mock inspection case studies

Mock Inspection Case Studies Jeanne Moldenhauer

Excellent Pharma Consulting (c) Jeanne Moldenhauer 2012 1

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(c) Jeanne Moldenhauer 2012 2

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


How Inspections are Performed •  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.


How Inspections are Performed •  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.)


How Inspections are Performed •  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


How Inspections are Performed •  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? (c) Jeanne Moldenhauer 2012 11

How Inspections are Performed – 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)


How Inspections are Performed – 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)?


How Inspections are Performed – 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


How Inspections are Performed •  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


How Inspections are Performed •  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????? (c) Jeanne Moldenhauer 2012 16

How Inspections are Performed •  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?


How Inspections are Performed •  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


How Inspections are Performed •  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


How Inspections are Performed •  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.


How Inspections are Performed •  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


How Inspections are Performed •  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


How Inspections are Performed •  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


How Inspections are Performed •  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………..,


How Inspections are Performed •  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


How Inspections are Performed •  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 things


How Inspections are Performed •  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

Objectionable Organisms

211.113 Disinfection

Environmental Monitoring

Media Fills

Microbiology


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 (c) Jeanne Moldenhauer 2012 50

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.


Timely Completin

211.192 No Root Cauae

Missing Documentation

Scientific Justification

Investigations


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…..



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] – 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..



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, 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 •  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, – 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 •  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, 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.


Missing

211.100 SOPs

Work Instructions

Records

Written Procedures


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…. (c) Jeanne Moldenhauer 2012 96

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.


Not Followed

211.160 Didn’t follow

Missing

Inadequate

Written Procedures -

Laboratory


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 –  In your response, your firm states that you

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

Physical

Micro

Chemistry

Visual Inspection

Testing of Products


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

Timely

Date Integrity

Accuracy

Properly Reviewed

Laboratory Records


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

Investigations

OVersight

Approvals

Complaints

Quality Responsibilities


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.

–  In your response, your firm states that you 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

Job Instructions

GMPs

Safety

Aseptic

Training, Education


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.


Syringes

211.84 Sotppers

Vials

Ampoules

Components


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

Efficacy

Physical Verification

Frequency

SOPs

Equipment Cleaning


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.


Followed

211.68 Computer Controls

SOPs

Reviewd

Equipment


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.


Design

211.42 Appropriate

Separate Areas

HVAC

Facilities


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.


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.


Not Working

211.58 Rust

Cracks

Chipped Paint

Maintenance of Facilities


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.


Each Step

211.111 Stability

Specified

Supported By data

Time Limitations


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.


MIN 11 - 15 –  In your response, your firm provided a report

entitled “ (b)(4) Study Report” to justify your use of a (b)(4) day hold time. This report, however, is inadequate because your study tested lots on Day (b)(4) that did not correspond to or match the lots tested on Day (b)(4) Your study should compare the same lot for microbial recovery on Day (b)(4) to Day (b)(4) to determine whether the bulk products originally tested still had levels of bioburden within your validated sterilization ranges.


MIN 11 - 15 –  In addition, your response failed to address

the inadequate investigations for those batches where the hold times of the bulk product exceeded your hold time limits.


Conclusions •  FDA is changing….

– Most expectations based upon good science


Contact Information •  [email protected] •  Office: +1.847.837.8191


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