The FDA Warning Letter Report 2021


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The quality control area is a particular focus of the inspectors during every FDA inspection. Here, violations of GMP regulations are found particularly frequently, as can be read in numerous warning letters.

This article describes the type and frequency of GMP deficiencies in the quality control laboratories of the inspected companies on the basis of a systematic review of the Warning Letters citations. The data scope of this analysis includes the published Warning Letters of the fiscal years 2017 to 2021 (Oct. 2016 to Sept. 2021), which were addressed to manufacturers of finished medicinal products and contract laboratories. The citations examined refer to the following sections of the Code of Federal Regulations (21 CFR):

Subpart I – Laboratory Controls
• 211.160 General requirements.
• 211.165 Testing and release for distribution.
• 211.166 Stability testing.

Subpart J – Records and Reports
• 211.194 Laboratory records.

The paragraphs 211.167 Special testing requirements, 211.170 Reserve samples, 211.173 Laboratory animals, 211.176 Penicillin contamination, which also belong to "Subpart I - Laboratory Controls", were not included in the analysis, as they are not or only occasionally cited in connection with GMP violations in the warning letters of the last 5 fiscal years.

The analysis of the frequency of GMP deficiencies assigned to the respective CFR paragraphs, considered over the period of 5 fiscal years, is shown in the chart in the next page.

According to this, the most frequent GMP deficiencies in the quality control area concern the tests prior to release of the product as well as stability tests; the latter were cited particularly frequently in the last fiscal year (2021).

The following describes the deviations from the requirements of the four CFR sections in the form of a summary of the GMP deficiencies as cited in the warning letters within the period under review.

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§211.160 General requirements. (Subpart I - Laboratory Controls)

Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

The deficiencies described in the warning letters with reference to paragraph 211.160 concern the following issues:

  • Unsuitable or non-validated test methods without scientifically supported significance are used, especially for microbiological controls.
  • Test specifications for incoming and final inspections are not available. Sampling plans are missing or unsuitable
  • Testing is done against unsuitable specifications.
  • Critical changes to electronic equipment in the QC laboratory are made in an uncontrolled manner. Uncontrolled manipulation of electronic data is possible.
  • Appropriate routine monitoring is lacking for the water system.

§211.165 Testing and release for distribution. (Subpart I- Laboratory Controls)

Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. o Finished products are released for sale without testing for compliance with specifications. This is the most common violation of GMP rules cited in the Warning Letters with reference to 211.165. In isolated cases, this deficiency also affects active substances that are released for further processing without appropriate compliance testing. o Non-validated test methods are used.

§211.166 Stability Testing. (Subpart I- Laboratory Controls) 

Your firm failed to establish and follow an adequate written testing  program designed to assess the stability characteristics  of drug products, and to use results of such stability testing  to determine appropriate storage conditions and expiration  dates. 

  • The test methods used in the studies do not demonstrate  stability.
  • The stability studies do not include current container  and closure systems.
  • Microbial stability or sterility of the products is not  tested.
  • Only short-term stability studies are carried out;  long-term studies to validate the declared shelf life  are missing.
  • There is no analytical recording or quantitative  measurement of impurities in the stability studies.
  • OOS results occur several times during the stability  study, but are not further investigated; nevertheless,  the study data serve to validate the shelf life. 
  • The analytical methods for the stability tests are not validated. 
  • There is no on-going stability testing programme.
  • Data from older studies are used to justify the shelf life; stability  studies involving the current supplier and the current production  site do not exist.
  • Stability studies are completely missing.

§211.194 Laboratory Records. (Subpart J - Records and Reports) 

Your firm failed to ensure that laboratory records included complete  data derived from all tests necessary to assure compliance with established  specifications and standards.

  • Documentation is incomplete, missing 
    - OOS results 
    - Root cause analysis of OOS results
    - Data from failed tests
    - Re-test data, data on which the information on the certificate  of analysis is based
    - Data on microbiological tests as well as relevant information  (e.g. incubation times, materials, etc.), data that  should actually be documented according to the audit trail
    - Batch numbers
    - Data on shelf life of standards 
  • Unofficial" records are used (uncontrolled Excel files or notes  accessible to everyone, which are later destroyed). 
  • Records are falsified, data is "invented"; audit trails are not secured  against manipulation. 
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The analysis of the warning letters shows that in many cases, the  basic requirements for GMP-compliant work in the quality control  laboratory as well as special requirements, e.g. for the performance  of stability studies, are violated; the frequency of the latter  has increased significantly in recent years. 

All in all, this kind of insight into the deficiency reports that repeatedly  appear in the warning letters and the scenarios described  there, some of them in detail, can be useful for preparing for an  upcoming FDA inspection. 


About the Author
Dr. Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and compliance topics.

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