ICH Q7A GMP

Guidance for APIs

and its Use During
Inspections

Office of Regional Operations

Center For Drug Evaluation and Research
U.S. Food and Drug Administration
Rockville, MD
1
 Processes Covered During API
Inspections Abroad - FY 2001
Chemical Synthesis
Nonsterile
81% Crude Bulk NEC
7%

Fermentation
Nonsterile
6%

Chemical Synthesis
Sterile
2%
Biotech/Crude Drug
Others
1%
3%

2
 Program Objectives

• Understand the scope of the Q7A guidance

• Recall how to use the guidance during

inspections

• Understand several controversial issues in

API production and how Q7A addresses
these issues
3
 Agenda

• What is ICH?
• Availability of Q7A on the Internet
• What is an intermediate and API?
• Regulatory status of APIs abroad and in US
• Guidance initiatives incorporated into Q7A
• Importance of Q7A
• Process characteristics – APIs Vs. Drug
Products
4
 Agenda

• Implementation of Q7A
• Status of Q7A and other GMP documents
• Use of Q7A during inspections
• Scope and meaning of “should”
• Applying Q7A
• API Starting Materials
• CGMP controls in API processes
5
 Agenda

• Process water quality

• Blending of intermediates/APIs
• In-process controls/process validation
• Impurity profiles
• Reprocessing and reworking
• Recovery of materials/solvents

6
 Questions on ICH Q7A?

Please call or FAX Questions to:

Phone: 1-800-218-4880

FAX: 1-866-806-6087

7
 What Is ICH?

International
Conference on
Harmonization
Of Technical Requirements for the
Registration of Pharmaceuticals
for Human Use 8
 What Is ICH?

• Established in 1990 between the European Union, Japan,

and United States

• Committed to reducing duplication during research and

development of new drugs while safeguarding quality,
safety and efficacy

• Developed over 40 guidance documents mostly

addressing technical/regulatory requirements for
registering new human drug products

9
 ICH Members

• Regulatory agencies
EMEA - European Union
MHLW - Japan
FDA - US
• Trade associations
EFPIA - Europe
JPMA - Japan
PhRMA - US
10
 ICH Technical Topics

Quality (chemical and pharmaceutical QA)

Q1, Stability Testing

Safety (in vitro and in-vivo pre-clinical studies)

S1, Carcinogenicity Testing

Efficacy (clinical studies in human subject)

E6, Good Clinical Practices

Multidisciplinary (cross-cutting topics)

M1, Medical Terminology

11
 ICH Quality Topics Checklist

Q1: Q1A(R): Stability Testing of New Q1C: Stability Testing for

Q1B: Photostability Testing 
Stability          Drugs and Products (Revised)  New Dosage Forms

Q1D: Bracketing and Matrixing

        
Designs for Stability Testing of Drug
Substances and Drug Products 

Q2A: Text on Validation of

Q2: Analytical Valid Q2B: Methodology
Analytical Procedures
ation
Q3A(R): Impurities in New Drug Q3B(R): Impurities in New Drug Q3C: Impurities: Residual
Q3: Impurities    
Substances (Revised) Products (Revised)  Solvents
Q4: Pharmacopoeias Q4: Pharmacopoeial Harmonisation
       
Q5: Biotechnological Q5B: Genetic Stability Q5C: Stability of Products
Q5A: Viral Safety Evaluation
Quality

Q5D: Cell Substrates

Q6A: Chemical Substances 

Q6: Specifications Q6B: Biotechnological Substances 
with its Decision Trees

Q7: GMP
Q7A:  GMP for Active Pharmaceutical Ingredients
                                
         12
 The ICH Process For
Harmonization Of Guidance
Step 5: Guidance incorporated into regulations or other
appropriate mechanisms and implemented in ICH regions.

Step 4: Final draft discussed by Steering Committee & “signed

off” by three regulatory parties. Adoption recommended.

Step 3: Regulatory consultation in the three ICH regions.

Consolidation of public comments.

Step 2: Agreement by the Steering Committee to release the draft consensus

text for wider consultation.

Step 1: Building of scientific consensus in joint regulatory/industry expert working

groups. Draft then forwarded to ICH Steering Committee.

13
 For Additional Information
On ICH

http://www.ifpma.org/ich1.html

14
 Availability of Q7A Guidance
on the Internet

http://www.fda.gov/cder/guidance/4286fnl.pdf
http://www.fda.gov/cber/gdlns/ichactive.pdf
http://www.emea.eu.int/pdfs/human/ich/410600en.pdf
http://www.ifpma.org/ich5q.html#gmp
http://www.picscheme.org/docs/pdf/gmpapi.pdf
http://www.nihs.go.jp/dig/ich/quality/q7a/Q7Astep4.pdf

15
 What Is an Intermediate?

• A material produced during API

processing that undergoes further
molecular change or purification before
it becomes the API

• May or may not be isolated

16
 What Is an Active
Pharmaceutical Ingredient?
• The intended use clause:

Any substance or mixture of substances

intended to be used in the manufacture
of a drug (medicinal) product and that,
when used in the production of a drug,
becomes an active ingredient of the
drug product.
17
 What Is an Active
Pharmaceutical Ingredient?
• The pharmacological activity clause:

Such substances are intended to

furnish pharmacological activity or
other direct effect in the diagnosis,
cure, mitigation, treatment, or
prevention of disease or to affect the
structure and function of the body.
18
 Regulatory Status of APIs
Abroad
• Since implementation of EU/US MRA and
issuance of Q7A, many countries are seeking
legal authority to inspect and regulate API
manufacturers

• Regulatory bodies worldwide are developing

enforcement policies and qualifying
personnel to inspect API manufacturers

19
Regulatory Status of APIs in the
United States
• Definition of “drug” in the Federal Food, Drug,
and Cosmetic Act encompasses APIs

• Section 501(a)(2)(B) of the Act requires that all

drugs be manufactured, processed, packed, and
held in accordance with current good
manufacturing practice

• CGMP regulations (21 CFR 210 and 211) apply

only to preparation of drug products
20
Regulatory Status of APIs in the
United States
“These CGMP regulations apply to
finished dosage form drugs (under 
210.3(b)(4) and 211.1) and are not binding
requirements for chemical manufacturing.”

Reference: Response to Comment 270 in the

Preamble to the September 29, 1978 revisions
to CGMP regulations (Page 45050)
21
Regulatory Status of APIs in the
United States
“The Commissioner maintains that these
regulations can serve as useful guidelines
in the manufacture of chemicals. The
agency plans to develop specific CGMP
regulations on production of bulk drugs.”

Reference: Response to Comment 270 in the

Preamble to the Sept. 29, 1978 revisions to
CGMP regulations (Page 45050)
22
API GMP Guidance Initiatives
Incorporated Into Q7A

23
 Importance of Q7A

• First internationally harmonized tripartite GMP

guidance developed jointly by industry and
regulators under ICH umbrella

• Establishes one global GMP standard for APIs

• Intended to provide mutual recognition of

GMPs in API production

24
 Importance Of Q7A

• Intended to facilitate API inspections

• Impacts any manufacturer that markets

APIs in ICH regions

• Addresses uniqueness of API processes

25
 Process Characteristics
API Vs. Drug Product

API Drug
Drug
API
Product
Product

Basic
Basic
Chemicals
Chemicals API
API

Different Raw Materials 26

 Process Characteristics
API Vs. Drug Product
Drug
Drug
API
API Product
Product
Chemical & Biological Physical Processing
Processing (granulating, dissolving,
(synthesis, fermentation, mixing, compressing)
extraction, purification)

Different Facilities, Equipment and Processes

27
 Characteristics of
API Processes
• APIs produced by chemical or enzymatic
reactions, recombinant DNA, fermentation,
recovery from natural materials, or a
combination of these processes

• Usually involves synthesis, extraction, or

crystallization resulting in significant changes to
starting materials/intermediates

• Typically include purification steps

28
 Characteristics of
Drug Product Processes

• Drug products formulated using bulk raw

materials that are usually subjected to
quality control by end users

• Generally involves physical processing and

manipulations

• Typically do not include purification steps

29
 Uniqueness of API Processes
Also Account for Differences In

 Process water quality

 Blending of intermediates and APIs
 In process controls
 Process validation
 Reprocessing/Reworks
 Recovery of materials and solvents
30
 Uniqueness of API Processes

• Does not influence GMP expectations for

laboratory controls and documentation

• No significant differences between a

laboratory testing dosage forms and one
testing APIs

31
 When Inspecting or Auditing
API Manufacturers

Please wear your

API hat!

DOSAGE

DEVICES
APIs
32
 Implementation Of Q7A

• Posted on European Agency for the

Evaluation of Medicinal Product’s
(EMEA’s) website in November 2000

• Published as Annex 18 to the European

Union’s (EU’s) Guide to Good
Manufacturing Practices in July 2001
33
 Implementation Of Q7A

• Notice of Availability (NOA) published in

Federal Register (Volume 66, No. 186)
on September 25, 2001

• Adopted by Japan’s Ministry of Health,

Labour and Welfare (MHLW) on
November 2, 2001
34
 Implementation Of Q7A

• Adopted by Australia’s Therapeutic

Goods Administration (TGA) in April
2001

• Adopted by Pharmaceutical Inspection

Convention/Pharmaceutical Inspection
Cooperation Scheme (PIC/S) in May
2001
35
 Implementation Of Q7A

• World Health Organization (WHO)

currently reviewing guidance to
determine if they should adopt Q7A and
promote it as an international standard
that fulfills the function of global
harmonization

36
 Q7A Industry Guidance
Disclaimer

“This guidance represents the Food and Drug

Administration’s (FDA’s) current thinking on this
topic. It does not create or confer any rights for
or on any person and does not operate to bind
FDA or the public. An alternative approach may
be used if such approach satisfies the
requirements of the applicable statutes and
regulations.”
37
 FDA’s Implementation of Q7A

• CDER is revising CP 7356.002F, but no

significant changes are planned in
inspectional or regulatory approach

• Use of one guidance by both regulators

and industry should facilitate inspections
and enhance GMP compliance

38
FDA’s Implementation of Q7A

• FDA’s March 1998 Draft Guidance for

Industry - Manufacturing, Processing, or
Holding Active Pharmaceutical
Ingredients will not be finalized

• Q7A supercedes FDA’s draft API

guidance
39
Status Of Q7A With Respect
To Other Documents
21PhRMA
CFR 211Guidelines
does not for
apply
Q7A is the
FDA’s Draft Guidance for
Production,
to manufacturePacking,
FDA’s Guide of to
APIs
Industry: Manufacturing,
Repacking or Holding
Inspection of BPCs of
definitive
Processing or Holding
DrugisSubstances
obsolete is
APIs will not be finalized
insufficient
GMP
guidance
for APIs!
40
 Use of Q7A During
API Inspections

• Refer to the Q7A guidance during

inspections to evaluate firm’s compliance
with GMP expectations

• If alternative methods or procedures are

in place, review firm’s justification and
determine if such alternatives are
scientifically sound and accomplish the
intended purposes
41
 Use of Q7A During
API Inspections

• Paraphrase the language in the

guidance when preparing inspectional
observations

• Don’t reference sections of Q7A in FDA

483 observations or EIR

42
 Section 1.3
Scope
• Applies to:

APIs manufactured for use in human drug

(medicinal) products

Sterile APIs, but only up to the point

immediately before the API is rendered sterile

43
 Section 1.3
Scope
• Applies to:

APIs manufactured by chemical synthesis,

extraction, cell culture/fermentation,
recovery from natural sources, or any
combination of these processes

APIs used in production of drug products

for clinical trials
44
 Section 1.3
Scope
• Applies to:

APIs produced using blood or plasma as raw materials

APIs or intermediates manufactured by cell culture or

fermentation using natural or recombinant organisms
(Chapter 18)

45
 Section 1.3
Scope
• Excludes:

All vaccines, whole cells, whole blood and plasma,

blood and plasma derivatives (plasma
fractionation) and gene therapy APIs

Bulk packaged drug (medicinal) products

Radiopharmaceuticals and medical gases

46
 Q7A Does Not Address

• Registration and filing requirements for

APIs

• Pharmacopoeial requirements

• APIs for use in veterinary drug products

47
 Section 1.1
Meaning Of “Should”

ICH Version

In this guide the term “should”

indicates recommendations that are
expected to apply unless shown to
be inapplicable or replaced by an
alternative demonstrated to provide
at least an equivalent level of quality
assurance.
48
 Section 1.1
Meaning Of “Should”

FDA Version

In this guide the term should identifies

recommendations that, when followed,
will ensure compliance with CGMPs.
An alternative approach may be used
if such approach satisfies the
requirements of the applicable
statutes. 49
 Table 1
Applying Q7A

50
Increasing GMP Expectations
 Applying Q7A

Chemical Manufacturing
Outside Covered
scope by Q7A

Production of Introduction of Isolation Physical

Production
API Starting API Starting   &  Processing &
of
Material Material Purification Packaging
Intermediates
51
 Applying Q7A

Classical Fermentation/

Outside Covered
scope by Q7A

Establishment Introduction of Isolation Physical

Cells into  &  Processing &
/Maintenance
of Working Fermentation Purification Packaging
Cell Banks
52
 Designating Where API
Production Begins

“The company should designate and

document the rationale for the point at
which production of the API begins. For
synthetic processes, this is known as the
point at which “API starting materials” are
entered into the process.”

53
 Designating Where API
Production Begins
“From this point on, appropriate GMP, as
defined in the guidance, should be
applied to these intermediate and/or API
manufacturing steps.”
C D E FI API
A B C D E FI API

54
 Definition
API Starting Materials

• Material used in production of an API that

is incorporated as a significant structural
fragment into the structure of the API

• May be an article of commerce, a material

purchased from one or more suppliers
under contract or commercial agreement,
or may be produced in-house

55
 Definition
API Starting Materials

• Are normally of defined chemical properties

and structure

56
 Important Clarification!

Q7A does not apply to steps prior to the

introduction of the defined API starting
material!

57
Why Initiate GMP Controls With
Use of API Starting Materials?
“As a general rule, however, it is reasonable to
expect GMP concepts to start to become
applicable at that point where a starting material
enters a biological or chemical synthesis or
series of processing steps, where it is known that
the end product will be a BPC.”

Reference: Sept. 1991 Guide to Inspection of

Bulk Pharmaceutical Chemicals, Page 3
58
Spectrum of CGMP Controls in
API Manufacturing
Controls increase as process
proceeds to final isolation
and purification steps

Apply GMP Degree of control

controls beginning depends on process
with the use of API and manufacturing
starting materials stage
59
 USP Expectations
Process Water Quality
Drug Products APIs
Potable water not
acceptable for Potable water
preparation of USP acceptable for
dosage forms preparation of USP
drug substances
Purified Water generally
used for non-sterile Purified water often
dosage production used in later isolation
and purification steps

60
 Section 4.3
Process Water Quality
• Water used in the manufacture of APIs
should be demonstrated to be suitable for its
intended use

• Unless otherwise justified, water should at a

minimum, meet WHO guidelines for drinking
(potable) water

61
 Section 4.3
Process Water Quality

• If tighter chemical and/or microbiological

specifications are necessary, these
should be established

62
 Section 4.3
Process Water Quality
• Water used in final isolation and purification steps
of a non-sterile API intended for producing a sterile
drug product should be monitored and controlled
for:

– Total microbial counts

– Objectionable organisms

– Endotoxins
63
 Section 8.4
Blending of Intermediates/APIs

APIs Drug products

Quality of material Blend Uniformity

introduced into blend 64
 Section 8.4
Blending of Intermediates/APIs

• Defined as the process of combining

materials within the same specification to
produce a homogeneous intermediate or
API

65
 Section 8.4
Blending of Intermediates/APIs

• Does not include:

– In process mixing of fractions from

single batches

– Combining fractions from several

batches for further processing
66
 Section 8.4
Blending of Intermediates/APIs
• OOS batches should not be blended with other
batches

• Acceptable blending operations include:

– Blending batches to increase batch size

– Blending tailings from batches of the same

intermediate/API to form a single batch
67
 Sections 8.4
Blending of Intermediates/APIs
• Each batch introduced into a blend should
have been:

– Manufactured using an established process

– Individually tested and found to meet

appropriate specifications prior to blending

68
 Sections 8.4
Blending of Intermediates/APIs
• Blended batch should be tested for
conformance to established
specifications, where appropriate

69
 Section 8.4
Blending of Intermediates/APIs

• Where physical attributes of the API are

critical, blending operations should be
validated to show homogeneity of the
combined batch

70
 Section 8.4
Blending of Intermediates/APIs
• Should include testing of critical attributes that may
be affected by the blending process, such as:

• Particle size distribution

• Bulk density

• Tap density

71
 Section 8.4
Blending of Intermediates/APIs

• If blending could adversely affect stability,

stability testing of final blended batches
should be performed

• Expiry or retest date of blended batch

should be based on the manufacturing
date of the oldest tailings or batch in the
blend
72
 Section 8.1
Critical Operations
• Critical weighing, measuring, or subdividing operations should be witnessed or
subjected to an equivalent control

• Other critical activities should be witnessed or subjected to an equivalent control

73
 Section 8.1
Process Deviations

• Any deviation should be documented and

explained

• Critical deviations should be investigated

74
 Section 8.2
Time Limits
• Should be met if specified in the master
production instruction

• Deviations from time limits should be

documented and evaluated

75
 Section 8.2
Time Limits
• May be inappropriate when processing to a target value where completion of
process steps are determined by in-process sampling and testing

• Intermediates held for further processing should be stored under appropriate

conditions to ensure suitability for use

76
 Section 8.3
In-Process Sampling & Controls

In-process controls and acceptance criteria should

be defined based on information gained during
developmental stage or from historical data

77
 Section 8.3
In-Process Sampling & Controls
• Type/extent of testing and acceptance criteria
depends on:

– Nature of intermediate or API

– Reaction or process step

– Degree of variability introduced by process

78
 Section 8.3
In-Process Sampling & Controls
• Less stringent in-process controls may be
appropriate in early processing steps

• Tighter controls may be appropriate for later

processing steps

A B C D E F API

Early Increasing GMPs

steps 79
 Section 8.3
In-Process Sampling & Controls
• Critical in-process controls should be in
writing and approved by the quality unit

• Qualified production personnel can perform

in-process controls and adjust process
without prior Q.C. approval if adjustments
are made within pre-established limits
approved by Q.C. unit
80
 Section 8.3
In-Process Sampling & Controls

Out of specification (OOS) investigations

are not normally needed for in-process
tests performed for the purpose of
monitoring and/or adjusting the process

OOS
81
 Process Validation
Dosage Forms Vs. APIs
Drug Products APIs

Validate all Validate critical

manufacturing steps, processing steps
such as cleaning, determined to
weighing, measuring, impact the quality
mixing, blending, and purity of the
filling, packaging and
API
labeling
82
 Definition Of Critical

“A process step, process condition, test

requirement, or any other relevant
parameter or item that must be controlled
within predetermined criteria to ensure that
the API meets its specification.”

83
 Section 12.1
Validation

• Should extend to those operations

determined to be critical to the quality and
purity of the API

• Critical parameters/attributes are normally

identified during the development stage
or from historical data, along with ranges
necessary for reproducible operations
84
 Examples of
Process Parameters
• Temperature
• Pressure
• Vacuum
• Time (Duration)
• Flow Rate
• Cooling Rate
• Agitation Speed
85
 Section 12.4
Prospective Validation

• Normally performed for all API processes

• Validation of API process should be completed

before commercial distribution of the final drug
product manufactured from that API

86
 Section 12.4
Concurrent Validation
• Conducted when data from replicate
production runs are unavailable:

– Limited number of API batches produced

– API batches produced infrequently

– API batches produced by a validated

process that has been modified
87
 Section 12.4
Concurrent Validation

• Batches can be released and used in

production of drug products for commercial
distribution based on thorough monitoring
and testing of the API batches

88
 Section 12.4
Retrospective Validation
• Exception for well established processes
used without significant changes to API
quality due to changes in:

– Raw materials
– Equipment
– Systems
– Facilities
– Production process
89
 Section 12.4
Retrospective Validation

• May be used where:

– Critical quality attributes and critical

process parameters have been identified

– Appropriate in-process acceptance criteria

and controls have been established

90
 Section 12.4
Retrospective Validation
• May be used where (Continued):

– Process/product failures attributed mostly

to operator error or sporadic equipment
failures unrelated to equipment suitability

– Impurity profiles have been established for

existing API
91
 Section 12.4
Retrospective Validation
• Batches should be

– Representative of all batches produced during the

review period, including those that failed
specifications

– Sufficient in number to demonstrate process

consistency

• Retained samples can be tested

92
 Section 12.6
Periodic Review-Validated Systems

• Systems/processes should be periodically

evaluated to verify that they are still
operating in a valid manner

• No need for revalidation if significant

changes have not been made and a
quality review confirms system or process
consistently produces acceptable material
93
 Section 19.6- Validation
of APIs Used In Clinical Trials
• Process validation normally inappropriate
because of

– Process changes during API development

– Production of a single or limited number of

API batches

94
 Section 19.6 – Validation
of APIs Used In Clinical Trials

• Process validation should be conducted in

accordance with Section 12 when batches
are produced for commercial use, even
when such batches are produced on a
pilot or small scale

95
 Section 11.2
Impurity Profiles

• Describes the identified and unindentified

impurities present in an API a typical
batch produced by a specific controlled
production process

96
 Section 11.2
Impurity Profiles

• Should include:

– Identity or some qualitative analytical

designation

– Range of each impurity observed

– Classification of each identified impurity

(e.g., inorganic, organic, solvent)
97
 Section 11.2
Impurity Profiles
• Impurity profile should normally be established
for each API except those derived from:

– Herbal origin

– Animal tissue origin

– Biotechnology

98
 Section 11.2
Impurity Profiles

The impurity profile should be compared

at appropriate intervals against the
impurity profile in the regulatory
submission or compared against historical
data in order to detect changes to the API
resulting from modifications in raw
materials, equipment operating
parameters, or the production process
99
 Reprocessing And Reworking

Dosage Forms APIs

Vague distinction Clear distinction

between activities between activities

Reprocessing is atypical Reprocessing is typical

Reprocessing rarely Reprocessing generally

improves drug quality improves API quality
100
 Definition of
Reprocessing

Introducing an intermediate or API,

including one that does not conform to
standards or specifications, back into the
process and repeating a crystallization
step or other appropriate chemical or
physical manipulation steps that are part
of the established manufacturing process

101
 Definition of
Reworking

Subjecting an intermediate or API that

does not conform to standards or
specifications to one or more processing
steps that are different from the
established manufacturing process to
obtain acceptable quality material

102
 Reprocessing Vs.
Reworking
Reprocessing Reworking

Intermediates and APIs Intermediates and APIs

Conforming or non-conforming
batches Only non-conforming batches

Subject batch to one or more Subject batch to one or more

steps that are part of established steps different from
process established process

103
 Section 14.2
Reprocessing

• Reprocessing of intermediates and APIs

is generally acceptable

• If reprocessing is used for a majority of

batches, it should be included as part of
the standard manufacturing process

104
 Section 14.2
Reprocessing
• Continuation of a process step after an
in-process control test shows it is
incomplete is considered part of the
normal process, not reprocessing

105
 Sections 14.3
Reworking

• Reason for non-conformance should be

investigated before reworking batches

• Reworked batches should be subjected to

appropriate evaluation, testing, stability testing,
if warranted, and documentation to show that
the reworked batches are of equivalent quality
to that produced by the original process

106
 Sections 14.3
Reworking

• Impurity profile of each reworked batch

should be compared against batches
manufactured by the established process

• Additional analytical methods may be

needed if routine methods are
inadequate to characterize reworked
batches
107
 Sections 14.3
Reworking
• Concurrent validation is appropriate

• Protocol should define

– Rework procedure
– How performed and expected results

• Interim results if only one batch

108
 Section 14.4
Recovery Of Materials/Solvents

• Recovery of solvents, reactants,

intermediates or the API from mother
liquor or filtrate is acceptable provided

– Approved procedures exist for recovery

– Recovered materials meet specifications

and are suitable for their intended use
109
 Definition Of
Mother Liquor
• The residual liquid that remains after
crystallization or isolation processes that
may contain:

– Unreacted materials
– Intermediates
– Levels of the API and/or impurities
110
 Section 14.4
Recovery Of Materials/Solvents
• Solvents can be recovered and reused in
the same processes or different processes
provided recovery procedures are controlled
and monitored

• Ensure solvents meet appropriate standards

before reuse or co-mingling

111
 Section 14.4
Recovery Of Materials/Solvents

• Fresh and recovered solvents can be

combined if adequate testing shows
suitability for use in manufacturing

• Use should be adequately documented

112
 Q7A Summary

• Pragmatic balance of What” vs. “How”

• Clarifies GMP expectations

• Not intended to ratchet up GMPs

• Should provide enough guidance to address

CGMP problems in API production
113