
adverse event be referred to us. The (Response) The final rule only applies various provisions. We address the need
comments stress accurate reporting of to persons who manufacture, package, for written procedures generally in
adverse events is essential to long term label, or hold a dietary supplement. We section IV of this document. We also
evaluations of a product’s safety. discuss the scope of this final rule in respond to individual comments on
(Response) Mandatory reporting detail in section VI of this document. specific provisions in the same section.
requirements to us regarding adverse In most cases, the person who
events related to dietary supplements receives a product complaint from a Final § 111.553 requires that you
are outside the scope of this rulemaking. consumer will be the manufacturer, establish and follow written procedures
This final rule addresses the internal packager, or distributor of the dietary to fulfill the requirements of this
processes and controls that persons who supplement. A distributor (also a subpart O. Under final § 111.570(b)(1)
manufacture, package, label, or hold ‘‘holder’’ under this final rule) who we require you to make and keep
dietary supplements must follow. receives a product complaint must records of such procedures. Such
Mandatory reporting to FDA of serious review and investigate that complaint to records would be required to be made
adverse events, however, is now determine whether the complaint relates available to us under the requirements
required as a result of the enactment of to a failure of the processes under the in subpart P.
the ‘‘Dietary Supplement and Non- control of the distributor, such as We encourage you to include in your
Prescription Drug Consumer Protection conditions of temperature, humidity, written procedures the recommendation
Act’’ (Public Law 109–462) signed into and light that could affect the identity, made in the 2003 CGMP Proposal for
law on December 22, 2006. The new law purity, strength, or composition of the you to consult with a health care
requires manufacturers, packers, or dietary supplement. If the distributor provider if you receive complaints that
distributors of such products to submit concludes the problem is unrelated to involve serious illness or injury. Even if
reports to FDA about serious adverse any process under the control of the the complaints are not required to be
events involving such products based distributor, the distributor should submitted to FDA under the newly
on specific information that they receive contact the manufacturer. Under the enacted ‘‘Dietary Supplement and Non-
from the public. Serious adverse events final rule, any person in the Prescription Drug Consumer Protection
are defined in the law as those events manufacturing chain who receives a Act’’ (Public Law 109–462), we
that result in death, a life-threatening product complaint—regardless of the encourage your company to notify us
situation, an inpatient hospitalization, a source—must comply with the about the product complaints.
persistent or significant disability or requirements in this subpart O. Manufacturers and distributors should
incapacity, or a congenital anomaly or (Comment 317) One comment be aware that this newly enacted law,
birth defect or one that requires medical suggests proposed § 111.95, which which requires reporting to FDA of
or surgical intervention to prevent such describes requirements for consumer ‘‘serious adverse events,’’ contains new
serious outcomes (based on reasonable complaints, could be combined with mandatory provisions that require
medical judgment). proposed § 111.85 which describes record retention of adverse event reports
As discussed in the preamble to the requirements for returned dietary separate from the requirements in this
2003 CGMP Proposal (68 FR 12157 at supplements. CGMP final rule concerning product
12217), however, we continue to (Response) We decline to adopt this complaints.
strongly recommend that firms that suggestion. In this final rule, we are
receive product complaints, that are not incorporating the requirements for E. What Requirements Apply to the
‘‘serious adverse events,’’ notify us returned dietary supplements into a Review and Investigation of a Product
about any illness or injury, because, for distinct subpart (final subpart N) that Complaint? (Final § 111.560)
example, we may have additional sets forth requirements for returned 1. Final § 111.560(a)(1)
expertise or data that may be helpful in dietary supplements. The procedures
investigating the complaint or described in final subpart O, which Final § 111.560(a)(1) requires a
determining whether the problem relate solely to the handling of product qualified person to review all product
applies to more than one product. In complaints rather than returned dietary complaints to determine whether the
light of the requirement in the final rule supplement products, are quite different product complaint involves a possible
to establish and follow written from those described in final subpart N, failure of a dietary supplement to meet
procedures for handling product which addresses the handling, review, any of its specifications, or any other
complaints, we encourage you to and possible reprocessing of returned requirements of part 111, including
include our recommendations in the product. those specifications and other
written procedures that you develop for (Comment 318) Some comments requirements that, if not met, may result
handling product complaints (see assert the proposed requirements for in a risk of illness or injury. Final
discussion of final § 111.553 in this complaints are different from those for § 111.560(a)(1) derives from proposed
section). food CGMPs. § 111.95(a).
(Comment 316) Some comments raise (Response) We are making no changes We did not receive comments specific
questions about who would be subject to the requirements after considering to proposed § 111.95(a).
2. Final § 111.560(a)(2), (b), and (c) unit focus on reviewing tasks performed product. However, we encourage firms
Final § 111.560(a)(2) requires a by others rather than on performing the to investigate all product complaints in
qualified person to investigate any tasks itself. a consistent way, regardless of whether
• We refer to ‘‘any product complaint the complaints relate to the quality of
product complaint that involves a
that involves a possible failure of a the dietary supplement.
possible failure of a dietary supplement
dietary supplement to meet any of its (Comment 321) Some comments
to meet any of its specifications, or any
specifications, or any other request clarification of statements made
other requirements of part 111,
requirements of this part [part 111], or terms used in the preamble to the
including those specifications and other
including those specifications and other 2003 CGMP Proposal regarding the
requirements that, if not met, may result
requirements that, if not met, may result handling of product complaints. In the
in a risk of illness or injury. Final
in a risk of illness or injury’’ rather than preamble discussion of proposed
§ 111.560(b) requires that quality control
to ‘‘a reasonable possibility of a § 111.95(c), we stated a consumer
personnel review and approve decisions relationship between the quality of a
by the qualified person about whether complaint about adverse effects ‘‘after
dietary supplement and an adverse consuming several dietary
or not to investigate a product event.’’ This is consistent with changes
complaint and the findings and supplements’’ is worthy of quality
that we are making to the definition of control unit investigation. One comment
followup action of any investigation the term ‘‘product complaint’’ in final
performed. Final § 111.560(c) requires asks about the meaning of ‘‘several’’ and
§ 111.3 (see section VI of this whether this example means that a
that the review and investigation extend document).
to all relevant batches and records. manufacturer is responsible for
• We continue to require that the consumers who take more than the
(Comment 319) Some comments review and investigation of the product
characterize the requirements of recommended dosage.
complaint extend to all relevant batches (Response) In our discussion of
proposed § 111.95 as a confusing and and records but simplify the language of
difficult scheme to review, investigate, proposed § 111.95(c) we addressed a
the requirement by removing the details, situation where a consumer had
and resolve customer complaints. These i.e., that the investigation must include
comments state the 2003 CGMP symptoms on more than one occasion
the batch records associated with the rather than a situation where a
Proposal would require extensive dietary supplement involved in the
human resources, recordkeeping, and consumer took more than the
consumer complaint and not specifying recommended dosage. However, firms
decisionmaking. that the investigation must extend to
(Response) We disagree that the 2003 must investigate any complaint of
other batches of dietary supplement. illness or injury even if a consumer
CGMP Proposal would require extensive Rather, we require that the investigation
human resources, recordkeeping, or reports that he/she has consumed more
must extend to all relevant batches and than the amount recommended on the
decisionmaking. The comments records.
provided no rationale for such product label to determine if the
The final rule provides firms
assertions. The 2003 CGMP Proposal complaint is related to CGMP.
flexibility on how to use its human
sets forth basic steps, i.e., review, resources. Nothing in subpart O would F. Under This Subpart, What Records
evaluation, and followup, that one preclude a qualified person among Must You Make and Keep? (Final
would need to take to appropriately designated quality control personnel to § 111.570)
address a product complaint. For those be designated to actually review product
product complaints for which there is a complaints and conduct investigations 1. Final § 111.570(a)
reasonable possibility of a relationship of any product complaint. If an Final § 111.570(a) requires you to
to an adverse event, the 2003 CGMP individual is so designated and make and keep the records required
Proposal would require that an conducts the investigation, reviews and under subpart O in accordance with
investigation be done by the quality approves the findings, and conducts subpart P. Final § 111.570(a) derives
control unit because we believe such an followup actions of any investigation from proposed § 111.95(f)(2) with
event would need more careful review performed, final § 111.560(b) would not changes associated with the
and followup. apply. reorganization.
To address the comments that found (Comment 320) Some comments We did not receive comments specific
proposed § 111.90 confusing, we have object to the requirement in proposed to proposed § 111.95(f)(2).
made the following changes in the final § 111.95(c) that consumer complaints
rule to simplify the procedures for are to be investigated only when there 2. Final § 111.570(b)(1)
handling product complaints: may be a relationship between product Final § 111.570(b)(1) requires you to
• We replaced the proposed quality and an adverse event. These make and keep a record of the written
procedure in which a qualified person comments suggest this provision be procedures for fulfilling the
determines whether a complaint should extended to any possible relationship requirements of subpart O. Final
be investigated by the quality control between dietary supplements and § 111.553 requires written procedures
unit with a procedure in which a adverse events, including those that for fulfilling the requirements of subpart
qualified person investigates any might be independent of whether the O. Those written procedures are
product complaint that involves a product is produced under CGMPs. considered a record under final
possible failure of a dietary supplement These comments consider there should § 111.570(b)(1).
to meet any requirements of part 111. be consistent procedures for handling
• We require an oversight function by 3. Final § 111.570(b)(2)
product complaints, regardless of
quality control personnel for the review whether the complaints relate to Final § 111.570(b)(2) requires you to
and evaluation of product complaints, product quality. make and keep a written record of every
but do not require that quality control (Response) The action requested in product complaint that is related to
personnel do any investigations. This is these comments is outside the scope of CGMP. Final § 111.570(b)(2) derives
consistent with other changes that we this rule, which specifically addresses from proposed § 111.95(e) which would
are making in response to comments CGMP requirements to ensure the require that you ‘‘* * * make and keep
that requested that the quality control quality of the dietary supplement a written record of every consumer
complaint that is related to good receives the product complaint may not XXI. Comments on Records and
manufacturing practices. For the know how the product was used. For Recordkeeping (Final Subpart P)
purposes of the regulations in this part, example, a consumer may make a A. Organization of Final Subpart P
a consumer complaint about product complaint by leaving a telephone
quality may or may not include message before or after business hours In the 2003 CGMP Proposal, the
concerns about a possible hazard to and neither describe how the product requirements for records and
health. However, a consumer complaint was used, nor leave contact information recordkeeping were set forth in
does not include an adverse event, so that the firm could followup with the proposed § 111.125. As shown in table
illness, or injury related to the safety of consumer. To address this comment, we 17 of this document, we are
a particular dietary ingredient provide in the final rule that the written reorganizing the requirements for
independent of whether the product is records and recordkeeping into a
record of the product complaint include
produced under good manufacturing distinct subpart (final Subpart P—
practices.’’ ‘‘the nature of the complaint including,
if known, how the product was used.’’ Records and Recordkeeping). Table 17
As a revision for consistency with the lists the sections in final subpart P and
definition of ‘‘product complaint’’ in (Comment 323) Some comments identifies the proposed provisions that
final § 111.3, final § 111.570(b)(2) does request clarification of statements made form the basis for the final rule.
not include the two full sentences from or terms used in the preamble to the
proposed § 111.95(e), as quoted in the 2003 CGMP Proposal regarding the TABLE 17.—DERIVATION OF SECTIONS
previous paragraph. handling of product complaints. In our IN FINAL SUBPART P
4. Final § 111.570(b)(2)(i) discussion of proposed § 111.95(e) we
recommended that consumer Final Rule 2003 CGMP
Final § 111.570(b)(2)(i) requires that Proposal
complaints and investigations be
the person who performs the
requirements of subpart O, at the time reported to us when consumption of a § 111.605 What require- § 111.125(a)
of performance, document and record dietary supplement may be related to ‘‘a ments apply to the and (b)
the performance. Final § 111.570(b)(2)(i) serious adverse event.’’ Some comments records you make and
is similar to proposed § 111.95(f)(1) with note that ‘‘serious’’ is not defined. keep?
changes associated with the (Response) The term ‘‘serious adverse § 111.610 What records § 111.125(b)
reorganization. event’’ is widely used in the industries must be made avail- and (c)
5. Final § 111.570(b)(2)(ii) we regulate. Our current forms for able to FDA?
reporting ‘‘serious adverse events’’ via
Final § 111.570(b)(2)(ii) requires that the MedWatch program do not define B. Highlights of Changes to the
the written record of the product the term, but instead list outcomes that Proposed Requirements for Records and
complaint include: (1) The name and were attributed to an adverse event. Recordkeeping
description of the dietary supplement;
These outcomes include death, life-
(2) the batch, lot, or control number of 1. Revisions
threatening, hospitalization (initial or
the dietary supplement, if available; (3)
the date the complaint was received and prolonged), disability, congenital The final rule reflects that it applies
the name, address, or telephone number anomaly, required intervention to to persons who manufacture, package,
of the complainant, if available; (4) the prevent permanent impairment/damage, label, or hold a dietary supplement
nature of the complaint including, if and ‘‘other.’’ As discussed in this unless subject to an exclusion in
known, how the product was used; (5) section, however, there is a new § 111.1.
the reply to the complainant, if any; and statutory requirement for mandatory 2. Changes After Considering Comments
(6) findings of the investigation and reporting to FDA of serious adverse
followup action taken when an events enacted in the ‘‘Dietary This final rule requires you to keep
investigation is performed. Final Supplement and Non-Prescription Drug written records required by this subpart
§ 111.570(b)(2) is similar to proposed Consumer Protection Act’’ (Public Law for either 1 year past the shelf life date,
§ 111.95(e)(1) through (e)(6) and 109–462). The new law does define if shelf life dating is used, or 2 years
includes a change we are making after ‘‘serious adverse events’’ as those events beyond the date of distribution of the
considering comments to proposed that result in death, a life-threatening last batch of dietary supplements
§ 111.95(e)(4) (discussed in the associated with those records (final
situation, an inpatient hospitalization, a
following paragraphs) which would § 111.605(a)).
persistent or significant disability or
have required that the consumer incapacity, or a congenital anomaly or C. General Comments on Proposed
complaint written record include ‘‘The birth defect or one that requires medical § 111.125
nature of the complaint including how or surgical intervention to prevent such
the consumer used the product.’’ On our (Comment 324) Some comments
serious outcomes (based on reasonable support the requirements in proposed
own initiative, we also made a change medical judgment). The law also has
to include the date the complaint was § 111.125 because documentation helps
specific provisions for how these to ensure CGMPs are consistently
received. serious adverse events are to be
(Comment 322) One comment notes followed and retention of records
submitted to FDA and record retention provides an effective trail when
proposed § 111.95(e)(4) would require
the written record of consumer for records relating to these and other subsequent problems need to be
complaints to include ‘‘how the adverse event reports. We anticipate identified and corrected.
consumer used the product.’’ The issuing guidance on implementation of Another comment asserts the
comment notes this information may the new statutory provisions. We recordkeeping requirements would
not always be available and suggests the encourage firms who are unsure as to represent a large burden for companies
words ‘‘where known’’ should be added. whether the nature of a reported adverse that manufacture vitamin and mineral
(Response) We agree that there can be event should be reported to FDA to supplements with a large number of
circumstances where the firm that contact us for assistance. active ingredients.
(Response) We agree that records are therefore, asserts CGMP records should tablets having a 2-year shelf life. The
useful in identifying manufacturing not be kept for more than 2 years. comment explains if the tablets are
problems and tracking the source of (Response) We believe a record compressed, tested, and approved for
failures in CGMPs. retention period for records related to packaging in August 2003, they would
We understand the burden on CGMP requirements should correlate generally be assigned an expiration date
manufacturers may be heavier for generally with the length of time that of August 2005 regardless of the date of
manufacturers who use many dietary product complaints are likely to arise packaging. The comment argues if the
ingredients and discuss the burden of related to the manufacture of a dietary tablets are held and later packaged in
the recordkeeping requirements in supplement. Such correlation will February 2004, records for this batch
sections XXVIII and XXIV of this increase the likelihood that, if a problem should only have to be kept for 1 year
document. However, we do not believe with a dietary supplement is identified beyond the expiration date (i.e., August
that may be associated with a violation 2006), rather than 3 years beyond the
that a manufacturer who elects to put
of CGMP, the dietary supplement packaging date (i.e., February 2007).
several components into one finished
manufacturer, packager, labeler, or (Response) In the scenario described
batch of dietary supplement would
holder will have access to the CGMP in the previous paragraph, where an
necessarily have a larger burden than
records associated with that dietary expiration date (shelf life) has been
one who, instead, elects to manufacture
supplement. In addition, we will have determined, records for this batch must
multiple dietary supplements each
access to such records at inspection. only be kept for 1 year beyond the
containing one component. We believe We have modified the final rule to expiration date (i.e., shelf life date). The
that the requirements, for example, for require a record retention period of 2 packaging date in the scenario has no
ensuring the identity, purity, strength, years beyond the date of distribution of effect on the amount of time records
and composition of each component in the last batch of dietary supplements must be kept. However, in the final rule,
a dietary supplement need to be the associated with those records or 1 year we have decided that it is more
same for a dietary supplement past the shelf life date, if shelf life appropriate to determine the record
containing one ingredient or component dating is used. retention period from the date of
and one containing multiple ingredients A significant portion of the dietary distribution rather than the ‘‘date of
or components. To the extent the supplement industry use shelf life manufacture.’’ The date on which the
comment is suggesting that the dating. It is likely that if there are manufacturer completes the
recordkeeping requirements for those product complaints related to a product manufacture of a batch of a dietary
who manufacture multivitamin/mineral these will arise during the shelf life of supplement (the date of manufacture)
dietary supplements (containing these products. To ensure there is does not necessarily indicate the
components) are too large and should be adequate time to examine the records, availability of the dietary supplement
less, the comment provided no basis for determine if there are related product in the marketplace. It is
such a change. manufacturing problems, and possible that such product could be
D. What Requirements Apply to the implement corrective actions, it is held for a period of time before entry
Records That You Make and Keep? necessary to require the retention of into the marketplace and possible
(Final § 111.605) records for 1 year past the shelf life date. consumer consumption. A more
This will help ensure that accurate time period for entry is
1. Final § 111.605(a) establishments have access to such calculated by the date of distribution.
Final § 111.605(a) requires you to records to perform the necessary CGMP Final § 111.605(a)(2) requires that
keep written records for 1 year past the actions. manufacturers, packagers, labelers, and
For those dietary supplements holders keep their records for 2 years
shelf life date, if shelf life dating is used,
without shelf life or expiration dating, from the date of distribution of the last
or 2 years beyond the date of
we believe that 2 years from the date of batch of dietary supplement associated
distribution of the last batch of dietary
distribution is a reasonable estimate of with those records. For products with a
supplements associated with those
the time needed to retain records in shelf life date, the records associated
records. Final § 111.605(a) derives from
order to address CGMP problems with those dietary supplements are
proposed § 111.125(a).
identified in product complaints. required to be kept for 1 year past the
(Comment 325) Several comments It is important to note that, as shelf life date of that particular dietary
suggest that the requirement in discussed in this section, the term supplement. Packagers and labelers that
proposed § 111.125(a) to keep records ‘‘shelf life dating,’’ includes shelf life return the product to the manufacturer
for 3 years beyond the date of dating as well as expiration dating and for distribution are not required to keep
manufacture should be modified. One ‘‘best if used by’’ dating. separate records under this subpart.
comment favors record retention for 3 We disagree with the comment that
years beyond the date of manufacture or suggests we require an expiration date 2. Final § 111.605(b)
for the shelf life of the product, on all products. Many products will not Final § 111.605(b) requires you to
whichever is longer. Some comments have a determinable expiration date due keep records as original records, true
state the rule should require to the state of knowledge about these copies (such as photocopies, microfilm,
establishment of an expiration date and products. We believe the manufacturer etc.), or as electronic records. Final
that the manufacturer should have the is in the best position to determine if its § 111.605(b) derives from proposed
option of retaining records for 1 year product requires an expiration date. § 111.125(b).
beyond the expiration date, when an (Comment 326) One comment We did not receive comments specific
expiration date has been established by requests clarification of the ‘‘date of to proposed § 111.125(b).
the manufacturer. Some comments manufacture.’’ The comment asserts if
3. Final § 111.605(c)
point out that under section 306(a) of an expiration date is shown on the label
the Bioterrorism Act, FDA is authorized of a product, the date of manufacture Final § 111.605(c) requires that all
to issue recordkeeping regulations with should be considered to be the date on electronic records comply with part 11
a record retention period of ‘‘not longer which the expiration date is based. The (21 CFR part 11). Final § 111.605(c)
than two years.’’ One comment, comment gives an example of vitamin C derives from proposed § 111.125(b).
(Comment 327) One comment XXII. Other Comments and where comments recommended aspects
believes part 11 should only apply to Miscellaneous of other CGMP programs, we considered
records that do not have paper those recommendations and, in some
A. Comments on Guidance Documents
counterparts. cases, incorporated certain
To Be Used With the Final Rule
recommendations into requirements in
(Response) This comment is beyond In the 2003 CGMP Proposal, we this final rule (e.g., the use of a
the scope of this CGMP rulemaking. invited comment on the usefulness of certificate of analysis).
(Comment 328) One comment guidance documents, education, In 2006, ANSI updated its Standard
suggests the proposed requirement that training, or other approaches and 173 (ANSI Standard 173) regarding
CGMP electronic records must comply potential sources of education and dietary supplements (Ref. 35). ANSI
with part 11 should be deleted because training that would assist industry Standard 173 contains provisions for
the FDA guidelines on part 11 have not efforts to implement the 2003 CGMP dietary supplement CGMP that are
yet been finalized. Proposal, if finalized as proposed (68 FR based, in part, on the industry
12157 at 12163). submission to FDA in November 1995,
(Response) Part 11 applies to (Comment 329) A few comments state which the agency published as part of
electronic CGMP records. Therefore, booklets, videos, seminars, and other its 1997 ANPRM. We considered
final § 111.605(c) requires that all training would be useful on topics such comments to the 1997 ANPRM, many of
electronic records, including electronic as sanitation, recordkeeping, quality which commented on the provisions of
signatures, must comply with part 11. assurance methods, microbiological the industry submission, and the
We have finalized guidance for testing, and botany. Another comment comments to the 2003 CGMP Proposal
industry. The guidance entitled ‘‘Part states a subset of CGMPs that focuses on in the course of developing this CGMP
11, Electronic Records; Electronic plant authenticity, purity, proper final rule. We have considered the
Signatures Scope and Application,’’ sets handling, and hygiene should be provisions contained in the updated
out our enforcement policies with developed for parties who exclusively ANSI Standard 173 and many of the
respect to certain aspects of part 11 (Ref. deal with bulk raw agricultural specific provisions contained in ANSI
33). The guidance is available at http:// commodities (with the exception of Standard 173 are similar to provisions
www.fda.gov/cder/guidance/ individual wildcrafters). If such CGMPs adopted in this final rule. For example,
5667fnl.htm. The guidance applies to are not developed, the comment both the ANSI standard and this CGMP
any CGMP electronic records and requests we develop guidance final rule have similar requirements on
signatures. documents on the identification, written procedures, personnel
cultivation, and handling of botanicals. qualifications, record retention, and
E. What Records Must Be Made The same comment also notes guidance quality control. However, we
Available to FDA? (Final § 111.610) specifically is needed on the use of determined that adopting the entire
microscopy to identify plants. ANSI Standard 173 would be
1. Final § 111.610(a) (Response) We acknowledge these impracticable. There are key provisions
Final § 111.610(a) requires you to comments and, in the future, we may which reflect major differences between
keep records, or copies of such records, issue guidance that relates to certain the latest ANSI Standard 173 and the
required by this final rule, readily dietary supplement CGMP CGMP final rule. Many of these
available during the retention period for requirements. differences are in the product testing
inspection and copying by FDA when B. Comments on Consideration for environment. For example, the ANSI
requested. Final § 111.610(a) derives Other CGMP Programs standard contains different product
from proposed § 111.125(c). We testing frequency and production stage
(Comment 330) One comment asserts requirements. We have extensively
responded in section V of this document several existing dietary supplement discussed the justification for the
to comments that we received on FDA’s CGMP programs (e.g., those developed particular testing requirements adopted
statutory authority to inspect and copy by the NNFA, NSF International, ANSI, in this CGMP final rule, which we
records. We made one editorial, and USP) are well designed and believe are no more burdensome than
nonsubstantive change from the represent useful examples for us to the ANSI Standard 173 requirements.
language in proposed § 111.125(c). We follow. The comment notes section For example, the ANSI Standard 173
removed the word ‘‘authorized’’ to 12(d) of the National Technology contains testing methods for metal or
prevent any confusion regarding Transfer and Advancement Act directs microbiological contaminants not
whether some authorization other than Federal agencies to use such voluntary included in the final rule. We found that
the statutory authority that provides the consensus standards whenever possible, providing flexibility for manufacturers
legal basis for this final rule is necessary as long as the standards are consistent to choose their own specific test
for our access to inspect and copy with Federal law and are practical. The methods was a more efficient way of
records. comment recommends we include reaching the goals of the CGMP final
standards from these existing CGMP rule than specifying and requiring
2. Final § 111.610(b) programs where suitable in the final particular tests. We support, however,
Final § 111.610(b) requires that if you rule. the use of the ANSI Standard 173 testing
(Response) In the development of the methods by manufacturers, where
use reduction techniques, such as
2003 CGMP Proposal and this final rule, appropriate, in complying with the
microfilming, you must make suitable
we carefully considered the comments requirements of this rule.
reader and photocopying equipment
that recommended aspects of other (Comment 331) Another comment
readily available to us. Final CGMP programs. For example, as states CGMPs that reflect common
§ 111.610(b) derives from proposed
discussed previously, the 1997 ANPRM elements and areas of uniqueness

§ 111.125(b). for this rule contained the entire text of should be placed in subcategories of
We did not receive any comments an outline presented to us by CGMPs as is the case with the current
specific to proposed § 111.125(b) and representatives of the dietary food CGMP model. The comment
final § 111.610(b). supplement industry. Furthermore, recommends we follow a similar
approach and establish subcategories of opportunity for comment during the bioterrorism. The comment
CGMPs for dietary supplements (e.g., for comment periods provided. We discuss recommends these rules be harmonized
vitamin-mineral and probiotic tablets). the public involvement in section I of to reduce costs and increase efficiencies
(Response) In the 1997 ANPRM, we this document. Further, the 2003 CGMP for manufacturers.
asked for comment about whether broad Proposal did contain an economic (Response) It is not clear what the
CGMP regulations would be adequate, analysis. We received extensive comment means when it states the 2003
or whether it would be necessary to comments on the economic analysis in CGMP Proposal works at ‘‘cross
address the operations of particular the 2003 CGMP Proposal. We have purposes’’ with the regulations issued
segments of the dietary supplement made several changes to the economic under the Bioterrorism Act or that we
industry (68 FR 12157 at 12174). Based analysis of this final rule in response to should ‘‘harmonize’’ the regulations
on the comments received to the 1997 these comments as discussed in section issued under the Bioterrorism Act with
ANPRM, we were persuaded that a XXIV of this document. Furthermore, the final rule establishing dietary
broad final rule is preferable to multiple we have made various changes in supplement CGMP requirements. We
regulations focused on particular response to comments to the CGMP have made every effort to consider the
segments of the dietary supplement requirements in this final rule. regulations issued under the
industry, or to general CGMP provisions Bioterrorism Act and their relationship
D. Comments on Implementation and to this final rule. There are different
plus subcategories applicable to Enforcement
segments of the dietary supplement purposes to the Bioterrorism Act and
industry. We stated in the 2003 CGMP (Comment 333) Several comments these CGMP requirements; however, we
Proposal that we would consider suggest postponing the effective date of have harmonized to the extent possible.
whether we needed to re-evaluate our the rule for 24 months to allow a (Comment 336) One comment states
decision to establish one set of voluntary inspection and compliance the 1-year compliance period for large
requirements for all dietary program to take effect in the interim. firms is reasonable as long as we modify
supplements (id.). This comment did One comment recommends adoption of the rule to better reflect existing CGMPs
not provide any basis to persuade us to a voluntary program similar to that of already in practice among responsible
re-evaluate the decision we made that a OSHA regulations in Title 29 of the companies. The comment also notes the
broad CGMP rule was appropriate. Code of Federal Regulations, where 3-year compliance period for small
Thus, in this final rule, we are companies would invite FDA inspection firms may be reasonable, but urges us to
establishing one set of requirements for without penalty or cost unless a serious enforce compliance of basic food GMP
all persons who manufacture, package, violation occurs. In cases of serious requirements, which some of these firms
label, or hold dietary supplements and violation, companies would have the may not be observing.
option to voluntarily correct the (Response) The effective date for this
not subject to an exclusion under final
problem and inform the public before final rule is 60 days after its date of
§ 111.1.
the effective date of the rule. publication in the Federal Register,
C. Comments on Public Involvement (Response) We disagree with these though we are staggering the
comments regarding the establishment compliance dates as described in
1. Public Involvement
of a voluntary compliance period. The sections VI and XXIV of this document.
(Comment 332) Several comments effective date of this final rule is 60 days Dietary supplement products in the
express general concerns with our after the date of its publication in the marketplace must already be in
public involvement process. Several Federal Register. However, as discussed compliance with all other statutory and
comments state additional public in sections VI and XXIV of this regulatory provisions that affect dietary
meetings and workshops are necessary document, we have staggered supplements.
to permit FDA, industry, and other compliance dates to 12 months, 24
stakeholders to work together to seek a E. Removal of References to Part 112
months, and 36 months, respectively,
more workable solution to dietary after the final rule’s publication date for The 2003 CGMP Proposal (68 FR
supplement CGMPs and to resolve businesses of over 500 employees, 12157 at 12175) had proposed the
differences of opinion. One comment businesses with under 500 employees heading and table of contents for part
states the differences of opinion but 20 or more employees, and 112. Proposed part 112 had the heading
identified by the comment process will businesses with less than 20 employees. ‘‘Restrictions for Substances Used in
not be meaningfully resolved without (Comment 334) Several comments Dietary Supplements.’’ At the time, we
active and forthright communication indicate they want differential treatment said that it was necessary to amend part
with stakeholders. According to the under the final rule based on the 112 because at that time the proposed
comment, we should establish a forum seriousness of a violation, others ask for rule for dietary supplements containing
prior to the publication of the final rule strict enforcement, and others ask how ephedrine alkaloids (62 FR 30678, June
to communicate our perception of these FDA would enforce against those who 4, 1997) had not been finalized and
differences of opinion. In another continually adulterate dietary included proposed revisions to part 111.
comment, a trade association expresses supplements. The 2003 CGMP Proposal for dietary
disappointment that our 2003 CGMP (Response) We consider these supplement CGMPs proposed using part
Proposal disregards industry efforts to comments to be outside the scope of this 111 and proposed the relocation of the
draft CGMPs over the last decade. final rule. In general, we would provide ‘‘Restrictions for Substances Used in
Another comment contends the guidance on our enforcement policy Dietary Supplements’’ to part 112. Since
proposal was rushed and the comment through the issuance of guidance the issuance of the 2003 CGMP
period was established without documents if we determine that any Proposal, the final rule for dietary
publication of a core economic analysis variance from full enforcement is supplements containing ephedrine
to support it. warranted. alkaloids has been finalized (69 FR

(Response) We disagree with these (Comment 335) Another comment 6788, February 11, 2004) and has been
comments. We believe there has been expresses concern the 2003 CGMP included in 21 CFR part 119. Thus,
sufficient public involvement given the Proposal works at ‘‘cross purposes’’ there is no need to reserve part 112 in
public meetings that were held and the with recent regulations associated with this final rule. The references to part
112 have been removed from the final manufacturing operation serves as the holders, distributors, warehousers,
rule. backbone to CGMP. The records will exporters, importers, large businesses,
show what is to be manufactured; what and small businesses.
XXIII. Paperwork Reduction Act of The recordkeeping requirements of
was, in fact, manufactured; and whether
1995 the final rule are set forth in each
the controls that the manufacturer put
This final rule contains information in place to control the identity, purity, subpart. In table 18 of this document we
collection requirements that are subject strength, and composition and limits on list the one-time burdens associated
to review by the Office of Management contaminants and to prevent with establishing written procedures. In
and Budget (OMB) under the Paperwork adulteration were effective. Further, table 19 of this document we list the
Reduction Act of 1995 (44 U.S.C. 3501– records will show whether and what annual burdens associated with
3520). The title, description, and deviations from control processes recordkeeping. In each table, where the
respondent description of the occurred, facilitate evaluation and same records are mentioned in more
information collection requirements are corrective action concerning these than one provision of a subpart, we list
given in the following paragraphs, with deviations (including, where necessary, the burden under the provisions
estimates of the one-time burden of whether associated batches of product corresponding to the heading, ‘‘Under
establishing written procedures and the should be recalled from the this subpart, what records must you
annual recordkeeping burden. Included marketplace), and enable a make and keep?’’ For some provisions
in the burden estimates are the time for manufacturer to assure that the listed in table 19, we did not estimate
reviewing instructions, searching corrective action was effective. Further, the annual frequency of recordkeeping
existing data sources, gathering and records will show whether and what because recordkeeping occasions consist
maintaining the data needed, and deviations from control processes of frequent brief entries of dates,
completing and reviewing each occurred, facilitate evaluation and temperatures, monitoring results, or
collection of information. corrective action concerning these documentation that specific actions
Title: Current Good Manufacturing deviations (including, where necessary, were taken. Information might be
Practice in Manufacturing, Packaging, whether associated batches of product recorded a few times a day, week, or
Labeling, or Holding Operations for should be recalled from the month. When the records burden
Dietary Supplements marketplace), and enable a involves frequent brief entries, we
Description: Section 402(g) of the act manufacturer to assure that the entered one as the default for the annual
gives us explicit authority to issue a rule corrective action was effective. In frequency of recordkeeping. For
establishing current good manufacturing addition, by requiring records, we will example, many of the records listed
practice requirements for dietary be able to ensure that you follow CGMPs under final § 111.35 in table 19, such as
supplements. Section 402(g)(1) of the so that you ensure the quality of your final § 111.35(b)(2) (documentation, in
act states that a dietary supplement is dietary supplements during individual equipment logs, of the date
adulterated if ‘‘it has been prepared, manufacturing, packaging, labeling, or of the use, maintenance, cleaning, and
packed, or held under conditions that holding operations. The final rule sanitizing of equipment), involve many
do not meet current good manufacturing establishes the minimum manufacturing short sporadic entries over the course of
practice regulations.’’ Section 402(g)(2) practices necessary to ensure that the year, varying across equipment and
of the act authorizes us to, by regulation, dietary supplements are manufactured, plants in the industry. We did not
‘‘prescribe good manufacturing practices packaged, labeled, or held in a manner attempt to estimate the actual number of
for dietary supplements.’’ Under section that will ensure the quality of the recordkeeping occasions for these
701(a) of the act (21 U.S.C. 371), FDA dietary supplements during provisions, but instead entered an
may issue regulations necessary for the manufacturing, packaging, labeling or estimate of the average number of hours
efficient enforcement of the act. Other holding operations. per year. We entered the default value
relevant legal authority is discussed in The records requirements of this final of 1 as the annual frequency of
section V of this document. rule include written procedures and recordkeeping for these and similar
We did not receive any direct records pertaining to: (1) Personnel; (2) provisions. For final § 111.35, the entry
comments on the Paperwork Reduction sanitation; (3) calibration of instruments for annual frequency is 1 as a default
Act analysis of the 2003 CGMP and controls; (4) calibration, inspection, representing a large number of brief
Proposal. Many comments on the or checks of automated, mechanical, or recordkeeping occasions.
estimated costs of the 2003 CGMP electronic equipment; (5) maintaining, In many rows of tables 18 and 19 of
Proposal stated that we underestimated cleaning, and sanitizing equipment and this document, we list a burden under
the annual number of batches of dietary utensils and other contact surfaces; (6) a single provision that covers the
supplements produced. Due to a water used that may become a written procedures or records described
contractor’s error, we did underestimate component of the dietary supplement; in several provisions. The burden of the
the number of batches produced. This (7) production and process controls; (8) master manufacturing record listed in
final paperwork reduction analysis quality control; (9) components, table 18 under final § 111.210 includes
corrects for this error. The final analysis packaging, labels and product received the burden for final § 111.205 because
also has been revised from the analysis for packaging and labeling; (10) master the master manufacturing record must
of the 2003 CGMP Proposal in order to manufacturing and batch production; include those written procedures.
incorporate the effects of revisions to (11) laboratory operations; (12) Similarly, the burden of the batch
the proposed regulation, including manufacturing operations; (13) production records listed in table 19
reorganization. packaging and labeling operations; (14) under final § 111.260 includes the
Records are an indispensable holding and distributing operations; (15) burden for records listed under final
component of CGMP. The records returned dietary supplements; and (16) § 111.255 because the batch production
required by this final rule provide the product complaints. records must include those records.
foundation for the planning, control, Description of Respondents: The annual frequency for batch
and improvement processes that Manufacturers, dietary supplement production records (and other records
constitute a quality control system. manufacturers, packagers and re- kept on a batch basis in table 19 of this
Implementation of these processes in a packagers, labelers and re-labelers, document) equals the annual number of
batches. The estimated burden for frequency for records that will not necessary, that will be kept for every
records kept by batch includes both necessarily be kept for every batch, such batch.
records kept for every batch and records as test results or material review and We estimate the burden of this
kept for some but not all batches. We disposition records, because such collection of information as follows:
use the annual number of batches as the records are part of records, if they are
TABLE 18.—ESTIMATED ONE-TIME BURDEN TO ESTABLISH WRITTEN PROCEDURES1

Number of Annual Frequency Hours per
21 CFR Section Total Records Total Hours
Recordkeepers per Recordkeeping Record
111.14 15,000 1 15,000 3.6 54,000
111.23 15,000 1 15,000 1 15,000
111.35 400 1 400 36 14,400
111.95 250 1 250 68 17,000
111.140 300 1 300 10.7 3,210
111.180 200 1 200 10 2,000
111.210 250 1 250 12 3,000
111.325 150 1 150 45 6,750
111.375 260 1 260 9 2,340
111.430 250 1 250 12.6 3,150
111.475 15,000 1 15,000 2.1 31,500
111.535 200 1 200 6 1,200
111.570 240 1 240 12 2,880
Total 156,430
1There are no capital costs or operating costs associated with the collection of information under this final rule.
TABLE 19.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

Number of Annual Frequency Total Annual Hours per
21 CFR Section Total Hours
Recordkeepers per Recordkeeping Records Record
111.14 15,000 4 60,000 1 60,000
111.23 15,000 1 15,000 0.2 3,000
111.35 400 1 400 12.5 5,000
111.95 250 1 250 45 11,250
111.140 240 1,163 279,120 1 279,120
111.180 240 1,163 279,120 1 279,120
111.210 240 1 240 2.5 600
111.260 145 1,408 204,160 1 204,160
111.325 120 1 120 15 1,800
111.375 260 1 260 2 520
111.430 50 1 50 12.6 630
111.475 15,000 1 15,000 0.4 6,000
111.535 110 4 440 13.5 5,940

111.570 240 600 144,000 0.5 72,000
Total 929,140
1There are no capital costs or operating costs associated with the collection of information under this final rule.
The burden estimates in tables 18 and The information collection provisions entities, the Regulatory Flexibility Act
19 of this document are based on our of this final rule have been submitted to requires agencies to analyze regulatory
institutional experience with other OMB for review. options that would lessen the economic
CGMP requirements and on data Prior to the effective date of this final effect of the rule on small entities. FDA
provided by Research Triangle Institute rule, we will publish a document in the finds that this final rule will have a
(RTI) in the ‘‘Survey of Manufacturing Federal Register announcing OMB’s significant economic impact on a
Practices in the Dietary Supplement decision to approve, modify, or substantial number of small entities.
Industry,’’ OMB Control Number 0910– disapprove the information collection The Unfunded Mandates Reform Act
0422, expiration date April 4, 2000 provisions in this final rule. An agency of 1995 (Public Law 104–4) requires
(Refs. E1 and E2). may not conduct or sponsor, and a cost-benefit and other analyses for rules
The estimates in both tables of the person is not required to respond to, a that would cost more than $100 million
number of firms affected by each collection of information unless it in a single year. The current (2005)
provision of the rule are based on the displays a currently valid OMB control inflation-adjusted statutory threshold is
percentage of manufacturers, packagers, number. $122 million. This final rule qualifies as
labelers, holders, distributors, and a significant rule under the statute.
warehousers that reported in the survey XXIV. Analysis of Impacts
1. Summary of the Economic Analysis
that they have not established written A. Introduction
SOPs or do not maintain records that We carry out the cost-benefit analyses
FDA has examined the impacts of this required for significant rules in the
would be required under the final rule.
Because we do not have survey results final rule under Executive Order 12866. Final Regulatory Impact Analysis, in
for general warehouses, we entered the Executive Order 12866 directs agencies section XXIV.B of this document. We
approximate number of facilities in that to assess all costs and benefits of perform the Final Regulatory Flexibility
category for those provisions covering available regulatory alternatives and, Analysis of the effects on the final rule
general facilities. For the dietary when regulation is necessary, to select on small businesses in section XXIV.C
supplement industry, the survey regulatory approaches that maximize of this document. We estimate that,
estimated that 1,460 firms would be net benefits (including potential once it is fully implemented 36 months
covered by this final rule, including economic, environmental, public health after the date of publication, the
manufacturers, packagers, labelers, and safety, and other advantages; quantifiable annual benefits from the
holders, distributors, and warehousers. distributive impacts; and equity). final rule will be about $44 million. The
The time estimates include the burden Executive Order 12866 classifies a rule benefits able to be quantified are
involved in documenting that certain as significant if it meets any one of a generated by more consistently
requirements are performed and in number of specified conditions, produced dietary supplements which
recordkeeping. We used an estimated including: Having an annual effect on will increase product safety, which
annual batch production of 1,408 the economy of $100 million, adversely reduces the number of acute illnesses
batches per year to estimate the burden affecting a sector of the economy in a and product recalls. In addition, the
of requirements that are related to the material way, adversely affecting final rule may generate benefits that we
number of batches produced annually, competition, or adversely affecting jobs. lack sufficient data to quantify. These
such as final § 111.260, ‘‘What must the A regulation is also considered a benefits we cannot quantify arise from
batch production record include?’’ The significant regulatory action if it raises dietary supplements manufactured
estimate of 1,408 batches per year is novel legal or policy issues. FDA has under a system to ensure quality, which
near the midpoint of the number of determined that this final rule will be an leads to a reduction in the number of
annual batches reported by survey economically significant regulation chronic illnesses and conditions.
firms. under Executive Order 12866 because it The final rule will lead to quantifiable
The length of time that CGMP records will have an annual effect on the costs of $16 million in the first year it
must be maintained is set forth in final economy of more than $100 million. takes effect, $120 million in the second
§ 111.605. Tables 18 and 19 of this The Small Business Regulatory year, and $190 million in the third year.
document reflect the estimated burdens Enforcement Fairness Act of 1996 After 3 years, the annual costs will be
for written procedures, record (Public Law 104–121) defines a major about $164 million. If we annualize the
maintenance, periodically reviewing rule for the purpose of congressional benefits and costs over 20 years at a 3
records to determine if they may be review as being likely to cause one or percent rate of discount, the annualized
discarded, and for any associated more of the following: An annual effect quantifiable benefits are $40 million and
documentation for that activity for on the economy of $100 million; a major annualized quantifiable costs are $153
records that will be required under part increase in costs or prices; significant million. These annualized benefits
111. We have not included a separate adverse effects on competition, include only those that we are able to
estimate of burden for those sections employment, productivity, or quantify. The total annualized benefits
that require maintaining records in innovation; or significant adverse effects may be larger than our estimate of $40
accordance with final § 111.605, but on the ability of U.S.-based enterprises million in quantifiable benefits because
have included those burdens under to compete with foreign-based of the benefits that we are not able to
specific provisions for keeping records. enterprises in domestic or export quantify.
For example, final § 111.255(a) requires markets. In accordance with the Small We have determined, based on
that the batch production records be Business Regulatory Enforcement information contained in this regulatory
prepared every time a batch is Fairness Act, OMB has determined that impact analysis as well as information
manufactured, and final § 111.255(d) this final rule will be a major rule for contained elsewhere in the preamble,
requires that batch production records the purpose of congressional review. that the benefits of this final rule justify
be kept in accordance with final FDA has examined the impacts of this the costs.
§ 111.605. The estimated burdens for final rule under the Regulatory The final rule will have a significant
both § 111.255(a) and (d) are included Flexibility Act (5 U.S.C. 601–612). If a economic effect on small businesses. We
under final § 111.260 (what the batch rule has a significant economic impact estimate that the annual costs will be
record must include). on a substantial number of small about $46,000 for an establishment with
fewer than 20 employees and $184,000 discussed below, it may be difficult for adulterated products are already illegal
for an establishment with 20 to 499 consumers to identify the attributes of to market. Two other comments support
employees. dietary supplements before the actual the 2003 CGMP Proposal only with
consumption of the good. Therefore, it modifications, and another comment
2. Summary of Comments on the
may be difficult, in the absence of some supports CGMP regulations, provided
Economic Analysis regulation of dietary supplement they reflect the current ‘‘best practices
We received numerous substantive manufacturing practices, for consumers of leading manufacturers.’’ Two
comments on the economic analysis of to differentiate between products comments assert that a ‘‘more rigorous’’
the 2003 CGMP Proposal. In general, produced under good manufacturing enforcement program would be more
comments from the dietary supplement practices, and those that are not, at the effective than dietary supplement CGMP
industry state that we underestimated point of purchase in the marketplace. In requirements in preventing adulteration.
the cost of the 2003 CGMP Proposal. terms of dietary supplements as Two comments state that a regulation
Specific comments from the industry credence goods, consumers may never would serve no useful purpose because
target the 2003 CGMP Proposal’s testing have adequate information on product of the ‘‘low level of harm identified in
requirements, which the comments characteristics even after the the industry.’’
characterize as ‘‘burdensome.’’ Many consumption of the good, making it One comment states that the 2003
comments address our estimate of the difficult for consumers to determine CGMP Proposal spells out design
number of batches of dietary what benefits each product offers. standards rather than performance
supplements firms produce in a year. Because problems can be undetectable, standards. According to the comment,
Many comments express the fear that, as establishments may not adopt the the 2003 CGMP Proposal spells out
a result of this 2003 CGMP Proposal, the necessary practices to ensure product procedures a firm must follow rather
prices consumers pay for dietary attributes are as they are intended than defining a specific outcome, such
supplements would increase unless required to do so by regulation. as a specified level of contamination.
dramatically. Nearly all economic Of course, the characteristics of This comment maintains that we should
comments mention potential adverse dietary supplements, as a type of food set a performance standard and then
effects of the 2003 CGMP Proposal on product, argue for some sort of allow manufacturers flexibility in how
small businesses, stating that many Government intervention in this market that standard is reached. Another
firms would have to stop in order to alleviate the specific market comment states that, although certain
manufacturing. A few comments state failures that lead to the types of dietary supplement ingredients may
that, if made final, the 2003 CGMP problems with dietary supplements that cause concern, this concern did not
Proposal would make dietary this rule addresses. There are many justify imposing ‘‘overbearing’’ and
supplements more expensive than types of interventions that may be used ‘‘broad’’ CGMP regulations for an entire
pharmaceuticals. Other comments to address market failure; FDA has industry. Another comment asserts that
address the following topics: examined the options and has the CGMPs as presented in the 2003
• FDA’s other assumptions, including determined that specific CGMPs are CGMP Proposal would serve as an anti-
the number of tests required for each necessary for dietary supplements. The competitive tool by allowing dominant
batch and the number of tests already rest of this regulatory impact analysis, manufacturers to increase their
being performed. and particularly section III.A of this dominance and make it more difficult
• Development of analytical methods. document, discusses why FDA has for new firms to enter the industry.
• Equipment and capital investment concluded that specific CGMPs are (Response) Those comments that
costs. necessary for dietary supplements. disagreed with our analysis provided no
• Recordkeeping costs. (Comment 337) We received several data or evidence to support the
• FDA’s estimation of benefits. comments on the need for the 2003 comment. Without such data or
We will summarize comments on CGMP Proposal. Four comments evidence, we have no basis upon which
individual substantive issues under the specifically support the proposal, to revise our analysis and continue to
appropriate subject headings and stating, in part, that they are pleased we use the analysis. Thus, we have not
respond. are addressing the issue of dietary made any changes based on these
supplement manufacturing. In addition, comments.
B. Final Regulatory Impact Analysis
one comment states that the 2003 CGMP
Whether or not these provisions are
1. The Need for the Final Current Good Proposal was a good step toward
performance or design standards is a
Manufacturing Practice Rule providing assurance that dietary
theoretical issue. Instead of specifically
The final rule is needed because supplements are as safe as prescription
choosing either design or performance
establishments that manufacture, and OTC drugs.
standards for all provisions of the rule,
Other comments express concern
package, label, or hold dietary FDA has chosen to provide flexibility to
about the 2003 CGMP Proposal. One
supplements may not have sufficient manufacturers whenever possible. For
comment generally supports it, but
market incentives to use controls to example, providing for the use of ‘‘safe
expresses concern that the statements
ensure that the characteristics of the and sanitary’’ water sources gives
we make regarding market incentives to
supplements are what consumers would manufacturers flexibility in deciding the
prevent adulteration and misbranding
choose to buy if they had full or best way to assure that ‘‘safe and
are inaccurate and misleading. The
adequate information. Dietary sanitary’’ water is used in the
comment points out that the incentive
supplements have the characteristics of manufacture of their products. There are
exists for firms to prevent adulterated
both experience goods and credence many areas of the rule where more than
products from entering the marketplace
goods.12 In terms of the acute illnesses one way is given to comply with a
because of their desire to avoid damage
particular provision. This flexibility

12An experience good is a product or service to their reputations. In addition,
allows manufacturers to choose the
where product characteristics such as quality or
price are difficult to observe in advance, but these utility impact is difficult or impossible for the
appropriate means to comply with the
characteristics can be ascertained upon consumer to ascertain even after consumption of provision that is the most cost-effective
consumption. A credence good is a good whose the good. for them.
We agree with the comments that (7) the 2003 CGMP Proposal.13 As a through rigorous end-product testing,
point out that existing statutes and result of comments on the 2003 CGMP which emphasizes the wrong stage of
regulations, concern for brand names, Proposal and our reconsideration of our production, but by ensuring quality
and voluntary industry standards position on several provisions, this final through an effective process control
provide some product safety and rule differs from the 2003 CGMP system.
quality. Nonetheless, continuing Proposal. Few comments discuss regulation of
problems in the industry provide (Comment 338) We received few only high-risk products. Those that did
evidence for the need for this final rule. comments on the option of fewer note that some ingredients would be of
From 2000 through 2005, there were a requirements for vitamins and minerals, public health concern and it would be
total of 75 recall actions in the dietary and the comments submitted did not preferable to test these ingredients only
supplement industry, including class 1, support this option. One comment rather than all ingredients.
2, and 3 recalls of vitamins and minerals supports one set of CGMPs that would (Response) The comments on the
and herbal and botanical supplements. apply to the entire industry rather than regulatory options did not provide
We will discuss these recalls, which fewer requirements for vitamins and evidence to directly support or oppose
accounted for about 4 percent of the minerals than for botanicals. Another those options but instead addressed
1,937 FDA food recall actions in 2000 comment states that having fewer particular issues such as testing or
through 2005, later in this document. requirements for vitamins and minerals coverage.
Most of these recalls occurred because would not be wise because of the large We took the comments on specific
establishments failed to adhere to number of people who take issues into account in the analysis of
product manufacturing or labeling multivitamin or mineral supplements. this final rule. We discuss them below
specifications. One comment supports more in the relevant parts of the analysis.
For a class 1 recall, there is a restrictive CGMP requirements, One comment supporting HACCP
reasonable probability of serious including further testing and quality stated that the detailed manufacturing
adverse health consequences or death; assurance requirements. and testing requirements of the 2003
for a class 2 recall, exposure to the We received two comments that CGMP Proposal would, compared with
product may cause temporary or support HACCP without other elements HACCP, stifle innovation. Although
medically reversible adverse health of the final rule. One comment echoes regulations that impose costs can divert
consequences; for a class 3 recall, an earlier comment made about resources away from innovation, the
exposure to the product is not likely to stressing outcomes and points to the costs of this final rule represent less
cause adverse health consequences. Full HACCP systems in the juice and seafood than 1 percent of industry revenues (see
compliance with the provisions of this industries as a way of ensuring effective table 35 of this document). Because
final rule could have prevented most of quality control design. The comment research and development expenditures
the recalls. We note also recall asserts that the detailed manufacturing account for a small fraction of total
classifications only track acute hazards, controls and testing requirements expenditures, any reduced expenditures
not long-term quality problems. Results spelled out in the 2003 CGMP Proposal on research and development associated
from ConsumerLab.com and other may actually stifle innovation. Another with this final rule will be a small
independent laboratory results provide comment echoes these thoughts, adding fraction of 1 percent of revenues. Thus,
further evidence of a need for this final that a HACCP approach could work in it seems unlikely that this rule would
rule (Refs. E3 through E6). Statistical tandem with a more traditional have the effect of stifling innovation. As
sampling methods were not used to specification and test approach. we explained in the economic analysis
collect the data reported in these We received one comment that of the 2003 CGMP Proposal, the HACCP
analyses. Therefore, although this specifically discusses requiring only option would not specify detailed
information provides anecdotal final product testing, but received manufacturing requirements but would
evidence of problems, the data may not numerous comments on final product also fail to ensure product quality (68
be representative of overall industry testing in general. The specific comment FR 12157 at 12222). In section X.I of this
practices. The information serves as did not support reliance on final document, we discuss why HACCP is
additional evidence of the existence of product testing only, stating it is not the not appropriate for dietary supplements.
problems. best or most appropriate control. In The comment supporting HACCP failed
Although the final rule will increase addition, the comment claims it is not to provide any data or any evidence to
the monetary cost of entering the dietary technically feasible in many cases and support its conclusion. Without such
supplement industry, the industry will is economically burdensome, a point data or evidence, we have no basis upon
remain highly competitive with more repeated in other general comments which to revise our analysis and
than a thousand competing producers about final product testing. In addition, continue to use the analysis.
and thousands more potential entrants. numerous comments point out that a 3. Coverage of the Final Rule
2. Regulatory Options firm cannot ‘‘test in quality,’’ meaning
The final rule applies to
that ensuring the quality of the dietary
We considered several regulatory supplement will not be achieved
establishments that manufacture,
options for dealing with current package, label, or hold dietary
manufacturing, packaging, labeling, and 13Options 1 through 6 were discussed in detail in supplements. Tables 20 and 21 of this
holding practices that may not ensure the 2003 CGMP Proposal (68 FR 12157 at 12221 document list the estimated number of
the quality of the dietary supplement. through 12223; March 13, 2003) and analyses of covered manufacturers, packagers,
The options considered include: (1) No costs were provided when possible. The principles labelers, holders, and other
of the options discussion have not changed and are
new regulatory action, (2) fewer still relevant for purposes of the requirements of the
establishments subject to the final rule.
requirements for vitamins and minerals, final rule. The 2003 CGMP proposal also included Table 20 shows the number of
(3) more restrictive regulations than the an Analysis of Impacts which contained some establishments categorized as
final rule, (4) HACCP without the other errors from a contractor’s report. We have corrected manufacturers, repackagers or
the analysis and have recalculated the costs of the
elements of the final rule, (5) final 2003 CGMP Proposal. These corrections and
relabelers, holders whose primary
product testing only, (6) a final rule for recalculations are discussed in section XXIV.B.9 of business is dietary supplements, and
high-risk products or hazards only, and this document. other (although not including other
holders and distributors). Table 21 general warehouses, wholesalers, and but are not otherwise involved in the
shows our estimate of the number of others that hold dietary supplements, industry.
TABLE 20.—COVERED ESTABLISHMENTS BY TYPE OF OPERATION FROM THE DIETARY SUPPLEMENT ENHANCED
ESTABLISHMENT DATABASE (DS–EED)
No. of Percent of
Establishment Type Establishments Establishments
Manufacturer 1,228 84.1
Repackager; relabeler 26 1.8
Holder 114 7.8
Establishments not already classified 92 6.3
Total 1,460 100.0
TABLE 21.—COVERED ESTABLISHMENTS THAT HOLD DIETARY SUPPLEMENTS

No. of
Type of Holders NAICS Code Establishments
General grocery wholesalers or drug wholesalers 424410 4,036
General warehouse 493110 4,415
Drug wholesalers 42420 7,418
Total 15,869
We consulted several sources to table 21 of this document. This total Vitamins and minerals accounted for
estimate the number of establishments differs from the total reported in the about 42 percent of sales. Sales of herbal
reported in this document. The number, analysis of the 2003 CGMP Proposal supplements, which have not grown in
1,460, is the estimated number of because the new classification system recent years, were half as large as sales
establishments in the DS-EED that allows us to identify more of vitamin and minerals, accounting for
manufacture, package, label, or hold establishments that would not hold about 21 percent of the total. Amino
dietary supplement products in the dietary supplements and therefore acids, proteins, animal extracts, tea-like
United States. In the analysis of the exclude them from the total. supplements, and other supplements
2003 CGMP Proposal, we included an Foreign firms that export dietary not otherwise classified accounted for
additional 106 U.S. establishments that supplements to the United States must the remainder of sales.
supplied dietary ingredients. Because satisfy the requirements of this final
rule. We do not have data on the There were no comments on the
those establishments are not covered in
number of foreign firms that export consumption baseline.
this final rule, we exclude them from
the total. RTI developed the DS-EED dietary supplements to the United b. Manufacturing. We contracted with
using FDA’s Official Establishment States. The small number of foreign RTI to conduct a survey of the dietary
Inventory and supplemented that source products in the FDA dietary supplement supplement industry to learn about both
with information from trade sales database suggests that relatively baseline (existing) manufacturing
organizations, trade shows, and few foreign firms export dietary practices and the existing standards
electronic databases (Refs. E1 and E2). supplements to the United States (Ref. used for manufacturing dietary
E7). The foreign firms that will be most ingredients and dietary supplements
To estimate the total number of affected by the final rule are suppliers
establishments that could hold dietary (Ref. E2). A sample of 966 dietary
of dietary ingredients. Although supplement establishments from the DS-
supplements but do not consider dietary suppliers of dietary ingredients are not
supplements as their primary business, EED database was selected from an
directly covered by the final rule, the estimated eligible population of 1,566
we first looked for a count of need of manufacturers to meet the
establishments that had North American firms in the industry (the total number
ingredient specifications required by the
Industrial Classification System of dietary supplement establishments
final rule will indirectly affect foreign
(NAICS) codes for wholesalers of included 106 ingredient manufacturers,
suppliers (as well as domestic
groceries or drugs. Next we looked for who are now excluded from the
suppliers).
a count of firms that met the description No comments were received on the requirements of the final rule). The
of warehouses for groceries or drugs. We economic analysis of the coverage of the eligibility criteria and the response rate
did not find a category devoted 2003 CGMP Proposal. for the survey are fully explained in the
exclusively to food and drug final report on the survey (Ref. E2). We
4. Baseline Practices
warehousing, so we concluded that further classified the target firms by

general warehousing most closely a. Consumption. Baseline risks product and by size. The product
corresponded to the set of depend on baseline consumption of categories were: (1) Vitamins and
establishments that would hold dietary dietary supplements. Total sales in 2004 minerals; (2) amino acids and proteins;
supplements. The results are shown in were about $20 billion (Ref. E8). (3) herbals and botanicals, including
extracts; and (4) supplements not If firms that manufacture dietary We received 238 completed surveys.
already classified. supplements have fewer than 500 Table 22 of this document shows the
The Small Business Administration employees, they are classified as small. number of completed surveys by
classifies companies as ‘‘small’’ based In addition, for purposes of this product and by size of establishment.
on the size of the entire company, analysis, we classify firms with fewer
including both parent and subsidiaries. than 20 employees as very small.
TABLE 22.—NUMBER OF COMPLETED SURVEYS BY SAMPLING STRATA

Size
Very Small (fewer Small (20 to 499 Large (500 or more Unknown Total
than 20 employees) employees) employees)
Vitamins and minerals 19 39 13 1 72
Amino acids, proteins 8 7 0 5 20
Herbals and botanicals, in-

cluding extracts 58 25 0 30 113
Supplements not already

classified 14 13 2 4 33
Total 99 84 15 40 238
(Comment 339) We received two poison control centers, reports to the The anecdotal evidence described
comments on manufacturers’ baseline agency, newspaper and magazine elsewhere in the preamble suggests that
practices. One comment expresses articles, and surveys of users. The many illnesses could have been caused
concern that, as the information is over literature review was conducted using by poor manufacturing processes, but
3 years old, it may no longer represent Medline, Healthstar, Aidsline, Cancerlit, there are only a few examples of
current industry practices. The second and OldMedline (Ref. E9). We found evidence that explicitly link illnesses to
comment questions the way we evidence of many adverse events manufacturing processes. Examples of
calculated the number of dietary associated with dietary supplements. illness that were linked directly to poor
supplement establishments that do not For example, in 2003, the American manufacturing practices include
follow any CGMP models. In the 2003 Association of Poison Control Centers vitamin D toxicity from excessive
CGMP Proposal, we state that survey received 24,412 reports on events vitamin D in multivitamins and cardiac
data reflect that 36 percent of surveyed associated with herbal dietary glycoside poisoning from botanical
establishments do not follow any CGMP supplements and 57,801 reports on dietary supplements contaminated with
models. The comment points out that events associated with vitamin and Digitalis lanata (Ref. E12).
26.5 percent of firms responded ‘‘no’’ to mineral supplements, with 8,653 of the With no direct evidence on the
the question, ‘‘Does this plant follow a herbal and 5,669 or the vitamin and number of illnesses caused by poor
published GMP model for the dietary mineral reports treated in health care manufacturing practices, we had to use
supplement products produced at this facilities (Ref. E10). In addition, we have an indirect approach. We based the
plant?’’ Furthermore, of the 63 that received many voluntary reports of approach on our recall records. Class 1
answered ‘‘no,’’ ‘‘at least’’ 29 of the illnesses caused by dietary supplements and class 2 recalls all involve defective
firms provided responses indicating the (Ref. E11).14 products that could have caused illness
reason they do not follow a published The vast majority of these events and if ingested. Although the recall data
GMP is that they did not manufacture those described in other sources we cannot be linked directly to illness data,
dietary supplement products. consulted, however, are reported as we have found anecdotes, surveys, and
(Response) Although the survey associated with the ingredients used in some medical literature on illnesses that
responses are now over 6 years old, they the products themselves, not with could be caused by avoidable dietary
represent the best information we have contamination or other results of poor supplement manufacturing mistakes.
on the industry and its practices. We manufacturing processes. Most of the We have recall data that show that
have, however, adjusted our estimated reports from poison control centers on manufacturing mistakes exist, so we can
costs to reflect the correction of the vitamins and minerals, for example, construct a plausible link between
results from the original survey. involved inappropriate ingestion by manufacturing mistakes and potential
children (Ref. E10). We have no direct illnesses or injuries. The number of
5. Baseline Risk evidence on how many illnesses can be illnesses associated with a
The current number of illnesses attributed to manufacturing processes. manufacturing problem leading to a
caused by poor dietary supplement recall is both variable and uncertain,
14Mandatory reporting to FDA of serious adverse
manufacturing practices requires data and could be anything from zero to
events is now required as a result of the enactment
linking illnesses to poor practices. of the ‘‘Dietary Supplement and Non-Prescription
quite large. Based on data from FDA
Because these data do not exist, we Drug Consumer Protection Act’’ (Public Law 109– food and dietary supplement recalls, we
looked for other information to provide 462), signed into law on December 22, 2006. The concluded that one reported illness per
indirect evidence on the problem. We new law requires manufacturers, packers, or recall is a plausible average, so we
distributors of such products to submit reports to
looked at many sources for information, FDA about serious adverse events involving such
assumed that a recall could be a proxy
including medical and other literature products based on specific information that they for a single reported illness associated
on adverse events, information from receive from the public. with a defective product.
Because there are no active With a multiplier of 10, the estimated Inpatient Sample, administered by the
surveillance systems for identifying number of illnesses per year is 118; with HHS Agency for Healthcare Research
adverse health events related to dietary a multiplier of 40, the total number of and Quality (Ref. E14).
supplements, we assume that the total illnesses per year is 472. Table 23 of this document contains
number of illnesses caused by poor We estimate that the monetary value
of the health losses for the hazards summaries of our measures of the health
manufacturing practices is substantially
listed in table 23 of this document as a costs potentially caused by known
greater than the number reported.15
Based on data for drug and vaccine weighted average of the values attached instances of hazards associated with
reporting rates in other studies, one to the different health outcomes poor dietary supplement manufacturing
study concluded that for dietary associated with each hazard. We processes for the decade 1990 through
supplements, reported illnesses estimate the health losses or fatal cases 1999. We estimated the health loss per
represent approximately 1 percent of as the monetary value of a statistical day for the different levels of illness
total illnesses (Ref. E13). We use the life, defined as the willingness to pay severity by summing the lost
associated multiplier, 100, in our for a small change in the probability of productivity (as measured by functional
baseline estimate and assume that death. We estimate the health losses for state) and the loss from pain and
reporting adverse health events due to non-fatal illnesses as the sum of: (1) The suffering (as measured by the symptom-
poorly manufactured dietary imputed value of lost productivity, (2) problem index). These losses per day
supplements occurs at the same rate as the imputed value of pain and suffering, can be interpreted as the difference
reporting adverse health events caused and (3) actual expenditures on medical between a day of normal health and a
for other reasons by dietary treatment. We measured lost day of suffering from the health
supplements. Other reporting rates and productivity (defined to include conditions caused by these defective
associated multipliers are, however, household and market productivity) products. The numerical scale is a
plausible. For some hazards that lead to indirectly with measures of functional relative baseline that rests on the notion
severe events only, we have used a state, which includes measures of of a quality-adjusted life day (QALD).
multiplier of 10; the Centers for Disease physical function. We estimated the The QALD for a day of normal health
Control and Prevention have used a losses caused by pain and suffering with
equals 1; the QALD for death equals 0.
multiplier of 38 for Salmonella a symptom-problem index. We combine
The loss of QALDs per illness equals the
infections and similar food-related the functional losses with the pain and
suffering into a single index of lost daily loss multiplied by the number of
illnesses. We show the sensitivity of
quality-adjusted life years (measured by days the illness lasts. We converted
benefits to the choice of multiplier
below. the Quality of Well-Being Index). We QALDs to dollars by multiplying the
From 1990 through 1999, we received then convert the quality-adjusted life index numbers by the dollar value of a
reports on an annual average of 11.8 years to dollars by multiplying the QALD. We computed the monetary
class 1 and class 2 recalls of dietary index numbers by the dollar value of a value of a QALD using three values
supplements related to manufacturing quality-adjusted life year. We used derived from three different values for a
problems. If we assume that each recall direct measures of medical costs, such quality-adjusted life year: $100,000,
is a proxy for a reported illness, then the as payments to physicians and $300,000, and $500,000. These yield
total number of illnesses per year is hospitals. We obtained data on the cost values per day of $274, $822, and
approximately 1,180. We recognize that of a hospital day and other medical $1,370. Our base measures use $822; we
our procedure generated uncertain costs from the Health Care Cost and show the effects of using other values in
estimates of the number of illnesses. Utilization Project’s Nationwide the sensitivity analysis.
TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990
AND 1999
Expected Value of Ill-

Number of Expected Value
Recall Class ness Times
Recalls of Illness Number of Recalls
Chemical
Copper salts 2 1 $489 $489
Digitalis 1 33 $37,442 $1,235,599
Ephedra 1 1 $177,237 $177,237
Hypervitaminosis A 1 2 $1,264 $2,528
Hypervitaminosis D 2 1 $1,366 $1,366
Lead poisoning (class 1) 1 1 $15,591 $15,591
Lead poisoning (class 2) 2 40 $10,436 $417,451
Niacin 2 2 $5,802 $11,603

Pyridoxine (Vitamin B6) 2 1 $12,085 $12,085
15Mandatory reporting to FDA of serious adverse of the ‘‘Dietary Supplement and Non-Prescription Drug Consumer Protection Act’’ (Public Law 109–
events is now required as a result of the enactment 462), signed into law on December 22, 2006.
TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990
AND 1999—Continued
Expected Value of Ill-

Number of Expected Value
Recall Class ness Times
Recalls of Illness Number of Recalls
Selenium poisoning (class 1) 1 1 $755,338 $755,338
Selenium poisoning (class 2) 2 6 $1,288 $7,731
Stannous fluoride 1 1 $1,266 $1,266
Superpotent zinc 2 1 $389 $389
Biological
Botulism (class 1) 1 1 $494,683 $494,683
Botulism (class 2) 2 1 $2,044 $2,044
Klebsiella Pneumonia 1 1 $774,178 $774,178
Salmonella (class 1) 1 4 $15,298 $61,191
Salmonella (class 2) 2 4 $778 $3,110
Allergenic
Lactose intolerance 2 1 $396 $396
Undeclared sulfites 1 1 $723 $723
Yellow #5 sensitivity 2 5 $723 $3,616
Yellow #6, red #40, blue #2 2 1 $1,595 $1,595
Physical
Glass fragments 2 1 $4,241 $4,241
Other
L-tryptophan (Eosinophilia-Myalgia Syndrome

(EMS)) 1 7 $1,135 $7,946
Total 118 $3,992,397
The hazards that occurred between in the table of what is characterized as reports of misbranded and adulterated
1990 and 1999 are not necessarily the ‘‘ordinary’’ recalls, since this case is dietary supplements are common.
same hazards that would occur today. analyzed separately as an example of a (Response) We are not changing the
For example, botulism is rare and may ‘‘rare catastrophic event.’’ The comment way we count recalls. Each different
no longer be a hazard associated with states that the outbreak of Digitalis recall will continue to be counted as a
dietary supplements, but recalls should also have not been included in separate recall. How recalls are counted,
involving botulism represent generic the recall list because it also was a rare however, does not affect the analysis.
examples of adulteration that could event. The comment asserts that FDA The method used in this analysis
occur with other substances in the announcements and media attention corresponds to an average of about one
absence of good manufacturing should have led to full reporting of any reported illness per recall action. A
practices. Also, we base our cost adverse events. particular event can lead to many recall
estimates on information from 1999, so Other comments generally refer to risk actions. If we changed the way we
it is appropriate to estimate benefits associated with dietary supplements. counted recalls so as to reduce the
from the same time. One comment states that botanical number of baseline recalls to correspond
(Comment 340) We received a supplements pose minimal risk if to events, the average reported illnesses
comment that took issue with the way dispensed directly to a patient rather per recall would rise in proportion. The
the recalls are counted. The comment than used in an unsupervised setting, estimated benefits would not change.
asserts it is more appropriate to count and that toxicology and adverse event We are no longer including the
each recall action as a separate recall, reports indicate that end-of-process outbreak of EMS in our analysis of
regardless of the number of different adulteration in herbal clinics is rare. By benefits. The product recalls associated
products affected. contrast, another comment states that with EMS occurred several years after
The same comment criticizes the adverse events related to dietary the outbreak that we are now excluding.
inclusion of the outbreak of supplement use led to hospital The continued benefit associated with
Eosinophilia-Myalgia Syndrome (EMS) admissions at one location and that preventing EMS is associated with
incorporating quality controls aimed at FDA of serious adverse events. This if ingested. In the 2003 CGMP Proposal,
such hazards. final rule includes requirements that we estimated the reduction of illnesses
will provide the information needed to from preventing catastrophic events by
6. Benefits
quickly and accurately conduct a using the public health effects of the
The benefits of this final rule come sufficient traceback in the case of an outbreak of EMS that resulted from
from ensuring the quality of dietary adverse event. This enhanced ability to consumption of contaminated L-
supplements. Dietary supplements track information related to serious tryptophan. We agree with comments
should contain the listed ingredients in adverse events will increase both the questioning the applicability of this
the listed amounts in product forms that accuracy and the speed of the response outbreak to CGMP, so we are no longer
disintegrate and dissolve. Dietary to such events, which may in many including the value of preventing this
supplements should not contain any cases reduce the number of illnesses or outbreak as a benefit of this rule.
contaminants that would adulterate the deaths associated with unsafe dietary
product under section 402(a)(1), (a)(2), We estimated the annual expected
supplements.
(a)(3), or (a)(4) of the act. (Comment 341) We received many health benefits for acute illnesses
Estimating the benefits of preventing comments on the estimated benefits. prevented by taking the values of
adulteration and contamination is Although we did receive comments that preventing particular illnesses and
straightforward, at least in theory. These stated the rule would benefit consumers weighing them by their likely incidence
benefits are the value of reducing the by enhancing public confidence in as indicated by recall data. The acute
risk of the acute illnesses and longer- dietary supplements, many comments illnesses prevented that we use to
term complications associated with state that the estimated benefits in the estimate benefits are not actual
physical, chemical, and microbiological 2003 CGMP Proposal were overstated. illnesses, but statistical illnesses
contamination (see table 23 of this In addition, one comment states that our (defined as the probability of illness
document). The direct value of estimates of benefits are double multiplied by the population at risk)
preventing recalls is another source of counted, because the outbreak of EMS prevented by the reduction in risk
benefits from preventing adulteration was included in the measure of benefits associated with this final rule. These
and contamination. We estimate the from preventing a large catastrophic recalls indicate recurring failures to
benefits of preventing adulteration and event as well as total benefits of ensure the quality of dietary
contamination by first estimating (based reduction of illnesses measured by supplements. Although each class 1 and
on recall data) the number and kinds of recalls. Furthermore, comments critical 2 recall is estimated to have resulted in
illnesses prevented, and then placing a of the benefits state the search cost some illnesses (which may have
value on preventing those illnesses. We model used in the analysis is not triggered the recall), there may also be
include the recall costs avoided by applicable or the benefits of reduced other manufacturing problems that did
industry as additional benefits of search costs do not exist, we lack not lead to recalls but that did lead to
preventing adulteration and evidence with which to base the illness. Both situations are part of the
contamination. estimate of reduced health care costs baseline number of illnesses and deaths
Estimating the value of ensuring the from elimination of rare catastrophic estimated.
quality of the dietary supplements and events, and recalls will not fall to zero We computed the expected health
that they are manufactured according to as a result of implementing CGMPs. benefits from preventing a single illness
their specifications is difficult in (Response) We agree with the
(of any type) associated with a recall as
practice because we lack the necessary comment that benefits were overstated
a weighted average of all potential
data on what is missing and how what because of the inclusion of the outbreak
of EMS. We no longer include the value illnesses. We then calculated the
is missing affects public health. Some average health benefits of preventing a
dietary supplements have authorized of preventing that or similar outbreaks
in our estimate of benefits. Although we single illness associated with a non-fatal
health claim labeling that allows them class 1 or a class 2 recall as:
to state their products may reduce the do not agree with the comments on the
risk of chronic illnesses or conditions. applicability of the search model as a Health costs prevented = (QALY x value
Ensuring that those supplements are measure of benefits, the empirical per QALY) + medical costs
manufactured consistently according to difficulties associated with quantifying We define QALY as the average quality-
the appropriate specifications will those benefits have led us to replace the adjusted life year per illness; as
increase their effectiveness in reducing search model with a qualitative explained earlier, we computed the
the risk of chronic illnesses. In this description. average by weighting the quality
analysis, we describe those benefits but We now explain each of the three adjusted life years lost for the
are not able to quantify them. sources of benefits: Reduced acute probability of each health outcome by
The benefits from the final rule, then, illnesses, fewer recalls, and reduced the expected frequency of that outcome.
will be: chronic illnesses and conditions.
• Reduced health costs associated a. Reduced health costs associated To estimate the number of acute
with a reduced number of acute with a reduced number of acute illnesses prevented, we started with the
illnesses (quantified), illnesses. The final rule will help ensure average number of recalls per year for
• Fewer product recalls (quantified), the quality of dietary supplements, the decade 1990 through 1999. The
and which will lead to improved safety of yearly averages for the decade were six
• Reduced health costs associated dietary supplements, reducing the class 1 recalls and seven class 2 recalls.
with a reduced number of chronic probability of acute illness or deaths As discussed previously, we then
illnesses and conditions (not caused by manufacturing problems. We assumed that these recalls represented
quantified). estimated the reduction of acute about 1 percent of all acute illnesses
This final rule could also enhance the illnesses by using our recall records as caused by the manufacturing problems
benefits of the ‘‘Dietary Supplement and evidence of possible illnesses; class 1 leading to the recalls. With that
Non-Prescription Drug Consumer and class 2 recalls of dietary assumption, we estimated that the
Protection Act’’ (Public Law 109–462), supplements all involved adulterated recalls represented about 530 acute
which requires mandatory reporting to products that could have caused illness illnesses from class 1 recalls and 650
acute illnesses from class 2 recalls.16 reflects increased controls in the into account recalls that this comment
The illnesses used to estimate the industry, then the benefits and costs of felt were erroneously included in the
benefits of the final rule represent a this final rule will be lower than what calculation of benefits from reduced
sample of acute illnesses that could we have estimated. illnesses.
occur without this final rule. We assume (Comment 342) We received (Response) We have not seen any new
that the benefits computed for the comments critical of the estimates of data or other information that would
average year from the decade 1990 reduced illness due to recalls. One lead us to change the 100-fold
through 1999 represent the annual comment points out that drugs, despite multiplier for our basic estimate. We
average benefits we should expect in the having stringent CGMP requirements, recognize that the multiplier is
future. We do not assume that the acute have a higher rate of recalls than dietary uncertain; different multipliers lead to
illnesses prevented in the future will be supplements, thus providing evidence different estimated numbers of illnesses
identical to those that occurred during that such requirements do not and different estimated benefits. With a
1990 through 1999. necessarily reduce recalls. Expanding multiplier of 10, estimated benefits are
on this thought, other comments state 10 percent of our baseline; with a
TABLE 24.—HEALTH BENEFITS ES- that we seem to assume that new CGMP multiplier of 40, estimated benefits are
TIMATED USING RECALL DATA requirements will reduce human error 40 percent of our baseline. The
FROM 1990 THROUGH 1999 to zero and no more recalls will occur, estimated benefits of this final rule,
which is said to be unrealistic. thus, move in proportion to the assumed
Estimated annual number 1,180 Other comments express concern multiplier. We recognize this
of acute illnesses pre- about the 100-fold multiplier used to uncertainty and show how it affects the
vented (530 class 1 and estimate the costs related to recall- estimated benefits in the sensitivity
650 class 2 recalls) associated illnesses. The comment states analysis. The multiplier implicitly
that we, besides referencing Walker assumes that the more severe illnesses
Dollar estimate of average $33,800
(2000) (Ref. E13 of this document (Ref. are more likely to be reported; the
health benefit for pre-
venting an acute illness E16 in the 2003 CGMP Proposal)), average reporting rate for all adverse
associated with a class provided no other information to events is assumed to be about 1 percent.
1 or class 2 recall substantiate the use of the 100-fold The average incorporates higher
multiplier and therefore are being reporting rates for more severe illnesses,
Estimated dollar estimate $40 million arbitrary. Any other number could be as and lower reporting rates for less severe
of annual health bene- accurate. In addition, other comments illnesses.
fits state that it is difficult to believe that the The comments on the severity weights
multiplier would be applicable to for Klebsiella pneumonia and ephedra
The estimated benefits are indeed recalls associated with Klebsiella did not persuade us to change these
sensitive to the choice of years. For 2000 pneumonia and selenium poisoning, estimates. We based the estimates on the
through 2005, there were 75 recalls: 29 and L-tryptophan, because the severity outcomes for severe events associated
class 1, 25 class 2, and 21 class 3. The of the illnesses would certainly have with these hazards. The Klebsiella
annual averages for 2000 through 2005 been associated with the highly weights come from the medical
are therefore 4.8 class 1, 4.2 class 2, and publicized recalls; that is, they would literature (Ref. E9); the ephedra weights
3.5 class 3 recalls. We estimate that not have gone unreported. are based on adverse events involving
about 80 percent of the class 1 and class Some comments present recalculated ephedrine alkaloids.
2 recalls were related to manufacturing benefits. One comment estimates The comparison of drug recalls to
problems (for 1990 through 1999 over benefits from fewer illnesses as a result dietary supplement recalls does not
95 percent of class 1 and class 2 recalls of the 2003 CGMP Proposal to be $10.9 provide data that would cause us to
stemmed from manufacturing million, rather than our estimate in the change our analysis. The drug industry
problems). With an average of 9 class 1 analysis of the 2003 CGMP Proposal of is far larger than the dietary supplement
and class 2 recalls per year, our baseline $39 million. This new estimate was industry and any such comparison
estimate of total associated illnesses arrived at by taking into account what would have to account for that
using 2000 through 2005 data is 900 (9 was characterized as double-counted difference as well as other differences.
x 100). If this final rule prevents 80 benefits which, as mentioned earlier, Expenditures on prescription drugs
percent of these events, then 720 were characterized as the inclusion of exceeded $200 billion in 2004.
illnesses will be prevented. We do not EMS in the measure of benefits from (Comment 343) We received many
use this estimate to calculate baseline preventing a large catastrophic event as comments regarding the use of the
benefits for this final rule because we do well as total benefits of reduction of outbreak of EMS in 1989 as a basis for
not have a comparably recent estimate illnesses measured by recalls. Another estimating health benefits from
of costs. If the reduced number of recalls comment re-estimates the benefits as preventing a catastrophic event. The
$16 million. This estimate was majority of the comments assert that
16In the uncertainty analysis in section XXIV.B.11 calculated assuming 100 percent of CGMPs would not have prevented the
of this document, we used a probability distribution potential illnesses related to Klebsiella outbreak. One comment expands this
to represent the uncertainty associated with the
number of illnesses. We modeled the number of
pneumonia were classified as severe assertion by stating our claim that
illnesses prevented for each class as the average (with none classified as deaths), and 50 testing requirements would reduce the
number of recalled products plus a negative percent of illnesses associated with the probability that contaminated
binomial distribution representing unknown cases. selenium recall were classified as ingredients would be released to the
The negative binomial distribution estimates the
number of failures (unknown cases) that will occur
serious and none were classified as public is incorrect, because it was not
before some number of successes (known cases) for deaths. This comment also disagrees known what, if any, contaminants
a given probability of success. In the negative with the assumption that 3 percent of caused the outbreak. Secondly, the
binomial distribution, we assumed that the the 100 potentially ill from the recall comment states that our claim that
numbers of recalls represented reported cases and
that the probability of reporting equaled 1 percent
associated with undeclared ephedra complaint files would allow for fast
(Ref. E13). The mean estimated number of illnesses would have died. Furthermore, this identification of an adverse health event
is 100 times the reported number of recalls. comment adjusts the benefits to take is also incorrect because the victims of
EMS did not know the L-tryptophan supplements, we estimate the number of (Response) We do not believe that
was the cause of their illnesses. annual recalls of dietary supplements recalls will fall to zero. We assume that
Two other comments question the that would be prevented by adherence the recalls identified as being
periodicity for a cycle of potential to CGMP requirements in the final rule. preventable by this final rule will fall to
catastrophic events due to dietary From 1990 to 1999, FDA received zero, but that mistakes and other
supplements. One comment suggests a reports on 195 recalls related to hazards will continue to generate
period of 70 years rather than our 30 manufacturing problems, an average of recalls. In the sensitivity analysis,
years. The other comment does not 19.5 recalls per year (Ref. E9). The however, we show the effects of a lower
suggest a period but rather states that, average figure reported here includes level of effectiveness in preventing
since we have no data to support the class 3 recalls. The number of units of recalls associated with manufacturing
cycle of 30 years, and we admit it is dietary supplements for each recalled problems.
difficult to know how likely rare events product varied, so we used a
are, it is possible that the total projected distribution per recall of 1,000 units to c. Reduced health costs associated
benefit could be zero. 34,000 units (Ref. E9). Product price with a reduced number of chronic
Lastly, other comments state that the (updated to 2004) also varies, with most illnesses and conditions. We cannot
benefits from preventing a rare prices falling between $6 per unit and quantify the value of ensuring that
catastrophic event are double-counted. $11 per unit; we used a most likely dietary supplements contain everything
These comments state these benefits are price of $8.50 per unit. We include an in the established specifications (and
double-counted because they are also adjustment for the goodwill lost by the nothing that is not in the specifications)
included in the estimation of benefits establishment as a result of the recall. because we lack the necessary data on
from reduced recalls. We multiply the direct cost of the recall what is missing and how what is
(Response) As stated previously, we by two in order to include the lost missing affects public health. The
are no longer including estimated goodwill. We also adjust for recalls that public health benefits are derived from
benefits from preventing a rare would likely not be prevented by the the reduced number of chronic illnesses
catastrophic event in the analysis of final rule. The result is an estimated and conditions. These benefits may
benefits. We continue to include the savings of $1.8 million in direct costs arise from known nutritional effects or
benefits of preventing statistical cases of and $1.8 million in goodwill, for a total from uncertain nutritional effects.
EMS in the annual health benefits, savings of about $3.6 million per year. d. Benefits from known nutritional
because several recalls of L-tryptophan, (Comment 344) We received several effects. Many of the nutritional benefits
which could be associated with EMS comments on our estimates of the of vitamins and minerals are known and
took place during the 1990 through 1999 reduction in recalls. As noted well-documented. For example, the
period.17 previously, a comment generally states Dietary Guidelines for Americans, 2005
b. Fewer products recalled. that drugs, despite having stringent
states that dietary supplements can be
Implementation of the final rule will CGMP requirements, have a higher rate
used to help meet the recommended
reduce the number of adulterated of recalls than dietary supplements,
intakes of vitamin B12, folic acid, and
products distributed to the public, thus providing evidence that CGMPs do
vitamin D (Ref. E15). The Institute of
which will reduce the number of not necessarily reduce recalls. Again,
Medicine’s Dietary Reference Intakes
products recalled. Process controls and other comments state that we seem to
hold the unrealistic assumption that the include statements that supplements
better recordkeeping will increase the
final rule will reduce human error to can be sources of several vitamins and
ability of establishments to produce
zero and no more recalls will occur. minerals (Ref. E16). We have recognized
dietary supplements according to
Another comment points out that the the use of supplements in authorized
specifications and to identify problems
assumption that the final rule would health claims for calcium and
before distribution. If adulterated
products are caught before they are cause the discovery of all adulteration is osteoporosis (§ 101.72) and folic acid
distributed or earlier in the production inconsistent with the requirement that and neural tube defects (§ 101.79).
process, they will not need to be firms keep complaint files. If the rule In table 25 of this document, we list
recalled. eliminates adulteration, the comment some of the health benefits associated
To estimate the direct benefits from states, then there should be no with the consumption of various dietary
fewer recalled adulterated dietary complaints to report. supplements.
TABLE 25. SELECTED HEALTH BENEFITS FROM CERTAIN DIETARY SUPPLEMENTS

Dietary Supplement User Benefit
Folic acid Women of child-bearing age Reduces the risk of neural tube defects
Calcium Children and adults Reduces the risk of osteoporosis
Iron Adolescent females and women of child-bearing age Reduces the risk of anemia
Vitamin D Children and adults; persons with dark skin, or with too little Reduces the risk of osteoporosis
exposure to sunlight
Vitamin B12 Persons over the age of 50 Reduces the risk of anemia
17We recognize, however, that the presence of L- EMS. The estimates in table 23 of this document assume that L-trypotophan represents a 0.1 percent
trypotophan only indicates a small probability of probability of EMS.
e. Benefits from uncertain nutritional reduce the probability of osteoporosis, neural tube defects, multiplied by the
effects. We do not know the full range which afflicts as many as 10 million value of preventing a neural tube defect.
of effects (or lack of effects) of most people over age 50 (about 8 million Neural tube defects involve large
dietary supplements. Vitamins and women and 2 million men). An medical expenses, and either early
minerals with known nutritional effects additional 34 million men and women death or permanent disability. The
in supplement form may have other may be at risk for developing lifetime medical costs alone are between
effects that we have yet to discover. Our osteoporosis (Ref. E17). If ensuring that $400,000 and $500,000 for spina bifida
uncertainty is particularly large with calcium supplements contain what they (Ref. E19, with values updated). In
respect to the nutritional effects of should reduces the risk of osteoporosis, recent rulemakings, we have used $5
herbal and botanical supplements. The the total osteoporosis health benefits million as the value of a statistical life,
evidence is still too mixed and associated with the final rule will be the defined as the willingness to pay for
incomplete to determine the effects of number of cases prevented multiplied reductions in small risks of premature
most of these substances. If, however, by the health costs per case. We death. Preventing a statistical death
herbal dietary supplements do indeed estimated the health costs per case as from anencephaly would therefore
have significant beneficial effects on the the sum of the direct medical costs, the generate benefits of $5 million to $6.5
risk of chronic illnesses and conditions, value of functional disability, and the million. For spina bifida, one estimate is
then if the final rule ensures that the value of the pain and suffering that an average case leads to a loss of
supplements consistently meet their associated with the illness. Cases range more than 15 quality-adjusted life years,
specifications, we should add those in severity from mild to severe. A mild for a monetized loss of close to $5
benefits to those from supplements case, for example, might lead to a loss million for a non-fatal case if valued at
having known nutritional effects. of utility (measured as quality-adjusted $300,000 per quality adjusted life year
The benefits of this final rule that we life years—a year of life adjusted for the (Ref. E20). The value of preventing a
can identify are those associated with individual’s health status) of 0.14 per case of spina bifida, then, is the sum of
the known effects. The product year for 9 years. If we apply a discount medical costs and the value of a saving
deficiency might be, for example, that rate of 7 percent to the years the the quality-adjusted life years, or about
packages contain some percentage less condition lasts, the loss of quality- $5 million ($450 million value of
or more of the necessary ingredient adjusted life years is about 0.9 (6.5 quality adjusted life years + $500,000
(such as calcium) than what is listed on discounted years x 0.14 lost utility per direct medical costs).
the label. The relationship between the year). In other rulemakings we have Estimating the total benefits of this
shortage or excess amount of the used a range of values for a quality- final rule requires estimates of the
ingredient and the probability of adjusted life year; the range has been numbers of chronic illnesses and
chronic illness would also have to be from $100,000 to $500,000, with a conditions whose incidence can be
taken into account in order to determine medium monetary value of $300,000 (68 further reduced by ensuring that dietary
the risk associated with the product FR 41434, July 11, 2003). With a value supplements contain what they should.
deficiencies. The increase in the per year of $300,000, the value of Because we have no information on the
probability of chronic illnesses may be preventing a mild case is about baseline number of chronic illnesses
negligible, less than, the same, or more $270,000 (0.9 x $300,000). caused by deficient or excessive
than the shortage or excess in the A severe case, by contrast, can lead to ingredients, or on the change in the
amount of the ingredient. The increase fractures and permanent disability. likelihood of chronic illness that will
in the probability of chronic illness Also, osteoporosis in women can occur occur as a result of the provisions of this
would also depend on how long the at early ages and last decades. If final rule, we cannot estimate the full
supplement contained a shortage or someone suffers from osteoporosis for benefits of ensuring that dietary
excess amount of the ingredient. 30 years, the discounted quality supplements contain what they should.
Suppose, for example, that a calcium adjusted life years lost would be 6.9 Our quantified benefits for this final
supplement contains 10 percent less (12.4 discounted years x 0.56 lost utility rule must therefore consist entirely of
calcium than it should for 1 year. If the per year). We estimate that medical the benefits from reducing the risks of
average consumer takes calcium costs for a severe case can be over acute illnesses and reducing the number
supplements for 20 years, would the 1- $17,000. The value of preventing a of product recalls. The total benefits
year deficiency of 10 percent increase severe, long-lasting case is therefore will be larger by an amount we are not
the probability of osteoporosis by more about $2.1 million ((6.9 x $300,000) + able to quantify.
or less than 0.5 percent (10 percent x (1/ $17,000). (Comment 345) We received many
20))? Folic acid and neural tube defects. comments about the estimated benefits
If we could determine the change in Many women of child-bearing age take as measured by the value of
the number of chronic illnesses dietary supplements to help ensure their hypothetical search time.
prevented by dietary supplements as a own health, and the health of their (Response) We are no longer using the
result of this final rule, we could children should they become pregnant. search model.
estimate benefits by multiplying the For example, 40 percent of women aged f. Total benefits. The total benefits
additional number of chronic illnesses 18 to 45 take supplements containing from the final rule are the sum of the
prevented by the value of preventing folic acid, which may reduce the value of health benefits from fewer
those illnesses. The values consumers probability that children will be borne acute illnesses, the value of fewer
place on preventing illness differ across with neural tube defects (Ref. E18). product recalls, and the value of the
illnesses and across consumers, and are Neural tube defects affect the spine health benefits from fewer chronic
related to the reasons they use dietary (spina bifida) and the brain illnesses. Table 26 of this document
supplements. We will illustrate the (anencephaly). About 3,000 pregnancies shows the total benefits.
method with two examples: Calcium are affected each year (Ref. E18). (Comment 346) One comment states
and osteoporosis and folic acid and The benefit of ensuring that folic acid that our total estimated benefits could
neural tube defects. supplements contain what they should be as little as $21 million.
Calcium and osteoporosis. Many equals the population at risk multiplied (Response) Our current estimate of
consumers take calcium supplements to by the reduction in the probability of total quantified benefits is $44 million
per year, once the final rule takes full and different assumptions generate • Large (500 or more employees).
effect. In addition, as discussed higher or lower quantifiable benefits. Although this consolidation glosses
previously, there are benefits to this rule Using plausible assumptions about the over the important differences across
that have not been quantified. The uncertain variables, we estimate that products, the purpose is to estimate the
unqualified benefits estimate is the total quantified benefits (using 1990 broad average costs of the rule.
mean of a range of estimates based on through 1999 data) most likely fall For each size category, we constructed
assumptions about reporting rates and within a range of $8 million to $64 a cost model that included every
the effectiveness of the final rule. million per year. provision of the final rule. We then
In the analysis of benefits for this rule attached a cost to each provision that
there are two large uncertainties: TABLE 26.—SUMMARY OF ANNUAL had an additional activity associated
Quantified underreporting of acute BENEFITS with it. Most provisions did not have
illnesses and injuries and nonquantified costs attached to them, because they
benefits associated with chronic Benefits Mean were either descriptive or the costs were
illnesses. Despite the best efforts by included elsewhere.
public health authorities, there will Fewer acute illnesses $40 million The costs will be the marginal, or
always be underreporting of illness and additional, costs of the activities
injuries. Where fatalities are concerned, Fewer product recalls $4 million producers undertake in response to the
unless there are litigation problems or Fewer chronic illnesses Not quantified
provisions of the final rule. In the cost
the potential for the spread of infectious model, we expressed the cost as cost per
disease, there is no incentive to do Total quantified benefits $44 million unit, with the unit being the
extensive forensic work to determine establishment, the number of
whether a fatality is related to the 7. Costs employees, or the annual number of
ingestion of a dietary supplement. This batches produced or affected.
leads to reporting most fatalities under The same changes in manufacturing b. Summary of general comments on
the most general International practices that produce benefits also have costs. We received many comments on
Classification of Diseases codes. We opportunity costs. Due to the increased the costs of the 2003 CGMP Proposal.
acknowledge the large uncertainties in expenditures of complying with this Many of the comments were general in
our estimate because of these factors. final rule, firms may spend fewer nature and addressed the belief that our
The degree of prevention of chronic resources on potentially costly activities economic analysis underestimated the
illnesses due to preventing super- or such as worker safety, product total costs of the 2003 CGMP Proposal,
subpotent dietary supplements depends development and marketing, or both first year costs and annual costs.
on two factors, both of which are highly voluntary testing of the efficacy of their Numerous comments point to the rule’s
uncertain. The first factor concerns products. The final rule will require testing requirements as the main cause
product benefit: How many dietary dietary supplement establishments to of the high costs. Comments also state
supplements have any beneficial effect adopt some new practices in order to that the analysis underestimates costs of
on chronic illnesses and how strong are manufacture, package, label, or hold hiring new workers, capital equipment,
those effects? Recent work in this area their products in compliance with and holding and distributing costs. In
so far has examined only a few dietary CGMP requirements. In some cases, addition, some comments point out that
supplements, with mixed results. Of establishments will make capital the economic analysis did not include
course, ensuring the potency of an improvements to the physical plant, add estimates of costs of holding reserve
ingredient that has adverse effects or has or replace equipment or controls, samples and tracking product
adverse interactions with drugs would perform additional maintenance, complaints.
subtract from the benefits. The second establish written procedures, keep As a result of the 2003 CGMP
factor is the incidence and effects of records, carry out tests, monitor Proposal, comments assert, product
subpotency and superpotency across production and process controls, or choice would decline, prices of existing
products and over time: How much of execute a variety of additional tasks that products would increase, and many
a difference in the product need there be they may not have previously businesses, particularly small
to generate a substantial adverse health performed. Not all firms will comply; businesses, would be forced to shut
effect? Because of these uncertainties, it some will go out of business or move down. One comment states there could
is virtually impossible to make any sort their plants to other countries and not be a decrease in spending on research
of quantitative statement about likely sell their product in the United States. and development. Some comments state
effects of a regulation ensuring against We estimated the additional costs of that the burden on business could be
superpotency and subpotency. production associated with the final alleviated by allowing the use of
Because of the uncertainties in rule and the leading regulatory options certificates of analysis for incoming raw
estimating the benefits associated with using the survey to estimate baseline materials and using a statistical, or more
both chronic and acute illnesses manufacturing practices (Ref. E2). flexible, testing regime instead of
associated with manufacturing practices a. Description of the costs. To estimate requiring final product testing on all
for dietary supplements, the decision to costs for the dietary supplement batches.
implement regulatory requirements industry, we initially divided the A comment from a trade association
becomes an exercise in weighing industry into four product categories representing ingredient suppliers and
quantitative and qualitative benefits to and three size categories. Because the manufacturers in the dietary
public health against expenditure of survey showed that there were only a supplement industry accepts our
scarce resources. By choosing to go few establishments in some categories, assumptions on the following variables:
forward with this rule, FDA is we consolidated the size and product • The number of control points,
exercising precaution with respect to into three size categories. The size • The average number of ingredients
uncertain risks. categories were: per product, and
In the uncertainty and sensitivity • Very small (fewer than 20 • The average cost per test.
analyses in section XXIV.B.11 of this employees), Other comments, however, state that
document, we show how uncertainty • Small (20 to 499 employees), and the average number of ingredients is
higher than estimated and that the • The number of tests already being (Response) The recordkeeping
average cost per test is higher than performed, requirements in the final rule differ
estimated; one comment from a • The costs to perform specific from the 2003 CGMP Proposal; revised
manufacturer states that its average cost analytical tests, and estimates are included in this final
was 2.5 times our estimate. These • The development of analytical regulatory impact analysis and
comments came from self-described methods. paperwork reduction analysis.
small firms. (Response) The final rule reduces the (Comment 352) We received a
(Comment 347) One comment states number of required tests. In the final favorable comment regarding the
that we failed to consider start-up costs. rule, we account for tests where no requirements for physical plant and
(Response) We include start-up costs analytical methods have been equipment, saying that, although the
(also referred to as set-up or one-time developed. We now require fewer tests, costs would be moderate, the result
costs) throughout this analysis. although we anticipate that some testing would be higher quality products.
(Comment 348) Many comments on will take place associated with the Another comment states that, although
the regulatory impact analysis targeted creation of certificates of analysis not unrealistic, the provision would be
our estimates of firms’ batches per year. required for component specifications very costly.
Nearly all comments about batches state and as verification for process controls. Other comments are more critical.
that our batch estimates are too low. For We now assume that the tests will be: One comment estimates that renovation
example, an industry trade groups • One identity test for each shipment expenses would amount to
claims our estimate of 309 batches per lot of incoming dietary ingredients (e.g., approximately $600 million over the
year for large firms is ‘‘implausibly vitamin C); entire industry, as opposed to our
low.’’ The same comment states that the • Tests of subsets of shipment lots by estimate of $45 million. This comment
distribution of the number of batches supplier firms to create certificates of states that the reason our estimates in
per firm of 309, 554, and 223 for large, analysis for identity of other the 2003 CGMP Proposal were too low
small, and very small firms is ‘‘illogical’’ components (e.g., sugar); is that we apply a reduction factor
because it does not make sense that • Tests of subsets of shipment lots for which assumes that 18 percent of very
large firms would have fewer batches other specifications in the certificates of small firms, 10 percent of small firms
per year than small firms. analysis; and 1 percent of large firms will have to
(Response) Due to a contractor’s error, • Tests of subsets of batches of make capital improvements. It is more
we used an inaccurate estimate of the dietary supplements for microbial, appropriate, the comment states, to
annual number of batches in the chemical, or physical contaminants; assume that most facilities will need to
analysis of the 2003 CGMP Proposal. • Tests of subsets of batches of renovate about 10 percent of their plant,
The analysis of the final rule corrects for dietary supplements for specifications; regardless of firm size. In addition, the
this error. The corrected mean numbers and requirement that plants have smooth,
of batches per firm are 444 for very • Tests for meeting requirements that hard surfaces on all floors, walls, and
small, 2,436 for small, and 1,164 for water used to manufacture dietary ceilings is unrealistic and would add
large firms. The corrected estimates of supplements complies with Federal, quite a bit of cost. The comment asserts
the number of batches continue to show State, and local requirements and does no company will have such surfaces
that small firms produce more batches not contaminate the dietary supplement. throughout the plant and this is not a
than large firms. Comments from self- We are not changing our estimate of requirement in either the food or drug
described small firms suggest that this the current prevalence of testing, which CGMP requirements. Other comments
distribution of batches is reasonable. is based on the survey of manufacturers echo the belief that capital expenditures
These comments state that small firms (Ref. E2). We would only revise this would be greater than our estimates and
produce many small batches of product estimate in light of new data of would be excessively burdensome. One
using machinery with smaller capacity comparable quality to that provided by comment estimates this cost at
than that used by large firms. Very small the survey. approximately $83,000 per facility.
firms produce the fewest number of (Comment 351) We did receive two The comment also estimates that a
batches per firm of the three size comments favorable to recordkeeping, large firm that needs to expand its
categories because of their much lower stating that master and production batch capacity could expect to incur costs of
output. records were good to adopt and that $240,000, as opposed to the $2,000 that
(Comment 349) One comment states associated costs will be minimal. One of the comment says we estimated for large
that we used faulty data in the economic the comments states that the level of firms. In addition, it is pointed out that
analysis. detail may be unrealistic for a small equipment costs could be burdensome
(Response) In accordance with our firm, but also states that any final to small firms, which likely do not have
information quality guidelines, we have regulation could be made more flexible well-equipped labs. This thought is
used the best available data in this for small manufacturers. affirmed by other comments that
analysis. As explained in the response Although there were favorable estimate that new equipment could cost
to comment 348, the survey results used comments, we received several anywhere from $50,000 to $1 million,
in the analysis of the 2003 CGMP comments critical of the recordkeeping with annual costs estimated between
Proposal included an inaccurate requirements. These comments make $15,000 and $100,000. In addition,
estimate of the number of batches of general statements that the economic expansion of laboratory space is
dietary supplements produced. We use analysis underestimates the estimated at $200 per square foot, as
the corrected estimate in the analysis of recordkeeping burden and some added opposed to the agency’s estimate of $50
this final rule. that these requirements go beyond the per square foot. Lastly, one comment
(Comment 350) Some comments CGMPs for food. In addition, several of suggests we work with the Internal
dispute the estimated testing costs. In the comments include firms’ own Revenue Service to allow for more rapid
particular, comments question our estimates of costs of complying with the depreciation of facility costs to help
assumptions on: recordkeeping requirement. Comments small businesses make facility upgrades.
• The number of tests required per estimate costs in the range of $11,000 to (Response) In the analysis of the 2003
batch, $64,000. CGMP Proposal, we estimated the
number of firms needing to make capital of business. Other comments state that opposed to our estimate of $24 million,
expenditures associated with the rule as allowing statistical testing regimes although another contains estimates as
a distribution, with the parameters of would also cut down on testing costs. high as $13.6 million annually for one
the distribution determined by the size (Response) As we already have firm. Two comments concede that some
of the facility. We assume that if a firm discussed in this section, we have finished product testing may be
does make a capital investment in reduced the amount of required testing necessary.
response to the rule, it would affect in this final rule. The final rule requires In addition, some comments state that
about 10 percent of the plant. With an testing the identity of every incoming our estimate of finished and raw
estimated cost of $50 per square foot, dietary ingredient. However, the final material testing is off by a multiple of
and the average size of a very small rule allows for use of certificates of three to six. One comment states that,
plant of about 25,000 square feet, the analysis in place of identity tests of for companies that have products which
cost per very small establishment other components and other tests of contain a large number of ingredients
making a capital investment would be incoming dietary ingredients and other expensive to test, very large costs will
about $125,000. With the average size of components. The final rule also allows be incurred. This comment also states
a small plant of about 70,000 square sound statistical testing regimes for that our cost estimates do not include
feet, the cost per small establishment finished products. We recognize, in-process testing, which they claim the
making a capital investment would be however, that it may be possible for a rule would clearly require. Specifically,
about $350,000. With the average size of manufacturer to demonstrate, through our analysis suggests that an average of
a large plant of about 600,000 square various methods and processes in use 2.5 in-process tests per batch are likely
feet, the cost per large establishment over time for its particular operation, to be needed at critical control points.
making a capital investment would be that a system of less than 100 percent In addition, the comment maintains that
about $3 million (Ref. E2). We assume identity testing would provide no our analysis showed that additional
that most facilities will not need to material diminution of assurance of the testing may be required for an average
make capital investments to meet the identity of the dietary ingredient as of 2.5 components of herbal products
sanitation requirements of this final rule compared to the assurance provided by and 7.5 components of vitamin
as, according to the survey results, most 100-percent identity testing. To provide products, but our estimates do not
establishments already meet the an opportunity for a manufacturer to include costs of the tests. Finally,
sanitation standards of this final rule. make such a showing and reduce the comments point out that, if the
This would not be possible if their frequency of identity testing of production system is properly
facilities were inadequate. We note that components that are dietary ingredients controlled, then a ‘‘reduced schedule’’
the final rule does not require smooth from 100 percent to some lower of final product testing is justified and
and hard surfaces throughout the plant. frequency, we decided to provide, in an that focusing excessive resources on
We estimated the capital costs as the interim final rule published elsewhere end-product testing does not constitute
costs of minor renovations to help meet in this issue of the Federal Register, a GMP. Quality controls should be built
sanitation requirements, not as the cost procedure that allows for submission to, into the production and process system
of, for example, expanding the size of a and review by, FDA of an alternative to from the beginning of the manufacturing
laboratory or some other technically the required 100-percent identity testing process.
sophisticated change. Although some of components that are dietary A comment also states that our
facilities may choose to expand ingredients, provided certain conditions estimates of firms that already test are
laboratories, the testing requirements of are met. inaccurate. The comment asserts that
this final rule should be able to be met (Comment 354) One comment states our estimates are overstated and they
by existing laboratory facilities within that our cost estimates are based on the also think we have understated that
or outside of the manufacturing assumption of only two ingredient tests, proportion of finished batches not
facilities. an assumption which the comment calls currently being tested. In addition, the
Working with the Internal Revenue into question. For multivitamins, one comment claims that ‘‘even large firms
Service on depreciation is beyond the comment estimates about 8 separate that are testing 90 percent of their
scope of our authority. We will provide tests and 16 separate assays, depending products are unlikely to be performing
advice on financing capital on the nutrients present. the exhaustive level of testing required
improvements through our small (Response) In the analysis of this final by the 2003 CGMP Proposal, namely
business representatives in the Office of rule, we assume one identity test per testing every component of every batch
Regulatory Affairs. incoming shipment lot of dietary of finished product.’’
(Comment 353) Many comments ingredients based on the revisions made The comments point out that our cost
address costs resulting from what to the final rule compared with the 2003 estimates do not include estimates for
industry describes as the exhaustive CGMP Proposal. the cost of developing methods of
testing requirements outlined in the (Comment 355) Many comments analysis for ingredients. At a minimum,
2003 CGMP Proposal. Comments point include individual estimates of testing one comment states this estimate should
out that the requirement to test every costs. For example, two comments be $2 million (the cost of 100 methods
ingredient would be very costly for estimate an average cost of about $100 at a minimum of $20,000 each). Several
firms large and small, with many firms per test, and other comments estimate comments point out that often there are
stating that they risk going out of averages as high as $360, as opposed to no existing scientifically valid analytical
business. In addition, several comments our estimate of about $60 per test. methods to test finished products,
add that the testing requirements would Several other comments claim that the especially botanical products. Another
do little to enhance product quality. costs of finished product testing alone comment states that costs of analytical
Many comments assert that allowing the would be ‘‘at least 100 times’’ greater testing are at least three times our
use of a certificate of analysis would than our estimates; other comments estimate, and could be as high as eight
reduce the amount of tests performed on state that testing costs would almost times our estimate. Because of this,
a shipment of incoming raw materials, equal the costs of manufacturing. One many comments call for the use of a
reducing redundant testing, and also comment estimates testing costs for certificate of analysis in place of
reducing the risk that a firm may go out firms of all sizes at $245 million, as analytical testing.
Another comment states some representing at least 10 percent of the batches produced, which we found to be
unintended consequences could occur products in the market. the case because of an erroneous
in the industry due to the testing According to the sample of listed calculation in the contractor’s report. In
requirements, including stress on the ingredients, vitamin and mineral the revised contract survey results, very
current contract laboratory facilities and products contain about 13 listed dietary small establishments produce an
in-house laboratories, and also increases ingredients. Other dietary supplements, average of 444 (revised from 223)
in holding costs, due to changes in turn- mainly herbals, contain about four listed batches per year, small establishments
around time at outside labs. Other dietary ingredients (Ref. E7). produce an average of 2,436 (revised
comments point to the loss of product Number of unlisted components. from 554) batches per year, and large
choice that could occur if the testing Dietary supplements are manufactured establishments produce an average of
requirements force manufacturers to go using solvents, binders, and lubricants 1,164 (revised from 309) batches per
out of business or discontinue certain that may not show up in the final year.
products. product. An industry source (Ref. E21) Number of final product tests per
(Response) In response to comments, says that four to six unlisted batch. We have reduced the number of
we have revised the testing components are typical per product, tests required for final products. We
requirements in the final rule. We also although fewer are certainly possible. assume that establishments will test a
have revised our estimates of the costs The minimum number is zero. Based on representative sample of batches to
of testing. In what follows, we describe industry data, we assume that the ensure that the final products meet
the estimated number and costs of tests number of unlisted components would specifications. We do not specify any
required by this final rule. be zero to six for vitamins and minerals, particular statistical sampling plan.
The final rule requires tests for and zero to four for herbal and other Costs per test. We estimate the costs
products. per test partly with published prices of
identity for each incoming shipment lot
Number of shipments (i.e., shipment independent laboratories as posted on
of dietary ingredient. Estimating the
lots) of ingredients and unlisted the Internet (Refs. E22 and E23), and
number of tests per batch is components. We have no direct partly from our conversations with FDA
complicated, because the tests are information on the number of shipment and industry experts on testing. Testing
required on the shipment lots and we lots of dietary ingredients and other costs vary according to frequency and
have data only on the number of batches components. We also have no complexity. The more frequently
of dietary supplements produced. For information on the number of shipments technicians perform tests, the lower are
example, if a shipment lot of some per lot or on the number of shipments the costs per test. Many tests require
dietary ingredient is used in six batches per batch. It is costly to store sophisticated equipment, such as gas
of final products, it would need to be components, so some establishments chromatography, high pressure liquid
tested for identity only once. The may buy many small lots of dietary chromatography, distillation, extraction,
number of required identity tests per ingredients and other components various spectrophotometers, and other
batch of final product will equal the rather than a few large lots. Crude types of equipment. Using sophisticated
number of dietary ingredients per batch, botanical and other ingredients are equipment requires trained personnel.
divided by the average number of inherently unstable and may lose their Even simple physical or organoleptic
batches per shipment lot (to account for stability in even a short time unless testing requires training or experienced
the production of multiple batches of costly temperature, humidity, and light personnel. The type of ingredient,
dietary supplements from single lots of controls are in place. We also know, compound, or product can also affect
components). In addition to the required however, that some dietary ingredient the cost because some are easily
identity tests, a subset of other suppliers produce and ship ingredients identified using routine or single step
components will be tested for identity in large lots. For dietary supplements techniques and others require multiple
(these tests are likely to be the produced using part of a large steps or complex techniques, especially
responsibility of suppliers and need production run of a dietary ingredient, if there are similar products that can be
only be done once per batch no matter the number of batches per shipment lot mistaken for the products being
how many recipients of those batches). could be large. Also, some producers identified. The type of defect tested for
The quantity and quality of evidence buy a single large shipment lot of a raw affects the cost; some defects can be
on the variables used to estimate the material and use it in many batches. We found visually if they are found on the
number of tests varies greatly. In this assume that as many as 12 batches per surface, but others are latent. Some tests
section, we explain the evidence and shipment lot of dietary ingredient is a require multiple samples or multiple
assumptions we used to construct the plausible maximum. Based on steps. In addition, tests require taking
formulas for the number of tests. consultation with industry (Ref. E21), and preparing samples, whose cost can
Number of dietary ingredients. We we assumed, in the cost calculation, that vary. By assuming a single distribution
based our measure of the number of 1 was the minimum and 12 the for testing costs, we may overestimate
dietary ingredients per product on a maximum number of batches produced testing costs for sectors or products with
sample of almost 3,000 dietary per lot, with 6.5 the average. We below-average costs and underestimate
supplement labels (Ref. E7). Although received no comments on our use of the testing cost for sectors with above-
some ingredients may be missing from assumption in the analysis of the average costs. In the cost model, for
the labels and some listed ingredients proposed rule and continue to use it in example, we distinguish between
may be missing from the products, the our analysis of the final rule. In the botanical ingredients and nonbotanical
ingredient list represents the best sensitivity analysis, we show how costs ingredients in the number of tests, but
evidence we have on what ingredients change when we change the not in average testing costs. If the
are used in dietary supplements. assumption. average cost of testing botanical
Although comments claimed that we Number of batches produced. We products is higher than the average cost
underestimated the number of have survey results on the number of for vitamins and minerals, the
ingredients, they offered no evidence batches produced per establishment distribution of costs may underestimate
that would persuade us to change our (Ref. E2). Several comments stated that total testing costs for botanical products.
estimates, which are based on a sample we underestimated the number of We do not have sufficient information
on the range of testing costs for range, so we selected $50 (the midpoint) percent produce other dietary
botanical ingredients to determine if the as most likely. supplements.
average cost of testing is higher or lower The number and cost of tests: • 69 percent of large manufacturers
than for other ingredients. Summary. We estimate the number of
produce vitamins and minerals; 31
The average cost per test is about $60, tests required of the representative
based on a range of costs we found on percent produce other dietary
manufacturer as a weighted average of
the Internet. This cost represents the full supplements.
the number of tests required for
cost of carrying out a test, including vitamins and minerals and the number Most establishments already conduct
collecting and storing the sample, the of tests required for all other some tests, or send samples out for
time for training the personnel who supplements (which were mainly herbal testing. We therefore adjusted the
carry out the test, and any associated products). The weights, shown as estimated testing costs of the final rule
records. We assume that $20 per test follows, differ by size of manufacturer: to include only required tests and to
represents a lower bound. Although • 24 percent of very small account for the testing costs currently
some Internet prices for tests are as high manufacturers produce vitamins and borne voluntarily by manufacturers. The
as $300, we assumed that, with frequent minerals; 76 percent produce other survey results showed how many
testing, $150 would be a more plausible dietary supplements. respondents were conducting various
upper bound average cost. The majority • 42 percent of small manufacturers types of tests.
of listed prices fell into the $20 to $80 produce vitamins and minerals; 58
TABLE 27.—VALUES USED TO ESTIMATE TESTING COSTS

Name Value or Distribution Used Source
Number of dietary ingredients per product Vitamins and minerals—13 Sample from 3,000 dietary supple-
batch All other categories—4 ment labels (Ref. E7)
Number of identity tests per dietary ingredient 1 identity test per ingredient lot Based on requirements of final rule
lot
Number of identity tests per other component 1 identity test per subset of component lots Assumption based on use of certifi-
lot cates of analysis for ingredients
Number of tests for specifications per ingre- 1 to 5 tests per subset of ingredient lots Assumption based on use of certifi-
dient lot cates of analysis for ingredients
Number of unlisted components 0 to 6 components for vitamins and minerals, 0 to 4 Ref. E21
for herbal and other products
Number of shipments (lots) of ingredients and 1 to 12 batches per shipment lot of dietary ingredients Assumption based on discussions
unlisted components with industry
Number of batches produced per year Very small establishments–444 Ref. E2

Small establishments–2,436
Large–1,164
Number of final product tests per batch 1 test per subset Based on requirements of the final
rule
Costs per test Beta pert distribution skewed rightward between $20 Refs. E22 and E23
and $150; $50 most likely; $60 average
(Comment 356) We received additional annual labor costs ranging labor in the industry. We assume that
comments on labor costs that would be between $25,000 and $350,000. various tasks required by the final rule
incurred as a result of the 2003 CGMP (Response) We used more recent would take some number of hours per
Proposal. All comments state that estimates to the average manufacturing year, per batch of product, or per square
personnel costs will increase wage cost of $26 per hour to estimate foot of physical plant.
significantly. One comment states that the cost of labor (Ref. E24). The Estimating costs. We initially gathered
the average manufacturing wage we comment that asserted Ph.D.-level information and made assumptions
used to estimate labor costs, $15.65, employees are needed to comply with about the full cost of a provision. We
the rule, provided no basis for this then adjusted these estimates to account
does not reflect the true cost of
assertion. We disagree that Ph.D.-level for the many activities already being
additional labor, since higher skilled
workers are needed for the tasks carried out, as well other activities that
employees, such as quality control required by this final rule because most would not have to be carried out by all
engineers and, as one comment asserts, of the costs estimated as labor costs all establishments. We used the survey to
Ph.D.-level employees, will need to be involved ordinary labor tasks such as estimate the likelihood that an
hired to comply with the rule. This sanitation, monitoring, and establishment will incur a cost. To get
comment states that, including benefits, recordkeeping. For more difficult or an estimate of the average cost of a
the wage actually ranges between $23.28 complicated tasks, more skilled workers provision (adjusted for baseline
and $72.00 per hour, depending on may be required, but the overall average activities) for each category, we
skill. Other comments estimate labor cost represents the best overall multiply the average cost per
estimate for valuing the average cost of establishment by the probability that the
establishment will need to undertake number of establishments in each size (number of small establishments x costs
the expense (one minus the probability category (from the survey) by the per small establishment) +
that the establishment is already doing average costs per establishment in that (number of large establishments x costs
it). For each provision of the final rule, category. We then adjust for the per large establishment) +
the simulation carried out the following establishments that did not respond to (number of warehouses x costs per
calculation: the survey but are believed to be in the warehouse).
Cost per unit of analysis for each industry. Two hundred thirty-eight The rule is complex and the industry
provision = establishments responded to the survey; is made up of very different kinds of
number of units of analysis per we estimate that 1,566 firms are in the firms, so cost estimates are averages
establishment x industry, including ingredient with, in some cases, large variances. The
probability that establishment incurs suppliers. The number of firms covered cost per unit, number of batches and
cost x by most of the provisions will therefore employees, and probability that the
cost per provision per establishment. be about 1,460. establishment would incur the cost all
We estimate both a setup cost (a one- We estimate total costs with the contain uncertainty. The values in table
time fixed cost) of the provision and an following calculation: 28 of this document are used in the cost
annual recurring cost. To get the total (Number of very small establishments x estimates, and are generated from
costs of the rule, we multiply the costs per very small establishment) + multiple sources.
TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS

Average wage per hour $26 Employment Index, Bureau of Labor Statistics
(Ref. E24)
Average size of establishments in square feet very small = 24,674 Ref. E2

small = 71,354
large = 596,000
Average number of employees very small = 7.6 Ref. E2

small = 95
large = 1,005
Procedures 8 to 16 hours setup time for small firms; 30 to Ref. E25

40 hours for large firms; annual cost is 10
percent of setup time per provision
Personnel sanitation 1 hour per week per worker Assumption, based on requirements of final
rule
Sanitation time for physical plant 1 hour per week for very small establish- Assumption, based on difference in average
ments; costs per small and large plants physical plant size
scaled in proportion to size of plant
Sanitation supervisor 1 hour per week Assumption, based on requirements of final

rule
Pest control setup costs $1,500 to $2,000 for very small establish- Ref. E26
ments; $1,800 to $2,400 for small estab-
lishments; $2,600 to $3,400 for large es-
tablishments. Average for each size estab-
lishment was midpoint ($1,750, $2,100,
$3,000)
Pest control annual costs $400 to $600 per month for very small estab- Ref. E26
lishments; $480 to $720 for small establish-
ments; $700 to $1,000 for large establish-
ments. Average for each size establish-
ment was the midpoint ($500, $600, $850)
Renovation cost $50 per square foot; with 0 to 20 percent of Based on construction costs and square feet
physical plant to be renovated, with 10 per- (Ref. E2)
cent most likely
Equipment replacement For very small establishments, 0 to $1,000; Assumption, based on size of establishments
costs per small and large plants scaled in (Ref. E2)
proportion to size of plant
Setup costs for automatic equipment $500 for hardware, 16 hours Software costs and assumptions about labor
hours
Annual costs for automatic equipment 10 percent of setup costs Assumption based on requirements of the
final rule
TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS—Continued

Sanitation of equipment and surfaces 5 hours per week for very small establish- Assumption based on average sizes of estab-
ments; costs per small and large plants lishments (Ref. E2)
scaled in proportion to size of plant
Holding products and dietary ingredients: Cap- Same as costs of equipment upgrades Based on average sizes of establishments
ital requirements (Ref. E2)
Default probabilities that establishments are For very small establishments, 0.2; for small Based on results of survey for other practices
not currently acting in accordance with a establishments, 0.05, for large establish- (Ref. E2)
provision ments, 0.01
The total setup costs for this final rule estimated costs. Using plausible $322 million, with a mean estimate of
will be $41 million, spread out over the assumptions about the uncertain $164 million. The rule will not be fully
36 months following the publication variables, we estimate that total effective until 36 months after the
date of the final rule. The annual costs, quantified costs most likely will fall publication date. Table 29 of this
once the final rule is fully implemented, within a range of $104 million to $322 document shows how the phase-in of
will be $164 million, with the two million per year. the final rule will generate the costs and
largest costs being $52 million for quantifiable benefits for the first 4 years.
8. Summary of Benefits and Costs
testing and $24 million for records. The Table 30 of this document shows the
estimated total cost is the mean of a We estimate that, once it is fully present and annualized values of costs
range of estimates based on the data and implemented, the annual quantified and quantifiable benefits over 20 years,
assumptions described in tables 27 and benefits from the final rule will be $8 calculated at discount rates of 3 percent
28 of this document. In the uncertainty million to $64 million, with a mean and 7 percent. We have determined,
and sensitivity analyses in section estimate of $44 million. However, there based in part on the analysis presented
XXIV.B.11 of this document, we show are potentially large benefits of the rule here, that the benefits, quantified and
how uncertainty and different that we were not able to quantify. The unquantified, of this final rule justify
assumptions generate higher or lower annual costs will be $104 million to the costs.
TABLE 29.—COSTS AND QUANTIFIABLE BENEFITS BY YEAR

1st year 2nd year 3rd year 4th year
Costs (in millions) $16 $120 $190 $164
Benefits (in millions) $3 $29 $44 $44
TABLE 30. PRESENT AND ANNUALIZED VALUES OF COSTS AND QUANTIFIABLE BENEFITS
Present value at 3 percent Present value at 7 percent Annualized Value over 20 Annualized Value over 20
(in billions) (in billions) years at 3 percent (in millions) years at 7 percent (in millions)
Costs $2.3 $1.6 $153 $149
Benefits $0.6 $0.4 $40 $39
In table 31 of this document we show for particular activities for some of the the benefits by type of benefit rather
the annual costs for each subpart of the subparts. We are unable to estimate than by provision of the final rule.
regulation. We identify selected costs benefits by subpart, because we estimate
TABLE 31.—COSTS BY SUBPART

Subpart Setup Cost (in millions) Annual Cost (in millions)
A. General provisions not applicable not applicable
B. Personnel $1.5 $15.7
C. Physical plant and grounds $34.0 $17.4
D. Equipment and utensils $0.9 $2.3

E. Establish production and process control system $0.5 $66.1

Subtotal for identity testing negligible $45.0
Subtotal for all other testing $0.3 $ 6.8
TABLE 31.—COSTS BY SUBPART—Continued

Subpart Setup Cost (in millions) Annual Cost (in millions)
F. Quality control negligible $2.1
G. Components, packaging, labels, and dietary supple-

ments received negligible $31.6
H. Master manufacturing record $0.1 negligible
I. Batch production record negligible $5.4
J. Laboratory operations $0.2 negligible
K. Manufacturing operations negligible $2.2
L. Packaging and labeling operations $0.1 $10.8
M. Holding and distributing $2.7 $0.5
N. Returned dietary supplements negligible $0.2
O. Product complaints $0.1 $4.5
P. Records and recordkeeping not applicable not applicable
Paperwork cost for all subparts $3.7 $24.2
(Comment 357) We received several supplements. We expect that the estimates are based on the comments
comments on the summary of the costs majority of these costs will be borne by received and the corrections made to the
and benefits. In general, the comments consumers of dietary supplements, who data.
state that we overestimated the benefits will likely respond to the increase in Using the same method as used in this
of the 2003 CGMP Proposal and prices by reducing consumption. final rule to determine benefits, we
underestimated the costs. Other The comments suggesting very high estimate that the quantifiable benefits of
comments assert that total estimated costs and very low benefits did not the 2003 CGMP Proposal would be
benefits of the 2003 CGMP Proposal persuade us that those extreme values
would not be $216.6 million, as approximately the same as the
were more likely than our estimates. We
estimated by us, but as low as $13.9 quantifiable benefits of the final rule,
recognize, however, that the
million. Comments also estimate first- $44 million per year.
uncertainties in our analysis make a
year costs as high as $629 million, with broad range of benefits and costs With the corrected estimated number
annual costs estimated as high as $860 possible. In the analysis of uncertainty, of batches produced, we estimate that
million. Other comments predict we will show the range of predicted the setup costs of the 2003 CGMP
product prices will increase, and benefits and costs. We also will show Proposal would be $51 million. If the
consumers will decrease consumption the sensitivity of costs and benefits to 2003 CGMP Proposal had been
of dietary supplements. certain key assumptions used in the finalized, the annual costs of complying
(Response) We agree with the analysis, and how changes in those with the requirements would be $282
comments stating that we assumptions can generate the extreme million, or about $118 million more
underestimated the costs and values cited in some comments. than this final rule. The 2003 CGMP
overestimated the quantified benefits of Proposal relied more on testing final
9. Benefits and Costs of Regulatory
the 2003 CGMP Proposal. We have products and other controls closer to the
Options
increased our estimate of costs in this end-product. Under the 2003 CGMP
final rule compared with the estimate in We considered several regulatory Proposal, for example, annual testing
the 2003 CGMP Proposal. We have options, including: (1) No new costs would be about $97 million.
decreased our estimate of quantified regulatory action, (2) fewer
benefits of the final rule compared with requirements for vitamins and minerals, 10. Cost Effectiveness Analysis
the estimate in the 2003 CGMP (3) more restrictive regulations than the
Proposal. As explained previously, we final rule, (4) HACCP without the other Both benefit-cost analysis and cost-
are unable to quantify all of the benefits elements of the final rule, (5) final effectiveness analysis provide a
of the final rule. These changes in the product testing only, (6) a final rule for systematic framework for identifying
estimated benefits and costs of this final high-risk products or hazards only, and and evaluating the likely outcomes of
rule reflect both the changes in the 2003 (7) the 2003 CGMP Proposal. Although alternative regulatory choices. OMB
CGMP Proposal and the changes in our we received no comments on our Circular A–4 requires that major
analysis in response to comments. analysis of the benefits and costs of rulemakings be supported by both types
We agree with the comment that part options 2 through 6, we received many of analysis wherever possible. A cost-
of the costs of this final rule will be comments on the estimated benefits and effectiveness analysis is particularly
passed on to consumers as higher prices costs of the 2003 CGMP Proposal. We useful when the primary benefits of the
for dietary supplements. The annual have now revised the estimated rulemaking are improved public health
costs of this final rule are less than 1 quantifiable benefits and costs of the
percent of total spending on dietary 2003 CGMP Proposal. The revised
and safety.18 The main advantage of 11. Uncertainties in the Analysis For the baseline estimates, we assume
measures of effectiveness are that they We used indirect measures of the $5 million is the value of a statistical
account for a rule’s impact on morbidity benefits of this final rule which required life and $300,000 is the value of a
(nonfatal illness, injury, impairment, several key assumptions that are critical quality-adjusted life year. The estimated
and quality of life) as well as premature for our estimates. With the exception of health benefits change with changes in
death. The inclusion of morbidity the recall benefit, which is based those valuations.
effects is important because some directly on our recall records, each Finally, we assume that the reported
illnesses (e.g., asthma) cause more component of the estimated benefits recalls that occurred from 1990 through
instances of pain and suffering than involves assumptions that reflect our 1999 represent the number and type of
they do premature death. uncertainty. The estimated costs also recalls that would have occurred but for
The primary benefits expected to embody key assumptions that reflect our the implementation of this regulation.
result from this rulemaking are reduced uncertainty. The cost model also relies on several
numbers of acute and chronic illnesses One assumption that affects both key assumptions. We assume that single
and reduced number of recalls involving estimated costs and estimated benefits is shipment lots of ingredients and
dietary supplement products. We were that manufacturing practices in the unlisted components will be used for
not able to quantify chronic illnesses industry will persist in the absence of many batches of final dietary
that could be avoided as a result of this additional regulation. If the trend in the supplement products. We assume that
rulemaking. We were able to determine market is toward the adoption of more all testing other than identity testing of
that we could avoid about $40 million manufacturing controls than we are incoming ingredients will be done on
annually in costs of acute illnesses and proposing here, then both the costs and representative samples. The number of
$4 million in avoided recalls as a result benefits of the rule will be less than we batches or lots tested will be the square
of improved dietary supplement estimate. If the market trend is toward root of n + 1, with n equal to the total
manufacturing. fewer voluntary controls, then both the number of batches or lots.
We can use the $40 million annually costs and benefits of the regulation will
in avoided acute illnesses costs to We also assume that the costs per test,
be greater than we estimate. which include the labor costs of
calculate a cost-effectiveness measure In addition to the general assumption
for this rule; $40 million in reduced selecting the samples and arranging for
about the effects of the rule, we rely on
illness costs translates into 48,662 the tests, will be between $20 and $150,
several key assumptions.
QALDs saved on an annual basis. Given We assume there is an average of one with $50 most likely.
that the annual costs of this final rule reported illness for each class 1 and 2 We first characterized the
are expected to be $164 million, the cost recall. uncertainties as a probability
of each QALD saved is $3,370. This is The frequency of actual illnesses is distribution. We ran 5,000 computer
an overestimate of the cost of a QALD 100 times the frequency of reported simulations to estimate both benefits
saved because we were unable to illnesses. We recognize that there is and costs. The simulations used
quantify the benefits of reduced chronic considerable uncertainty about the distributions (given in the tables and the
illness as a result of this rulemaking. factor of 100. text) in place of point estimates.
TABLE 32.—DISTRIBUTION OF SIMULATION RESULTS FOR ANNUAL BENEFITS AND COSTS

5th Percentile Mean 95th Percentile
Annual costs (in millions) $109 $164 $260
Annual quantified benefits (in millions) $36 $44 $54
The Monte Carlo computer the sensitivity analysis, we use values of effects of reporting rates of 2.5 percent
simulations give the distributions of $3 million for a statistical life and and 10 percent.
estimated benefits and costs. If the $100,000 for a quality-adjusted life year (Comment 358) Several comments
underlying distributions fully capture to generate a ‘‘low’’ estimate of health questioned our assumption that the final
the uncertainty of the estimates, then benefits and values of $7 million and rule will eliminate the recalls used to
the simulation results give a full picture $500,000 to generate a ‘‘high’’ estimate. estimate benefits.
of the uncertainty. With uncertain (Response) We do not assume that all
The reporting rate of illnesses
distributions used in the simulations, recalls will be eliminated; we only
however, the ranges reported in the associated with dietary supplements is
unknown, which makes our estimate of assume that the recalls caused by
tables may not fully capture the manufacturing problems identified
uncertainties of the analysis. An the total number of illnesses highly
previously will be eliminated if the rule
alternative way to show the uncertainty uncertain. We use 1 percent as the
is fully effective. If the rule is not fully
is to see how sensitive the results are to average reporting rate, which implies effective, then the quantified benefits
plausible changes in certain key that total illness are 100 times our will be less than we have estimated. In
assumptions. We start with benefits. estimate of reported illnesses. Although the following discussion we show the
For our baseline estimated benefits of we assume this reporting rate is the effects of different assumptions about
this final rule, we use a $5 million value most plausible for illnesses associated the effectiveness of the final rule.
for a statistical life (VSL) and a $300,000 with dietary supplements, the evidence The quantified benefits depend on the
value for a quality-adjusted life year. In supporting it is not strong. We show the hazards found in recalled products
18It should be noted that many of the benefits of
this rule are quality benefits that are not quantified

and will not be part of this analysis.
between 1990 and 1999. The 69 recalls recalls for the decade. In this sensitivity also consider the effects of using the
in 1998 dominate the estimate, analysis we estimate the effect of annual average number of recalls from
accounting for 58 percent of class 1 and excluding 1998 from the data used to 2000 through 2005 to estimate benefits.
class 2 recalls, and 35 percent of all estimate average annual benefits. We
TABLE 33.—SENSITIVITY OF BENEFITS

Estimated Annual Benefits
Description (after 3 years) (in millions)
Final rule $44
VSL = $3 million and $/QALY = $100,000 (baselines are $5 million and $300,000) $24
VSL = $7 million and $/QALY = $500,000 (baselines are $5 million and $300,000) $64
Each recall represents one illness, with reporting rate of 10 percent (baseline is 1 percent) $8
Each recall represents one illness, with reporting rate of 2.5 percent (baseline is 1 percent) $20
Final rule reduces manufacturing recalls by 80 percent (baseline is 100 percent) $35
Exclude 1998 recalls from estimate, so average annual number of manufacturing recalls is 14 (baseline is
19.5) $27
Average annual number of manufacturing recalls = 2000–2005 average, so average per year is 10 (baseline
is 19.5) $26
In the sensitivity analysis of annual or decreased, or if our original data batches by estimating costs for 50
costs, we change assumptions about the overstated or understated the correct percent less and 50 percent more
numbers covered by the rule, the number, then the estimated costs will be batches than estimated from the survey.
number of batches produced per either too low or too high. We show the The number of shipment lots and the
establishment, the number of lots per effects of different numbers for one
cost per test determine identity testing
batch, the average costs per test, and the arbitrarily lower number covered and
costs, the single largest contributor to
rate of verification testing. one arbitrarily higher number covered.
The number of establishments The number of batches produced is annual costs. We show how the costs
covered is uncertain because we based our basic measure of output. Annual vary if the average number of batches
it on voluntary survey responses and costs therefore vary directly with this per lot is 1 or 12. We vary the average
other evidence from the 1990s. If the measure and its components. We show cost per test from $20 to $100.
number of establishments has increased how the costs depend on the number of
TABLE 34.—SENSITIVITY OF COSTS

Estimated Annual Cost
Description (after 3 years) (in millions)
Final rule $164
Number of covered establishments is 1,300 (baseline is 1,460) $148
Number of covered establishments is 1,600 (baseline is 1,460) $178
Number of batches are 50 percent of baseline (baseline is 444, 2,436, and 1,164) $104
Number of batches are 150 percent of baseline (baseline is 444, 2,436, and 1,164) $224
1 batch of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5) $322
12 batches of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5) $136
Average cost per test is $20 (baseline is $60) $129
Average cost per test is $100 (baseline is $60) $197
We combine the results of the costs will be $104 million to $322 required by the Regulatory Flexibility
sensitivity analyses to generate overall million. Act (5 U.S.C. 601–612). If a rule has a
ranges for benefits and costs. We significant economic impact on a
C. Final Regulatory Flexibility Analysis

estimate that, once it is fully substantial number of small entities, the
implemented, the annual benefits, able 1. Introduction Regulatory Flexibility Act requires
to be quantified, from the final rule will We have examined the economic agencies to analyze regulatory options
be $8 million to $64 million; the annual implications of this final rule as that would lessen the economic effect of
the rule on small entities. We find that wholesalers, and other holders likely to establishments depending on current
this final rule will have a significant be covered by this regulation to be practices and the types of products
economic impact on a substantial 15,689, of which 15,421 are small manufactured, packaged, labeled, or
number of small entities. businesses. held. We estimated the range of current
The small establishments that will be practices using the survey of the
2. Economic Effects on Small Entities
affected by the final rule are those industry. The cost model, which we
a. Number of small entities affected. establishments that will have to perform describe in detail in section XXIV.B.7 of
The final rule will affect many small the various required activities, and this document, divided establishments
entities. A small business in this would not have done so without the by size, which allowed us to estimate
industry is any establishment with rule. We determined estimated baseline the distribution of costs per
fewer than 500 employees. For purposes (pre-CGMP requirements) establishment for each size and product
of the cost-benefit analysis, we also manufacturing practices with the survey class. Table 35 of this document shows
looked at the category we call very small of the industry (Ref. E2). The survey the cost per establishment for very small
establishments: Establishments with asked representative respondents to and small establishments. For
fewer than 20 employees. Based on the answer a series of questions, including comparison, we include the estimated
survey (Ref. E2), we estimated that 774 how many employees they had and average cost per large establishment and
establishments, 53 percent of the total what their existing practices were. From the median revenues for each size
establishments, could be classified as the survey, we determined that small category. As table 35 of this document
very small (under 20 employees) and establishments do not now follow all of shows, costs per establishment are
526 as small (20 to 499 employees), the provisions of the final rule. Those proportionally higher for very small
which is 36 percent of the total that do not follow all the applicable than for large establishments. The
establishments. Based on the results of provisions will incur a cost to do so. table’s most striking result is that annual
the survey (Ref. E2), we estimated the b. Costs to small entities. costs are highest for small (20 to 499
total number of warehouses, Implementation costs vary across employees) establishments.
TABLE 35.—COSTS PER ESTABLISHMENT, BY SIZE

Setup Costs per Annual Costs per Median Annual Revenue per
Establishment Establishment Establishment
Very small establishments $26,000 $46,000 Under $1 million
Small establishments $20,000 $184,000 $5 to $10 million
Large establishments $31,000 $69,000 $10 to $50 million
Warehouses, wholesalers, and other holders $360 $1,000 Not applicable
TABLE 36.—TOTAL COSTS BY ESTABLISHMENT SIZE

Percent of Total Setup Percent of Total Annual
Setup Costs Annual Costs
Costs Costs
Very small establishments $20 million 49 percent $38 million 23 percent
Small establishments $10 million 24 percent $98 million 60 percent
Large establishments $5 million 12 percent $11 million 7 percent
Warehouses, wholesalers, and other holders $6 million 15 percent $17 million 10 percent
Small establishments that do not average costs, could be hard pressed to We ran the model for the final rule.
perform a substantial number of the continue to operate. Some of these may The model predicts that, as a result of
actions required by the final rule will decide it is too costly and either change the final rule, 140 very small and 32
bear relatively high costs for compliance product lines or go out of business. small dietary supplement manufacturers
with the provisions of this final rule. We use a model developed under will be at risk of going out of business.
Although the final rule will raise contract by Eastern Research Group to The model estimates the number of
product prices, the price increase estimate the effects of FDA regulations workers in those firms to be about 2,250.
(which would largely be determined by on small businesses (Ref. E27). The The regulatory costs of this final rule
changes made by large establishments)
model is designed to assess the effects will also discourage new small
may be much smaller than the increase
of a wide range of potential regulatory businesses from entering the industry.
in the average costs of very small
activities, ranging from HACCP to The dietary supplement has been
producers. The average burden to very
small establishments will be about 4 product labeling. CGMP regulations are characterized by substantial entry of
included as a potential regulatory small businesses. Although we cannot
percent of annual revenue. The average

burden to small establishments will be activity. The model allows us to predict quantify how much that will change, we
1.5 to 3 percent of annual revenue. the probability and frequency of small expect that the rate of entry of very
Establishments with above average business failure as a result of our small and small businesses will
costs, and even establishments with regulations. decrease.
3. Regulatory Options 4. Description of Recordkeeping and Some small firms estimate annual
Reporting testing costs for the 2003 CGMP
a. Exemptions for small entities. The Proposal as high as $600,000, as
burden on small establishments would The Regulatory Flexibility Act
requires a description of the opposed to the $60,000 per year
be reduced if they were exempt from estimated by us. Another firm estimates
some provisions of the final rule. Most recordkeeping and reporting required
for compliance with this final rule. This setup costs in the range of 4 to 7 times
entities (we estimate close to 90 percent) our estimate and annual costs 8 to 30
affected by this final rule, however, are final rule will require the preparation of
records. As described in the 2003 CGMP times our estimate. Comments also
small. Exempting small establishments express concern that we have
from some or all of its provisions would Proposal, Preliminary Regulatory Impact
Analysis, written records or electronic underestimated the number of
substantially reduce benefits. businesses forced to close if this rule is
documents must be kept that
b. Longer compliance periods. demonstrate that specific actions made final as proposed; one comment
Lengthening the compliance period occurred in the manufacturing process states that the rule would cause 50
provides some regulatory relief for in compliance with the final rule. percent of small businesses to shut
businesses with fewer than 500 Records that will be required in this down. Some comments assert that this
employees. The longer compliance final rule will demonstrate that rule is anti-competitive: That is, the
period will allow additional time for corrective actions were taken; that comments claim that this rule will make
setting up recordkeeping, making equipment, instruments, and controls dietary supplement manufacturing so
capital improvements to the physical used in laboratory operations and expensive that only large companies
plant, purchasing new or replacement quality control were installed and will survive. In addition, a few
equipment, and other one-time calibrated properly; that maintenance comments note the loss of product
expenditures. It will also delay the programs were followed; and that the choice, innovation, and domestic
impact of the annual costs of results of any testing show that employment that accompany firm
compliance. We have given businesses components or dietary supplements closures, in addition to the increase in
with fewer than 20 employees an meet the established specifications. prices of products made by remaining
additional 24 months and businesses The compliance cost of recordkeeping firms. In addition, another comment
with fewer than 500 but 20 or more is the sum of both the initial design and suggests that foreign manufacturers will
employees an additional 12 months for printing of the recordkeeping be at an advantage because they will not
compliance. The final rule, then, will be documents and the recurring costs of have to comply with the rule’s
phased-in over 36 months, with firms maintaining the records. The cost of requirements.
with 500 or more employees complying training personnel to use the new Some comments reiterate the points
after 12 months, firms with under 500 documents is a recurring cost depending made earlier that the use of statistical
but 20 or more employees after 24 on how frequently documents are sampling and supplier certificates of
months, and firms with fewer than 20 modified, how often personnel turn analysis could help reduce the burden
employees after 36 months. The cost over, and how complicated the tasks are on small business.
savings of delay may well be larger than that are being recorded. The recurring One comment states that it would be
simply the present value of the delay costs are measured by the workers’ wage extremely costly for small firms to come
because the firms with fewer than 500 rate multiplied by the expected labor into compliance with the 2003 CGMP
employees may also be able to reduce hours necessary for a written or Proposal, especially because, as several
their compliance costs by taking electronic record and the time necessary firms pointed out, small firms often
advantage of increases in industry for management to review the records to produce batches that are small in size.
knowledge and experience in see that actions are documented A few comments, however, say that
implementing these regulations. accurately. In addition, electronic small firms should be made to comply
c. Reduced requirements in the final records necessitate recurring time spent with the new rule at the same time as
rule. The modification of requirements ensuring that the equipment is serviced large firms.
in this final rule, compared with the and maintained properly. We received many comments on the
2003 CGMP Proposal, significantly compliance period of this rule. Some of
reduce the costs borne by small 5. Summary these comments favor the extended
businesses. We estimate the average The final rule will have a significant compliance periods granted to small
setup costs under the 2003 CGMP economic impact on a substantial and very small firms. Other comments
Proposal to be $25,000 for very small number of small entities. do not support the compliance periods,
establishments and $40,000 for small (Comment 359) We received many stating that they are not long enough for
establishments. We estimate that the comments on the 2003 CGMP Proposal firms to set up recordkeeping systems,
annual costs of the 2003 CGMP Proposal Preliminary Regulatory Flexibility make capital improvements, and so on.
would be $90,000 for very small Analysis. Nearly all of the comments Other comments do not favor granting
establishments and $300,000 for small addressing small business state that the small firms more time to comply. Three
establishments. The final rule therefore requirements of the 2003 CGMP comments state that granting small firms
reduces annual costs for very small Proposal, the testing requirements in a longer compliance period defeats the
establishments to about half of the particular, would be an enormous purpose of the rule, by making it
estimated costs of the proposed rule and burden on small business. Other difficult for consumers to determine
reduces costs for very small comments assert that, because of this which dietary supplements comply with
establishments to about 60 percent of burden, the rule is in violation of the the CGMPs and which do not yet
the estimated costs of the 2003 CGMP Regulatory Flexibility Act. In addition, comply. Another comment suggests that
Proposal. Under the 2003 CGMP comments assert small business will be products made by firms not in
Proposal, 216 very small and 50 small particularly burdened by the rule and compliance 1 year after the rule’s
businesses would be at risk of going out that consumers will see little effective date be labeled to say, ‘‘This
of business, over 50 percent more than improvement in product safety as a product may not conform to government
under the final rule. result. standards for purity and potency.’’
Other comments propose a single D. Unfunded Mandates U.S. exports demanded, particularly in
compliance period for all firms. The Unfunded Mandates Reform Act comparison with exports from countries
(Response) We disagree with of 1995 (Public Law 104–4) requires that do not implement similar
comments that the burden of this final regulations. We expect this effect to be
cost-benefit and other analyses for rules
rule violates the Regulatory Flexibility insignificant, because under the final
that would cost more than $100 million
Act. The act requires agencies to rule the increases in the price of U.S.
in a single year. The current (2005)
consider the burden of their regulatory exports (and resulting decreases in
inflation-adjusted statutory threshold is
proposals on small entities, analyze and quantity demanded) will be quite small.
$122 million. This final rule qualifies as
consider effective alternatives that
a significant rule under the statute. Most XXV. Analysis of Environmental
reduce the burden on small entities, and
of the requirements of the Unfunded Impact
make their analyses available for public
Mandates are fulfilled in the Executive
comment. We have considered the We have carefully considered the
Order 12866 analysis. The requirements
burden of this final rule on all covered potential environmental effects of this
firms, including small businesses, and under the Unfunded Mandates Reform
Act of 1995 include assessing the rule’s action. We have concluded under 21
as a result have modified certain CFR 25.30(h) that this action is of a type
requirements to reduce the costs of the effects on future costs; productivity;
particular regions, communities, or that does not individually or
final rule as compared with the 2003 cumulatively have a significant effect on
CGMP Proposal. In addition, small industrial sectors; economic growth; full
employment; job creation; and exports. the human environment. Therefore,
businesses are allowed more time to neither an environmental assessment
comply with the rule. The burden on The future costs from the rule are the
recurring costs, which reach their long- nor an environmental impact statement
small businesses remains large, but the is required.
Regulatory Flexibility Act does not term value in the third year after the
require agencies to adopt regulations effective date of this rule. These costs XXVI. Federalism
that impose the least burden on small would be incurred, directly or
indirectly, by the establishments that We have analyzed this final rule in
entities. In addition, the Data Quality accordance with the principles set forth
Act has been fulfilled by using the most manufacture, process, pack, label,
transport, distribute, receive, hold, or in Executive Order 13132. We have
objective data available. In this analysis,
import dietary supplements or determined that the final rule does not
we used data from surveys and from
ingredients. Recurring costs from the contain policies that have substantial
other Federal agencies. Although more
regulatory requirements will be incurred direct effects on the States, on the
data are desirable, we consider the
in each future year. Table 29 of this relationship between the National
quality of the data used in this analysis
document summarizes the annual future Government and the States, or on the
and in the references to be the best
recurring costs. distribution of power and
available and sufficient to fulfill the
The costs, direct and indirect, of the responsibilities among the various
requirements of the Regulatory
rule will be shared among levels of government. Furthermore, we
Flexibility and Data Quality Acts.
We have reduced the amount of manufacturers, processors, packagers, did not receive any comments from
testing required in this final rule in transporters, receivers, holders, and States or their representative
response to comments on the burden of importers of dietary supplements or organizations regarding to our analysis
testing costs on the 2003 CGMP ingredients, as well as domestic of the proposed rule regarding the
Proposal. As explained in Section consumers. Much of the higher costs principles set forth in Executive Order
XXIV.B.7 of this document, we incurred by domestic suppliers of 13132. Accordingly, we conclude that
underestimated costs in the proposed dietary supplement products as a result the final rule does not contain policies
rule because of an error in a contractor’s of these regulations will be passed on to that have federalism implications as
report. We have corrected the cost consumers as higher prices. The higher defined in the Executive order and,
calculations, including estimated testing prices will be offset by the benefits from consequently, a federalism summary
costs, for this final regulatory flexibility these regulations. impact statement is not required.
analysis. Although this final regulation is XXVII. References
We note that foreign firms that sell significant, we do not expect it to
dietary supplements in the United substantially affect national The following references have been
States are required to be in compliance productivity, growth, jobs, or full placed on display in the Division of
with the final rule. employment. The dietary supplement Dockets Management (HFA–305), Food
In response to comments on the industry is too small a part of the and Drug Administration, 5630 Fishers
number of firms likely to go out of domestic economy to influence overall Lane, rm. 1061, Rockville, MD 20857,
business, we have used our small economic activity. and may be seen by interested persons
business model to estimate that 172 This final rule will require additional between 9 a.m. and 4 p.m., Monday
small and very small firms will be at controls throughout the production and through Friday. (FDA has verified the
risk of going out of business. Many other distribution chain for the manufacture Web site addresses, but FDA is not
small firms—some of them already of dietary supplements. The additional responsible for any subsequent changes
experiencing financial difficulties–may costs will increase the total costs of to the Web sites after this document
see their financial condition worsen as production and distribution for all of publishes in the Federal Register.)
a result of this final rule. the regulated products, including 1. U.S. Food and Drug Administration,
We disagree with the comments that products sold within the United States Memorandum of Site Visit, August 10, 1999,
oppose longer compliance periods for and across national borders. These to General Nutrition Products, Inc.,
small businesses. The additional time increased costs will be partly passed on Greenville, SC. Memorandum dated October
25, 1999 by Roslyn F. Powers, Ph.D., Center
will only slightly delay the full to consumers in the form of higher for Food Safety and Applied Nutrition.
implementation (and full benefits) of prices, which will tend to reduce the 2. U.S. Food and Drug Administration,
this final rule, and may provide the quantity demanded of the regulated Memorandum of Site Visit, August 11, 1999,
margin of survival for some small products. The increased prices of U.S. to Perrigo Company of South Carolina, Inc.,
businesses. exports could reduce the quantity of Greenville, SC. Memorandum dated October
25, 1999 by Roslyn F. Powers, Ph.D., Center Infections of the gastrointestinal tract, 2nd (Press releases available at http://
for Food Safety and Applied Nutrition. ed. Eds: Blaser MJ, Smith PD, Ravdin JI, www.fda.gov/oc/po/firmrecalls/
3. U.S. Food and Drug Administration, Greenberg HB, Guerrant RL. Lippincott archive_2001.html).
Memorandum of Site Visit, August 17, 1999, Williams & Wilkins, Philadelphia, 2002. 27. ‘‘Sanitizing Rinses (for previously
to Takeda Vitamin and Food, Inc., Pages 669–697. cleaned food-contact surfaces), DIS/TSS–4
Wilmington, NC. Memorandum dated 17. Skirrow MB, Blaser MJ. Campylobacter Efficacy Data Requirements’’ Disinfectant
October 25, 1999 by Roslyn F. Powers, Ph.D., jejuni. In, Infections of the gastrointestinal Technical Science Section (DIS/TSS), U.S.
Center for Food Safety and Applied tract, 2nd ed. Eds: Blaser MJ, Smith PD, Environmental Protection Agency, Jan 30,
Nutrition. Ravdin JI, Greenberg HB, Guerrant RL. 1979. Available on the Internet at http://
4. U.S. Food and Drug Administration, Lippincott Williams & Wilkins, Philadelphia, www.epa.gov/oppad001/dis_tss_docs/dis-
Memorandum of Site Visit, September 21, 2002. Pages 720–739. 04.htm.
1999, to Pharmavite Corporation, San 18. Griffin PM, Mead PS, Sivapalasingam 28. ‘‘Guide to Minimize Microbial Food
Fernando, CA. Memorandum dated October S. Escherichia coli O157:H7 and other Safety Hazards for Fresh Fruits and
25, 1999 by Roslyn F. Powers, Ph.D., Center enterohemorrhagic E. coli. In, Infections of Vegetables,’’ U.S. Food and Drug
for Food Safety and Applied Nutrition. the gastrointestinal tract, 2nd ed. Eds: Blaser Administration, October 26, 1998. Available
5. U.S. Food and Drug Administration, MJ, Smith PD, Ravdin JI, Greenberg HB, on the Internet at http://www.cfsan.fda.gov/
Memorandum of Site Visit, September 21, Guerrant RL. Lippincott Williams & Wilkins, ~dms/prodguid.html.
1999, to Shaklee Manufacturing Center, Philadelphia, 2002. Pages 627–642. 29. Human Drug CGMP Notes, Volume 5,
Norman, OK. Memorandum dated October 19. Information accessed February 2005. Number 4, Division of Manufacturing and
25, 1999 by Roslyn F. Powers, Ph.D., Center Available at http://www.fsis.usda.gov/ Product Quality, Office of Compliance,
for Food Safety and Applied Nutrition. Science/Microbiology/index.asp. Center for Drug Evaluation and Research, U.
6. U.S. Food and Drug Administration, 20. DePaola A, Ulaszek J, Kaysner CA, S. Food and Drug Administration, December
Memorandum of Site Visit, September 22, Tenge BJ, Nordstrom JL, Wells J, Puhr N, 1997. Available on the Internet at http://
1999, to Botanicals International, Long Gendel SM. Molecular, serological, and www.fda.gov/cder/hdn/cnotesd7.pdf.
Beach, CA. Memorandum dated October 25, virulence characteristics of Vibrio 30. ‘‘Action Levels For Poisonous Or
1999 by Roslyn F. Powers, Ph.D., Center for parahaemolyticus isolated from Deleterious Substances In Human Food And
Food Safety and Applied Nutrition. environmental, food, and clinical sources in Animal Feed,’’ Industry Activities Staff,
7. Slifman NR, Obermeyer WR, Aloi BK, North America and Asia. Applied and Center for Food Safety and Applied
Musser SM, Correll WA, Cichowicz SM, Betz Environmental Microbiology 2003;69:3999– Nutrition, U.S. Food and Drug
JM, Love LA. Contamination of Botanical 4005. Administration, August 2000. Available on
Dietary Supplements by Digitalis Lanata. The 21. Monsalud RG, Magbanua FO, Tapay the Internet at http://www.cfsan.fda.gov/
New England Journal of Medicine. LM, Hedreyda CT, Olympia MS, Migo VP, ~lrd/fdaact.html.
1996;339:806–11. Kurahashi M, Yokota A. Identification of 31. ‘‘Hazard Analysis and Critical Control
8. U.S. Food and Drug Administration, pathogenic and non-pathogenic Vibrio strains Point Principles and Application
‘‘Aloe Commodities International, Inc., from shrimp and shrimp farms in the Guidelines,’’ National Advisory Committee
Recalls Solutions IE Ageless Formula II Due Philippines. Journal of General and Applied on Microbiological Criteria for Foods, August
to Excess Vitamin D.’’ March 26, 2004. Microbiology 2003;49:309–314. 14, 1997.
Information accessed on June 22, 2006. 22. do Nascimento SM, dos Fernandes 32. ‘‘Draft Report of the Food Advisory
Available at http://www.fda.gov/bbs/topics/ Vieira RH, Theophilo GN, dos Prazeres Committee Dietary Supplement Working
news/2004/NEW01043.html. Rodrigues D, Vieira GH. Vibrio vulnificus as Group on Ingredient Identity Testing and
9. Juran’s Quality Control Handbook (J.M. a health hazard for shrimp consumers. Records and Retention,’’ FDA Food Advisory
Juran, editor in chief & Frank M. Gryna, Revista do Instituto de Medicina Tropical de Committee Dietary Supplement Working
associate editor, 4th ed., 1988). São Paulo 2001;43:263–266. Group, Center for Food Safety and Applied
10. U.S. Food and Drug Administration, 23. Hackney CR, Ray B, Speck ML. Nutrition, FDA, June 25, 1999.
‘‘RECALLS AND FIELD CORRECTIONS: Incidence of Vibrio parahaemolyticus in and 33. ‘‘Guidance for Industry Part 11,
FOODS—CLASS I. Enforcement Report,’’ microbiological quality of seafoods in North Electronic Records; Electronic signatures—
November 24, 2004. Information accessed on Carolina. Journal of Food Protection Scope and Application’’, available at http://
July 11, 2006. Available at http:// 1980;43:769–773. www.fda.gov/cder/guidance/5667fnl.htm.
www.fda.gov/bbs/topics/enforce/2004/ 24. Morris JG. ‘‘Noncholera’’ Vibrio 34. ‘‘Dietary Supplement Labels: Key
ENF00875.html. species. In, Infections of the gastrointestinal Elements,’’ U.S. Department of Health and
11. Lee LA, Ostroff SM, McGee HB, tract, 2nd ed. Eds: Blaser MJ, Smith PD, Human Services (HHS). Office of the
Johnson DR, Downes FP, Cameron DN, Bean Ravdin JI, Greenberg HB, Guerrant RL. Inspector General (OIG), Publication No.
NH. An outbreak of shigellosis at an outdoor Lippincott Williams & Wilkins, Philadelphia, OEI–01–01–00120. Available on the Internet
music festival. American Journal of 2002. Pages 557–571. at http://oig.hhs.gov/oei/reports/oei–01–01–
Epidemiology 1991;133:608–15. 25. Ibrahim YK; Olurinola PF, Comparative 00120.pdf.
12. ‘‘Guidance for Industry: Product Microbial Contamination Levels in Wet 35. NSF International Standard/American
Recalls, Industry Removals and Corrections,’’ Granulation and Direct Compression National Standard. 2006. Dietary
Division of Compliance Management and Methods of Tablet Production. Supplements.
Operations, Office of Enforcement, Office of Pharmaceutica Acta Helvetiae 1991; 66(11): E1. Research Triangle Institute (RTI).
Regulatory Affairs, U.S. Food and Drug 298–301. Economic Characterization of the Dietary
Administration, November 3, 2003. Available 26. U.S Food and Drug Administration, Supplement Industry. Contract No. 223–96–
on the Internet at http://www.fda.gov/oc/ FDA Talk Paper, Solgar Vitamin and Herb 2290: Task Order 3, March 1999.
industry/default.htm or available at http:// Company Recalls Solgar’s Digestive Aid 100’s E2. Research Triangle Institute (RTI).
www.fda.gov/opacom/7alerts.html. Dietary Supplements Because of Possible Survey of Manufacturing Practices in the
13. ISO 9001, Quality Management Salmonella Contamination, April 26, 2001; Dietary Supplement Industry. Contract No.
Systems—Requirements. International Karuna Corporation, Karuna Corporation 223–96–2290: Task Order 6, May 2000.
Organization for Standardization. 3rd ed. Recalls HCl Nutritional Product Because of Revised, March 2004.
2000. Possible Health Risk, May 17, 2001; Licata E3. ‘‘Herbal Rx: The Promises and Pitfalls.’’
14. H.R. Conf. Rep. No. 107–481, at 135 Enterprises, Licata Enterprises Recalls 1999. Consumer Reports (March): 44–48.
(2002). Digestive Aid Products Because of Possible E4. ConsumerLab. 2000. Independent tests
15. U.S. Food and Drug Administration, Health Risk, May 18, 2001; Natural Organics, of herbal, vitamin, and mineral supplements.
Memorandum dated April 14, 2005, Tracy Inc., Natural Organics, Inc. Cooperates in the Accessed on March 16, 2005 at http://
Summers, Center for Food Safety and Recall of Digestive Aid Dietary Supplements www.consumerlab.com/results.
Applied Nutrition. Because of Possible Salmonella E5. Rothman, G. ‘‘Herbal Remedy Rip-
16. Pegues DA, Ohl ME, Miller SI. Contaminated Raw Material Supplied by offs.’’ Dallas/Fort Worth Magazine (April):
Salmonella, including Salmonella Typhi. In, American Laboratories, Inc., May 22, 2001. 39–44.
E6. Saper, Robert B., Stefanos N. Kales, Health and Human Services, Office of the PART 111—CURRENT GOOD
Janet Parquin, Michael J. Burns, David M. Surgeon General, 2004. MANUFACTURING PRACTICE IN
Eisenberg, Roger B. Davis, and Russell S. E18. Centers for Disease Control and MANUFACTURING, PACKAGING,
Phillips. ‘‘Heavy Metal Content of Ayurvedic Prevention. ‘‘Use of Vitamins Containing
Herbal Medicine Products.’’ Journal of the LABELING, OR HOLDING
Folic Acid Among Women of Childbearing OPERATIONS FOR DIETARY
American Medical Association 292
Age—United Sates, 2004.’’ Morbidity and SUPPLEMENTS
(December 15, 2004): 2868–2873.
E7. Research Triangle Institute (RTI). Mortality Weekly Report (MMWR) 2004;
Dietary Supplement Sales Information. 53:847–850. Subpart A—General Provisions
Contract No. 223–96–2290: Task Order 4, E19. Botto, Lorenzo B, Cynthia A. Moore, Sec.
October, 1999. Muin J. Khoury, and J. David Erickson, 111.1 Who is subject to this part?
E8. National Nutritional Foods ‘‘Neural Tube Defects.’’ New England Journal 111.3 What definitions apply to this part?
Association. Facts about the Nutrition of Medicine 341 (November 11, 1999): 1509– 111.5 Do other statutory provisions and
Industry. National Nutritional Foods 1519. regulations apply?
Association NNFA facts and stats. Accessed E20. Alison E. Kelly, Anne C. Haddix,
on November 29, 2004. Available at http:// Subpart B—Personnel
Kelley S. Scanlon, Charles G. Helmick, and
www.naturalproductsassoc.org/. 111.8 What are the requirements under this
Joseph Mulinare, ‘‘Cost-Effectiveness of
E9. U.S. Food and Drug Administration, subpart B for written procedures?
Memorandum, McCarthy, P. and B. Timbo, Strategies to Prevent Neural Tube Defects.’’
111.10 What requirements apply for
Center for Food Safety and Applied In Cost-Effectiveness in Health and Medicine, preventing microbial contamination from
Nutrition, Report of Adverse Health edited by Marthe R. Gold, Joanna A. Siegel, sick or infected personnel and for
Outcomes Associated With the Consumption Louise B. Russell, and Milton C. Weinstein. hygienic practices?
of Dietary Supplements Which Were (New York: Oxford University Press, 1996), 111.12 What personnel qualification
Prepared Using Poor Manufacturing pp. 313–348. requirements apply?
Practices, June 11, 2001. E21. U.S. Food and Drug Administration, 111.13 What supervisor requirements
E10. Watson, W. A., T.L. Litovitz, W. Memorandum: Vardon, P., Center for Food apply?
Klein-Schwartz, G. C. Rodgers, Jr., J. Youniss, Safety and Applied Nutrtion. Conversation 111.14 Under this subpart B, what records
N. Reid, W.G. Rouse, R. S. Rembert, and D. must you make and keep?
with industry expert regarding inventory
Borys. ‘‘2003 Annual report of the American
practices, April 4, 2000. Subpart C—Physical Plant and Grounds
Association of Poison Control Centers Toxic
Exposure Surveillance System.’’ American E22. Plant Bioactives Research Institute.
111.15 What sanitation requirements apply
Journal of Emergency Medicine 22 ‘‘Costs for Analysis.’’ Accessed on April 10, to your physical plant and grounds?
(September 2004): 335–392. 2000. Available at http://www.plant- 111.16 What are the requirements under
E11. U.S. Food and Drug Administration, bioactives.com. this subpart C for written procedures?
Memorandum, Koehler, K. M.: Tally of AERs E23. Industrial Laboratories, Fees, 111.20 What design and construction
Regarding Dietary Supplements, May 30, Methods, and Analytical Capabilities of requirements apply to your physical
2000. Laboratories–Summary. Summary of prices plant?
E12. U.S. Food and Drug Administration, listed on the Internet, 1999. 111.23 Under this subpart C, what records
‘‘RECALLS AND FIELD CORRECTIONS: E24. Bureau of Labor Statistics, Employer must you make and keep?
FOODS—CLASS I. Enforcement Report,’’ Costs for Employee Compensation—
November 24, 2004. Information accessed on Subpart D—Equipment and Utensils
September 2005, U.S. Department of Labor:
June 22, 2006. Available at http:// 111.25 What are the requirements under
www.fda.gov/bbs/topics/enforce/2004/ 05–2279; http://www.bls.gov/NCS/ect/
this subpart D for written procedures?
ENF00875.html; Slifman NR, Obermeyer WR, home.htm. 111.27 What requirements apply to the
Aloi BK, Musser SM, Correll WA, Cichowicz E25. Eastern Research Group (ERG). equipment and utensils that you use?
SM, Betz JM, Love LA. Contamination of ‘‘Economic Analysis of Proposed Revisions to 111.30 What requirements apply to
Botanical Dietary Supplements by Digitalis the Good Manufacturing Practices Regulation automated, mechanical, or electronic
Lanata. The New England Journal of for Medical Devices.’’ Contract No. 223–31– equipment?
Medicine. 1996;339:806–11; U.S. Food and 8100: Task Order 1, pp. 4–23 to 4–25, 111.35 Under this subpart D, what records
Drug Administration, ‘‘Aloe Commodities November, 1993. must you make and keep?
International, Inc., Recalls Solutions IE E26. U.S. Food and Drug Administration,
Ageless Formula II Due to Excess Vitamin Subpart E—Requirement to Establish a
Memorandum: McLaughlin, C., Center for Production and Process Control System
D.’’ March 26, 2004. Information accessed on
Food Safety and Applied Nutrition, Costs of
June 22, 2006. Available at http:// 111.55 What are the requirements to
www.fda.gov/bbs/topics/news/2004/ Pest Control, 2000. implement a production and process
NEW01043.html. E27. Eastern Research Group (ERG). Model control system?
E13. Walker, A. M. ‘‘The Relation Between for Estimating the Impacts of Regulatory 111.60 What are the design requirements
Voluntary Notification and Material Risk in Costs on the Survival of Small Businesses for the production and process control
Dietary Supplement Safety.’’ Harvard School and its Application to Four FDA-Regulated system?
of Public Health, March 9, 2000. Industries; Final Report. Contract No. 223– 111.65 What are the requirements for
E14. HCUP, Healthcare Cost and 01–2461, Task Order 1, July 12, 2002. quality control operations?
Utilization Project. Agency for Healthcare 111.70 What specifications must you
Research and Quality, Rockville, MD. http:// List of Subjects in 21 CFR Part 111 establish?
www.ahrq.gov/data/hcup/. 111.73 What is your responsibility for
E15. U.S. Departments of Health and Dietary foods, Drugs, Foods, determining whether established
Human Services and Agriculture. Dietary Packaging and containers. specifications are met?
Guidelines for Americans, 2005. 111.75 What must you do to determine
E16. Institute of Medicine, Food and ■ Therefore, under the Federal Food, whether specifications are met?
Nutrition Board. Dietary Reference Intakes Drug, and Cosmetic Act and under 111.77 What must you do if established
Tables—The Complete Set, http:// authority delegated to the Commissioner specifications are not met?
www.iom.edu/CMS/3788.aspx. Accessed on of Food and Drugs, FDA is amending 21 111.80 What representative samples must
December 3, 2004. CFR chapter I by adding part 111 to read you collect?
E17. U.S. Department of Health and as follows: 111.83 What are the requirements for
Human Services. Bone Health and reserve samples?
Osteoporosis: A Report of the Surgeon 111.87 Who conducts a material review and
General. Rockville, MD: U.S. Department of makes a disposition decision?
111.90 What requirements apply to Subpart I—Production and Process Control 111.510 What requirements apply when a
treatments, in-process adjustments, and System: Requirements for the Batch returned dietary supplement is received?
reprocessing when there is a deviation or Production Record 111.515 When must a returned dietary
unanticipated occurrence or when a 111.255 What is the requirement to supplement be destroyed, or otherwise
specification established in accordance establish a batch production record? suitably disposed of?
with § 111.70 is not met? 111.260 What must the batch record 111.520 When may a returned dietary
111.95 Under this subpart E, what records include? supplement be salvaged?
must you make and keep? 111.525 What requirements apply to a
Subpart J—Production and Process Control returned dietary supplement that quality
Subpart F—Production and Process Control System: Requirements for Laboratory control personnel approve for
System: Requirements for Quality Control Operations reprocessing?
111.103 What are the requirements under 111.303 What are the requirements under 111.530 When must an investigation be
this subpart F for written procedures? this subpart J for written procedures? conducted of your manufacturing
111.105 What must quality control 111.310 What are the requirements for the processes and other batches?
personnel do? laboratory facilities that you use? 111.535 Under this subpart N, what records
111.110 What quality control operations are 111.315 What are the requirements for must you make and keep?
required for laboratory operations laboratory control processes?
111.320 What requirements apply to Subpart O—Product Complaints
associated with the production and
process control system? laboratory methods for testing and 111.553 What are the requirements under
111.113 What quality control operations are examination? this subpart O for written procedures?
required for a material review and 111.325 Under this subpart J, what records 111.560 What requirements apply to the
disposition decision? must you make and keep? review and investigation of a product
111.117 What quality control operations are complaint?
Subpart K—Production and Process
111.570 Under this subpart O, what records
required for equipment, instruments, and Control System: Requirements for
must you make and keep?
controls? Manufacturing Operations
111.120 What quality control operations are 111.353 What are the requirements under Subpart P—Records and Recordkeeping
required for components, packaging, and this subpart K for written procedures? 111.605 What requirements apply to the
labels before use in the manufacture of 111.355 What are the design requirements records that you make and keep?
a dietary supplement? for manufacturing operations? 111.610 What records must be made
111.123 What quality control operations are 111.360 What are the requirements for available to FDA?
required for the master manufacturing sanitation?
record, the batch production record, and 111.365 What precautions must you take to Authority: 21 U.S.C. 321, 342, 343, 371,
manufacturing operations? prevent contamination? 374, 381, 393; 42 U.S.C. 264.
111.127 What quality control operations are 111.370 What requirements apply to
required for packaging and labeling rejected dietary supplements? Subpart A—General Provisions
operations? 111.375 Under this subpart K, what records
§ 111.1 Who is subject to this part?
111.130 What quality control operations are must you make and keep?
required for returned dietary (a) Except as provided by paragraph
Subpart L—Production and Process Control (b) of this section, you are subject to this
supplements? System: Requirements for Packaging and
111.135 What quality control operations are part if you manufacture, package, label,
Labeling Operations
required for product complaints? or hold a dietary supplement, including:
111.140 Under this subpart F, what records 111.403 What are the requirements under (1) A dietary supplement you
must you make and keep? this subpart L for written procedures?
111.410 What requirements apply to
manufacture but that is packaged or
Subpart G—Production and Process packaging and labels? labeled by another person; and
Control System: Requirements for 111.415 What requirements apply to filling, (2) A dietary supplement imported or
Components, Packaging, and Labels and assembling, packaging, labeling, and offered for import in any State or
for Product That You Receive for Packaging related operations? territory of the United States, the
or Labeling as a Dietary Supplement 111.420 What requirements apply to District of Columbia, or the
111.153 What are the requirements under repackaging and relabeling? Commonwealth of Puerto Rico.
this subpart G for written procedures? 111.425 What requirements apply to a (b) The requirements pertaining to
111.155 What requirements apply to packaged and labeled dietary holding dietary supplements do not
components of dietary supplements? supplement that is rejected for
distribution? apply to you if you are holding those
111.160 What requirements apply to dietary supplements at a retail
111.430 Under this subpart L, what records
packaging and labels received? establishment for the sole purpose of
111.165 What requirements apply to a direct retail sale to individual
product received for packaging or Subpart M—Holding and Distributing
labeling as a dietary supplement (and for
consumers. A retail establishment does
111.453 What are the requirements under not include a warehouse or other storage
distribution rather than for return to the this subpart M for written procedures?
supplier)? facility for a retailer or a warehouse or
111.455 What requirements apply to
111.170 What requirements apply to holding components, dietary
other storage facility that sells directly
rejected components, packaging, and supplements, packaging, and labels? to individual consumers.
labels, and to rejected products that are 111.460 What requirements apply to
received for packaging or labeling as a § 111.3 What definitions apply to this part?
holding in-process material?
dietary supplement? 111.465 What requirements apply to The definitions and interpretations of
111.180 Under this subpart G, what records holding reserve samples of dietary terms in section 201 of the Federal
must you make and keep? supplements? Food, Drug, and Cosmetic Act (the act)
Subpart H—Production and Process 111.470 What requirements apply to apply to such terms when used in this
distributing dietary supplements? part. For the purpose of this part, the
Control System: Requirements for the
111.475 Under this subpart M, what records
Master Manufacturing Record following definitions also apply:

111.205 What is the requirement to Actual yield means the quantity that
establish a master manufacturing record? Subpart N—Returned Dietary Supplements is actually produced at any appropriate
111.210 What must the master 111.503 What are the requirements under step of manufacture or packaging of a
manufacturing record include? this subpart N for written procedures? particular dietary supplement.
Batch means a specific quantity of a (1) May have public health use in the manufacture of a dietary
dietary supplement that is uniform, that significance; supplement.
is intended to meet specifications for (2) May cause a component or dietary Reserve sample means a
identity, purity, strength, and supplement to decompose; representative sample of product that is
composition, and that is produced (3) Indicate that the component or held for a designated period of time.
during a specified time period according dietary supplement is contaminated Sanitize means to adequately treat
to a single manufacturing record during with filth; or cleaned equipment, containers, utensils,
the same cycle of manufacture. (4) Otherwise may cause the or any other cleaned contact surface by
Batch number, lot number, or control component or dietary supplement to be a process that is effective in destroying
number means any distinctive group of adulterated. vegetative cells of microorganisms of
letters, numbers, or symbols, or any Must is used to state a requirement. public health significance, and in
combination of them, from which the Pest means any objectionable insect or substantially reducing numbers of other
complete history of the manufacturing, other animal including birds, rodents, microorganisms, but without adversely
packaging, labeling, and/or holding of a flies, mites, and larvae. affecting the product or its safety for the
batch or lot of dietary supplements can Physical plant means all or any part consumer.
be determined. of a building or facility used for or in Theoretical yield means the quantity
Component means any substance connection with manufacturing, that would be produced at any
intended for use in the manufacture of packaging, labeling, or holding a dietary appropriate step of manufacture or
a dietary supplement, including those supplement. packaging of a particular dietary
that may not appear in the finished Product complaint means any supplement, based upon the quantity of
batch of the dietary supplement. communication that contains any components or packaging to be used, in
Component includes dietary ingredients allegation, written, electronic, or oral, the absence of any loss or error in actual
(as described in section 201(ff) of the expressing concern, for any reason, with production.
act) and other ingredients. the quality of a dietary supplement, that Water activity (aw) is a measure of the
Contact surface means any surface could be related to current good free moisture in a component or dietary
that contacts a component or dietary manufacturing practice. Examples of supplement and is the quotient of the
supplement, and those surfaces from product complaints are: Foul odor, off water vapor pressure of the substance
which drainage onto the component or taste, illness or injury, disintegration divided by the vapor pressure of pure
dietary supplement, or onto surfaces time, color variation, tablet size or size water at the same temperature.
that contact the component or dietary variation, under-filled container, foreign We means the U.S. Food and Drug
supplement, occurs during the normal material in a dietary supplement Administration (FDA).
course of operations. Examples of container, improper packaging, You means a person who
contact surfaces include containers, mislabeling, or dietary supplements that manufactures, packages, labels, or holds
utensils, tables, contact surfaces of are superpotent, subpotent, or contain dietary supplements.
equipment, and packaging. the wrong ingredient, or contain a drug § 111.5 Do other statutory provisions and
Ingredient means any substance that or other contaminant (e.g., bacteria, regulations apply?
is used in the manufacture of a dietary pesticide, mycotoxin, glass, lead). In addition to this part, you must
supplement and that is intended to be Quality means that the dietary comply with other applicable statutory
present in the finished batch of the supplement consistently meets the provisions and regulations under the act
dietary supplement. An ingredient established specifications for identity, related to dietary supplements.
includes, but is not necessarily limited purity, strength, and composition, and
to, a dietary ingredient as defined in limits on contaminants, and has been Subpart B—Personnel
section 201(ff) of the act. manufactured, packaged, labeled, and
In-process material means any § 111.8 What are the requirements under
held under conditions to prevent
this subpart B for written procedures?
material that is fabricated, compounded, adulteration under section 402(a)(1),
blended, ground, extracted, sifted, (a)(2), (a)(3), and (a)(4) of the act. You must establish and follow written
sterilized, derived by chemical reaction, Quality control means a planned and procedures for fulfilling the
or processed in any other way for use systematic operation or procedure for requirements of this subpart.
in the manufacture of a dietary ensuring the quality of a dietary § 111.10 What requirements apply for
supplement. supplement. preventing microbial contamination from
Lot means a batch, or a specific Quality control personnel means any sick or infected personnel and for hygienic
identified portion of a batch, that is person, persons, or group, within or practices?
uniform and that is intended to meet outside of your organization, who you (a) Preventing microbial
specifications for identity, purity, designate to be responsible for your contamination. You must take measures
strength, and composition; or, in the quality control operations. to exclude from any operations any
case of a dietary supplement produced Representative sample means a person who might be a source of
by continuous process, a specific sample that consists of an adequate microbial contamination, due to a
identified amount produced in a number of units that are drawn based on health condition, where such
specified unit of time or quantity in a rational criteria, such as random contamination may occur, of any
manner that is uniform and that is sampling, and that are intended to material, including components, dietary
intended to meet specifications for ensure that the sample accurately supplements, and contact surfaces used
identity, purity, strength, and portrays the material being sampled. in the manufacture, packaging, labeling,
composition. Reprocessing means using, in the or holding of a dietary supplement.
Microorganisms means yeasts, molds, manufacture of a dietary supplement, Such measures include the following:
bacteria, viruses, and other similar clean, uncontaminated components or (1) Excluding from working in any
microscopic organisms having public dietary supplements that have been operations that may result in
health or sanitary concern. This previously removed from manufacturing contamination any person who, by
definition includes species that: and that have been made suitable for medical examination, the person’s
acknowledgement, or supervisory products in areas where components, supplements, or contact surfaces. The
observation, is shown to have, or dietary supplements, or any contact methods for adequate ground
appears to have, an illness, infection, surfaces are exposed, or where contact maintenance include:
open lesion, or any other abnormal surfaces are washed; and (1) Properly storing equipment,
source of microbial contamination, that (9) Taking any other precautions removing litter and waste, and cutting
could result in microbial contamination necessary to protect against the weeds or grass within the immediate
of components, dietary supplements, or contamination of components, dietary vicinity of the physical plant so that it
contact surfaces, until the health supplements, or contact surfaces with does not attract pests, harbor pests, or
condition no longer exists; and microorganisms, filth, or any other provide pests a place for breeding;
(2) Instructing your employees to extraneous materials, including (2) Maintaining roads, yards, and
notify their supervisor(s) if they have or perspiration, hair, cosmetics, tobacco, parking lots so that they do not
if there is a reasonable possibility that chemicals, and medicines applied to the constitute a source of contamination in
they have a health condition described skin. areas where components, dietary
in paragraph (a)(1) of this section that supplements, or contact surfaces are
could result in microbial contamination § 111.12 What personnel qualification exposed;
requirements apply? (3) Adequately draining areas that
of any components, dietary
supplements, or any contact surface. (a) You must have qualified may contribute to the contamination of
(b) Hygienic practices. If you work in employees who manufacture, package, components, dietary supplements, or
an operation during which adulteration label, or hold dietary supplements. contact surfaces by seepage, filth or any
of the component, dietary supplement, (b) You must identify who is other extraneous materials, or by
or contact surface could occur, you must responsible for your quality control providing a breeding place for pests;
use hygienic practices to the extent operations. Each person who is (4) Adequately operating systems for
necessary to protect against such identified to perform quality control waste treatment and disposal so that
contamination of components, dietary operations must be qualified to do so they do not constitute a source of
supplements, or contact surfaces. These and have distinct and separate contamination in areas where
hygienic practices include the responsibilities related to performing components, dietary supplements, or
following: such operations from those contact surfaces are exposed; and
(1) Wearing outer garments in a responsibilities that the person (5) If your plant grounds are bordered
manner that protects against the otherwise has when not performing by grounds not under your control, and
contamination of components, dietary such operations. if those other grounds are not
supplements, or any contact surface; (c) Each person engaged in maintained in the manner described in
(2) Maintaining adequate personal manufacturing, packaging, labeling, or this section, you must exercise care in
cleanliness; holding, or in performing any quality the plant by inspection, extermination,
(3) Washing hands thoroughly (and control operations, must have the or other means to exclude pests, dirt,
sanitizing if necessary to protect against education, training, or experience to and filth or any other extraneous
contamination with microorganisms) in perform the person’s assigned functions. materials that may be a source of
an adequate hand-washing facility: contamination.
§ 111.13 What supervisor requirements
(i) Before starting work; and (b) Physical plant facilities. (1) You
apply?
(ii) At any time when the hands may must maintain your physical plant in a
have become soiled or contaminated; (a) You must assign qualified clean and sanitary condition; and
(4) Removing all unsecured jewelry personnel to supervise the (2) You must maintain your physical
and other objects that might fall into manufacturing, packaging, labeling, or plant in repair sufficient to prevent
components, dietary supplements, holding of dietary supplements. components, dietary supplements, or
equipment, or packaging, and removing (b) Each supervisor whom you use contact surfaces from becoming
hand jewelry that cannot be adequately must be qualified by education, training, contaminated.
sanitized during periods in which or experience to supervise. (c) Cleaning compounds, sanitizing
components or dietary supplements are § 111.14 Under this subpart B, what agents, pesticides, and other toxic
manipulated by hand. If hand jewelry records must you make and keep? materials. (1) You must use cleaning
cannot be removed, it must be covered (a) You must make and keep records compounds and sanitizing agents that
by material that is maintained in an required under this subpart B in are free from microorganisms of public
intact, clean, and sanitary condition and accordance with subpart P of this part. health significance and that are safe and
that effectively protects against (b) You must make and keep the adequate under the conditions of use.
contamination of components, dietary following records: (2) You must not use or hold toxic
supplements, or contact surfaces; (1) Written procedures for fulfilling materials in a physical plant in which
(5) Maintaining gloves used in the requirements of this subpart B; and components, dietary supplements, or
handling components or dietary (2) Documentation of training, contact surfaces are manufactured or
supplements in an intact, clean, and including the date of the training, the exposed, unless those materials are
sanitary condition. The gloves must be type of training, and the person(s) necessary as follows:
of an impermeable material; trained. (i) To maintain clean and sanitary
(6) Wearing, where appropriate, in an conditions;
effective manner, hair nets, caps, beard Subpart C—Physical Plant and (ii) For use in laboratory testing
covers, or other effective hair restraints; Grounds procedures;
(7) Not storing clothing or other (iii) For maintaining or operating the
personal belongings in areas where § 111.15 What sanitation requirements physical plant or equipment; or
components, dietary supplements, or apply to your physical plant and grounds? (iv) For use in the plant’s operations.
any contact surfaces are exposed or (a) Grounds. You must keep the (3) You must identify and hold
where contact surfaces are washed; grounds of your physical plant in a cleaning compounds, sanitizing agents,
(8) Not eating food, chewing gum, condition that protects against the pesticides, pesticide chemicals, and
drinking beverages, or using tobacco contamination of components, dietary other toxic materials in a manner that
protects against contamination of sewage system or through other contact surfaces, with microorganisms,
components, dietary supplements, or adequate means. chemicals, filth, or other extraneous
contact surfaces. (h) Bathrooms. You must provide material. Your physical plant must
(d) Pest control. (1) You must not your employees with adequate, readily have, and you must use, separate or
allow animals or pests in any area of accessible bathrooms. The bathrooms defined areas of adequate size or other
your physical plant. Guard or guide must be kept clean and must not be a control systems, such as computerized
dogs are allowed in some areas of your potential source of contamination to inventory controls or automated systems
physical plant if the presence of the components, dietary supplements, or of separation, to prevent contamination
dogs will not result in contamination of contact surfaces. and mixups of components and dietary
components, dietary supplements, or (i) Hand-washing facilities. You must supplements during the following
contact surfaces; provide hand-washing facilities that are operations:
(2) You must take effective measures designed to ensure that an employee’s (1) Receiving, identifying, holding,
to exclude pests from the physical plant hands are not a source of contamination and withholding from use, components,
and to protect against contamination of of components, dietary supplements, or dietary supplements, packaging, and
components, dietary supplements, and any contact surface, by providing labels that will be used in or during the
contact surfaces on the premises by facilities that are adequate, convenient, manufacturing, packaging, labeling, or
pests; and and furnish running water at a suitable holding of dietary supplements;
(3) You must not use insecticides, temperature. (2) Separating, as necessary,
fumigants, fungicides, or rodenticides, (j) Trash disposal. You must convey, components, dietary supplements,
unless you take precautions to protect store, and dispose of trash to: packaging, and labels that are to be used
against the contamination of (1) Minimize the development of in manufacturing from components,
components, dietary supplements, or odors; dietary supplements, packaging, or
contact surfaces. (2) Minimize the potential for the labels that are awaiting material review
(e) Water supply. (1) You must trash to attract, harbor, or become a and disposition decision, reprocessing,
provide water that is safe and sanitary, breeding place for pests; or are awaiting disposal after rejection;
at suitable temperatures, and under (3) Protect against contamination of (3) Separating the manufacturing,
pressure as needed, for all uses where components, dietary supplements, any packaging, labeling, and holding of
water does not become a component of contact surface, water supplies, and different product types including
the dietary supplement. grounds surrounding your physical different types of dietary supplements
(2) Water that is used in a manner plant; and and other foods, cosmetics, and
such that the water may become a (4) Control hazardous waste to pharmaceutical products;
component of the dietary supplement, prevent contamination of components, (4) Performing laboratory analyses
e.g., when such water contacts dietary supplements, and contact and holding laboratory supplies and
components, dietary supplements, or surfaces. samples;
any contact surface, must, at a (k) Sanitation supervisors. You must (5) Cleaning and sanitizing contact
minimum, comply with applicable assign one or more employees to surfaces;
Federal, State, and local requirements supervise overall sanitation. Each of (6) Packaging and label operations;
and not contaminate the dietary these supervisors must be qualified by and
supplement. education, training, or experience to (7) Holding components or dietary
(f) Plumbing. The plumbing in your develop and supervise sanitation supplements.
physical plant must be of an adequate procedures. (d) Be designed and constructed in a
size and design and be adequately manner that prevents contamination of
installed and maintained to: § 111.16 What are the requirements under components, dietary supplements, or
(1) Carry sufficient amounts of water this subpart C for written procedures? contact surfaces.
to required locations throughout the You must establish and follow written (1) The design and construction must
physical plant; procedures for cleaning the physical include:
(2) Properly convey sewage and liquid plant and for pest control. (i) Floors, walls, and ceilings that can
disposable waste from your physical be adequately cleaned and kept clean
plant; § 111.20 What design and construction and in good repair;
(3) Avoid being a source of requirements apply to your physical plant? (ii) Fixtures, ducts, and pipes that do
contamination to components, dietary Any physical plant you use in the not contaminate components, dietary
supplements, water supplies, or any manufacture, packaging, labeling, or supplements, or contact surfaces by
contact surface, or creating an holding of dietary supplements must: dripping or other leakage, or
unsanitary condition; (a) Be suitable in size, construction, condensate;
(4) Provide adequate floor drainage in and design to facilitate maintenance, (iii) Adequate ventilation or
all areas where floors are subject to cleaning, and sanitizing operations; environmental control equipment such
flooding-type cleaning or where normal (b) Have adequate space for the as airflow systems, including filters,
operations release or discharge water or orderly placement of equipment and fans, and other air-blowing equipment,
other liquid waste on the floor; and holding of materials as is necessary for that minimize odors and vapors
(5) Not allow backflow from, or cross maintenance, cleaning, and sanitizing (including steam and noxious fumes) in
connection between, piping systems operations and to prevent areas where they may contaminate
that discharge waste water or sewage contamination and mixups of components, dietary supplements, or
and piping systems that carry water components and dietary supplements contact surfaces;
used for manufacturing dietary during manufacturing, packaging, (iv) Equipment that controls
supplements, for cleaning contact labeling, or holding; temperature and humidity, when such
surfaces, or for use in bathrooms or (c) Permit the use of proper equipment is necessary to ensure the
hand-washing facilities. precautions to reduce the potential for quality of the dietary supplement; and
(g) Sewage disposal. You must mixups or contamination of (v) Aisles or working spaces between
dispose of sewage into an adequate components, dietary supplements, or equipment and walls that are adequately
unobstructed and of adequate width to Subpart D—Equipment and Utensils (v) Maintained to protect components
permit all persons to perform their and dietary supplements from being
duties and to protect against § 111.25 What are the requirements under contaminated by any source.
contamination of components, dietary this subpart D for written procedures? (4) Equipment and utensils you use
supplements, or contact surfaces with You must establish and follow written must have seams that are smoothly
clothing or personal contact. procedures for fulfilling the bonded or maintained to minimize
requirements of this subpart D, accumulation of dirt, filth, organic
(2) When fans and other air-blowing
including written procedures for: material, particles of components or
equipment are used, such fans and
(a) Calibrating instruments and dietary supplements, or any other
equipment must be located and
controls that you use in manufacturing extraneous materials or contaminants.
operated in a manner that minimizes the
or testing a component or dietary (5) Each freezer, refrigerator, and
potential for microorganisms and
supplement; other cold storage compartment you use
particulate matter to contaminate
(b) Calibrating, inspecting, and to hold components or dietary
components, dietary supplements, or
checking automated, mechanical, and supplements:
contact surfaces;
electronic equipment; and (i) Must be fitted with an indicating
(e) Provide adequate light in: (c) Maintaining, cleaning, and thermometer, temperature-measuring
(1) All areas where components or sanitizing, as necessary, all equipment, device, or temperature-recording device
dietary supplements are examined, utensils, and any other contact surfaces that indicates and records, or allows for
processed, or held; that are used to manufacture, package, recording by hand, the temperature
(2) All areas where contact surfaces label, or hold components or dietary accurately within the compartment; and
are cleaned; and supplements. (ii) Must have an automated device
(3) Hand-washing areas, dressing and for regulating temperature or an
§ 111.27 What requirements apply to the
locker rooms, and bathrooms. automated alarm system to indicate a
equipment and utensils that you use?
significant temperature change in a
(f) Use safety-type light bulbs, (a) You must use equipment and manual operation.
fixtures, skylights, or other glass or utensils that are of appropriate design, (6) Instruments or controls used in the
glass-like materials when the light construction, and workmanship to manufacturing, packaging, labeling, or
bulbs, fixtures, skylights or other glass enable them to be suitable for their holding of a dietary supplement, and
or glass-like materials are suspended intended use and to be adequately instruments or controls that you use to
over exposed components or dietary cleaned and properly maintained. measure, regulate, or record
supplements in any step of preparation, (1) Equipment and utensils include temperatures, hydrogen-ion
unless your physical plant is otherwise the following: concentration (pH), water activity, or
constructed in a manner that will (i) Equipment used to hold or convey; other conditions, to control or prevent
protect against contamination of (ii) Equipment used to measure; the growth of microorganisms or other
components or dietary supplements in (iii) Equipment using compressed air contamination must be:
case of breakage of glass or glass-like or gas; (i) Accurate and precise;
materials. (iv) Equipment used to carry out (ii) Adequately maintained; and
(g) Provide effective protection against processes in closed pipes and vessels; (iii) Adequate in number for their
contamination of components and and designated uses.
dietary supplements in bulk (v) Equipment used in automated, (7) Compressed air or other gases you
fermentation vessels, by, for example: mechanical, or electronic systems. introduce mechanically into or onto a
(2) You must use equipment and component, dietary supplement, or
(1) Use of protective coverings; utensils of appropriate design and contact surface or that you use to clean
(2) Placement in areas where you can construction so that use will not result any contact surface must be treated in
eliminate harborages for pests over and in the contamination of components or such a way that the component, dietary
around the vessels; dietary supplements with: supplement, or contact surface is not
(3) Placement in areas where you can (i) Lubricants; contaminated.
check regularly for pests, pest (ii) Fuel; (b) You must calibrate instruments
infestation, filth or any other extraneous (iii) Coolants; and controls you use in manufacturing
materials; and (iv) Metal or glass fragments; or testing a component or dietary
(4) Use of skimming equipment. (v) Filth or any other extraneous supplement. You must calibrate:
material; (1) Before first use;
(h) Use adequate screening or other (vi) Contaminated water; or (2) At the frequency specified in
protection against pests, where (vii) Any other contaminants. writing by the manufacturer of the
necessary. (3) All equipment and utensils you instrument and control; or
§ 111.23 Under this subpart C, what use must be: (3) At routine intervals or as
records must you make and keep? (i) Installed and maintained to otherwise necessary to ensure the
facilitate cleaning the equipment, accuracy and precision of the
(a) You must make and keep records
utensils, and all adjacent spaces; instrument and control.
required under this subpart C in
(ii) Corrosion-resistant if the (c) You must repair or replace
accordance with subpart P of this part.
equipment or utensils contact instruments or controls that cannot be
(b) You must make and keep records components or dietary supplements; adjusted to agree with the reference
of the written procedures for cleaning (iii) Made of nontoxic materials; standard.
the physical plant and for pest control. (iv) Designed and constructed to (d) You must maintain, clean, and
(c) You must make and keep records withstand the environment in which sanitize, as necessary, all equipment,
that show that water, when used in a they are used, the action of components utensils, and any other contact surfaces
manner such that the water may become or dietary supplements, and, if used to manufacture, package, label, or
a component of the dietary supplement, applicable, cleaning compounds and hold components or dietary
meets the requirements of § 111.15(e)(2). sanitizing agents; and supplements.
(1) Equipment and utensils must be (c) Routinely calibrate, inspect, or (vi) Identify the recalibration method
taken apart as necessary for thorough check the equipment to ensure proper used, and reading or readings found, if
maintenance, cleaning, and sanitizing. performance. Your quality control accuracy or precision or both accuracy
(2) You must ensure that all contact personnel must periodically review and precision limits for instruments and
surfaces, used for manufacturing or these calibrations, inspections, or controls were not met; and
holding low-moisture components or checks; (vii) Include the initials of the person
dietary supplements, are in a dry and (d) Establish and use appropriate who performed the calibration and any
sanitary condition when in use. When controls for automated, mechanical, and recalibration.
the surfaces are wet-cleaned, they must electronic equipment (including (4) Written records of calibrations,
be sanitized, when necessary, and software for a computer controlled inspections, and checks of automated,
thoroughly dried before subsequent use. process) to ensure that any changes to mechanical, and electronic equipment;
(3) If you use wet processing during the manufacturing, packaging, labeling, (5) Backup file(s) of current software
manufacturing, you must clean and holding, or other operations are programs (and of outdated software that
sanitize all contact surfaces, as approved by quality control personnel is necessary to retrieve records that you
necessary, to protect against the and instituted only by authorized are required to keep in accordance with
introduction of microorganisms into personnel; and subpart P of this part, when current
components or dietary supplements. (e) Establish and use appropriate software is not able to retrieve such
When cleaning and sanitizing is controls to ensure that the equipment records) and of data entered into
necessary, you must clean and sanitize functions in accordance with its computer systems that you use to
all contact surfaces before use and after intended use. These controls must be manufacture, package, label, or hold
any interruption during which the approved by quality control personnel. dietary supplements.
contact surface may have become (i) Your backup file (e.g., a hard copy
contaminated. If you use contact § 111.35 Under this subpart D, what
records must you make and keep? of data you have entered, diskettes,
surfaces in a continuous production
(a) You must make and keep records tapes, microfilm, or compact disks)
operation or in consecutive operations
required under this subpart D in must be an exact and complete record
involving different batches of the same
accordance with subpart P of this part. of the data you entered.
dietary supplement, you must
(b) You must make and keep the (ii) You must keep your backup
adequately clean and sanitize the
following records: software programs and data secure from
contact surfaces, as necessary.
(4) You must clean surfaces that do (1) Written procedures for fulfilling alterations, inadvertent erasures, or loss;
not come into direct contact with the requirements of this subpart, and
components or dietary supplements as including written procedures for: (6) Documentation of the controls that
(i) Calibrating instruments and you use to ensure that equipment
frequently as necessary to protect
controls that you use in manufacturing functions in accordance with its
against contaminating components or
or testing a component or dietary intended use.
dietary supplements.
(5) Single-service articles (such as supplement;
(ii) Calibrating, inspecting, and Subpart E—Requirement to Establish a
utensils intended for one-time use,
checking automated, mechanical, and Production and Process Control
paper cups, and paper towels) must be:
(i) Stored in appropriate containers; electronic equipment; and System
(iii) Maintaining, cleaning, and
and § 111.55 What are the requirements to
(ii) Handled, dispensed, used, and sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces implement a production and process
disposed of in a manner that protects control system?
against contamination of components, that are used to manufacture, package,
label, or hold components or dietary You must implement a system of
dietary supplements, or any contact production and process controls that
surface. supplements;
(2) Documentation, in individual covers all stages of manufacturing,
(6) Cleaning compounds and
equipment logs, of the date of the use, packaging, labeling, and holding of the
sanitizing agents must be adequate for
maintenance, cleaning, and sanitizing of dietary supplement to ensure the quality
their intended use and safe under their
equipment, unless such documentation of the dietary supplement and that the
conditions of use;
(7) You must store cleaned and is kept with the batch record; dietary supplement is packaged and
sanitized portable equipment and (3) Documentation of any calibration, labeled as specified in the master
utensils that have contact surfaces in a each time the calibration is performed, manufacturing record.
location and manner that protects them for instruments and controls that you
§ 111.60 What are the design requirements
from contamination. use in manufacturing or testing a
for the production and process control
component or dietary supplement. In system?
§ 111.30 What requirements apply to your documentation, you must:
automated, mechanical, or electronic (i) Identify the instrument or control (a) Your production and in-process
equipment? calibrated; control system must be designed to
For any automated, mechanical, or (ii) Provide the date of calibration; ensure that the dietary supplement is
electronic equipment that you use to (iii) Identify the reference standard manufactured, packaged, labeled, and
manufacture, package, label, or hold a used including the certification of held in a manner that will ensure the
dietary supplement, you must: accuracy of the known reference quality of the dietary supplement and
(a) Design or select equipment to standard and a history of recertification that the dietary supplement is packaged
ensure that dietary supplement of accuracy; and labeled as specified in the master
specifications are consistently met; (iv) Identify the calibration method manufacturing record; and
(b) Determine the suitability of the used, including appropriate limits for (b) The production and in-process
equipment by ensuring that your accuracy and precision of instruments control system must include all
equipment is capable of operating and controls when calibrating; requirements of subparts E through L of
satisfactorily within the operating limits (v) Provide the calibration reading or this part and must be reviewed and
required by the process; readings found; approved by quality control personnel.
§ 111.65 What are the requirements for (d) You must establish specifications (B) The certificate of analysis includes
quality control operations? for dietary supplement labels (label a description of the test or examination
You must implement quality control specifications) and for packaging that method(s) used, limits of the test or
operations in your manufacturing, may come in contact with dietary examinations, and actual results of the
packaging, labeling, and holding supplements (packaging specifications). tests or examinations;
operations for producing the dietary Packaging that may come into contact (C) You maintain documentation of
supplement to ensure the quality of the with dietary supplements must be safe how you qualified the supplier;
dietary supplement and that the dietary and suitable for its intended use and (D) You periodically re-confirm the
supplement is packaged and labeled as must not be reactive or absorptive or supplier’s certificate of analysis; and
specified in the master manufacturing otherwise affect the safety or quality of (E) Your quality control personnel
record. the dietary supplement. review and approve the documentation
(e) For each dietary supplement that setting forth the basis for qualification
§ 111.70 What specifications must you you manufacture you must establish (and re-qualification) of any supplier.
establish? product specifications for the identity, (b) You must monitor the in-process
(a) You must establish a specification purity, strength, and composition of the points, steps, or stages where control is
for any point, step, or stage in the finished batch of the dietary necessary to ensure the quality of the
manufacturing process where control is supplement, and for limits on those finished batch of dietary supplement to:
necessary to ensure the quality of the types of contamination that may (1) Determine whether the in-process
dietary supplement and that the dietary adulterate, or that may lead to specifications are met; and
supplement is packaged and labeled as adulteration of, the finished batch of the (2) Detect any deviation or
specified in the master manufacturing dietary supplement to ensure the quality unanticipated occurrence that may
record. of the dietary supplement. result in a failure to meet specifications.
(b) For each component that you use (f) If you receive a product from a (c) For a subset of finished dietary
in the manufacture of a dietary supplier for packaging or labeling as a supplement batches that you identify
supplement, you must establish dietary supplement (and for distribution through a sound statistical sampling
component specifications as follows: rather than for return to the supplier), plan (or for every finished batch), you
(1) You must establish an identity you must establish specifications to must verify that your finished batch of
specification; provide sufficient assurance that the the dietary supplement meets product
(2) You must establish component product you receive is adequately specifications for identity, purity,
specifications that are necessary to identified and is consistent with your strength, composition, and for limits on
ensure that specifications for the purity, purchase order. those types of contamination that may
strength and composition of dietary (g) You must establish specifications adulterate or that may lead to
supplements manufactured using the for the packaging and labeling of the adulteration of the finished batch of the
components are met; and finished packaged and labeled dietary dietary supplement. To do so:
(3) You must establish limits on those supplements, including specifications (1) You must select one or more
types of contamination that may that ensure that you used the specified established specifications for identity,
adulterate or may lead to adulteration of packaging and that you applied the purity, strength, composition, and the
the finished batch of the dietary specified label. limits on those types of contamination
supplement to ensure the quality of the that may adulterate or that may lead to
dietary supplement. § 111.73 What is your responsibility for adulteration of the dietary supplement
(c) For the in-process production: determining whether established that, if tested or examined on the
specifications are met?
(1) You must establish in-process finished batches of the dietary
specifications for any point, step, or You must determine whether the supplement, would verify that the
stage in the master manufacturing specifications you establish under production and process control system
record where control is necessary to § 111.70 are met. is producing a dietary supplement that
help ensure that specifications are met § 111.75 What must you do to determine meets all product specifications (or only
for the identity, purity, strength, and whether specifications are met? those product specifications not
composition of the dietary supplements (a) Before you use a component, you otherwise exempted from this provision
and, as necessary, for limits on those must: by quality control personnel under
types of contamination that may (1) Conduct at least one appropriate paragraph (d) of this section);
adulterate or may lead to adulteration of test or examination to verify the identity (2) You must conduct appropriate
the finished batch of the dietary of any component that is a dietary tests or examinations to determine
supplement; ingredient; and compliance with the specifications
(2) You must provide adequate (2) Confirm the identity of other selected in paragraph (c)(1) of this
documentation of your basis for why components and determine whether section;
meeting the in-process specifications, in other applicable component (3) You must provide adequate
combination with meeting component specifications established in accordance documentation of your basis for
specifications, will help ensure that the with § 111.70(b) are met. To do so, you determining compliance with the
specifications are met for the identity, must either: specification(s) selected under
purity, strength, and composition of the (i) Conduct appropriate tests or paragraph (c)(1) of this section, through
dietary supplements and for limits on examinations; or the use of appropriate tests or
those types of contamination that may (ii) Rely on a certificate of analysis examinations conducted under
adulterate or may lead to adulteration of from the supplier of the component that paragraph (c)(2) of this section, will
the finished batch of the dietary you receive, provided that: ensure that your finished batch of the
supplement; and (A) You first qualify the supplier by dietary supplement meets all product
(3) Quality control personnel must establishing the reliability of the specifications for identity, purity,
review and approve the documentation supplier’s certificate of analysis through strength, and composition, and the
that you provide under paragraph (c)(2) confirmation of the results of the limits on those types of contamination
of this section. supplier’s tests or examinations; that may adulterate, or that may lead to
the adulteration of, the dietary (2) The tests and examinations that materials meet specifications
supplement; and you use must include at least one of the established in accordance with
(4) Your quality control personnel following: § 111.70(c), and as applicable,
must review and approve the (i) Gross organoleptic analysis; § 111.70(a);
documentation that you provide under (ii) Macroscopic analysis; (c) Representative samples of a subset
paragraph (c)(3) of this section. (iii) Microscopic analysis; of finished batches of each dietary
(d)(1) You may exempt one or more (iv) Chemical analysis; or supplement that you manufacture,
product specifications from verification (v) Other scientifically valid methods. which you identify through a sound
requirements in paragraph (c)(1) of this (i) You must establish corrective statistical sampling plan (or otherwise
section if you determine and document action plans for use when an established every finished batch), before releasing
that the specifications you select under specification is not met. for distribution to verify that the
paragraph (c)(1) of this section for § 111.77 What must you do if established
finished batch of dietary supplement
determination of compliance with specifications are not met? meets product specifications established
specifications are not able to verify that in accordance with § 111.70(e), and as
(a) For specifications established
the production and process control applicable, § 111.70(a);
under § 111.70(a), (b)(2), (b)(3), (c), (d),
system is producing a dietary (e), and (g) that you do not meet, quality (d) Representative samples of each
supplement that meets the exempted control personnel, in accordance with unique shipment, and of each unique lot
product specification and there is no the requirements in subpart F of this within each unique shipment, of
scientifically valid method for testing or part, must reject the component, dietary product that you receive for packaging
examining such exempted product supplement, package or label unless or labeling as a dietary supplement (and
specification at the finished batch stage. such personnel approve a treatment, an for distribution rather than for return to
In such a case, you must document why, in-process adjustment, or reprocessing the supplier) to determine whether the
for example, any component and in- that will ensure the quality of the received product meets specifications
process testing, examination, or finished dietary supplement and that established in accordance with
monitoring, and any other information, the dietary supplement is packaged and § 111.70(f), and as applicable,
will ensure that such exempted product labeled as specified in the master § 111.70(a); and
specification is met without verification manufacturing record. No finished batch (e) Representative samples of each lot
through periodic testing of the finished of dietary supplements may be released of packaged and labeled dietary
batch; and for distribution unless it complies with supplements to determine whether the
(2) Your quality control personnel § 111.123(b). packaging and labeling of the finished
must review and approve the (b) For specifications established packaged and labeled dietary
documentation that you provide under under § 111.70(b)(1) that you do not supplements meet specifications
paragraph (d)(1) of this section. meet, quality control personnel must established in accordance with
(e) Before you package or label a reject the component and the § 111.70(g), and as applicable,
product that you receive for packaging component must not be used in § 111.70(a).
or labeling as a dietary supplement (and manufacturing the dietary supplement. § 111.83 What are the requirements for
for distribution rather than for return to (c) For specifications established reserve samples?
the supplier), you must visually under § 111.70(f) that you do not meet, (a) You must collect and hold reserve
examine the product and have quality control personnel must reject the samples of each lot of packaged and
documentation to determine whether product and the product may not be labeled dietary supplements that you
the specifications that you established packaged or labeled for distribution as distribute.
under § 111.70 (f) are met. a dietary supplement.
(b) The reserve samples must:
(f)(1) Before you use packaging, you § 111.80 What representative samples (1) Be held using the same container-
must, at a minimum, conduct a visual must you collect? closure system in which the packaged
identification of the containers and and labeled dietary supplement is
The representative samples that you
closures and review the supplier’s distributed, or if distributing dietary
must collect include:
invoice, guarantee, or certification to supplements to be packaged and
(a) Representative samples of each
determine whether the packaging labeled, using a container-closure
unique lot of components, packaging,
specifications are met; and system that provides essentially the
and labels that you use to determine
(2) Before you use labels, you must, at whether the components, packaging, same characteristics to protect against
a minimum, conduct a visual and labels meet specifications contamination or deterioration as the
examination of the label and review the established in accordance with one in which it is distributed for
supplier’s invoice, guarantee, or § 111.70(b) and (d), and as applicable, packaging and labeling elsewhere;
certification to determine whether label § 111.70(a) (and, when you receive (2) Be identified with the batch, lot,
specifications are met. components, packaging, or labels from a or control number;
(g) You must, at a minimum, conduct supplier, representative samples of each (3) Be retained for 1 year past the
a visual examination of the packaging unique shipment, and of each unique lot shelf life date (if shelf life dating is
and labeling of the finished packaged within each unique shipment); used), or for 2 years from the date of
and labeled dietary supplements to (b) Representative samples of in- distribution of the last batch of dietary
determine whether you used the process materials for each manufactured supplements associated with the reserve
specified packaging and applied the batch at points, steps, or stages, in the sample, for use in appropriate
specified label. manufacturing process as specified in investigations; and
(h)(1) You must ensure that the tests the master manufacturing record where (4) Consist of at least twice the
and examinations that you use to control is necessary to ensure the quantity necessary for all tests or
determine whether the specifications identity, purity, strength, and examinations to determine whether or
are met are appropriate, scientifically composition of dietary supplements to not the dietary supplement meets
valid methods. determine whether the in-process product specifications.
§ 111.87 Who conducts a material review specifications for identity, purity, why meeting in-process specifications,
and makes a disposition decision? strength, and composition; and for in combination with meeting
Quality control personnel must limits on those types of contamination component specifications, will help
conduct all required material reviews that may adulterate or may lead to ensure that the identity, purity, strength,
and make all required disposition adulteration of the finished batch of the and composition of the dietary
decisions. dietary supplement; and supplement are met;
(4) Documentation for why the results (d) Reviewing and approving the
§ 111.90 What requirements apply to documentation setting forth the basis for
treatments, in-process adjustments, and
of appropriate tests or examinations for
reprocessing when there is a deviation or the product specifications selected why the results of appropriate tests or
unanticipated occurrence or when a under § 111.75(c)(1) ensure that the examinations for each product
specification established in accordance dietary supplement meets all product specification selected under
with § 111.70 is not met? specifications; § 111.75(c)(1) will ensure that the
(a) You must not reprocess a rejected (5) Documentation for why any finished batch of the dietary supplement
dietary supplement or treat or provide component and in-process testing, meets product specifications;
an in-process adjustment to a examination, or monitoring, and any (e) Reviewing and approving the basis
component, packaging, or label to make other information, will ensure that a and the documentation for why any
it suitable for use in the manufacture of product specification that is exempted product specification is exempted from
a dietary supplement unless: under § 111.75(d) is met without the verification requirements in
(1) Quality control personnel conduct verification through periodic testing of § 111.75(c)(1), and for why any
a material review and make a the finished batch, including component and in-process testing,
disposition decision to approve the documentation that the selected examination, or monitoring, or other
reprocessing, treatment, or in-process specifications tested or examined under methods will ensure that such exempted
adjustment; and § 111.75 (c)(1) are not able to verify that product specification is met without
(2) The reprocessing, treatment, or in- the production and process control verification through periodic testing of
process adjustment is permitted by system is producing a dietary the finished batch;
§ 111.77; supplement that meets the exempted (f) Ensuring that required
(b) You must not reprocess any product specification and there is no representative samples are collected;
dietary supplement or treat or provide scientifically valid method for testing or (g) Ensuring that required reserve
an in-process adjustment to a examining such exempted product samples are collected and held;
component to make it suitable for use in specification at the finished batch stage. (h) Determining whether all
the manufacture of a dietary specifications established under
supplement, unless: Subpart F—Production and Process § 111.70(a) are met; and
(1) Quality control personnel conduct Control System: Requirements for (i) Performing other operations
a material review and make a Quality Control required under this subpart.
disposition decision that is based on a § 111.110 What quality control operations
§ 111.103 What are the requirements under
scientifically valid reason and approves this subpart F for written procedures? are required for laboratory operations
the reprocessing, treatment, or in- associated with the production and process
process adjustment; and You must establish and follow written control system?
(2) The reprocessing, treatment or in- procedures for the responsibilities of the
Quality control operations for
process adjustment is permitted by quality control operations, including
laboratory operations associated with
§ 111.77; written procedures for conducting a
the production and process control
(c) Any batch of dietary supplement material review and making a
system must include:
that is reprocessed, that contains disposition decision, and for approving
(a) Reviewing and approving all
components that you have treated, or to or rejecting any reprocessing.
laboratory control processes associated
which you have made in-process § 111.105 What must quality control with the production and process control
adjustments to make them suitable for personnel do? system;
use in the manufacture of the dietary Quality control personnel must (b) Ensuring that all tests and
supplement must be approved by ensure that your manufacturing, examinations required under § 111.75
quality control personnel and comply packaging, labeling, and holding are conducted; and
with § 111.123(b) before releasing for operations ensure the quality of the (c) Reviewing and approving the
distribution. dietary supplement and that the dietary results of all tests and examinations
supplement is packaged and labeled as required under § 111.75.
§ 111.95 Under this subpart E, what
records must you make and keep? specified in the master manufacturing § 111.113 What quality control operations
(a) You must make and keep records record. To do so, quality control are required for a material review and
required under this subpart E in personnel must perform operations that disposition decision?
accordance with subpart P of this part. include: (a) Quality control personnel must
(b) Under this subpart E, you must (a) Approving or rejecting all conduct a material review and make a
make and keep the following records: processes, specifications, written disposition decision if:
(1) The specifications established; procedures, controls, tests, and (1) A specification established in
(2) Documentation of your examinations, and deviations from or accordance with § 111.70 is not met;
qualification of a supplier for the modifications to them, that may affect (2) A batch deviates from the master
purpose of relying on the supplier’s the identity, purity, strength, or manufacturing record, including when
certificate of analysis; composition of a dietary supplement; any step established in the master
(3) Documentation for why meeting (b) Reviewing and approving the manufacturing record is not completed
in-process specifications, in documentation setting forth the basis for and including any deviation from
combination with meeting component qualification of any supplier; specifications;
specifications, helps ensure that the (c) Reviewing and approving the (3) There is any unanticipated
dietary supplement meets the documentation setting forth the basis for occurrence during the manufacturing
operations that adulterates or may lead (a) Reviewing all receiving records for dietary supplement (and for distribution
to adulteration of the component, components, packaging, and labels; rather than for return to the supplier) for
dietary supplement, or packaging, or (b) Determining whether all which sufficient assurance is not
could lead to the use of a label not components, packaging, and labels provided to adequately identify the
specified in the master manufacturing conform to specifications established product and to determine that the
record; under § 111.70 (b) and (d); product is consistent with your
(4) Calibration of an instrument or (c) Conducting any required material purchase order.
control suggests a problem that may review and making any required
disposition decision; § 111.127 What quality control operations
have resulted in a failure to ensure the
(d) Approving or rejecting any are required for packaging and labeling
quality of a batch or batches of a dietary operations?
supplement; or treatment and in-process adjustments of
components, packaging, or labels to Quality control operations for
(5) A dietary supplement is returned.
make them suitable for use in the packaging and labeling operations must
(b)(1) When there is a deviation or
manufacture of a dietary supplement; include:
unanticipated occurrence during the (a) Reviewing the results of any visual
production and in-process control and
(e) Approving, and releasing from examination and documentation to
system that results in or could lead to ensure that specifications established
adulteration of a component, dietary quarantine, all components, packaging,
and labels before they are used. under § 111.70(f) are met for all
supplement, or packaging, or could lead products that you receive for packaging
to the use of a label not specified in the § 111.123 What quality control operations and labeling as a dietary supplement
master manufacturing record, quality are required for the master manufacturing (and for distribution rather than for
control personnel must reject the record, the batch production record, and return to the supplier);
component, dietary supplement, manufacturing operations? (b) Approving, and releasing from
packaging, or label unless it approves a (a) Quality control operations for the quarantine, all products that you receive
treatment, an in-process adjustment, or master manufacturing record, the batch for packaging or labeling as a dietary
reprocessing to correct the applicable production record, and manufacturing supplement (and for distribution rather
deviation or occurrence. operations must include: than for return to the supplier) before
(2) When a specification established (1) Reviewing and approving all they are used for packaging or labeling;
in accordance with § 111.70 is not met, master manufacturing records and all (c) Reviewing and approving all
quality control personnel must reject the modifications to the master records for packaging and label
component, dietary supplement, manufacturing records; operations;
package or label, unless quality control (2) Reviewing and approving all batch (d) Determining whether the finished
personnel approve a treatment, an in- production-related records; packaged and labeled dietary
process adjustment, or reprocessing, as (3) Reviewing all monitoring required supplement conforms to specifications
permitted in § 111.77. under subpart E; established in accordance with
(c) The person who conducts a (4) Conducting any required material § 111.70(g);
material review and makes the review and making any required (e) Conducting any required material
disposition decision must, at the time of disposition decision; review and making any required
performance, document that material (5) Approving or rejecting any disposition decision;
review and disposition decision. reprocessing; (f) Approving or rejecting any
(6) Determining whether all in- repackaging of a packaged dietary
§ 111.117 What quality control operations process specifications established in supplement;
are required for equipment, instruments, accordance with § 111.70(c) are met; (g) Approving or rejecting any
and controls? (7) Determining whether each relabeling of a packaged and labeled
Quality control operations for finished batch conforms to product dietary supplement; and
equipment, instruments, and controls specifications established in accordance (h) Approving for release, or rejecting,
must include: with § 111.70(e); and any packaged and labeled dietary
(a) Reviewing and approving all (8) Approving and releasing, or supplement (including a repackaged or
processes for calibrating instruments rejecting, each finished batch for relabeled dietary supplement) for
and controls; distribution, including any reprocessed distribution.
(b) Periodically reviewing all records finished batch.
for calibration of instruments and (b) Quality control personnel must not § 111.130 What quality control operations
controls; approve and release for distribution: are required for returned dietary
(1) Any batch of dietary supplement supplements?
(c) Periodically reviewing all records
for calibrations, inspections, and checks for which any component in the batch Quality control operations for
of automated, mechanical, or electronic does not meet its identity specification; returned dietary supplements must
equipment; and (2) Any batch of dietary supplement, include:
(d) Reviewing and approving controls including any reprocessed batch, that (a) Conducting any required material
to ensure that automated, mechanical, does not meet all product specifications review and making any required
or electronic equipment functions in established in accordance with disposition decision; including:
accordance with its intended use. § 111.70(e); (1) Determining whether tests or
(3) Any batch of dietary supplement, examination are necessary to determine
§ 111.120 What quality control operations including any reprocessed batch, that compliance with product specifications
are required for components, packaging, has not been manufactured, packaged, established in accordance with
and labels before use in the manufacture of labeled, and held under conditions to § 111.70(e); and
a dietary supplement? prevent adulteration under section (2) Reviewing the results of any tests
Quality control operations for 402(a)(1), (a)(2), (a)(3), and (a)(4) of the or examinations that are conducted to
components, packaging, and labels act; and determine compliance with product
before use in the manufacture of a (4) Any product received from a specifications established in accordance
dietary supplement must include: supplier for packaging or labeling as a with § 111.70(e);
(b) Approving or rejecting any salvage (v) Explanation of what you did with components that you receive and any lot
and redistribution of any returned the component, dietary supplement, of components that you produce in a
dietary supplement; packaging, or label; manner that allows you to trace the lot
(c) Approving or rejecting any (vi) A scientifically valid reason for to the supplier, the date received, the
reprocessing of any returned dietary any reprocessing of a dietary name of the component, the status of the
supplement; and supplement that is rejected or any component (e.g., quarantined, approved,
(d) Determining whether the treatment or in-process adjustment of a or rejected); and to the dietary
reprocessed dietary supplement meets component that is rejected; and supplement that you manufactured and
product specifications and either (vii) The signature of the individual(s) distributed.
approving for release, or rejecting, any designated to perform the quality (2) You must use this unique
returned dietary supplement that is control operation, who conducted the identifier whenever you record the
reprocessed. material review and made the disposition of each unique lot within
§ 111.135 What quality control operations disposition decision, and of each each unique shipment of components
are required for product complaints? qualified individual who provides that you receive and any lot of
Quality control operations for product information relevant to that material components that you produce.
complaints must include reviewing and review and disposition decision. (e) You must hold components under
approving decisions about whether to conditions that will protect against
Subpart G—Production and Process contamination and deterioration, and
investigate a product complaint and Control System: Requirements for
reviewing and approving the findings avoid mixups.
Components, Packaging, and Labels
and followup action of any investigation and for Product That You Receive for § 111.160 What requirements apply to
performed. Packaging or Labeling as a Dietary packaging and labels received?
§ 111.140 Under this subpart F, what Supplement (a) You must visually examine each
records must you make and keep? immediate container or grouping of
(a) You must make and keep the immediate containers in a shipment for
this subpart G for written procedures?
records required under this subpart F in appropriate content label, container
You must establish and follow written damage, or broken seals to determine
accordance with subpart P of this part.
(b) You must make and keep the procedures for fulfilling the whether the container condition may
following records: requirements of this subpart G. have resulted in contamination or
(1) Written procedures for the § 111.155 What requirements apply to deterioration of the packaging and
responsibilities of the quality control components of dietary supplements? labels.
operations, including written (a) You must visually examine each (b) You must visually examine the
procedures for conducting a material immediate container or grouping of supplier’s invoice, guarantee, or
review and making a disposition immediate containers in a shipment that certification in a shipment to ensure
decision and written procedures for you receive for appropriate content that the packaging or labels are
approving or rejecting any reprocessing; label, container damage, or broken seals consistent with your purchase order.
(2) Written documentation, at the time to determine whether the container (c) You must quarantine packaging
of performance, that quality control condition may have resulted in and labels before you use them in the
personnel performed the review, contamination or deterioration of the manufacture of a dietary supplement
approval, or rejection requirements by components; until:
recording the following: (b) You must visually examine the (1) You collect representative samples
(i) Date that the review, approval, or of each unique shipment, and of each
supplier’s invoice, guarantee, or
rejection was performed; and unique lot within each unique
(ii) Signature of the person performing certification in a shipment you receive
to ensure the components are consistent shipment, of packaging and labels and,
the review, approval, or rejection; and at a minimum, conduct a visual
(3) Documentation of any material with your purchase order;
(c) You must quarantine components identification of the immediate
review and disposition decision and
before you use them in the manufacture containers and closures;
followup. Such documentation must be
of a dietary supplement until: (2) Quality control personnel review
included in the appropriate batch
(1) You collect representative samples and approve the results of any tests or
production record and must include:
(i) Identification of the specific of each unique lot of components (and, examinations conducted on the
deviation or the unanticipated for components that you receive, of each packaging and labels; and
occurrence; unique shipment, and of each unique lot (3) Quality control personnel approve
(ii) Description of your investigation within each unique shipment); the packaging and labels for use in the
into the cause of the deviation from the (2) Quality control personnel review manufacture of a dietary supplement
specification or the unanticipated and approve the results of any tests or and release them from quarantine.
occurrence; examinations conducted on (d)(1) You must identify each unique
(iii) Evaluation of whether or not the components; and lot within each unique shipment of
deviation or unanticipated occurrence (3) Quality control personnel approve packaging and labels in a manner that
has resulted in or could lead to a failure the components for use in the allows you to trace the lot to the
to ensure the quality of the dietary manufacture of a dietary supplement, supplier, the date received, the name of
supplement or a failure to package and including approval of any treatment the packaging and label, the status of the
label the dietary supplement as (including in-process adjustments) of packaging and label (e.g., quarantined,
specified in the master manufacturing components to make them suitable for approved, or rejected); and to the
record; use in the manufacture of a dietary dietary supplement that you distributed;
(iv) Identification of the action(s) supplement, and releases them from and
taken to correct, and prevent a quarantine. (2) You must use this unique
recurrence of, the deviation or the (d)(1) You must identify each unique identifier whenever you record the
unanticipated occurrence; lot within each unique shipment of disposition of each unique lot within
each unique shipment of packaging and § 111.170 What requirements apply to in the finished batch from batch to
labels. rejected components, packaging, and batch.
labels, and to rejected products that are (b) The master manufacturing record
(e) You must hold packaging and received for packaging or labeling as a
labels under conditions that will protect must:
dietary supplement?
against contamination and deterioration, (1) Identify specifications for the
You must clearly identify, hold, and points, steps, or stages in the
and avoid mixups. control under a quarantine system for manufacturing process where control is
§ 111.165 What requirements apply to a
appropriate disposition any component, necessary to ensure the quality of the
product received for packaging or labeling packaging, and label, and any product dietary supplement and that the dietary
as a dietary supplement (and for that you receive for packaging or supplement is packaged and labeled as
distribution rather than for return to the labeling as a dietary supplement (and specified in the master manufacturing
supplier)? for distribution rather than for return to record; and
the supplier), that is rejected and (2) Establish controls and procedures
(a) You must visually examine each unsuitable for use in manufacturing,
immediate container or grouping of to ensure that each batch of dietary
packaging, or labeling operations. supplement that you manufacture meets
immediate containers in a shipment of
product that you receive for packaging § 111.180 Under this subpart G, what the specifications identified in
or labeling as a dietary supplement (and records must you make and keep? accordance with paragraph (b)(1) of this
for distribution rather than for return to (a) You must make and keep records section.
the supplier) for appropriate content required under this subpart G in (c) You must make and keep master
label, container damage, or broken seals accordance with subpart P of this part. manufacturing records in accordance
to determine whether the container (b) You must make and keep the with subpart P of this part.
condition may have resulted in following records: § 111.210 What must the master
contamination or deterioration of the (1) Written procedures for fulfilling manufacturing record include?
received product. the requirements of this subpart. The master manufacturing record
(2) Receiving records (including must include:
(b) You must visually examine the
records such as certificates of analysis, (a) The name of the dietary
supplier’s invoice, guarantee, or
suppliers’ invoices, and suppliers’ supplement to be manufactured and the
certification in a shipment of the
guarantees) for components, packaging, strength, concentration, weight, or
received product to ensure that the and labels and for products that you
received product is consistent with your measure of each dietary ingredient for
receive for packaging or labeling as a each batch size;
purchase order. dietary supplement (and for distribution (b) A complete list of components to
(c) You must quarantine the received rather than for return to the supplier); be used;
product until: and (c) An accurate statement of the
(1) You collect representative samples (3) Documentation that the weight or measure of each component to
of each unique shipment, and of each requirements of this subpart were met. be used;
unique lot within each unique (i) The person who performs the (d) The identity and weight or
shipment, of received product; required operation must document, at measure of each dietary ingredient that
the time of performance, that the will be declared on the Supplement
(2) Quality control personnel review required operation was performed.
and approve the documentation to Facts label and the identity of each
(ii) The documentation must include: ingredient that will be declared on the
determine whether the received product (A) The date that the components,
meets the specifications that you ingredients list of the dietary
packaging, labels, or products that you
established under § 111.70(f); and supplement;
receive for packaging or labeling as a (e) A statement of any intentional
(3) Quality control personnel approve dietary supplement were received; overage amount of a dietary ingredient;
the received product for packaging or (B) The initials of the person (f) A statement of theoretical yield of
labeling as a dietary supplement and performing the required operation; a manufactured dietary supplement
release the received product from (C) The results of any tests or
expected at each point, step, or stage of
quarantine. examinations conducted on
the manufacturing process where
components, packaging, or labels, and of
(d)(1) You must identify each unique control is needed to ensure the quality
any visual examination of product that
lot within each unique shipment of of the dietary supplement, and the
you receive for packaging or labeling as
received product in a manner that expected yield when you finish
a dietary supplement; and
allows you to trace the lot to the manufacturing the dietary supplement,
(D) Any material review and
supplier, the date received, the name of including the maximum and minimum
disposition decision conducted on
the received product, the status of the percentages of theoretical yield beyond
components, packaging, labels, or
received product (e.g., quarantined, which a deviation investigation of a
products that you receive for packaging
approved, or rejected), and to the batch is necessary and material review
or labeling as a dietary supplement.
product that you packaged or labeled is conducted and disposition decision is
and distributed as a dietary supplement. Subpart H—Production and Process made;
Control System: Requirements for the (g) A description of packaging and a
(2) You must use this unique
Master Manufacturing Record representative label, or a cross-reference
identifier whenever you record the to the physical location of the actual or
disposition of each unique lot within § 111.205 What is the requirement to representative label;
each unique shipment of the received establish a master manufacturing record? (h) Written instructions, including the
product.
(a) You must prepare and follow a following:

(e) You must hold the received written master manufacturing record for (1) Specifications for each point, step,
product under conditions that will each unique formulation of dietary or stage in the manufacturing process
protect against contamination and supplement that you manufacture, and where control is necessary to ensure the
deterioration, and avoid mixups. for each batch size, to ensure uniformity quality of the dietary supplement and
that the dietary supplement is packaged supplement, that you distribute to label specified in the master
and labeled as specified in the master another person for packaging or manufacturing record; and
manufacturing record; labeling; (3) The results of any tests or
(2) Procedures for sampling and a (b) The identity of equipment and examinations conducted on packaged
cross-reference to procedures for tests or processing lines used in producing the and labeled dietary supplements
examinations; batch; (including repackaged or relabeled
(3) Specific actions necessary to (c) The date and time of the dietary supplements), or a cross-
perform and verify points, steps, or maintenance, cleaning, and sanitizing of reference to the physical location of
stages in the manufacturing process the equipment and processing lines such results;
where control is necessary to ensure the used in producing the batch, or a cross- (l) Documentation at the time of
quality of the dietary supplement and reference to records, such as individual performance that quality control
that the dietary supplement is packaged equipment logs, where this information personnel:
and labeled as specified in the master is retained; (1) Reviewed the batch production
manufacturing record. (d) The unique identifier that you record, including:
(i) Such specific actions must include assigned to each component (or, when (i) Review of any monitoring
verifying the weight or measure of any applicable, to a product that you receive operation required under subpart E of
component and verifying the addition of from a supplier for packaging or labeling this part; and
as a dietary supplement), packaging, (ii) Review of the results of any tests
any component; and
and label used; and examinations, including tests and
(ii) For manual operations, such
(e) The identity and weight or examinations conducted on
specific actions must include:
measure of each component used; components, in-process materials,
(A) One person weighing or finished batches of dietary supplements,
measuring a component and another (f) A statement of the actual yield and
a statement of the percentage of and packaged and labeled dietary
person verifying the weight or measure; supplements;
and theoretical yield at appropriate phases
of processing; (2) Approved or rejected any
(B) One person adding the component reprocessing or repackaging; and
and another person verifying the (g) The actual results obtained during
any monitoring operation; (3) Approved and released, or
addition. rejected, the batch for distribution,
(4) Special notations and precautions (h) The results of any testing or
examination performed during the batch including any reprocessed batch; and
to be followed; and (4) Approved and released, or
(5) Corrective action plans for use production, or a cross-reference to such
rejected, the packaged and labeled
when a specification is not met. results;
dietary supplement, including any
(i) Documentation that the finished
repackaged or relabeled dietary
Subpart I—Production and Process dietary supplement meets specifications
supplement.
Control System: Requirements for the established in accordance with (m) Documentation at the time of
Batch Production Record § 111.70(e) and (g); performance of any required material
(j) Documentation, at the time of review and disposition decision.
§ 111.255 What is the requirement to performance, of the manufacture of the
establish a batch production record? (n) Documentation at the time of
batch, including: performance of any reprocessing.
(a) You must prepare a batch (1) The date on which each step of the
production record every time you master manufacturing record was Subpart J—Production and Process
manufacture a batch of a dietary performed; and Control System: Requirements for
supplement; (2) The initials of the persons Laboratory Operations
(b) Your batch production record performing each step, including:
must include complete information (i) The initials of the person § 111.303 What are the requirements under
relating to the production and control of responsible for weighing or measuring this subpart J for written procedures?
each batch; each component used in the batch; You must establish and follow written
(c) Your batch production record must (ii) The initials of the person procedures for laboratory operations,
accurately follow the appropriate master responsible for verifying the weight or including written procedures for the
manufacturing record and you must measure of each component used in the tests and examinations that you conduct
perform each step in the production of batch; to determine whether specifications are
the batch; and (iii) The initials of the person met.
(d) You must make and keep batch responsible for adding the component to
§ 111.310 What are the requirements for
production records in accordance with the batch; and the laboratory facilities that you use?
subpart P of this part. (iv) The initials of the person
You must use adequate laboratory
responsible for verifying the addition of
§ 111.260 What must the batch record facilities to perform whatever testing
components to the batch;
include? (k) Documentation, at the time of and examinations are necessary to
The batch production record must performance, of packaging and labeling determine whether:
include the following: (a) Components that you use meet
operations, including:
(a) The batch, lot, or control number: specifications;
(1) The unique identifier that you (b) In-process specifications are met
(1) Of the finished batch of dietary assigned to packaging and labels used, as specified in the master manufacturing
supplement; and the quantity of the packaging and labels record; and
(2) That you assign in accordance used, and, when label reconciliation is (c) Dietary supplements that you
with § 111.415(f) for the following: required, reconciliation of any manufacture meet specifications.
(i) Each lot of packaged and labeled discrepancies between issuance and use
dietary supplement from the finished of labels; § 111.315 What are the requirements for
batch of dietary supplement; (2) An actual or representative label, laboratory control processes?
(ii) Each lot of dietary supplement, or a cross-reference to the physical You must establish and follow
from the finished batch of dietary location of the actual or representative laboratory control processes that are
reviewed and approved by quality Subpart K—Production and Process supplements that are not under a
control personnel, including the Control System: Requirements for material review against contamination
following: Manufacturing Operations and mixups with those that are under a
(a) Use of criteria for establishing material review;
appropriate specifications; § 111.353 What are the requirements under (h) Performing mechanical
this subpart K for written procedures? manufacturing steps (such as cutting,
(b) Use of sampling plans for
obtaining representative samples, in You must establish and follow written sorting, inspecting, shredding, drying,
accordance with subpart E of this part, procedures for manufacturing grinding, blending, and sifting) by any
of: operations. effective means to protect the dietary
(1) Components, packaging, and § 111.355 What are the design supplements against contamination, by,
labels; requirements for manufacturing for example:
(2) In-process materials; operations? (1) Cleaning and sanitizing contact
(3) Finished batches of dietary You must design or select surfaces;
supplements; manufacturing processes to ensure that (2) Using temperature controls; and
(4) Product that you receive for product specifications are consistently (3) Using time controls.
met. (i) Using effective measures to protect
packaging or labeling as a dietary
against the inclusion of metal or other
supplement (and for distribution rather
§ 111.360 What are the requirements for foreign material in components or
than for return to the supplier); and
sanitation? dietary supplements, by, for example:
(5) Packaged and labeled dietary
You must conduct all manufacturing (1) Filters or strainers,
supplements. (2) Traps,
operations in accordance with adequate
(c) Use of criteria for selecting (3) Magnets, or
sanitation principles.
appropriate examination and testing (4) Electronic metal detectors.
methods; § 111.365 What precautions must you take (j) Segregating and identifying all
(d) Use of criteria for selecting to prevent contamination? containers for a specific batch of dietary
standard reference materials used in You must take all the necessary supplements to identify their contents
performing tests and examinations; and precautions during the manufacture of a and, when necessary, the phase of
(e) Use of test methods and dietary supplement to prevent manufacturing; and
examinations in accordance with contamination of components or dietary (k) Identifying all processing lines and
established criteria. supplements. These precautions major equipment used during
include: manufacturing to indicate their
§ 111.320 What requirements apply to (a) Performing manufacturing
laboratory methods for testing and contents, including the name of the
examination?
operations under conditions and dietary supplement and the specific
controls that protect against the batch or lot number and, when
(a) You must verify that the laboratory potential for growth of microorganisms necessary, the phase of manufacturing.
examination and testing methodologies and the potential for contamination;
are appropriate for their intended use. (b) Washing or cleaning components § 111.370 What requirements apply to
(b) You must identify and use an that contain soil or other contaminants; rejected dietary supplements?
appropriate scientifically valid method (c) Using water that, at a minimum, You must clearly identify, hold, and
for each established specification for complies with the applicable Federal, control under a quarantine system for
which testing or examination is required State, and local requirements and does appropriate disposition any dietary
to determine whether the specification not contaminate the dietary supplement supplement that is rejected and
is met. when the water may become a unsuitable for use in manufacturing,
§ 111.325 Under this subpart J, what
component of the finished batch of packaging, or labeling operations.
records must you make and keep? dietary supplement;
(d) Performing chemical, § 111.375 Under this subpart K, what
(a) You must make and keep records microbiological, or other testing, as
records must you make and keep?
required under this subpart J in necessary to prevent the use of (a) You must make and keep records
accordance with subpart P of this part. contaminated components; required under this subpart K in
(b) You must make and keep the (e) Sterilizing, pasteurizing, freezing, accordance with subpart P of this part.
following records: refrigerating, controlling hydrogen-ion (b) You must make and keep records
(1) Written procedures for laboratory concentration (pH), controlling of the written procedures for
operations, including written humidity, controlling water activity manufacturing operations.
procedures for the tests and (aw), or using any other effective means
examinations that you conduct to Subpart L—Production and Process
to remove, destroy, or prevent the
determine whether specifications are Control System: Requirements for
growth of microorganisms and prevent
met; Packaging and Labeling Operations
decomposition;
(2) Documentation that laboratory (f) Holding components and dietary § 111.403 What are the requirements under
methodology established in accordance supplements that can support the rapid this subpart L for written procedures?
with this subpart J is followed. growth of microorganisms of public You must establish and follow written
(i) The person who conducts the health significance in a manner that procedures for packaging and labeling
testing and examination must prevents the components and dietary operations.
document, at the time of performance, supplements from becoming
that laboratory methodology established adulterated; § 111.410 What requirements apply to
in accordance with this subpart J is (g) Identifying and holding any packaging and labels?
followed. components or dietary supplements, for (a) You must take necessary actions to
(ii) The documentation for laboratory which a material review and disposition determine whether packaging for dietary
tests and examinations must include the decision is required, in a manner that supplements meets specifications so
results of the testing and examination. protects components or dietary that the condition of the packaging will
ensure the quality of your dietary whether the dietary supplement meets to the mixup, contamination, or
supplements; specifications established in accordance deterioration of components, dietary
(b) You must control the issuance and with § 111.70(g); and supplements, packaging, and labels.
use of packaging and labels and (h) Suitably disposing of labels and
reconciliation of any issuance and use packaging for dietary supplements that § 111.460 What requirements apply to
discrepancies. Label reconciliation is are obsolete or incorrect to ensure that holding in-process material?
not required for cut or rolled labels if a they are not used in any future (a) You must identify and hold in-
100-percent examination for correct packaging and label operations. process material under conditions that
labels is performed by appropriate protect against mixup, contamination,
§ 111.420 What requirements apply to
electronic or electromechanical and deterioration.
repackaging and relabeling?
equipment during or after completion of
finishing operations; and (a) You may repackage or relabel (b) You must hold in-process material
(c) You must examine, before dietary supplements only after quality under appropriate conditions of
packaging and labeling operations, control personnel have approved such temperature, humidity, and light.
packaging and labels for each batch of repackaging or relabeling.
(b) You must examine a representative § 111.465 What requirements apply to
dietary supplement to determine
sample of each batch of repackaged or holding reserve samples of dietary
whether the packaging and labels supplements?
relabeled dietary supplements to
conform to the master manufacturing
determine whether the repackaged or (a) You must hold reserve samples of
record; and
relabeled dietary supplements meet all dietary supplements in a manner that
(d) You must be able to determine the
specifications established in accordance
complete manufacturing history and protects against contamination and
with § 111.70(g).
control of the packaged and labeled deterioration. This includes:
(c) Quality control personnel must
dietary supplement through (1) Holding the reserve samples under
approve or reject each batch of
distribution. conditions consistent with product
repackaged or relabeled dietary
§ 111.415 What requirements apply to supplement prior to its release for labels or, if no storage conditions are
filling, assembling, packaging, labeling, and distribution. recommended on the label, under
related operations? ordinary storage conditions; and
§ 111.425 What requirements apply to a
You must fill, assemble, package, packaged and labeled dietary supplement (2) Using the same container-closure
label, and perform other related that is rejected for distribution? system in which the packaged and
operations in a way that ensures the You must clearly identify, hold, and labeled dietary supplement is
quality of the dietary supplement and control under a quarantine system for distributed, or if distributing dietary
that the dietary supplement is packaged appropriate disposition any packaged supplements to be packaged and
and labeled as specified in the master and labeled dietary supplement that is labeled, using a container-closure
manufacturing record. You must do this rejected for distribution. system that provides essentially the
using any effective means, including the
following: same characteristics to protect against
§ 111.430 Under this subpart L, what
(a) Cleaning and sanitizing all filling records must you make and keep? contamination or deterioration as the
and packaging equipment, utensils, and (a) You must make and keep records one in which you distribute the dietary
dietary supplement packaging, as required under this subpart L in supplement for packaging and labeling
appropriate; accordance with subpart P of this part. elsewhere.
(b) Protecting manufactured dietary (b) You must make and keep records (b) You must retain reserve samples
supplements from contamination, of the written procedures for packaging for 1 year past the shelf life date (if shelf
particularly airborne contamination; and labeling operations. life dating is used), or for 2 years from
(c) Using sanitary handling the date of distribution of the last batch
procedures; Subpart M—Holding and Distributing of dietary supplements associated with
(d) Establishing physical or spatial the reserve samples, for use in
separation of packaging and label this subpart for M written procedures? appropriate investigations.
operations from operations on other
You must establish and follow written
components and dietary supplements to § 111.470 What requirements apply to
procedures for holding and distributing
prevent mixups; distributing dietary supplements?
operations.
(e) Identifying, by any effective
means, filled dietary supplement You must distribute dietary
§ 111.455 What requirements apply to
containers that are set aside and held in holding components, dietary supplements,
supplements under conditions that will
unlabeled condition for future label packaging, and labels? protect the dietary supplements against
operations, to prevent mixups; (a) You must hold components and contamination and deterioration.
(f) Assigning a batch, lot, or control dietary supplements under appropriate § 111.475 Under this subpart M, what
number to: conditions of temperature, humidity, records must you make and keep?
(1) Each lot of packaged and labeled and light so that the identity, purity,
dietary supplement from a finished strength, and composition of the (a) You must make and keep records
batch of dietary supplement; and, components and dietary supplements required under this subpart M in
(2) Each lot of dietary supplement, are not affected. accordance with subpart P of this part.
from a finished batch of dietary (b) You must hold packaging and (b) You must make and keep the
supplement, that you distribute to labels under appropriate conditions so following records:
another person for packaging or that the packaging and labels are not
labeling. adversely affected. (1) Written procedures for holding
(g) Examining a representative sample (c) You must hold components, and distributing operations; and
of each batch of the packaged and dietary supplements, packaging, and (2) Records of product distribution.
labeled dietary supplement to determine labels under conditions that do not lead
Subpart N—Returned Dietary (1) Written procedures for fulfilling (1) Written procedures for fulfilling
Supplements the requirements of this subpart N. the requirements of this subpart,
(2) Any material review and (2) A written record of every product
§ 111.503 What are the requirements under disposition decision on a returned complaint that is related to good
this subpart N for written procedures? manufacturing practice,
dietary supplement;
You must establish and follow written (3) The results of any testing or (i) The person who performs the
procedures to fulfill the requirements of examination conducted to determine requirements of this subpart must
this subpart. compliance with product specifications document, at the time of performance,
§ 111.510 What requirements apply when a established under § 111.70(e); and, that the requirement was performed.
returned dietary supplement is received? (4) Documentation of the reevaluation (ii) The written record of the product
by quality control personnel of any complaint must include the following:
You must identify and quarantine
dietary supplement that is reprocessed (A) The name and description of the
returned dietary supplements until
and the determination by quality control dietary supplement;
quality control personnel conduct a (B) The batch, lot, or control number
material review and make a disposition personnel of whether the reprocessed
dietary supplement meets product of the dietary supplement, if available;
decision. (C) The date the complaint was
specifications established in accordance
§ 111.515 When must a returned dietary with § 111.70(e). received and the name, address, or
supplement be destroyed, or otherwise telephone number of the complainant, if
suitably disposed of? Subpart O—Product Complaints available;
You must destroy, or otherwise (D) The nature of the complaint
§ 111.553 What are the requirements under including, if known, how the product
suitably dispose of, any returned dietary this subpart O for written procedures?
supplement unless the outcome of a was used;
material review and disposition You must establish and follow written (E) The reply to the complainant, if
decision is that quality control procedures to fulfill the requirements of any; and
personnel do the following: this subpart O. (F) Findings of the investigation and
(a) Approve the salvage of the followup action taken when an
§ 111.560 What requirements apply to the
returned dietary supplement for review and investigation of a product
investigation is performed.
redistribution or complaint?
(b) Approve the returned dietary Subpart P—Records and
(a) A qualified person must: Recordkeeping
supplement for reprocessing. (1) Review all product complaints to
§ 111.520 When may a returned dietary determine whether the product § 111.605 What requirements apply to the
supplement be salvaged? complaint involves a possible failure of records that you make and keep?
You may salvage a returned dietary a dietary supplement to meet any of its (a) You must keep written records
supplement only if quality control specifications, or any other required by this part for 1 year past the
personnel conduct a material review requirements of this part 111, including shelf life date, if shelf life dating is used,
and make a disposition decision to those specifications and other or 2 years beyond the date of
allow the salvage. requirements that, if not met, may result distribution of the last batch of dietary
in a risk of illness or injury; and supplements associated with those
§ 111.525 What requirements apply to a (2) Investigate any product complaint records.
returned dietary supplement that quality that involves a possible failure of a (b) Records must be kept as original
control personnel approve for records, as true copies (such as
dietary supplement to meet any of its
reprocessing? photocopies, microfilm, microfiche, or
specifications, or any other
(a) You must ensure that any returned requirements of this part, including other accurate reproductions of the
dietary supplements that are those specifications and other original records), or as electronic
reprocessed meet all product requirements that, if not met, may result records.
specifications established in accordance in a risk of illness or injury. (c) All electronic records must comply
with § 111.70(e); and (b) Quality control personnel must with part 11 of this chapter.
(b) Quality control personnel must review and approve decisions about
approve or reject the release for § 111.610 What records must be made
whether to investigate a product available to FDA?
distribution of any returned dietary complaint and review and approve the
supplement that is reprocessed. (a) You must have all records required
findings and followup action of any under this part, or copies of such
§ 111.530 When must an investigation be investigation performed. records, readily available during the
conducted of your manufacturing (c) The review and investigation of retention period for inspection and
processes and other batches? the product complaint by a qualified copying by FDA when requested.
If the reason for a dietary supplement person, and the review by quality (b) If you use reduction techniques,
being returned implicates other batches, control personnel about whether to such as microfilming, you must make
you must conduct an investigation of investigate a product complaint, and the suitable reader and photocopying
your manufacturing processes and each findings and followup action of any equipment readily available to FDA.
of those other batches to determine investigation performed, must extend to
all relevant batches and records. Dated: May 8, 2007.
compliance with specifications.
Andrew C. von Eschenbach,
§ 111.535 Under this subpart N, what § 111.570 Under this subpart O, what Commissioner of Food and Drugs.
records must you make and keep? records must you make and keep?
Dated: May 8, 2007.
(a) You must make and keep records (a) You must make and keep the
required under this subpart N in records required under this subpart O in Michael O. Leavitt,
accordance with subpart P of this part. accordance with subpart P of this part. Secretary of Health and Human Services.
(b) You must make and keep the (b) You must make and keep the [FR Doc. 07–3039 Filed 6–22–07; 8:45 am]
following records: following records: BILLING CODE 4160–01–S

Rule: Food For Human Consumption: Current Good Manufacturing Practice&#8212 Dietary Supplements Manufacturing, Packaging, Labeling, or Holding Operations

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Rule: Food For Human Consumption: Current Good Manufacturing Practice&#8212 Dietary Supplements Manufacturing, Packaging, Labeling, or Holding Operations

Diunggah oleh

Hak Cipta:

Format Tersedia

Monday,

June 25, 2007

21 CFR Part 111

DEPARTMENT OF HEALTH AND 1. Overview (Proposed § 111.2)

G. Under This Subpart, What Records 1. Final § 111.70(a) Control Operations

1. Final § 111.127(a) and (b) 3. Final § 111.165(c) 3. Changes After Considering

B. Highlights of Changes to the Filling, Assembling, Packaging, C. General Comments on Proposed

1. Final § 111.410(a) Proposed Requirements for and Recordkeeping

A—General Provisions 111.1 A—General Provisions 111.1

B—Personnel 111.10 B—Personnel 111.8 (new)

C—Physical Plant 111.15 C—Physical Plant and 111.15

F—Production and Process 111.103 (new)

G—Production and Process 111.153 (new)

H—Production and Process 111.205 (formerly proposed

I—Production and Process 111.255 (formerly proposed

J—Production and Process 111.303 (new)

K—Production and Process 111.353 (new)

L—Production and Process 111.403 (new)

F—Holding and Distributing 111.80 M—Holding and Distributing 111.453 (new)

N—Returned Dietary Sup- 111.503 (new)

G—Consumer Complaints 111.95 O—Product Complaints 111.553 (new)

dietary supplements do not, by Failure to properly clean components, authority.

individual comments on specific personnel, etc. For example, if the

§ 111.15(c)(3) is similar to proposed contact surfaces on the premises by supplements.

establish and follow written procedures manufacturer. According to these

(Response) These CGMP requirements equipment. If the manufacturer failed to

provision of § 111.75(a)(1)(i). with the production

Final § 111.110(a) requires that § 111.110(c) derives from proposed

material review and made the • If there is any unanticipated occurrences.

requires that quality control personnel calibrations, inspections, or checks.

component even if it does not meet underlying principle of these CGMP

dietary ingredient, including the safety

be required. The purpose of this supplement and to the product label of

disposition decision if a batch deviates ‘‘validated testing method,’’ for each

circumstances. recommendation from a contract rule give companies the flexibility to

accordance with adequate sanitation against the potential for growth of

2. Final § 111.365(b) manufactured in a foreign country contamination of the dietary

dietary supplements and ingredients (Response) As written, proposed

Final § 111.465(b) requires you to comments. Therefore, final § 111.475

safety, identity, strength, quality, or disposition decision and do not require

dietary ingredient or dietary supplement investigation is to determine whether

discussed previously, the 1997 ANPRM elements and areas of uniqueness

to support it. warranted. alkaloids has been finalized (69 FR

TABLE 18.—ESTIMATED ONE-TIME BURDEN TO ESTABLISH WRITTEN PROCEDURES1

111.14 15,000 1 15,000 3.6 54,000

111.23 15,000 1 15,000 1 15,000

111.35 400 1 400 36 14,400

111.95 250 1 250 68 17,000

111.140 300 1 300 10.7 3,210

111.180 200 1 200 10 2,000

111.210 250 1 250 12 3,000

111.325 150 1 150 45 6,750

111.375 260 1 260 9 2,340

111.430 250 1 250 12.6 3,150

111.475 15,000 1 15,000 2.1 31,500

111.535 200 1 200 6 1,200

111.570 240 1 240 12 2,880

TABLE 19.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

111.14 15,000 4 60,000 1 60,000

111.23 15,000 1 15,000 0.2 3,000

111.35 400 1 400 12.5 5,000

111.95 250 1 250 45 11,250

111.140 240 1,163 279,120 1 279,120