Microbiology FDA 483 : Written record of investigation incomplete (unexplained discrepancies), appropriate conclusions and follow-up

Observation

Written records of investigations into unexplained discrepancies, the failure of a batch or any of its components to meet specifications, do not always include the appropriate conclusions and follow-up.

Facility Type

Non-Sterile Manufacturing

Firm / Company

AGC Biologics Inc.

System

Quality System

Details

Your firm failed to conduct prompt and thorough deviation investigations to identify appropriate root causes and to implement sustainable corrective action and preventive action (CAPA). With respect to deviations related to  drug substance that were due to close in 2022 and in 2023 prior to the initiation of the inspection (up to February 2, 2023), approximately 60% of closed deviations closed late and there are over 80 open deviations that are past due.

 

(A) Routine environmental monitoring trend investigations are still pending at the initiation of inspection: DEV-03*** (created on 07/Mar/2021); DEV-0*** (created on 25/Jun2/2021); DEV-05*** (created on 12/Aug/2021); DEV-05*** (created on 16/Aug/2021); DEV- 10*** (created on 01/May/2022); DEV-1*** (created on 27/Jul/2022); DEV-1*** (created on 20/Aug/2022); and DEV-1*** (created on 08/Oct/2022).

 

(B)  The following process specific monitoring excursions are still under investigation at the initiation of inspection.

  • DEV-I 1*** was created on 03Sep2022 for viable air excursion in Room ***
  • DEV-1***  was created on 27Nov2022 for viable air excursion in Room ***
  • DEV-1*** was created on 29Nov2022 for personnel monitoring in *** Fill Room ***

 

(C) DEV-1*** was initiated on 03Sep2022 for a primary operator personnel monitoring excursion. An investigation was not completed until 23Jan2023 with a due date of ***. The post-operation personnel monitoring of the *** operator who performed *** and filling resulted in the growth of EM plates which exceeded alert and action limits for multiple sites of the body. The *** operator also had EM results which exceeded alert limits. No CAPA was implemented to address this excursion at the *** filling process, a highly critical step which could impact the product quality and contaminate the ISO 5 environment.

The investigation was performed four months later on 27Dec2022, which concluded that the plates could be contaminated during the handling or transfer process of plates. The late investigation could raise a potential risk of microbial control in the filling room and related process. The environmental monitoring of filling room and batch results cannot be used to justify not having a CAPA to correct and prevent similar events. In addition, based on the filling process we observed on February 6, 2023, the personnel monitoring plates were closed and wrapped with *** in filling room by microbiologist before transferred to QC lab, thus the contamination risk during transfer is relatively low. The investigation is inadequate.

 

(D) DEV-1*** was initiated on l5Sep2022 for a bioburden excursion result of ** CFU/10 mL TAMC (alert limit ** CFU/10 mL) for ***. An investigation was not completed until 27Jan2023. The investigation conclusion indicated that all other factors from *** were ruled out except manpower, which implied the potential contamination source from operators or QC associates. However, no CAPA was implemented to address this excursion after investigation, which is inadequate.

 

(E) A leak was found on a terminal HEPA filter (ID 1***) located in Solution Preparation Suite (Room ***) during a routine HEPA certification conducted by a service contractor’s technician on 03Aug2022. A small puncture in the filter was identified and patched using *** sealant. No deviation was initiated to investigate the potential impact of the HEPA failure on the process solutions prepared in the suite.

Record Date

02/2023

FEI Number

3000209996

Country

USA

Citation Type

483

Audit Duration (Days)

Investigators

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FDA 483 relevant to Microbiology

Disclaimer: The purpose of this article is to provide helpful information on FDA 483s related to microbiological issues. This article represents 483 information in Tabular form for quick access and easy navigation. Information for this article is derived from “Form FDA 483” (Inspectional Observation). This article is not intended to replace the information provided by the FDA, nor is it guaranteed to be complete, always refer official FDA site for details.

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Microbiology FDA 483 (Jiangsu Hengrui Pharmceuticals): Container closure systems do not provide adequate protection against foreseeable external factors

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Product contact equipment including *** stopper drums, *** were sterilized without outer wrapping and transferred from Grade A cart to Inside of the RABS without cover in Workshop *** Filling Room ***.

Microbiology FDA 483 (Jubilant Radiopharmacies): The movement of first air in the ISO 5 area is blocked or disrupted

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Microbiology FDA 483 (Eugia Pharma Specialities): Aseptic processing areas are deficient regarding the system for monitoring environmental conditions

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Surface monitoring of the filling and stoppering machine is not performed in a timely manner following the completion of aseptic filling operations to ensure the data is representative of the environmental conditions at the time of filling. For example:

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