FDA Warning Letters of the Fiscal Year 2022: the "Top Ten" GMP Deficiencies

The systematic analysis of the GMP deficiencies recorded during an inspection reflects, on the one hand, what FDA inspectors focus on and, on the other hand, provides clues for preparing for an upcoming inspection by the FDA. The sometimes quite detailed descriptions of the GMP violations are facilitated by topic-related statistics, which are carried out annually by Concept Heidelberg in the context of the respective completed fiscal year.

In the fiscal year 2022 (Oct. 2021 - Sept. 2022), a total of 42 Warning Letters were sent to medicinal product manufacturers, each explicitly describing the GMP deficiencies in connection with the paragraphs of 21 CFR 211. After analysing these "Drugs" Warning Letters, the "hit parade" of the 10 most frequently cited GMP sins looks as follows:

• 211.22     Responsibilities of quality control unit (Subpart B - Organization and Personnel) - cited in 23 Warning Letters
  
• 211.192   Product record review (Subpart J - Records and Reports) - cited in 19 Warning Letters
  
• 211.165   Testing and release for distribution (Subpart I - Laboratory Controls) - cited in 17 Warning Letters
  
• 211.100   Written procedures; deviations (Subpart F - Production and Process Controls) - cited in 16 Warning Letters
  
• 211.84     Testing and approval or rejection of components, drug product containers, and closures (Subpart E - Control of Components 
                    and Drug Product Containers and Closures) - cited in 14 Warning Letters
  
• 211.67     Equipment cleaning and maintenance (Subpart D - Equipment) - cited in 13 Warning Letters
  
• 211.166   Stability Testing (Subpart I - Laboratory Controls) - cited in 11 Warning Letters
  
• 211.160   General requirements (Subpart I - Laboratory Controls) - cited in 10 Warning Letters
  
• 211.68     Automatic, mechanical, and electronic equipment (Subpart D - Equipment) - cited in 8 Warning Letters
  
• 211.42     Design and construction features (Subpart C - Buildings and Facilities) - cited in 4 Warning Letters
  
• 211.113   Control of microbiological contamination (Subpart F - Production and Process Controls) - cited in 4 Warning Letters
  
• 211.188   Batch production and control records (Subpart J - Records and Reports) - cited in 4 Warning Letters

First on this list is paragraph 211.22, which sets out the requirements for the quality assurance unit in terms of its responsibilities. The GMP violations described in the 23 Warning Letters can be grouped as follows:

QA review of batch documentation and batch release

• QA releases batches that have been tested using non-validated methods.
• QA releases batches prior to review of manufacturing documentation.

Responsibilities of the Quality Unit towards contract manufacturers and contract laboratories

• There are no quality agreements. 
•  There is no release procedure for starting materials or components for product manufacture at the contract manufacturer. 
• QA does not ensure that the test methods of the contract laboratory are validated.

QA's responsibility for procedural instructions, SOPs, GMP documents

• Procedural instructions for the following GMP-relevant processes are missing:
  - batch release
  - Quality-critical manufacturing processes, operation of production equipment
  - clarification of deviations in the laboratory (OOS results)
  - microbiological tests on the end product
  - Implementation of CAPAs
  - Dealing with complaints, returns and recalls
  - Evaluation of changes
  - Ongoing stability tests
  - Annual product review

QA responsibility for root cause analysis in case of deviations

• Root cause analysis does not take place; instead, unjustified and not scientifically sound corrective measures are taken (e.g. increasing the preservative content ensures that the previously too high microbial count in the product is again in compliance with specifications).

QA responsibility for trained personnel

• QA does not take care of the training of staff in quality-critical areas such as processing complaints from customers, returns processing, etc.

This compilation shows: Most violations of basic GMP rules are closely related to the quality unit's failure to take responsibility. Ultimately, the GMP deficiencies associated with the other paragraphs of 21 CRF 211 also result from this failure of quality assurance.

A more detailed analysis of the warning letters of fiscal year 2022 will appear in one of the next issues of the GMP Journal.