Overview of Inspection Issues with Legacy Products

Transcription

1 Overview of Inspection Issues with Legacy Products Presented by Simone E. Pitts Consumer Safety Officer, USFDA Team Biologics

2 Objective To provide some examples of recent inspectional observations related to Team Biologics inspections and facilitate discussions of these issues Not an expansive list or a discussion about trends

3 Examples of References used by Team Biologic Investigators Compliance Program: Inspection of Biological Drug Products (CBER) formation/complianceactivities/enforcement/complianceprograms/ucm pdf 21 CFR Part 200 DRUGS: GENERAL 21 CFR Part 211 CGMP for Finished Pharmaceuticals

4 Examples of References used by Team Biologic Investigators 21 CFR Part BIOLOGICAL PRODUCTS: GENERAL t=600 Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice ion/guidances/ucm pdf

5 Quality Including, but not limited to: Sterility failures and investigations Environmental monitoring excursions Water monitoring excursions Personnel monitoring excursions Stability testing Media Fill results (failures and/or growth observed in vials)

6 Quality Failure to thoroughly investigate endotoxin failures that resulted in 44 rejected batches Issue: Inadequate investigations

7 Quality FDA-483 observations could include: Discrepancy and failure investigations related to manufacturing and testing; documented, evaluated, and thoroughly investigated, including corrective actions and follow-up where appropriate Failure to conduct investigations into unexplained discrepancies or The failure of a batch or any of its components to meet specifications whether or not the batch was distributed. [Are/were] not always documented [Do/did] not always include the conclusions and/or follow-up [Do/did] not always extend to other batches of the product [Do/did] not always extend to other products with the associated discrepancies

8 Quality Review of random BPDRs (particularly those that are serious). If there are serious issues such as media fill failures, stability failures or sterility failures or any other issue that has the potential to affect distributed product, these issues should be reported in a BPDR. Reporting of Biological Product Deviations (BPDs) Reportable BPDs [are/were] not submitted to CBER, or [are/were] not submitted within the required timeframe

9 Production Failure to assure that appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, are established and followed. Such procedures include validation of all aseptic and sterilization processes. Issue: Recurring endotoxin OOT Issues: Deficient environmental monitoring program; media fills

10 Production Manufacturing controls in place for both the containing and the manufacturing processes are inadequate to control bioburden and endotoxin. Issue: Continued OOS results for bioburden and endotoxin even after several corrective and preventive actions were implemented.

11 Production The firm failed to investigate the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed. Issues: Failure to document all OOS; failure to perform certain investigations

12 Production Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications. Issues: Failure to conduct sterility failure investigations and incomplete investigations; other incomplete investigations; lack of documented corrective/preventive actions

13 Production Blockages that lead to excessive filtration times during the blockages of the nanofilters, were noted during the current inspection, as well as during a previous inspection. No root cause has been found for these filtration issues. Issue: Unresolved viral filtration problems

14 Production Failure to follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile [21 CFR (b)]. For example, during aseptic filling operations for vaccine X, an operator was observed with head and torso over partially stoppered vials while loading vials onto lyophilization trays.

15 Production The firm failed to establish an adequate system for monitoring environmental conditions of aseptic processing areas [21 CFR (c)(10)(iv)]. For example: There is no documentation that monitoring covers all production shifts and is performed during active operations. There is no assurance that monitoring is at the locations where critical operations are performed.

16 Production Media fill failure investigations are inadequate. For example, the root cause analysis does not always provide information about all potential root causes investigated and the rationale for eliminating or retaining potential root causes for the media failures.

17 Materials/Facility & Equipment Controls for the purified water system at your facility are inadequate to prevent bioburden and endotoxin excursions. Issues: Numerous excursions (gram negative bacteria); system disinfection

18 Materials The firm failed to withhold from use each lot of components until the lot was sampled, tested, or examined, as appropriate, by the quality control unit. Issue: Lack of procedures for bioburden testing of an incoming material

19 Materials Failure to assure that container closure systems provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of bulk drug substances and sterile solutions used in production. For example: Study 1234 did not include an assessment of the effect of storage conditions. This container/closure is used for bulk drug substances. Product X sterile filtered solutions used in the manufacture of vaccines are stored in containers for 24 months. Validation studies have not been conducted to assure container/closure integrity. There is no assurance that the 1000 ml bottles with screw cap closures used to store frozen bulk product are non-reactive, additive or adsorptive

20 Facility & Equipment You failed to assure an adequate system for monitoring environmental conditions. Issue: Air is not monitored for viable organisms throughout the filling operations

21 Facilities & Equipment Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including validation of all aseptic processes. Issues: failure to follow environmental monitoring procedures; lack of an SOP; sterilization validation; practices; deficient monitoring

22 Facilities & Equipment Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance Issue: Equipment maintenance

23 Laboratory Failures (OOS Investigations) Adherence to an adequate Out of Specification (OOS) procedure Deviations from the written procedures [are/were] not recorded and/or justified (a) Failure to conduct investigations into unexplained discrepancies or the failure of a batch or any of its components to meet specifications:

24 Laboratory The firm s disinfectant effectiveness study is incomplete in that the study did not evaluate the effectiveness of the disinfectants in use on fungi and spore forming microorganisms. Spore forming microorganisms have been routinely isolated in the manufacturing facility.

25 Questions? Thank you!