Mock Inspection Case Studies

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Regulatory inspections have had a significant impact on the number of drug shortages and companies facing adverse regulatory actions.
Review of the inspection trends can be useful in assessing the regulatory status of your own company and help aid in the preparation for upcoming inspections. This session from IVT's Contamination and Control Week provides an in-depth, practical look at some of the recent Warning Letters and discusses current trends.

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Mock Inspection Case Studies

  1. 1. Mock Inspection Case Studies Jeanne Moldenhauer Excellent Pharma Consulting (c) Jeanne Moldenhauer 2012 1
  2. 2. For more information on microbiology andFDA inspections, visit www.ivtnetwork.com . Use the promo code SLIDE1 for a 10% discount on a membership! (c) Jeanne Moldenhauer 2012 2
  3. 3. Agenda1. Overview2. Today’s Inspection Process3. Top Items in the Last Year4. Conclusion (c) Jeanne Moldenhauer 2012 3
  4. 4. 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 (c) Jeanne Moldenhauer 2012 4
  5. 5. 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 (c) Jeanne Moldenhauer 2012 5
  6. 6. 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 (c) Jeanne Moldenhauer 2012 6
  7. 7. 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 (c) Jeanne Moldenhauer 2012 7
  8. 8. 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. (c) Jeanne Moldenhauer 2012 8
  9. 9. 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.) (c) Jeanne Moldenhauer 2012 9
  10. 10. 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 (c) Jeanne Moldenhauer 2012 10
  11. 11. 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
  12. 12. 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) (c) Jeanne Moldenhauer 2012 12
  13. 13. 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)? (c) Jeanne Moldenhauer 2012 13
  14. 14. 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 (c) Jeanne Moldenhauer 2012 14
  15. 15. 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 (c) Jeanne Moldenhauer 2012 15
  16. 16. 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
  17. 17. 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? (c) Jeanne Moldenhauer 2012 17
  18. 18. 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 (c) Jeanne Moldenhauer 2012 18
  19. 19. 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 (c) Jeanne Moldenhauer 2012 19
  20. 20. 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. (c) Jeanne Moldenhauer 2012 20
  21. 21. 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 (c) Jeanne Moldenhauer 2012 21
  22. 22. 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 (c) Jeanne Moldenhauer 2012 22
  23. 23. 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 (c) Jeanne Moldenhauer 2012 23
  24. 24. 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……….., (c) Jeanne Moldenhauer 2012 24
  25. 25. 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 (c) Jeanne Moldenhauer 2012 25
  26. 26. 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 thingsJeanne Moldenhauer 2012 (c) 26
  27. 27. 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? (c) Jeanne Moldenhauer 2012 27
  28. 28. •  How does this translate into inspection observations? (c) Jeanne Moldenhauer 2012 28
  29. 29. Inspection Observations 211.113 DisinfectionObjectionable MicrobiologyOrganisms Environmental Monitoring Media Fills (c) Jeanne Moldenhauer 2012 29
  30. 30. 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. (c) Jeanne Moldenhauer 2012 30
  31. 31. 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. (c) Jeanne Moldenhauer 2012 31
  32. 32. 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. (c) Jeanne Moldenhauer 2012 32
  33. 33. 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. (c) Jeanne Moldenhauer 2012 33
  34. 34. 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. (c) Jeanne Moldenhauer 2012 34
  35. 35. 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. (c) Jeanne Moldenhauer 2012 35
  36. 36. 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. (c) Jeanne Moldenhauer 2012 36
  37. 37. 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. (c) Jeanne Moldenhauer 2012 37
  38. 38. 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. (c) Jeanne Moldenhauer 2012 38
  39. 39. 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. (c) Jeanne Moldenhauer 2012 39
  40. 40. 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. (c) Jeanne Moldenhauer 2012 40
  41. 41. 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. (c) Jeanne Moldenhauer 2012 41
  42. 42. 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. (c) Jeanne Moldenhauer 2012 42
  43. 43. 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. (c) Jeanne Moldenhauer 2012 43
  44. 44. 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. (c) Jeanne Moldenhauer 2012 44
  45. 45. 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. (c) Jeanne Moldenhauer 2012 45
  46. 46. 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. (c) Jeanne Moldenhauer 2012 46
  47. 47. 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. (c) Jeanne Moldenhauer 2012 47
  48. 48. 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. (c) Jeanne Moldenhauer 2012 48
  49. 49. 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. (c) Jeanne Moldenhauer 2012 49
  50. 50. 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
  51. 51. WL: 320-12-05•  Please provide your firm’s evaluation of the impact on products produced during this period. –  This is a repeat observation….. (c) Jeanne Moldenhauer 2012 51
  52. 52. 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, (c) Jeanne Moldenhauer 2012 52
  53. 53. 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. (c) Jeanne Moldenhauer 2012 53
  54. 54. 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. (c) Jeanne Moldenhauer 2012 54
  55. 55. 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. (c) Jeanne Moldenhauer 2012 55
  56. 56. 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. (c) Jeanne Moldenhauer 2012 56
  57. 57. 211.192 No Root CauaeTimelyCompletin Investigations Missing Documentation Scientific Justification (c) Jeanne Moldenhauer 2012 57
  58. 58. 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) (c) Jeanne Moldenhauer 2012 58
  59. 59. 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….. (c) Jeanne Moldenhauer 2012 59
  60. 60. 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] –  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.. (c) Jeanne Moldenhauer 2012 60
  61. 61. WL-320-11-002•  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’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. (c) Jeanne Moldenhauer 2012 61
  62. 62. WL-320-11-002–  Additionally, your firm does not perform challenge testing to the sterility media with environmental isolates from the environmental monitoring program. (c) Jeanne Moldenhauer 2012 62
  63. 63. 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. (c) Jeanne Moldenhauer 2012 63
  64. 64. 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. (c) Jeanne Moldenhauer 2012 64
  65. 65. 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. (c) Jeanne Moldenhauer 2012 65
  66. 66. 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. (c) Jeanne Moldenhauer 2012 66
  67. 67. 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. (c) Jeanne Moldenhauer 2012 67
  68. 68. 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. (c) Jeanne Moldenhauer 2012 68
  69. 69. 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. (c) Jeanne Moldenhauer 2012 69
  70. 70. 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. (c) Jeanne Moldenhauer 2012 70
  71. 71. 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. (c) Jeanne Moldenhauer 2012 71
  72. 72. 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]. (c) Jeanne Moldenhauer 2012 72
  73. 73. 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. (c) Jeanne Moldenhauer 2012 73
  74. 74. 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. (c) Jeanne Moldenhauer 2012 74
  75. 75. 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: (c) Jeanne Moldenhauer 2012 75
  76. 76. 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. (c) Jeanne Moldenhauer 2012 76
  77. 77. 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. (c) Jeanne Moldenhauer 2012 77
  78. 78. 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). (c) Jeanne Moldenhauer 2012 78
  79. 79. 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. (c) Jeanne Moldenhauer 2012 79
  80. 80. 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. (c) Jeanne Moldenhauer 2012 80
  81. 81. 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. (c) Jeanne Moldenhauer 2012 81
  82. 82. 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. (c) Jeanne Moldenhauer 2012 82
  83. 83. 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. (c) Jeanne Moldenhauer 2012 83
  84. 84. 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. (c) Jeanne Moldenhauer 2012 84
  85. 85. 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. (c) Jeanne Moldenhauer 2012 85
  86. 86. 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. (c) Jeanne Moldenhauer 2012 86
  87. 87. 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. (c) Jeanne Moldenhauer 2012 87
  88. 88. 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. (c) Jeanne Moldenhauer 2012 88
  89. 89. 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. (c) Jeanne Moldenhauer 2012 89
  90. 90. 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. (c) Jeanne Moldenhauer 2012 90
  91. 91. 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. (c) Jeanne Moldenhauer 2012 91
  92. 92. 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. (c) Jeanne Moldenhauer 2012 92
  93. 93. 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. (c) Jeanne Moldenhauer 2012 93
  94. 94. 211.100 SOPs WrittenMissing Procedures Work Instructions Records (c) Jeanne Moldenhauer 2012 94
  95. 95. 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… (c) Jeanne Moldenhauer 2012 95
  96. 96. 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
  97. 97. 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)]. (c) Jeanne Moldenhauer 2012 97
  98. 98. 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. (c) Jeanne Moldenhauer 2012 98
  99. 99. 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. (c) Jeanne Moldenhauer 2012 99
  100. 100. 211.160 Didn’t follow WrittenNot Followed Procedures - Laboratory Missing Inadequate (c) Jeanne Moldenhauer 2012 100
  101. 101. 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. (c) Jeanne Moldenhauer 2012 101
  102. 102. 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
  103. 103. 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)]. (c) Jeanne Moldenhauer 2012 103
  104. 104. 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. (c) Jeanne Moldenhauer 2012 104
  105. 105. 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. (c) Jeanne Moldenhauer 2012 105
  106. 106. 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.. (c) Jeanne Moldenhauer 2012 106
  107. 107. 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. (c) Jeanne Moldenhauer 2012 107
  108. 108. 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. (c) Jeanne Moldenhauer 2012 108
  109. 109. 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. (c) Jeanne Moldenhauer 2012 109
  110. 110. 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. (c) Jeanne Moldenhauer 2012 110
  111. 111. 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. (c) Jeanne Moldenhauer 2012 111
  112. 112. 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. (c) Jeanne Moldenhauer 2012 112
  113. 113. 211.167 Micro Testing ofPhysical Products Chemistry Visual Inspection (c) Jeanne Moldenhauer 2012 113
  114. 114. 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)]. (c) Jeanne Moldenhauer 2012 114
  115. 115. 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. (c) Jeanne Moldenhauer 2012 115
  116. 116. 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. (c) Jeanne Moldenhauer 2012 116
  117. 117. 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. (c) Jeanne Moldenhauer 2012 117
  118. 118. 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. (c) Jeanne Moldenhauer 2012 118
  119. 119. 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. (c) Jeanne Moldenhauer 2012 119
  120. 120. 211.194 Date Integrity LaboratoryTimely Records Accuracy Properly Reviewed (c) Jeanne Moldenhauer 2012 120
  121. 121. 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. (c) Jeanne Moldenhauer 2012 121
  122. 122. 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. (c) Jeanne Moldenhauer 2012 122
  123. 123. 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. (c) Jeanne Moldenhauer 2012 123
  124. 124. 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. (c) Jeanne Moldenhauer 2012 124
  125. 125. 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. (c) Jeanne Moldenhauer 2012 125
  126. 126. 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. (c) Jeanne Moldenhauer 2012 126
  127. 127. 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. (c) Jeanne Moldenhauer 2012 127
  128. 128. 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. (c) Jeanne Moldenhauer 2012 128
  129. 129. 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. (c) Jeanne Moldenhauer 2012 129
  130. 130. 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. (c) Jeanne Moldenhauer 2012 130
  131. 131. 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. (c) Jeanne Moldenhauer 2012 131
  132. 132. 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. (c) Jeanne Moldenhauer 2012 132
  133. 133. 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. (c) Jeanne Moldenhauer 2012 133
  134. 134. 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. (c) Jeanne Moldenhauer 2012 134
  135. 135. 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
  136. 136. 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. (c) Jeanne Moldenhauer 2012 136
  137. 137. 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). (c) Jeanne Moldenhauer 2012 137
  138. 138. 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. (c) Jeanne Moldenhauer 2012 138
  139. 139. 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. (c) Jeanne Moldenhauer 2012 139
  140. 140. 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. (c) Jeanne Moldenhauer 2012 140
  141. 141. 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
  142. 142. 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. (c) Jeanne Moldenhauer 2012 142
  143. 143. 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. (c) Jeanne Moldenhauer 2012 143
  144. 144. 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). (c) Jeanne Moldenhauer 2012 144
  145. 145. 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. (c) Jeanne Moldenhauer 2012 145
  146. 146. 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. (c) Jeanne Moldenhauer 2012 146
  147. 147. 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. (c) Jeanne Moldenhauer 2012 147
  148. 148. 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. (c) Jeanne Moldenhauer 2012 148
  149. 149. 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). (c) Jeanne Moldenhauer 2012 149
  150. 150. 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. (c) Jeanne Moldenhauer 2012 150
  151. 151. 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. (c) Jeanne Moldenhauer 2012 151
  152. 152. 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. (c) Jeanne Moldenhauer 2012 152
  153. 153. 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. (c) Jeanne Moldenhauer 2012 153
  154. 154. 211.22 OVersight QualityInvestigations Responsibilities Approvals Complaints (c) Jeanne Moldenhauer 2012 154
  155. 155. 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. (c) Jeanne Moldenhauer 2012 155
  156. 156. 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, (c) Jeanne Moldenhauer 2012 156
  157. 157. 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. (c) Jeanne Moldenhauer 2012 157
  158. 158. 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. (c) Jeanne Moldenhauer 2012 158
  159. 159. 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. (c) Jeanne Moldenhauer 2012 159
  160. 160. 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. (c) Jeanne Moldenhauer 2012 160
  161. 161. 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. (c) Jeanne Moldenhauer 2012 161
  162. 162. May 24, 2011–  Finally, your response failed to provide a plan to ensure that the QCU will carry out its responsibilities in the future. (c) Jeanne Moldenhauer 2012 162
  163. 163. 211.25 GMPs Training,JobInstructions Education Safety Aseptic (c) Jeanne Moldenhauer 2012 163
  164. 164. 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)]. (c) Jeanne Moldenhauer 2012 164
  165. 165. 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. (c) Jeanne Moldenhauer 2012 165
  166. 166. 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. (c) Jeanne Moldenhauer 2012 166
  167. 167. 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. (c) Jeanne Moldenhauer 2012 167
  168. 168. 211.84 SotppersSyringes Components Vials Ampoules (c) Jeanne Moldenhauer 2012 168
  169. 169. 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. (c) Jeanne Moldenhauer 2012 169
  170. 170. 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 suppliers CoA. (c) Jeanne Moldenhauer 2012 170
  171. 171. 211.67 Physical Verification EquipmentEfficacy Cleaning Frequency SOPs (c) Jeanne Moldenhauer 2012 171
  172. 172. 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. (c) Jeanne Moldenhauer 2012 172
  173. 173. 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. (c) Jeanne Moldenhauer 2012 173
  174. 174. 211.68 Computer ControlsFollowed Equipment SOPs Reviewd (c) Jeanne Moldenhauer 2012 174
  175. 175. 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)]. (c) Jeanne Moldenhauer 2012 175
  176. 176. 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. (c) Jeanne Moldenhauer 2012 176
  177. 177. 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. (c) Jeanne Moldenhauer 2012 177
  178. 178. 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. (c) Jeanne Moldenhauer 2012 178
  179. 179. 211.42 AppropriateDesign Facilities Separate Areas HVAC (c) Jeanne Moldenhauer 2012 179
  180. 180. 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. (c) Jeanne Moldenhauer 2012 180
  181. 181. 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
  182. 182. 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. (c) Jeanne Moldenhauer 2012 182
  183. 183. 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 (c) Jeanne Moldenhauer 2012 183
  184. 184. 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 employees gown. (c) Jeanne Moldenhauer 2012 184
  185. 185. 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, (c) Jeanne Moldenhauer 2012 185
  186. 186. 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. (c) Jeanne Moldenhauer 2012 186
  187. 187. 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. (c) Jeanne Moldenhauer 2012 187
  188. 188. 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. (c) Jeanne Moldenhauer 2012 188
  189. 189. 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)]. (c) Jeanne Moldenhauer 2012 189
  190. 190. 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. (c) Jeanne Moldenhauer 2012 190
  191. 191. 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. (c) Jeanne Moldenhauer 2012 191
  192. 192. 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. (c) Jeanne Moldenhauer 2012 192
  193. 193. 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. (c) Jeanne Moldenhauer 2012 193
  194. 194. 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. (c) Jeanne Moldenhauer 2012 194
  195. 195. 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. (c) Jeanne Moldenhauer 2012 195

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