FDA Regulatory Trends, Warning Letters and

Enforcement Action
Dawn Tavalsky

Jade (with her mother) Fabry disease USA

www.genzyme.com |
 Office of Regulatory Affairs (ORA)
http://www.fda.gov/ora/

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 Freedom of Information Act Reading Room

http://www.fda.gov/AboutFDA/CentersOffices/officeofGlobalRegulatoryOperationsandPolicy
/ORA/ORAElectronicReadingRoom/default.htm

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 FDA Inspection Process

FDA Office Site Location

1. Select Site 4. Arrive (482)

5. Review Records
2. Contact Site 6. Interview Staff
3. Schedule Site

9. Write Report (EIR) 7. Present Findings

10. Classify Inspection 8. Depart (483)

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 Overview of FDA Enforcement Actions

FDA Form 483 Inspectional Observation

Warning Letter
Product Recall
Seizure
(Preliminary) Injunction
Consent Decree
Civil Prosecution

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 FDA Forms

There are actually several forms used by the

FDA in the field:

FD481 (Establishment Inspection Report)

FD482 (Notice of Inspection)
FD483 (Inspection Observation Form)
FD484 (Receipt for Samples)
FD463a (Affidavit)

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 Inspectional Priorities

FDA has indicated that the following

areas are (GMP) inspectional priorities:
High risk products
Prescription drug manufacturers
Sterile drug manufacturers
New facilities not yet inspected

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 14% of all Observations Made in 2013 were
Related to Cleaning
Ref No Frequency Short Description Long Description

21 CFR Written procedures not Written procedures are not [established] [followed] for the cleaning and maintenance of equipment,
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211.67(b) established/followed including utensils, used in the manufacture, processing, packing or holding of a drug product.

Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent
21 CFR Cleaning / Sanitizing /
211.67(a)
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Maintenance
[malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug
product.

21 CFR SOPs not followed / Written production and process control procedures are not [followed in the execution of production and
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211.100(b) documented process control functions] [documented at the time of performance].

Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate
21 CFR Equipment Design, Size
211.63
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and Location
design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and
maintenance].

Training--operations, Employees are not given training in [the particular operations they perform as part of their function] [current
21 CFR
211.25(a)
44 GMPs, written good manufacturing practices] [written procedures required by current good manufacturing practice
procedures regulations].

Drug product production and control records, are not [reviewed] [approved] by the quality control unit to
21 CFR Quality control unit
211.192
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review of records
determine compliance with all established, approved written procedures before a batch is released or
distributed. Specifically, ***

Written procedures for cleaning and maintenance fail to include [assignment of responsibility] [maintenance
and cleaning schedules] [description in sufficient detail of methods, equipment and materials used]
21 CFR Written procedures fail to [description in sufficient detail of the methods of disassembling and reassembling equipment as necessary
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211.67 b) include to assure proper cleaning and maintenance] [instructions for removal or obliteration of previous batch
identification] [instructions for protection of clean equipment from contamination prior to use] [parameters
relevant to the operation]. Specifically, ***

21 CFR
Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the [room]
211.42(c)(1 20 Cleaning System
0)(v) [equipment] to produce aseptic conditions. Specifically, ***

Buildings used in the manufacture, processing, packing or holding of drug products are not [maintained in a
21 CFR Sanitation--buildings not
211.56(a)
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clean, free of infestation
clean and sanitary condition] [free of infestation by rodents, birds insects, and other vermin]. Specifically,
8 ***
 Short
Ref No Frequency Long Description
Description
Written records
21 CFR Written records of major equipment [cleaning] [maintenance] [use] are not included in individual equipment
18 kept in
211.182 logs. Specifically, ***
individual logs
Written
21 CFR sanitation There is a lack of written procedures [assigning responsibility] [providing cleaning schedules] [describing in
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211.56(b) procedures sufficient detail the methods, equipment and materials to be used] for sanitation. Specifically, ***
lacking
Cleaning/maint
21 CFR
12 enance records Records are not kept for the [maintenance] [cleaning] [sanitizing] [inspection] of equipment. Specifically, ***
211.67(c)
not kept
Buildings of
21 CFR Suitable Size, Buildings used in the manufacture, processing, packing, or holding of a drug product do not have the suitable
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211.42(a) Construction, [size] [construction] [location] to facilitate cleaning, maintenance, and proper operations. Specifically, ***
Location
Containers &
21 CFR Closures Clean, Drug product [containers] [closures] were not [clean] [sterilized and processed to remove pyrogenic
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211.94(c) Sterilized, properties] to assure that they are suitable for their intended use. Specifically, ***
Pyrogen-free
21 CFR Equipment not
4 You did not implement procedures to ensure that all your equipment is clean. Specifically, ***
212.30(b) clean
Written
procedures Written procedures are lacking for the use of [rodenticides] [insecticides] [fungicides] [fumigating agents]
21 CFR
3 lacking for use [cleaning and sanitizing agents] designed to prevent the contamination of [equipment] [components] [drug
211.56(c)
of pesticides product containers] [closures] [packaging, labeling materials] [drug products]. Specifically, ***
etc.
21 CFR Cleaning
Procedures for the cleaning and maintenance of equipment are deficient regarding assignment of
211.67(b)( 2 SOP/responsibil
responsibility for cleaning and maintaining equipment. Specifically, ***
1) ity
21 CFR
Floors, walls, Aseptic processing areas are deficient in that [floors] [walls] [ceilings] are not smooth and/or hard surfaces
211.42(c)( 2
ceiling surfaces that are easily cleanable. Specifically,***
10)(i)
Storage off
21 CFR Bagged or boxed components of drug product [containers] [closures] are not [stored off the floor] [suitably
2 Floor, Spaced
211.80(c) spaced to allow cleaning and inspection]. Specifically, ***
Suitably

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 Ref No Frequency Short Description Long Description

Personnel dating/
21 CFR The persons [performing] [double-checking] the cleaning and maintenance are not [dating] [signing or
2 signing equipment
211.182 initialing] the equipment cleaning and use log. Specifically, ***
log

21 CFR Records of checks You did not keep a record of checks of the [production area] [all equipment in the production area] for
2
212.50(d) made cleanliness and suitability immediately before use. Specifically,***

Each laboratory used to conduct testing of [components] [in-process materials] [finished PET drug
21 CFR
2 Testing procedures products] does not [have written procedures] [follow written procedures] for the conduct of each
212.60(a)
test. Specifically,***

21 CFR Cleaning Procedures for the cleaning and maintenance of equipment are deficient regarding maintenance and
1
211.67(b)(2) SOPs/schedules cleaning schedules, including, where appropriate, sanitizing schedules. Specifically, ***

Procedures for the cleaning and maintenance of equipment are deficient regarding sufficient detail of
21 CFR Cleaning the methods, equipment, and materials used in the cleaning and maintenance operation, and the
1
211.67(b)(3) SOPs/instructions methods of disassembly and reassembling equipment as necessary to assure proper cleaning and
maintenance. Specifically, ***

Cleaning
21 CFR Procedures for the cleaning and maintenance of equipment are deficient regarding the removal or
1 SOPs/equipment
211.67(b)(4) obliteration of the previous batch identification. Specifically, ***
identification

21 CFR Cleaning Procedures for the cleaning and maintenance of equipment are deficient regarding inspection of the
1
211.67(b)(6) SOP/inspection equipment for cleanliness immediately before use. Specifically, ***

Written Procedures
21 CFR There are no written [standards or specifications] [methods of testing] [methods of cleaning] [methods
1 to Remove
211.94(d) of sterilization] [methods of processing] to remove pyrogenic properties. Specifically, ***
Pyrogens

21 CFR Equipment not You did not document your activities in accordance with your procedures for cleaning all of your
1
212.30(b) properly installed equipment. Specifically,***

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 Recent Recalls

Hospira initiates nationwide recall of Lactated Ringers and 5% Dextrose

Injection due to visible particulates (mold contamination)

Analysis of the primary container and overwrap indicated a puncture in

the same physical location, causing the primary container to leak.

Bristol-Myers Squibb initiates recall of Coumadin (warfarin sodium) for

injection due to presence of visible particulate matter

Baxter initiates nationwide recall of Brevibloc Premixed Injection due to

presence of particulate matter (subvisible particulates of iron oxide that are
agglomerating)

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 Warning Letters

Failure to ensure equipment is cleaned in a reproducible and effective manner to prevent

contamination of a material that would alter the quality of the APIs.

Your firm failed to ensure the non-dedicated (b)(4) was adequately cleaned after
use. Specifically, during three separate walk-throughs of the facility taking place over five
days, our inspection found what appeared to be product residue in the (b)(4) despite the
clean label on the equipment. This represents a potential for cross-contamination of the
APIs manufactured in this equipment.

In addition, your firm failed to perform adequate cleaning validation studies for your non-
dedicated equipment. For example, your firm failed to perform recovery studies to ensure
product residues could be detected during the cleaning validation studies.

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 Warning Letter Continued

Your firms response to this observation stated that you are performing revised cleaning
validation studies. We remain concerned that this corrective action is not extensive
enough to determine the extent and impact of the problem.

In your response, provide a detailed action plan for an investigation into the impact on the
quality of previously released product, along with your risk assessment. Additionally,
provide an action plan for ensuring adequate cleaning in the interim, prior to completion
of the validation studies, such as cleaning verification sampling with appropriate
acceptance criteria. Furthermore, provide a report summarizing the revised cleaning
validation studies that your firm has been conducting, addressing the issues discussed
above. Your response should also include the establishment of a training program for
operators, quality unit personnel, and managers to improve cleaning competencies.

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 Warning Letter

Failure to adequately complete and follow written procedures for cleaning equipment and
its release for use in API manufacture, and to maintain adequate records of major
equipment useage.

Your firm failed to ensure that employees adequately cleaned____after use. Your _____
equipment cleaning standard operating procedures require that employees visually inspect
equipment after the cleaning process. Our inspection found_____in the manufacturing
workshop for _______with various levels of contamination and foreign objects inside,
including what looked like the remains of a pen in one of the ________. Your employees
had labeled this equipment as clean. These _______ are used for the manufacture of
multiople APIs.

In addition, your firms production system did not maintain equipment logs or other
documents that adequately record manufacturing operations performed on individual
pieces of equipment.

We note that your production operation supervisors and Quality Unit failed to detect and
correct these deficient cleaning practices

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 Warning Letter Continued

Your response is in adequate because it does not address the extent of these deficient
practices throughout your facility, or the impact on the quality of your active ingredients.
Additionally, you do not commit to maintain equipment logs or other documents that record
all of the manufacturing operations performed on individual pieces of equipment.

In response to this letter, you should prepare and implement a corrective action plan
sufficient to address and prevent the recurrence of these deficiencies. The corrective action
plan should detail the systemic improvements to be made, including, but not limited to,
improved management oversight of cleaning operations, commitment to maintain individual
equipment records (e.g., equipment logs), and training all relevant personnel in cleaning
procedures. You should also demonstrate the sufficiency and effectiveness of this corrective
action plan.

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 Warning Letter

Your firm failed to perform operations related to the manufacture, processing, and packing
of penicillin in facilities separate from those used for other drug products for human use.
(21 CFR 211.42(d))

Specifically, your firm produces non-penicillin and penicillin containing finished product in
Werk II using shared equipment. As such, all non-penicillin products produced in your
facility are potentially adulterated with penicillin, and constitute a potential serious
allergenic hazard to patients who are sensitive to beta-lactams.

In your response to the inspectional observation related to inadequate cleaning validation

on shared equipment in Werk II, you indicate that you will revalidate your processes by
the end of 2013. As stated above for your API production, you failed to provide a
commitment that the manufacture of penicillin containing products would be fully and
comprehensively segregated and that proper decontamination of this facility would occur
If it is to be used for non-penicillin production in the future.

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 Warning Letter Continued

Additionally you failed to provide assurance that products currently marketed in the U.S. are
not contaminated with penicillin. The current practices at your facility present an
unacceptable risk of penicillin contamination. We acknowledge your March 18, 2014
voluntary recall of products derived from Penicillium that may have undecleard penicillin. In
your response to this letter, describe all of the actions you will implement to prevent
potential contamination of non-penicillin products with penicillin. Additionally, provide your
plan for addressing products made in the shared finished product facility that were released
into U.S. distribution.

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 483 Citing's

Engineer 1 confirmed that there exists no record of cycle development used to set
your ____________process parameters for cleaning

There is no record to demonstrate that the routine load configurations do not

exceed the validated load configurations established via the __________ process.

Equipment and utensils are not cleaned, maintained, and sanitized at appropriate
intervals to prevent malfunctions and contamination that would alter the safety,
identity, strength, quality or purity of the drug product.

The logbook used to document the use and cleaning of the ______ bioreactor used
in the production of________does not include documentation on the buffers used
to standardize the pH measuring probes prior to the equipment use in production.

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 483 Citing's

Your firm released API where production records contained missing information. For
example, our inspection uncovered a Cleaning report where the rinse sample pH was
entered as nil despite the pH being a requirement to ensure the equipment is clean.

Your visual inspection post CIP is inadequate in that the logbook shows the
cleaning as successful however, upon entry into the tank, a ring at the liquid air
interface was seen.

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 483 Citing's

On 7/22/2014 we observed Quality Assurance (QA) inspectors perform cleaning

verification procedures on your________equipment. After the sampling for API
residue and cleaning agent residue was completed, we observed residual rayon
fibers on the inner surface of the equipment. The trace rayon fiber strands
measured up to 1.2cm in length. Your written procedure Equipment Swab, Rinse
Preparation and Sampling does not instruct employees to perform visual
inspection check of the swab location after swabbing nor does it instruct the
cleaning of the swab area post sampling.

Written procedures for cleaning and maintenance fail to include description in

sufficient detail of methods, equipment, and materials used and instructions for
protection of clean equipment from contamination prior to use.

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 483 Citing's

With respect to contaminated bioreactor deviation investigations:

There was no assessment of cleaning for utilized glassware which has not been
validated

The cleaning post contamination was not cleaning verified despite the fact that
your validated cleaning cycle was not assessed for removal of excessive
contamination due to bioburden

Equipment and utensils are not maintained at appropriate intervals to prevent

malfunctions and contamination that would alter the safety, identity, strength,
quality, purity of the drug product. (including the lyophilizer)

Visual failures after CIP/COP are not captured in deviations and your firm allows
for one recleaning of the equipment. The quality unit does not review the
cleaning logs and is therefore not notified of the failures

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 Staying Vigilant

All FDA actions are costly not only from a monetary perspective but also from a
reputation and staff retention perspective.

It is vital that we all stay vigilant with the c in cGMP by reviewing often the findings that
are being made throughout the industry.

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 Questions?

Dawn Tavalsky
Senior Director Quality Assurance Technical Services
Genzyme, a Sanofi Company

Dawn.tavalsky@genzyme.com

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