Mock Inspection Case Studies

Mock Inspection Case Studies
Jeanne Moldenhauer
Excellent Pharma Consulting
(c) Jeanne Moldenhauer 2012 1

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Agenda

1. Overview

2. Today’s Inspection Process

3. Top Items in the Last Year

4. Conclusion


The FDA is coming…..
•  Regardless of the regulator, we continue
to have significant levels of fear when we
face a regulatory inspection
–  Concerns about what will be inspected
–  Concerns about job performance issues
–  Are there skeletons in the closet


How Inspections Are Performed
•  Promises of
–  A new friendlier FDA
–  Collaborative Involvement – providing
guidance
–  More time spent on the production and/or
laboratory floor
–  Emphasis on scientific justification


How Inspections Are Performed
•  The reality
–  A new friendlier FDA
–  Collaborative Involvement – providing
guidance
–  More time spent on the production and/or
laboratory floor
–  Emphasis on scientific justification


How Inspections are Performed
•  The Plant Tour (approximately 1 day)
–  Looking for a snapshot view of your
performance
–  Compares procedures from one filling line to
another
–  Compares procedures from one type of
product to another


•  Notified of items they want to review (lists
specified in CPMG 7356.002)
–  Last two years of change controls
–  Last two years of deviations/investigations
–  Listing of SOPs
–  Last two years of complaints
–  Last two years of OOS’
–  Information on sterility test false positives
–  Etc.


•  Observation in the Plant
–  Spent time in each filling area, e.g., watching
an entire batch’s production (about 30- 50% of
the total inspection time)
•  Evaluated
–  aseptic behavior
–  Interventions
–  gowning (including that of individuals on the tour with
him)
–  cleaning and disinfection procedures used, - got a
flashlight and looked inside of equipment claimed to be
cleaned (fibers, glass particles, etc.)


•  Observation in the Plant
–  Looked at items beyond filling of the product
•  Compounding: is the glassware depyrogenated? If
you are weighing out product items, should be.
•  Condition of Equipment: cracks, rust, good
condition, alarms
•  Visual Inspection Procedures: consistency in
inspection, number and types of examples in the
defect samples
•  Tracked process from receipt of materials through
product disposition


•  Used the information from the
observations to guide the rest of the
record reviews for the inspection
–  For example: If questions arose in visual
inspection
•  Look at SOPs for visual inspection
•  Look at qualification of visual inspectors
•  Look at the sample sets of defects
•  Does QA control/release the sample sets
•  Do they look at media fill units? If so, are these in
the sample set?

–  For example: If questions arose in aseptic
behavior/gowning
•  Look at SOPs for aseptic behavior and gowning
•  Look at qualification of individuals
•  Look at training of operators
•  Look at qualifications of trainers
•  Look at content of training
•  Look at who is responsible for their behavior, e.g.,
quality or production oversight
•  Expected: QA oversight of each production batch
with thorough documentation (even though it
wasn’t a biologic)

–  For example: if environmental sampling
locations did not make sense to the
investigator
•  Looked at risk assessment for sample sites
•  Looked at smoke study data to support the
appropriateness of sample sites
•  Looked at the data obtained for sampling, trend
reports
•  Looked at growth promotion for the media lots, did
you use environmental samples?
•  Can you track which samples were taken when?
•  Do you sample under worst case conditions (end)?

–  For example: observations of poor
maintenance of equipment
•  Look at preventative maintenance
•  Look at corrective maintenance
–  Is it just caca
•  Look at frequency of maintenance
•  Look at change control records
•  Look at deviation records


•  For example, bad practices used during
sanitization and/or did not sanitize when
they should
–  Looked at disinfectant qualification, did it use
environmental samples
–  Compared materials of construction to the
materials tested in the disinfectant
qualification
–  Ideal cleaning: Covering each and every
surface completely


•  For example, bad practices used during
sanitization and/or did not sanitize when
they should
–  Looked at procedures for cleaning/sanitization
–  Batch record pages/log books for cleaning
sanitization
•  Can you verify that every step was done and done
correctly
•  Does QA review/approve these documents
•  If there are documentation errors, why did reviewer
sign/approve them?????

•  More questions/justification for
environmental monitoring sample sites
and locations
–  Risk assessment is not enough
–  How do you know that you would be able to
collect the organisms from that site?
–  Do you have enough samples to support the
production batch?


•  Environmental Monitoring
–  Wanted site maps with all sample sites
identified
–  Wanted assessment based upon each
production of extra samples to take, based
upon aseptic behavior


•  Grade B areas
–  Didn’t find it sufficient to characterize
representative samples
–  Push for all isolates to be characterized to
genus/species in Grade B areas


•  Typical to have at least one other
inspector concentrated on the laboratory
–  Observes all the laboratories at the site
–  Strong emphasis on Deviations and OOS
investigations
–  Strong emphasis on whether all steps are
documented fully, e.g., standard preparation.
Key is: Can you prove they did everything in
the SOP from the documentation?
–  Are you following USP, e.g., suitability tests,
%RSD, etc.

•  Lesser interest in media fills, other than
design of the test
–  People know you are watching, so they are on
their best behavior
–  Reality of behavior is seen in routine
production
–  Review of SOPs/Batch Records
•  Do you document all the process design
requirements from the Aseptic Guidance?
–  E.g., routine interventions, worst case conditions


•  Record Reviews
–  Used to assess whether bad practices
observed are a result of not being a procedure
or are in a procedure and not followed
–  Only represented about 30% of the time at the
site
–  Provide documentation to support/dispute
their observations


•  The Responsibilities of Quality
–  The more poor practices, the greater the
indictment on quality
–  Should have a detailed list showing the
differences between what is done by QA and
QC (even though there is no distinction in the
CFR)
•  Quality Assurance is responsible for deviations
after confirming it is an OOS, and after 1st
extension


•  The Responsibilities of Quality
•  Quality Assurance is responsible for logbooks,
review of original data used to generate C of A’s,
batch record review, review of protocols and
SOPs, etc.
•  Quality Assurance oversight of manufacturing
–  Qualified and certified to do the oversight
•  Quality Control documents need QA review/
approval……
•  QA is responsible for everything………..,


•  A lot more feedback during the inspection
and during daily wrap-up meetings

•  More specific comments on exactly what
they want to see in the documents

•  All sampling, procedures, root causes,
should be based upon good science


•  More expectation to find the root cause or
probable root cause

•  If you let production do steps for
microbiology or quality, how did you train
and qualify them to do it? How do you
assess them going forward?

•  More picture taking, and physically
checking thingsJeanne Moldenhauer 2012
(c) 26

•  Internal Audits
–  Wanted to see the templates for the internal
audit
–  Information on who performs them, e.g., is QA
part of the team?


•  How does this translate into inspection
observations?


Inspection Observations

211.113
Disinfection

Objectionable Microbiology
Organisms

Environmental
Monitoring

Media
Fills


WL: 320-12-01
–  In addition, the (b)(4)“) Dynamic Airflow
Visualization” video provided in your firm’s
response shows an operator spraying his
hands with (b)(4)(b)(4)(b)(4)%directly over the
air viable microbial plate. This practice is
unacceptable because the environmental
monitoring results from plates sprayed with )
(b)(4)% may be inaccurate and may not
reflect the actual microbiological environment
of the Class 100 (ISO 5) room.


WL: 34-11
•  Your firm has not established appropriate
written procedures designed to prevent
microbiological contamination of drug
products purporting to be sterile [21 C.F.R.
§ 211.113(b)].
–  For example, your firm’s written procedures
for environmental monitoring, disinfection, and
your process simulation media have not been
validated.


WL: 34-11
–  Specifically, your firm has not demonstrated
the ability of reconstituted beta-lactamase at a
concentration of (b)(4) IU (0.1ml/1L Sterile
Water for Injection) to neutralize
cephalosporins in the Tryptic Soy Broth (TSB)
used in aseptic process simulation studies
(i.e., media fills) or in your surface swab
sampling solution.


WL: 34-11
–  Furthermore, you have not demonstrated the
ability of the neutralizing agents in the surface
sampling plates purchased by your firm to
neutralize the cephalosporin drug products
manufactured at your firm.
–  In your response, you state that you will
determine the residual amount of
cephalosporin and then determine the amount
of neutralizing agent required.


WL: 34-11
–  Your response is inadequate because you
have not provided a scientific rationale that
demonstrates a correlation between the
residual cephalosporin recovered to the
necessary amount of beta-lactamase.
–  In addition, your firm provided procedure (b)
(4), “Cephalosporin Residue Determination
during Filling Process,” to demonstrate the
effectiveness of the amount of penase
enzyme used to neutralize residual antibiotic
during environmental surface sampling.

WL: 34-11
–  We cannot determine the adequacy and/or
effectiveness of your corrective action
because you have not provided the data from
this study.


WL: 320-11-015
•  Your firm has not established or followed appropriate
written procedures designed to prevent microbiological
contamination of drug products purporting to be sterile
[21 C.F.R. § 211.113(b)]. For example,
–  Your firm’s environmental monitoring is inadequate in relation to
personnel monitoring.
–  Our investigators found that gowns worn by operators working in
the aseptic processing areas are only monitored (b)(4) per week.
Additionally, gloves are only monitored at the (b)(4) the shift. We
are concerned with the fact that operators performing critical
operations may not be adequately monitored.


WL: 320-11-015
–  Therefore, there is no assurance that your environmental
monitoring program is capable of detecting all microbiological
contaminants.
–  Since personnel can significantly affect the quality of the
environment, a robust personnel monitoring program should
be in place in order to be compliant with CGMPs. Your response
indicates that SOP/QC/049 was revised to require additional
monitoring of gloves after (b)(4) for personnel involved in aseptic
connections on filling line and filtration activities apart from
regular monitoring at the (b)(4) of the shift. It is your
responsibility to ensure that all personnel involved in aseptic
gowns per (b)(4)/per (b)(4).
–  The technician performing the air sampling held the probe close
to the HEPA filter face rather than (b)(4) as specified in section
4.5 of your written procedure SOP/QC/049.


WL: 320-11-015
–  During the inspection, the investigators were provided
with retraining records for technicians performing
active air sampling.
–  Your responses and corrective actions related to
items 2a and 2b of this letter failed to indicate the
disposition of exhibit batches that were
manufactured during the time when personnel and air
sampling monitoring was inadequate. Provide
information on the disposition of these batches.


May 24, 2011
•  Your firm has failed to establish appropriate written
procedures designed to prevent objectionable
microorganisms in products not required to be sterile [21
C.F.R. § 211.113(a)].
–  For example, your firm’s microbial limit specifications for finished
product permits a microbial load in your drug product that could
allow the presence of objectionable and potentially pathogenic
organisms in your topical OTC drug products. In addition, your
firm does not specifically test for Staphylococcus aureus or
Pseudomonas aeruginosa that should be absent from topical
drug preparations.


May 24, 2011
–  In your response, your firm states that you will review
all raw material specifications to determine if the
current specifications should be changed or whether
to add further quality control tests. Your response,
however, is inadequate because you do not mention a
similar review for the appropriateness of your current
specifications as it is applied to finished products and
fails to propose a timeframe for completion.


WL: 320-11-016
•  Your firm has not established appropriate written
procedures designed to prevent microbiological
contamination of drug products purporting to be sterile
[21 C.F.R. § 211.113(b)]. For example,
–  During the aseptic filling of two injection batches on filling line (b)
(4), where (b)(4) injection for the U.S. is filled, employees were
observed following poor aseptic techniques. Specifically,
movements inside the class A area were not slow and
deliberate; operators and an engineer were observed
with exposed facial skin during the filling operation;
and a forcep was observed in a class B (ISO 6) area
and was then used to remove fallen ampoules from
the aseptic processing line in the class A (ISO 5)
area.

WL: 320-11-016
–  Employees who perform critical duties in your aseptic filling line
(b)(4) did not participate in an (b)(4) line qualification (process
simulation) during 2010, 2009, and 2008.
–  The tubing ends used to connect the solution tanks to the filling
line (b)(4) are not protected prior to sterilization to reduce the
potential of contamination after sterilization, and prior to the
aseptic connection.


WL: 320-12-01
•  The qualification of your disinfectant (b)(4)
failed to demonstrate that it is suitable and
effective to remove microorganisms from
different surfaces. Specifically, this
disinfectant failed to meet qualification
criteria when challenged with multiple
organisms.


WL: 320-12-01
•  Your disinfectant qualification for (b)(4)
and (b)(4) bi-spore disinfectants
documented that the log reduction criteria
(Bacteria ≥ 4, Fungi ≥ 3) was not met
when challenged with multiple organisms
in a variety of surfaces.


WL: 320-12-01
•  After disinfection, you recovered
Micrococcus luteus on vinyl, (b)(4),
stainless steel, glass, and wall laminate
and Enterobacter cloacae, Rhodococcus
sp, Burkholderia cepacia, Pseudomonas
aeruginosa, ethylobacterium
mesophilicum and, Acinetobacter lwoffi on
glass.


WL: 320-12-01
•  However, your procedures for routine
cleaning of the aseptic manufacturing area
continue to require the use of unqualified
disinfectants during days (b)(4) through
(b)(4) of your disinfectant program.
•  Your firm’s response indicates …However,
you did not include documentation to
support this conclusion.


WL-320-11-009
•  Your firm has not established or followed
appropriate written procedures designed
to prevent microbiological contamination of
drug products purporting to be sterile [21
C.F.R. § 211.113(b)]. For example,
–  In June 2010, your firm failed to identify the
organisms recovered from a sterility test for
[Product] lot #OF100. Identification of
microorganisms recovered from a sterility test
is essential when conducting a sterility failure
investigation.

WL-320-11-009
–  In addition, the identification of organisms is
also a fundamental part of any investigation of
environmental or personnel monitoring
excursions.
–  Your firm’s failure to identify organisms
recovered from a sterility test was also
discussed during the December 2008
inspection.


WL-320-11-009
–  We recognize that your firm voluntarily
recalled the [Product Name], Lot#0F151A,
which was part of the February 2010
production campaign in which there was a
significant concern regarding environmental
contamination levels. We expect all
procedures related to the response for an out-
of-limit environmental monitoring sample or a
sterility failure to include the appropriate
evaluation and remedial measures, as
appropriate.


WL: 320-12-05
•  Your media fill studies were insufficient to
establish that the aseptic process is in
control. During media fill studies, you
failed to establish appropriate criteria for
reconciliation of filled vials (total units
evaluated/incubated as compared to the
total number of units filled) resulting in
inconsistent and inaccurate media fill
results.
•  No justification for discrepancies

WL: 320-12-05
•  Please provide your firm’s evaluation of
the impact on products produced during
this period.
–  This is a repeat observation…..


MIN 11 - 15
•  Your firm has not established appropriate
written procedures designed to prevent
microbiological contamination of drug
products purporting to be sterile per 21
CFR 211.113(b). For example,


MIN 11 - 15
–  Your firm released several batches of sterile
ophthalmic eye drops without adequately
validating your aseptic process. According to
your raw material specification sheets and
your list of batches manufactured, your
aseptically manufactured products are filled
into 15mL bottles; however, your process (b)
(4) bottles which did not represent the
products that would be manufactured.


MIN 11 - 15
–  In your response, your firm states that (b)(4)
were successfully completed by the time the
product was shipped to the customer. Your
response is inadequate because you have not
provided any assurances that your aseptic
process was in a state of control during the
manufacture of sterile drug products which
were subsequently distributed.


MIN 11 - 15
–  Your firm has not established written and
approved specifications to assure suitability of
each lot of the (b)(4) filters used for
sterilization.


MIN 11 - 15
–  In your response, your firm provided a draft
specification sheet for the (b)(4) sterilizing
filter. Your response, however, is inadequate
because your firm has failed to provide a
justification for the specifications (e.g. (b)(4))
listed for each filter. In addition, we note that
your specification sheet allows for the use of
multiple filter manufacturers. The validation of
each approved model of sterilizing filter
should be assessed and documented.


211.192 No Root
Cauae

Timely
Completin Investigations

Missing
Documentation
Scientific
Justification


WL-320-12-05
•  Your firm has not thoroughly investigated
the failure of a batch or any of its
components to meet its specifications
whether or not the batch has already been
distributed [21 CFR § 211.192]. For
example, the inspection revealed that your
firm failed to conduct an adequate
investigation of the crystallization of the
solution in your finished product (b)(4)


WL-320-12-05
•  Injectable ((b)(4) mg/mL). Five out of eight
lots (62.5%) of your finished product (b)(4)
Injectable ((b)(4) mg/mL) reviewed during
the inspection contained crystals in the
vials as follows: …
•  These lots were released for distribution to the
United States. You submitted a field alert to FDA
on August 05, 2011, after the conclusion of this
inspection.
•  Failed to find a root cause…..

WL-320-12-05
components to meet its specifications,
distributed. [21 CFR § 211.192]
–  You failed to extend investigations to other
batches of the same product and other
products that may have been associated with
the failure
–  Written investigation records failed to include
your conclusions and follow-up. For example..

WL-320-11-002
distributed [21 C.F.R. § 211.192].
–  For example, your firm’s microbiology
laboratory does not perform species
identification on a routine basis of the yeast
and molds detected in your production area.
There was no identification raw data available
for the media fill that failed in November 2009.

WL-320-11-002
–  Additionally, your firm does not perform
challenge testing to the sterility media with
environmental isolates from the environmental
monitoring program.


NWE-09-11W
distributed [21 C.F.R. § 211.192]. For
example,
–  Your firm has routinely failed to thoroughly
investigate and identify root causes when
environmental monitoring data exceeds the
action limit.


NWE-09-11W
–  In your response, your firm states that you
have hired a consultant to assess the
environmental data and subsequently,
repaired the facility.
–  Your response, however, is inadequate
because your firm failed to investigate
adequacy of your disinfectant procedures,
frequencies, and preparation as part of your
investigation for environmental samples that
exceeded action levels in the critical and
supporting clean areas.

NWE-09-11W
–  For example, your firm’s disinfection program
included insufficient use of sporicidal agents.
It is essential that environmental control is
continually maintained throughout your
aseptic processing facility.


NWE-09-11W
–  Furthermore, we evaluated your
environmental data from 2008 to 2010 and
are concerned with the lack of comprehensive
investigations when mold and bacteria were
identified in your aseptic filling facility that
exceeded action levels. Your aseptic process
relies on manual manipulations and
interventions where personnel are in close
proximity to open product, and poor
environmental control poses a significant risk
of contamination.


NWE-09-11W
–  Your risk assessment for microbial and
particulate contamination of products
produced at your facility failed to properly
evaluate excursions associated with the filling
room area adjacent to the lyophilizer in which
vials are manually transferred from the filling
line to the lyophilizer. Furthermore, your
assessment did not provide a plan of action to
effectively investigate future environmental
excursions.


NWE-09-11W
–  Your firm has failed to thoroughly investigate
the cause of repeated leaks of heat transfer
fluid around shelf 3 in your lyophilizer and its
impact on product.
–  In your response, your firm states that you will
develop methods to detect the transfer fluid in
product and evaluate the medical risk of the
transfer fluid. Your response, however, is
inadequate because your proposal only relies
on the detection of heat transfer fluid.


NWE-09-11W
–  Your proposal fails to take corrective actions
that ensure the source of the leak (e.g.,
tubing) is addressed and whether engineering
measures will be taken to prevent the leak
from occurring in the future. Furthermore, your
firm has failed to adequately identify all
impacted lots.


MIN 11 - 15
components to meet its specifications,
distributed, as per 21 CFR 211.192. For
example,
–  You failed to investigate environmental
monitoring data recorded in your aseptic
processing suite, which failed to meet your
established limits.


MIN 11 - 15
–  Your response states that you have revised
your environmental monitoring form to allow
space for explanation when needed; however,
your response is not adequate.
–  You have not investigated the cause of the
environmental monitoring results that
exceeded the limits on your “Performance
Qualification Data HVAC Validation” and
“Routine Environmental Monitoring”
worksheets, nor have you justified your
assessment of the product impact caused by
those excursions.

MIN 11 - 15
–  Your firm failed to investigate the failure to
sample and test water used in the
manufacture of [Product Name] [Batch
NUMBER] and [Product Name] [BATCH
NUMBER].


MIN 11 - 15
–  Your response states that there is no
microbial requirement in the USP for purified
water as a reason for not testing water for
microbial quality.
–  Routine evaluation of the acceptability of the
quality of water used in the manufacture of
drug products is a fundamental part of good
manufacturing practices.


MIN 11 - 15
–  In addition, we also note that your procedures
require the microbial testing of your purified
water. Your response is inadequate because
you failed to identify corrective actions to
prevent a recurrence.


CBER-11-02
•  You failed to thoroughly investigate any
unexplained discrepancy, or the failure of
a batch or any of its components to meet
any of its specifications, and failed to
extend the investigation to other batches
of the same drug product and other drug
products that may have been associated
with the specific failure or discrepancy [21
CFR 211.192]. For example:


CBER-11-02
–  The April 2010, investigation initiated to
determine a root cause for Adverse Events for
fever and convulsions in children is
inadequate in that:
•  There is no documentation of the Adverse Event
investigation. SOP # (b)(4) 11209 titled “Corrective
and Preventive Action,” requires documentation of
actual or potential problems which may affect the
quality and reliability of products, processes or
quality systems.


CBER-11-02
•  The procedure requires that activities and
decisions are to be documented such that there is
traceability of Corrective and Preventive Actions
(CAPA) from the initial identification of problems to
the implementation of solutions and the follow up
to evaluate effectiveness.
•  There was a limited analysis of the manufacturing
process to determine why there was a substantial
increase in Adverse Event reports of fever and
convulsions in the 2010 Southern Hemisphere
influenza season in comparison to previous
seasons.


CBER-11-02
•  There was no analysis of all critical parameters
and critical processing steps to try to determine
differences in the 2010 lots associated with
Adverse Event reports compared to lots from
previous seasons. For example:
–  Raw material lots, virus inactivation, virus splitting, yield
and quality of product at each production step were not
compared for lots associated with Adverse Events and
lots prepared the previous season.
–  The Quality Review Report detailing the outcome of the
manufacturing investigation indicates that batch records
were reviewed for trivalent bulk formulation, filling and
packaging but there was no discussion of evaluation of
upstream processing (b)(4), inactivation, virus splitting,
(b)(4).

CBER-11-02
–  The Quality Review Report indicates that the A/
California/7/2009 (H1N1) strain appears to have a (b)(4)
content, which could have contributed to the Adverse
Events. The information was received in July 2010. You
confirmed that A/California/7/2009 (H1N1) had a (b)(4)
level of (b)(4), but have not initiated testing of the 2010
influenza vaccine lots to determine differences in (b)(4)
content compared to 2009 strains.
–  There was no evaluation of the testing of raw material,
and potential impact on manufacturing, of (b)(4) lots of
[PRODUCT NAME] which failed ID tests performed via
(b)(4) but were accepted for use. An investigation was
not initiated to determine the reason for identification
failures and the vendor was never contacted to inquire
about the possible changes to [NAME] lots.


CBER-11-02
–  Without further investigation into possible changes to
[PRODUCT NAME], the (b) (4) of the lots failing
identification were included into the (b)(4) of acceptable
(b)(4) B) The April 2010, failure investigation initiated to
investigate dark particles found in thimerosal containing
multi-dose vials is inadequate in that:
»  The investigation focused on multi-dose vials only.
This decision was based on a retrospective review of
data for syringes, rather than an actual visual
examination to determine that no dark particles have
formed in syringes since release.
»  A leachable study on product at the end of shelf life
was initiated to determine if the container closure
system contributed to dark particles found in
influenza virus vaccine in multi-dose vials.


CBER-11-02
»  Only one multi-dose vial lot and one syringe lot
representing product distributed to the U.S. were
included in this study. There is no statistical rationale
for use of this sample size.


WL: 320-11-013
•  Your firm has not thoroughly investigated the
failure of a batch or any of its components to
meet its specifications whether or not the batch
has already been distributed [21 C.F.R. §
211.192]. For example,
–  Investigations related to Field Alert Reports (FARs)
submitted to the agency during 2009 and 2010,
regarding your packaging and labeling system are
found to be inadequate. Your inability to
implement appropriate corrections to prevent
future significant problems raises concerns
regarding the robustness of your quality
system.

WL: 320-11-013
–  Your investigation into the April 12, 2010 event
attributed the root cause to a human error. You
concluded that unlabeled bottles of (b)(4) tablets were
reintroduced into the packaging line packaged with
the (b)(4)mg labels. Your investigation regarding the
March 24, 2011 event also attributed human error as
the root cause of the problem. In this case the label
printer manufacturer (PI) and labeling operations at
Production Block-(b)(4) were also related to the
product mixup problems.


WL: 320-11-013
–  We are concerned with your inability to
conduct a thorough evaluation of your
packaging and labeling systems and identify
problems that may lead to subsequent or new
incidents of product/labeling mix-ups. It is your
responsibility to determine the appropriate
corrective actions that will reduce the
possibility of future product/labeling mix-up
problems.


WL: 320-11-013
–  Your response to this letter should include a detailed
action plan describing the changes and improvements
made in your packaging and labeling operations that
will prevent recurrence of similar or new violations.
Also include an evaluation of products packaged
during the same campaign and that may also be also
be affected by the root cause assigned.


WL: 320-11-016
–  The inspection documented that (b)(4)
Injection, batch # (b)(4), failed the sterility test.
Your quality control unit repeated the test on a
new sample to confirm the original result prior
to initiating an investigation. The quality
control unit’s decision to perform a retest
without conclusive assignable laboratory
cause is not in accord with USP <71> and is
an unacceptable practice.


WL: 320-11-016
–  The retest again revealed non-sterility.
Although the lot was eventually rejected, there
is no assurance that other lots manufactured
and filled in the same production line were not
contaminated. The inspection found that the
results were valid and that no laboratory error
was identified. However, no investigation of
the manufacturing process and facility
controls was performed to identify the root
cause of the sterility failure.


WL: 320-11-016
–  This information from the failure investigation
also helps determine how many additional
other batches may be affected.
–  Please note that when microbial growth is
observed, a lot should be considered
nonsterile and an investigation conducted. An
initial positive test would be invalid only in an
instance in which microbial growth can be
unequivocally ascribed to laboratory error.


WL: 320-11-016
–  Only if conclusive and documented evidence
clearly shows that the contamination occurred
as part of testing should a new test be
performed. When available evidence is
inconclusive, batches should be rejected as
not conforming to sterility requirements. After
considering all relevant factors concerning the
manufacture of the product and testing of the
samples, the comprehensive written
investigation should include specific
conclusions and identify corrective actions.


WL: 320-11-016
–  Please include in the response to this letter a
copy of your final sterility failure investigation
report for (b)(4) Injection, batch # (b)(4). Your
response should include a detailed
explanation of your root cause analysis and
the corrective actions implemented to prevent
recurrence of the event(s) that lead to the
contamination of the lot. Your firm should also
indicate if a media fill was conducted as part
of your sterility failure evaluation.


WL: 320-11-016
–  If so, provide a copy of the media fill protocol
and report as part of your response to this
letter. Also include a list of all lots of sterile
drug products manufactured at your facility
that initially failed the sterility test, and that
were released based on a passing re-sample
or re-test result. Provide the product name,
original test and re-test date, microorganism
isolated and product destination.


WL: 320-11-016
–  We noted during our review that SOP No. JZ-
V/JV-051: “Proceeding in case of unexpected
result obtainment” references the FDA
Guidance for Industry: Investigating Out-of-
Specification Test Results for Pharmaceutical
Production. Please note that the scope of this
guidance is intended for chemistry-based
laboratory testing of drugs regulated by
CDER, and not for microbiological testing
investigations.


WL: 320-11-016
–  For information on sterility testing, see Section
XI of the FDA’s Guidance on Sterile Drug
Products Produced by Aseptic Processing.
–  Your response includes procedural
corrections and training of your analyst.
Please describe in your response to this letter
the specific training offered and corrections
made.


211.100
SOPs

Written
Missing Procedures

Work
Instructions

Records


WL-320-12-05
–  While (b)(4) #8 and #15 were identical in the
construction of their external (b)(4), they
contained different internal configurations.
Your firm did not validate the use of (b)(4) #8,
and product manufactured in this (b)(4) had a
slower dissolution rate than product
manufactured in (b)(4) #15. The slower
dissolution rate resulted in a recall of 16 lots…


WL-320-12-05
•  In your response, you state that there are
controls in place to control variability in the
process and in the final product. Your
response, however, is inadequate
because you do not adequately address
the need to prospectively assess the
adequacy of these controls through
completion of successful process
validation studies.
•  This is a repeat observation….

WL-320-12-05
•  Your firm does not have adequate written
procedures for production and process
controls designed to assure that the drug
products you manufacture have the
identity, strength, quality, and purity they
purport or are represented to possess [21
CFR § 211.100(a)].


May 24, 2011
•  Your firm does not have adequate written procedures for
production and process controls designed to assure that
the drug products you manufacture have the identity,
strength, quality, and/or purity they purport or are
represented to possess [21 C.F.R. § 211.100(a)]. For
example,
–  Your firm’s mixing operations for bulk drugs have not been
validated to ensure homogeneity.
–  Your firm has failed to evaluate the holding time and handling
(e.g., transfer from mixing kettles to intermediate storage
containers) of bulk drugs during and after intermediate
storage to ensure the bulk drugs continue to meet
established specifications prior to filling.


May 24, 2011
–  There has been no testing of finished products to
verify that the transfers to intermediate storage
containers, and conditions and duration of storage, do
not adversely affect the drug products.
–  We acknowledge your proposed actions to validate
the mixing operation and establish holding times for
intermediate storage. However, your response does
not address the establishment of storage conditions
associated with the holding times or specify a
timeframe for completion.


211.160
Didn’t follow

Written
Not Followed
Procedures -
Laboratory

Missing

Inadequate


WL: 320-12-01
•  The inspection revealed that the laboratory
investigations [numbers] were conducted
without having Form B completed and
approved by your Quality Unit, as required
by your procedure.


WL: 320-12-01
•  Atypical Results Procedure” establishes
that the Form B is intended to document
any retest, root cause investigation, and
whether any remedial corrective and
preventative actions are required. Your
firm’s response indicates that although the
Form B was not used, the quality of the
investigations is equivalent to those
investigations in which the Form B was
completed. BUT… no support for
conclusions (c) Jeanne Moldenhauer 2012 102

Wl-320-11-002
•  Your firm has not established scientifically
sound and appropriate specifications,
standards, sampling plans, and test
procedures designed to assure that
components, in-process materials, and
drug products conform to appropriate
standards of identity, strength, quality, and
purity [21 C.F.R. § 211.160(b)].


Wl-320-11-002
–  For example, at the time of the inspection the
validation data for several laboratory methods
was incomplete or unavailable (i.e., total
viable aerobic count for the API, total viable
aerobic plate count of raw materials, and
bacterial endotoxin testing for ((b)(4)).
–  However, you approved the validation for
these methods without the complete data in
place.


Wl-320-11-002
•  Your firm did not establish a schedule for the
cleaning with an agent designed to kill spores,
although mold continued to be found in the class
10,000 area. Our investigators observed that the
mold contamination had not been eliminated at the
time of the inspection in July 2010, almost a year
after the initial discovery.
–  We are concerned that your firm has not
properly evaluated the risk these deviations
pose to the products that have been released
and distributed.


WL-320-11-002
–  Your firm has not provided a scientific
justification to ensure the product available in
the United States (U.S.) market is in
compliance with CGMP standards.
–  Please provide a list of all the products and
lots shipped to the U.S. that remain within
expiration, and any additional corrective
actions you plan to initiate..


WL-320-11-002
–  It is important that you take appropriate
actions to address these deficiencies and
notify us if any actions are planned for lots of
sterile drug products manufactured by your
[NAMED] facility, and include your rationale.


WL: 34-11
–  For example, your firm stores the recovered
microbial isolates so that the microbes can be
identified at a future date.
–  Your firm stores these isolates for up to three
months without any data to demonstrate that
the microbial isolates would remain viable
during the entire storage period.


WL: 34-11
have revised your procedure (b)(4),
“Microorganism Identification and Related
Tests,” to reduce the storage period of the
microbial isolates to (b)(4) days. Your
response, however, does not provide your
justification to demonstrate that the microbial
isolates are viable at (b)(4) days.


May 24, 2011
•  Your firm has not established scientifically sound and
appropriate specifications, standards, sampling plans,
and test procedures designed to assure that
components, in-process materials, and drug products
conform to appropriate standards of identity, strength,
quality, and purity [21 C.F.R. § 211.160 (b)]. For
example,
–  Your firm has failed to provide a scientific justification for how the
samples of bulk drugs are representative of the lot when they are
collected only from the top of the kettle. Also, the
samples are taken using a re-usable spatula sprayed
with 70% isopropyl alcohol immediately before use.


May 24, 2011
–  The presence of the alcohol on the spatulas could
affect the validity of the test results.
–  Your firm has failed to validate your Standard Operating
Procedure (SOP) (b)(4), “Microbiological Testing of Cosmetics,
Raw Materials and Finished Products,” to show the
absence of growth inhibition by the tested drug
products.
–  Your firm has failed to verify the assay methods for zinc oxide,
titanium dioxide, and salicylic acid under actual conditions of use
to determine the amount of active ingredients in your
sunscreen products.


May 24, 2011
–  We acknowledge your proposed actions to validate all
test methods and establish procedures for sampling,
cleaning, preventing cross-contamination, and storing
intermediate drug materials. However, your response
does not specify any timeframes for completion.


211.167
Micro

Testing of
Physical Products

Chemistry

Visual
Inspection


WL: 34-11
•  Your firm does not have appropriate
laboratory testing to determine if each
batch of drug products, purporting to be
sterile, conform to such requirements [21
C.F.R. § 211.167(a)].


WL: 34-11
–  For example, your firm only uses (b)(4) IU of
the required (b)(4) IU of beta-lactamase
neutralizing agent (as per your validation
studies) for the purpose of inhibiting the
antimicrobial properties of [PRODUCT NAME]
during sterility testing.


WL: 34-11

–  In addition, your firm does not include
Escherichia coli as part of your test organisms
despite your protocol, “Validation of Antibiotic
Neutralizer Effectiveness,” (b)(4), stating that
Escherichia coli is the most sensitive
challenge organism for evaluating if the
antibiotic was effectively neutralized.


WL: 34-11
–  In your response, your firm provided protocol
(b)(4), “Method Validation Protocol for
Recovery studies from PVDF Filter Membrane
of Steritest EZ Sterility Testing System
Surfaces,” that describes the amount of
[NAME] Sodium recovered from the Steritest
EZ Sterility Testing System and correlates it to
the amount of neutralizer required by your
original neutralizer effectiveness study.


WL: 34-11
–  Your response, however, is inadequate
because your firm has failed to provide any
scientific data to justify the correlation
between the use of (b)(4) IU of beta-
lactamase to (b)(4) of [NAME] or the use of
(b)(4) IU of beta-lactamase to (b)(4) of
[NAME] Sodium.
–  In addition, future validations should include
those products that proved to be most difficult
to neutralize in your original validation.


WL: 34-11
–  Please provide scientific data to justify the
correlation between the amount of beta-
lactamase required to neutralize a specific
amount of [NAME] drug product.
–  Further, please provide information that
demonstrates the beta-lactamase
effectiveness at this concentration. Future
validations should ensure that you include the
rationale for your choice of cephalosporin(s)
included in the validation.


211.194 Date
Integrity

Laboratory
Timely Records

Accuracy

Properly
Reviewed


WL: 320-11-013
•  Your firm’s laboratory records fail to
include complete data derived from all
tests necessary to assure compliance with
established specifications and standards
[21 C.F.R. § 211.194]. For example,
–  On December 13, 2010, the FDA investigator
observed a microbiological plate that
contained one (1) large colony forming unit
(CFU) of mold.


WL: 320-11-013
–  However, your firm’s laboratory
documentation reported 0 CFU for the same
microbiological plate.
–  The inspection found that the laboratory
manager had documented “NIL,” (i.e. no
growth for this plate), while the same
laboratory manager confirmed microbial
growth in the presence of the investigators.
Later during the inspection, the FDA
investigator asked to see the original plate
and was told that it had been destroyed.

WL: 320-11-013
–  On December 21, 2010, your firm prepared a
corrective and preventive action (CAPA)
stating that the laboratory manager misread
the plate count, and that this deficiency was
the result of a human error. We are concerned
that your firm lacks documentation to support
this conclusion and moreover, that the original
plate was destroyed during the FDA
inspection, as reported.


WL: 320-11-013
–  Your response of January 13, 2011, raises
some additional concerns as it includes a
photo of the original plate that your firm stated
was destroyed and a second photo of a plate
that was allegedly misread. Please explain
this discrepancy.
–  We are concerned that this is a repeat
violation. During the inspection of Unit VI
conducted in May 2007, investigators also
reported your failure to document positive
results for a microbial plate that was
confirmed as containing microbial growth.

WL: 320-11-013
–  On December 17, 2010, the investigator noted
that many microbial plates containing
environmental monitoring and personnel
samples, collected on December 12, 2010
during production, were missing from the
incubator. Your response confirmed that 33 of
150 (22%) of the personnel monitoring
samples were missing and that in one
instance, 9 of 10 samples were missing for a
single operator.


WL: 320-11-013
–  Your response indicates that no missing
plates were reported for the period of January
2009 through November 2010. We have
determined that this conclusion is not reliable
because neither reconciliation procedures nor
data regarding the number of microbial plates
used for environmental monitoring and
microbiology laboratory samples were
available at the time.


WL: 320-11-013
–  Please explain how your firm determined the
effectiveness of this review of 2009 and 2010
plates, without having a procedure in place for
the reconciliation.
–  Our inspection found that your environmental
monitoring data for 2009 and 2010 reported
no alert or action level results in the Grade (b)
(4) areas used to manufacture products
intended for the U.S. market.


WL: 320-11-013
–  This finding is questionable in that during an
FDA visit to your microbiology laboratory on
December 13, 2010, twenty-eight (28)
plates, collected as part of the environmental
monitoring program were found inside an
incubator in the microbiology laboratory with
visible growth of microorganisms. According
to your response to the inspectional
observations, many of the microorganisms
recovered were identified as “new
isolates”,which had not been previously
recovered in Unit VI.

WL: 320-11-013
–  We are concerned that similar situations were
observed by other FDA investigators during
previous inspections conducted in November
10 – 17, 2005, and May 7 – 15, 2007. This
disproportionate detection of microbial
contamination during FDA inspections
questions the validity of the data generated
by your microbiology laboratory.


WL: 320-11-013
–  Accurate and reliable microbial management
data is essential to support the aseptic
processing operations used during the
manufacturing of sterile active pharmaceutical
ingredients (API) and finished drug product
intended for distribution in the United States.


WL: 320-11-013
•  Your firm has not established or followed
appropriate written procedures designed to
prevent microbiological contamination of drug
products purporting to be sterile [21 C.F.R. §
211.113(b)].
–  For example, during the December 2010
inspection, the investigators found that your
SOPs related to your environmental programs
failed to adequately identify (e.g., diagrams)
the locations where active and passive
environmental monitoring samples are to be
collected from.

WL: 320-11-013
–  The inspection also found that your procedure
for environmental sampling does not require
that employees be sampled (b)(4) time they
exit the Class (b)(4) clean rooms.
–  This deficiency increases our concern
regarding the reliability of the data generated
and your ability to identify the source of your
microbial contamination.


WL: 320-11-013
–  We expect that SOPs related to
Environmental Monitoring include sufficient
instructions to ensure that the plates intended
to detect microbial growth are appropriately
located. These procedures should also
include specific instructions for the collection
of microbiological samples.


WL: 320-11-013
–  Your firm needs to establish a robust
environmental monitoring program capable of
generating meaningful data, and that would
serve as an early warning system to detect
possible environmental contaminants that
may impact the sterility of the sterile APIs and
finished drug products manufactured at your
facility.


WL: 320-11-013
–  There is no assurance that your current
environmental monitoring program is capable
of detecting microbiological contaminants.
–  In addition to the items listed above, the
inspection uncovered additional deficiencies
that increase our concerns regarding the
validity of the data generated in the
microbiology laboratory, and the quality of the
sterile API and finished drug products
manufactured at your facility. These issues
include, but are not limited, to:
•  (c) Jeanne Moldenhauer 2012 135

WL: 320-11-013
–  Discrepancies in the procedures and
documentation practices related to use of
extra plates to replace missing or damaged
plates that are collected as part of the
environmental monitoring program.
–  The device used to handle (b)(4) stoppers
during the aseptic filling of sterile API is not
sampled. Failure to follow established
procedures for control of all pages in the
batch production records.


WL: 320-11-015
•  Your firm’s laboratory records fail to
include complete data derived from all
tests necessary to assure compliance with
established specifications and standards
[21 C.F.R. § 211.194]. For example,
–  Your microbiologists reported the MA 5 and
MA 6 microbiological plates as “nil” while each
plate contained one (1) colony forming unit
(CFU).


WL: 320-11-015
–  On January 21, 2011, the FDA investigator
observed the microbiological plates, MA 5 and
MA 6, from air sampling locations in the Class
100/Grade A laminar air flow cabinet in the
Microbiology Lab. Each microbiological plate
contained one (1) CFU/m3. Your
microbiologists reported these microbiological
plates as “nil” on your form FM/QC/252-9
Quality Control Department Record of
Environmental Monitoring of Microbiology
Laboratory.


WL: 320-11-015
–  However, the action limit for these sample
locations is (b)(4) CFU/m3 which requires an
investigation per your procedure SOP/QC/049
entitled Environment Monitoring of Aseptic
Area by Settle Plate, Air Sampling, Surface
Sampling (RODAC Plate) and Personnel
Hygiene for Viable Count. The results as
originally reported on your form FM/QC/252-9
would not have prompted an investigation.


WL: 320-11-015
–  The microbiological growth found on settle
plate MS 4 was incorrectly identified and
reported as a typical microorganism when
compared against your firm’s library/
photographs of typical environmental flora.
–  Your microbiologists identified the growth on
the MS 4 plate as typical flora.


WL: 320-11-015
–  However, the FDA investigator found that
when compared with your normal
environmental flora, the growth should have
been reported as atypical since the
microorganism identified is not included in
firm’s library/photographs of typical
environmental flora. Your written procedure
SOP QC/049 requires further identification of
microbial growth not included in your firm’s
library/photographs. The results originally
reported on your form FM/QC/252-9 (typical
flora) would not have prompted further
identification. (c) Jeanne Moldenhauer 2012 141

WL: 320-11-015
–  Your response recognized that the
microbiologists should have classified the MS
4 microorganism as atypical. Moreover, your
response indicated that an investigation was
performed and microbiologists were retrained.
–  You stated that as part of your corrective
actions two microbiologists will observe
counts for three months to “rule out any
possibility of erroneous reporting.” However,
during the inspection, the FDA investigator
observed two microbiologists reading plates
and recording data.

WL: 320-11-015
–  Therefore, your corrective action plan does
not adequately address the observation, nor
does it appear to improve on current practices
for reading plates and recording data.
Additionally, the revised form used to
document the microbiologist observation lacks
appropriate identification of the microbiologist
performing the task at the time of the final
reading of the plates.


WL: 320-11-015
–  You are responsible for the accuracy and
integrity of the data generated by your firm.
We are concerned that trained microbiologists
employed by your firm were unable to
accurately identify microbial growth on
environmental monitoring plates. Additionally,
there is no assurance that such errors have
not occurred previously (during the
manufacture of exhibit batches for application
products pending with FDA).


WL: 320-11-015
–  Provide a more comprehensive corrective
action plan to ensure the integrity of all data
used to assess the quality and purity of all
drugs manufactured at your facility, including
any registration lots.
–  Accurate and reliable microbiological data is
essential to support the aseptic processing
operations used during the manufacturing of
sterile finished drug products intended for
distribution in the United States.


WL: 320-11-015
–  Your response includes retraining
documentation related to identifying
environmental isolates as typical/atypical and
observation of microbial growth, as well as
retraining on SOP QC/049. According to
information provided to the FDA investigators
during the inspection, the Microbiology
Laboratory is staffed by (b)(4) microbiologists.
The training attendance sheets in your
response do not include the same individuals.


WL: 320-11-015
–  For example, 10 QC personnel attended the
training on observation and counting of
colonies on environmental monitoring plates
held on January 22, 2011; and, only 8 QC
personnel attended the training on identifying
typical/atypical environmental isolates during
environmental monitoring plate observation.


WL: 320-11-015
–  Explain this discrepancy and provide
documentation confirming that all employees
have been retrained. Additionally, provide
documentation of specific training offered to
all employees regarding the importance of
following CGMP, and ensuring that they
accurately report all required tests.


WL: 320-11-015
–  You are responsible for the accuracy and
integrity of the data generated by your firm.
We are concerned that trained microbiologists
employed by your firm were unable to
accurately identify microbial growth on
environmental monitoring plates. Additionally,
there is no assurance that such errors have
not occurred previously (during the
manufacture of exhibit batches for application
products pending with FDA).


WL: 320-11-015
–  Provide a more comprehensive corrective
action plan to ensure the integrity of all data
used to assess the quality and purity of all
drugs manufactured at your facility, including
any registration lots.
–  Accurate and reliable microbiological data is
essential to support the aseptic processing
operations used during the manufacturing of
sterile finished drug products intended for
distribution in the United States.


WL: 320-11-015
–  Your response includes retraining
documentation related to identifying
environmental isolates as typical/atypical and
observation of microbial growth, as well as
retraining on SOP QC/049. According to
information provided to the FDA investigators
during the inspection, the Microbiology
Laboratory is staffed by (b)(4) microbiologists.


WL: 320-11-015
–  The training attendance sheets in your
response do not include the same individuals.
For example, 10 QC personnel attended the
training on observation and counting of
colonies on environmental monitoring plates
held on January 22, 2011; and, only 8 QC
personnel attended the training on identifying
typical/atypical environmental isolates during
environmental monitoring plate observation.


WL: 320-11-015
–  Explain this discrepancy and provide
documentation confirming that all employees
have been retrained. Additionally, provide
documentation of specific training offered to
all employees regarding the importance of
following CGMP, and ensuring that they
accurately report all required tests.


211.22
OVersight

Quality
Investigations Responsibilities

Approvals

Complaints


WL 320-12-01
•  The inspection documented that the visual
inspection certification program (VIC) for
(b)(4)g ((b)(4)cc and (b)(4)cc) and (b)(4)g
((b)(4)cc) finished product does not
adequately challenge the technician(s)
performing the inspection. The visual
inspection competency (VIC) program only
requires that (b)(4) of the five critical
defects be included in the challenge set
but… you have more defects.

May 24, 2011
•  Your firm has failed to establish an
adequate quality control unit with the
responsibility and authority to approve or
reject all components, drug product
containers, closures, in-process materials,
packaging material, labeling, and drug
products [21 C.F.R. § 211.22(a)]. For
example,


May 24, 2011
–  Your Quality Control Unit (QCU) failed to
reject a lot of [NAME] component (lot (b)(4))
after it failed specifications for yeast, mold,
and Aerobic Plate Count. The lot was
released and used to manufacture three lots
of (b)(4) [PRODUCT NAME] (lots (b)(4)).
–  Your QCU failed to detect an employee
miscalculating the microbial results for three
lots of (b)(4) [PRODUCT NAME] (lots (b)(4))
finished products by not applying a dilution
factor of 10-2.

May 24, 2011
–  The correct calculation of the results would
have shown that these products were Out-of-
Specification (OOS). The three lots of (b)(4)
[PRODUCT NAME] were released and
distributed by the QCU based on the
erroneous results.
–  Your QCU failed to detect multiple
discrepancies in sample weights and dilution
factors between the analyst’s notebook and
the Calculation Sheet.


May 24, 2011
–  As a result, incorrect data was recorded for
multiple products and finished products not
meeting specifications were released.
Specifically, a lot of (b)(4) SPF 30 (lot (b)(4))
was released and distributed even though it
did not meet the established specification of
(b)(4)% label claim. The correct calculation
would have reported a (b)(4)% label claim.


May 24, 2011
–  Your QCU did not require a second,
independent person to review the raw data,
calculations and records before releasing
these lots for distribution.
have removed the employees responsible for
the laboratory data errors from employment.
However, you have not explained in any detail
how you intend to handle all affected lots or
whether you would report these issues to the
own-label distributors.

May 24, 2011
–  Additionally, your response did not propose a
timeframe for completing the proposed
corrective actions. We acknowledge the
results of the retesting for Zinc and Titanium
performed by the third party laboratory.
However, the response does not include any
documentation of the procedure by which your
firm qualified the laboratory or demonstrated
its use of a validated methodology.


May 24, 2011
–  Finally, your response failed to provide a plan
to ensure that the QCU will carry out its
responsibilities in the future.


211.25
GMPs

Training,
Job
Instructions Education

Safety

Aseptic


WL-320-11-09
•  Your firm failed to ensure that each person
engaged in the manufacture, processing,
packing, or holding of a drug product has
the education, training, and experience, or
any combination thereof, to enable that
person to perform the assigned functions.
[21 C.F.R. § 211.25(a)].


WL-320-11-09
–  For example, On September 6 and 9, 2010,
operators involved in the cleaning operations
and aseptic connections during filling, were
observed demonstrating incorrect aseptic
techniques to prevent product contamination.
We expect that operators who conduct
operations within aseptic processing areas be
properly trained and monitored to ensure that
proper aseptic techniques are utilized during
all operations.


May 24, 2011
•  Your firm has failed to ensure that each person engaged
in the manufacture, processing, packing, or holding of a
drug product has the education, training, and
experience, or any combination thereof, to enable that
person to perform their assigned functions [21 C.F.R. §
211.25(a)].
–  For example, the employees of your firm, including a member of
your quality control staff, admitted to our investigators that they
were unaware of and were not trained to follow your SOP for
handling deviations. There were at least two instances in which
an OOS investigation was not conducted.


May 24, 2011
–  While your response proposes to provide training to
all employees, it does not provide documentation that
you have initiated the training and does not specify a
timeframe for completion. In addition, your response
fails to specifically address how the proposed training
will ensure that all employees will be trained in SOPs
that are relevant to their job functions.


211.84
Sotppers

Syringes Components

Vials

Ampoules


WL-320-12-05
•  Your firm has not conducted at least one
specific identity test and has not
established the reliability of the supplier’s
analyses through appropriate validation of
the supplier’s test results at appropriate
intervals [21 CFR § 211.84(d)(2)].
–  For example, your firm accepts and relies
upon the Certificate of Analysis (CoA) from
your stopper suppliers without conducting
adequate vendor qualification.


WL-320-12-05
–  Notably, your firm does not routinely test for
endotoxin on incoming stopper lots, and lacks
justification for not conducting this testing. In
your response, your firm commits to
implement a new procedure for
microbiological testing of stoppers for
endotoxin content and to validate the reliability
of the supplier's CoA.


211.67
Physical
Verification

Equipment
Efficacy
Cleaning

Frequency

SOPs


WL-320-12-05
•  Your firm has not cleaned and maintained
equipment at appropriate intervals to
prevent contamination that would alter the
safety, identity, strength, or quality of the
drug product [21 CFR § 211.67(a)].
–  For example, investigators observed that
several pieces of equipment, including your,
(b)(4) were still dirty after cleaning had been
completed and verified by a supervisor.


WL-320-12-05
–  In your response, you state these were
isolated instances and that there is no impact
to product.
–  However, this is a repeated violation ….
–  We are concerned that your firm has been
cited for inadequate cleaning during a number
of previous inspections, and that you have
promised corrective actions but our
inspections continue to reveal problems in this
area of CGMP.


211.68
Computer
Controls

Followed Equipment

SOPs

Reviewd


WL: 34-11
•  Your firm has failed to exercise
appropriate controls over computer or
related systems to assure that changes in
master production and control records, or
other records, are instituted only by
authorized personnel [21 C.F.R §
211.68(b)].


WL: 34-11
–  For example, your firm lacks control of the (b)
(4) computer system which monitors
equipment, room differential pressure, room
humidity, and stability chambers.
–  Although the system is password protected for
temperature and humidity set points, all
employees have access to the room where
the (b)(4) computer system is located and the
external hard drive is not password protected.


WL: 34-11
–  During the inspection we observed that an
employee was able to alter or delete data
without a password and save the changed file.
–  In your response, your firm states that
additional controls were implemented
including validating the remote access to the
(b)(4) computer, password protecting the
room where the computer is stored, and
limiting the (b)(4) control room to authorized
personnel only.


WL: 34-11
–  Although your corrective actions may
adequately address the protection of the (b)
(4) computer from non-traceable changes,
your firm has not taken a global approach to
this deficiency. It is our expectation that your
other manufacturing and laboratory
computerized systems will be reviewed to
ensure similar deficiencies do not exist.


211.42
Appropriate

Design Facilities

Separate
Areas
HVAC


WL- 320-11-002
•  Your firm has not established separate or
defined areas or such other control
systems to prevent contamination during
aseptic processing
•  [21 C.F.R. § 211.42(c)]. For example,
–  There is no documentary evidence of in-situ
air pattern analysis (e.g., smoke studies)
conducted at critical areas to demonstrate
unidirectional airflow and sweeping action
over and away from the product under
dynamic conditions.

WL- 320-11-002
–  Your firm failed to demonstrate that the
appropriate design and controls are in place
to prevent turbulence and stagnant air in the
critical area.
–  It is essential that you evaluate airflow
patterns for turbulence that can act as a
channel for air contamination.
–  The studies should be well documented with
written conclusions, and should include an
evaluation of the impact of aseptic
manipulations (e.g., interventions) and the
equipment design. Moldenhauer 2012
(c) Jeanne 181

WL- 320-11-002
–  Your aseptic processing control systems and
operations do not provide assurance that the
production rooms and equipment maintain
aseptic conditions.
–  Additionally, your environmental monitoring
practices do not include adequate routine
examination of the facilities and equipment to
ensure that possible contaminants can be
detected.


WL- 320-11-002
–  The inspection documented mold
contamination in the class 100 production
room and poor conditions of a wall in the
freeze dryer room, even though maintenance
is conducted on the freeze dryer every (b)(4)
months. An incident report, initiated in
November 2009, identifies holes in the ceiling
and visible light coming from the roof near the
ventilation system, bubbling of the vinyl and
disintegration of the wall under vinyl in the
freeze dryer room


WL- 320-11-002
–  visible black mold on the wall, a poor drain
system for the freeze dryer steam venting
system, and a soft (spongy) wall.
–  Operators involved in the filling operations for
the sterile drug products manufactured at your
facility do not practice adequate aseptic
techniques to prevent product contamination.
The environmental monitoring performed at
the end of the production run consist of
sampling the chest and the hand most
frequently used (right or left) of the
employee's gown.

WL-320-11-009
•  Your firm has not established separate or
defined areas or such other control
systems as necessary to prevent
contamination or mix-ups during aseptic
processing. [21 C.F.R. § 211.42(c)]. For
example,


WL-320-11-009
–  The airflow velocity inside critical areas of the
aseptic processing operations of Line (b)(4)
was found unacceptable by FDA. The
documentary evidence of in-situ air pattern
analysis (e.g., smoke studies) reviewed during
the inspection confirmed this condition.
–  With respect to aseptic processing in critical
areas, you should be able to demonstrate
unidirectional airflow and sweeping action
over and away from the product under
dynamic conditions.

WL-320-11-009
–  Please note that proper design and control
prevents turbulence and stagnant air in the
critical areas. It is crucial that airflow patterns
are evaluated for turbulence that can act as a
channel for contamination, and that any
deficient conditions are addressed.
–  Your environmental monitoring program does
not give assurance that environmental
contaminants are reliably detected. Your
practice of collecting samples from the gloves
of operators, from left and right hands on
alternate days is unacceptable.

WL-320-11-009
–  In addition, your SOP fails to include
instructions for the location and duration of
samples collected in the critical aseptic
processing areas.
–  An adequate environmental monitoring
program should be established by your firm. It
should capture meaningful data and act as an
early warning system to detect possible
environmental contaminants that may impact
the sterility of drug products manufactured at
your facility that purport to be sterile.


NWE-09-11W
•  Your firm has failed to establish separate
or defined areas or such other control
systems for your firm’s aseptic processing
areas, including a system for monitoring
environmental conditions [21 C.F.R. §
211.42(c)(10)(iv)].


NWE-09-11W
•  For example, your firm has failed to
include the communication devices and a
transfer cart as part of your environmental
monitoring program. These items are used
in your filling suite and are not sterilized,
which could compromise product sterility.


NWE-09-11W
•  In your response, your firm states that you
will revise procedures for sanitizing
equipment that is transferred into the filling
suite and require sampling after use in the
filling suite. Your response, however, is
inadequate because you did not indicate
whether you will qualify this sanitization
process.


NWE-09-11W
•  Your firm has failed to establish separate
or defined areas or such other control
systems for your firm’s aseptic processing
areas, including temperature and humidity
controls [21 C.F.R. § 211.42(c)(10)(ii)].
–  For example, your firm fails to control the
humidity in your clean rooms which is
necessary to protect the drug product and
minimize the risk of environmental
contamination.


NWE-09-11W
–  In your response, your firm justifies the lack of
humidity control by relying on humidity
monitoring and obtaining client concurrence
when high values are obtained. Your
response is inadequate because it is your
responsibility to ensure that appropriate
humidity controls are in place.


MIN 11 - 15
•  Your firm does not have an adequate
system for monitoring environmental
conditions in aseptic processing areas, as
per 21 CFR 211.42(c)(10)(iv)]. For
example,
–  Your firm does not have written procedures
for environmental monitoring during aseptic
processing, including sampling frequency,
sampling locations, or procedures for alert
and action levels.


MIN 11 - 15
–  In your response you state that you have
revised your environmental monitoring form to
include a place for explanations and that you
are developing an environmental monitoring
procedure.
–  You also state that your acceptance criteria
currently listed on your worksheets is your
action limit. You are required to ensure all
sampling locations, sampling frequency, and
alert and action levels are justified by a
scientific rationale.

MIN 11 - 15
–  We request you provide your alert levels. If
these levels have not already been
established, provide the timeframe within
which they will be established.


211.58
Rust

Maintenance
Not Working of Facilities

Cracks

Chipped
Paint


NWE-09-11W
•  Your firm has failed to maintain buildings
used in the manufacture, processing,
packing, or holding of a drug product in a
good state of repair [21 C.F.R. § 211.58].
–  For example, holes, cracks, chipping and
peeling paint were observed in your aseptic
facility that could lead to contamination and
increase the risk to product quality.


NWE-09-11W
–  In your response, your firm states that you will
repair the facility defects and implement a
Standard Operating Procedure (SOP) to
identify defects in the future.
–  It is important that you create and institute an
environment that will ensure that employees
are encouraged and are responsible to
identify and report quality issues when first
observed.


NWE-09-11W
–  Furthermore, your response did not establish
engineering controls (e.g., measures to
prevent damage to walls, alternate
construction materials that reduce the need
for repairs, etc.) to prevent the reoccurrence
of facility defects.


211.111
Stability

Time
Each Step Limitations

Specified

Supported
By data


MIN 11 - 15
•  Your firm failed to establish time limits for
the completion of each phase of
production to assure the quality of the drug
product per 21 CFR 211.111. For
example,
–  Your firm has failed to provide a justification
for the hold times (i.e., (b)(4)) used in current
batch records for sterile ophthalmic eye drop
products.


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