The FDA Warning Letter Report 2020
A look at the warning letters to pharmaceutical companies of the last 9 months of the current fiscal year (Oct. 2019 - June 2020) shows that the most frequent GMP violations found by FDA inspectors during their visits to production sites are essentially the same as those of the previous fiscal year 2019 (see Fig. 1). They refer to deviations from regulations formulated in the following paragraphs of 21 CFR 211:
Fig. 1: Comparison of the frequencies of the cited paragraphs of 21 CRF 211
§211.84 Testing and approval or rejection of components, drug product containers, and closures. (Subpart D- Equipment) cited in 24 Warning Letters
§211.100 Written procedures; deviations. (Subpart F-Production and Process Controls) cited in 24 Warning Letters
§211.22 Responsibilities of quality control unit. (Subpart B- Organization and Personnel) cited in 23 Warning Letters
§211.165 Testing and release for distribution (Subpart I-Laboratory Controls) cited in 23 Warning Letters
§211.192 Production record review. (Subpart J-Records and Reports) cited in 19 Warning Letters
§211.67 Equipment cleaning and maintenance. (Subpart D- Equipment) cited in 11 Warning Letters
§211.166 Stability testing. (Subpart I-Laboratory Controls) cited in 10 Warning Letters
In the following, these GMP violations of the first 9 months of the fiscal year 2020 will be viewed from a broader perspective that places more emphasis on the "lessons learnt" aspect. First, however, a look at the systematics of the GMP Warning Letters.
Recommendation
5/6 February 2025
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The structure of FDA-Warning Letters
Most GMP-Warning Letters are based on the following scheme:
1. Introduction:
- Indication of the production site inspected and the time of the inspection
- Indication of general violations of GMP requirements according to 21 CFR Parts 210 and 211.
- Confirmation with reference to the Food, Drug, and Cosmetic Act that the products manufactured at this site are not in compliance with GMP ("adulterated").
- Confirmation with brief justification that the company's response to the deficiency report (Form 483) sent out shortly after the inspection was reviewed and found to be inadequate.
2. Description of the observed GMP violations:
- General description of the deficiency, including the paragraph from 21 CFR 211 (usually highlighted in bold). "Your firm failed to..."
- Detailed description with details of the area, product batches, personnel present, documents and, in some cases, the course of a non-GMP-compliant procedure, etc.
3. Brief description of the company's response to Form 483 regarding the GMP violation in question - "Your response stated that...".
4. Justification by the FDA as to why the response is considered "inadequate" - "Your response is inadequate...".
5. Request for additional documents - "In response to this letter, provide ...".
The following extended analysis of the main "GMP sins" refers to the 3 most frequent violations related to the 21 CFR sections 211.84, 211.100, 211.22, 211.165 and 211.192. The following passages from the Warning Letters are considered:
- The general description of the GMP deficiencies (2.)
- The additional demand for documents (5.)
The text passages describing the FDA's document requirements represent an extract from all Warning Letters of the period under consideration (Oct. 2019 - June 2020). They represent the essence of what formulations are used in the individual Warning Letters, each with a different weighting.
§211.84 Testing and approval or rejection of components, drug product containers, and closures. (Subpart D-Equipment)
General description of GMP deficiencies:
"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality."
"Your firm failed to conduct at least one test to verify the identity of each component of a drug product."
"Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals."
FDA request for documents ("In response to this letter, provide ..." ):
- A compilation of chemical and microbiological specifications for incoming inspection and release by Quality Control of all components required for the manufacture of the drug product.
- A description of how the components are tested for compliance with the specifications.
- Information to establish a robust reliability check of the information on the supplier's Certificates of Analysis. The FDA also requires information on the initial validation and periodic re-validation of this information.
- A declaration of commitment to perform at least one identity check for each component batch as an incoming inspection.
- A summary of the results of the incoming inspections of all components performed as part of the reliability check of the supplier certificates.
- An SOP on the Supplier Certificate Validation Program.
- A summary of the procedures for qualification and supervision of external laboratories that perform tests on finished medicinal products.
- A report on the comprehensive review of the entire material system. This report should include information on the qualification of all component, packaging and closure system suppliers and on expiration dates or re-testing periods. The FDA also wants to see a credible justification that quality control is able to prevent the use of unsuitable materials.
§211.100 Written procedures; deviations. (Subpart F-Production and Process Controls)
General description of GMP deficiencies:
"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess."
FDA request for documents ("In response to this letter, provide ..."):
- A summary of the Process Validation Program. The program should include information on process performance qualification and continuous monitoring of intra-batch and inter-batch variations that demonstrate that the manufacturing process is under control throughout the life cycle of the product.
- Deadlines for process performance qualification for each drug on the market.
- Process Performance Qualification Protocols
- SOPs for the qualification of production buildings, rooms and equipment.
§211.22 Responsibilities of quality control unit. (Subpart B- Organization and Personnel)
General description of GMP deficiencies:
"Failure to establish an adequate quality unit with adequate facilities and procedures to ensure that drugs are manufactured in compliance with CGMP regulations and meet established specifications for identity, strength, quality, and purity."
FDA request for documents ("In response to this letter, provide ..."):
- A comprehensive assessment and remediation plan to ensure that the quality unit has the authority and resources necessary to effectively perform its duties. This plan should outline
- Whether all procedures are robust and appropriate,
- according to which requirements the quality unit monitors all procedures in connection with the production processes,
- that the quality unit carries out a final review for each batch with the associated data before its release decision,
- that the supervision by the quality unit, the examination and approval of cause investigations in case of deviations and the transfer of duties of the quality unit to third parties serve to ensure the product quality.
If there are GMP deficiencies for certain areas or facilities, such as the documentation system or water supply, the FDA requires the relevant documents (SOPs, protocols, etc.).
§211.165 Testing and release for distribution. (Subpart I-Laboratory Controls) General
General description of GMP deficiencies:
"Your firm failed to 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".
"Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms and your firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods."
FDA request for documents ("In response to this letter, provide ..."):
- A review of all routine work in the laboratory including all analytical procedures, technical equipment and the competence of the laboratory staff. As part of this review, a CAPA plan for the rehabilitation of the laboratory system and a procedure to ensure the effectiveness of the CAPA plan must be submitted.
- A list of all analytical methods, specifications and standard operating procedures used for final product testing before market release.
- A summary of test results from retrospective testing of retained samples of all product batches shipped to the United States. Test results should include information on identity, active ingredient content, and other appropriate chemical and microbiological quality characteristics.
- Information on corrective actions taken on OOS results (notification to customers, recalls)
- If the final product testing is outsourced to third parties: Summary of the procedure for qualification and evaluation of the performance of external testing laboratories. It must be demonstrated that the methods used in the testing laboratory have been validated beforehand.
§211.192 Production record review. (Subpart J-Records and Reports)
General description of GMP deficiencies:
"Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed."
Recommendation
10-12 February 2025
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FDA request for documents ("In response to this letter, provide ..."):
- A comprehensive evaluation of the procedure to be followed in case of deviations. This includes OOS results in quality control, deviations from quality parameters in production, supply systems (e.g. water) and complaints about quality defects in the finished drug.
- CAPA plans to improve deviation management in the areas concerned; to this end, the relevant documents, e.g. validation plans and protocols of the water system, of production processes or SOPs for handling OOS results must be attached
- A standard operating procedure to verify the effectiveness of CAPA measures.
The useful "lessons learnt" from the analysis of the Warning Letters consist on the one hand in the observation of the most frequently cited GMP violations; on the other hand, the analysis of what the FDA requires of the inspected companies in terms of evidence and documents relating to GMP deficiencies provides valuable information for the review of quality systems and operational procedures in GMP-relevant areas. Knowing which documentation the FDA is particularly interested in can be very useful in preparing for an inspection.
Note: In the ECA Members Area, you will soon find the complete analysis of the "Top Ten Failures" of the Warning Letters of the fiscal year 2020 according to the systematics presented in this article. This will provide you with a comprehensive compilation of the documents that should not be missing from any FDA inspection.
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.
