GMP Hot Spots as seen in the Warning Letters
At the end of each GMP compliant production process and prior to the release for distribution the batch has to be tested for compliance with the specifications laid down. For the US-American economic area the requirements for release testing of batches of the finished product as described in the Code of Federal Regulations, 21 CFR 211.165 Testing and release for distribution, are mandatory. The six sections of this paragraph contain the following provisions:
(a) Prior to release each batch of the finished product shall be tested for compliance with the specifications. This includes testing of identity and strength of the active ingredient. Where sterility and/or pyrogen testing are conducted on shortlived radiopharmaceuticals, such radiopharmaceuticals may be released prior to the test results being available provided such testing is carried out as soon as possible.
(b) There shall be appropriate laboratory testing of each batch of drug product required to be free of objectionable microorganisms.
(c) Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested. Such written procedure shall be followed.
(d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria. This is the condition for their release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels.
(e) The accuracy, sensitivity, specificity, and reproducibility of test methods employed shall be established and documented. Such validation and documentation may be accomplished in accordance with § 211.194(a)(2) .
(f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate quality standards, specifications, and any other relevant criteria.
This is the basis on which the FDA evaluates whether the quality control in companies producing drug products is compliant with GMP.
The Guides to Inspections contain guidelines for the FDA inspectors for their work on site:
FDA Guide to Inspections of Pharmaceutical Quality Control Laboratories (July 1993)
FDA Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories (July 1993)
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In spite of the fact that it is a basic GMP requirement to release a batch only after final testing has been carried out, and although this is described clearly and explicitly in the pharmaceutical guidelines, FDA inspectors repeatedly encounter in some cases serious GMP violations in the area of quality control of finished products when they carry out inspections on site.
The following chart shows the percentage of Warning Letters addressed to manufacturers of drug products because of deficiencies concerning the requirements of 211.165 over a period of five years.
The percentage of Warning Letters citing 211.165 has settled at a little over 40% in the last two fiscal years. In absolute numbers this means 30 Warning Letters in the FY 2023 and 18 in the FY 2022.
Categorisation of GMP Deficiencies Associated with the Release Testing of the Finished Product
The deficiencies described in the Warning Letters can be divided into the following categories:
No Microbiological Testing
One of the GMP deficiencies cited most often in the Waning Letters is the lack of testing of the finished product for objectionable microorganisms according to 211.165(b). FDA inspectors have observed this especially at producers of hand sanitizers.
Incomplete Release Testing
This deficiency is described nearly as often. Contrary to the requirements of 211.165(a) according to which release testing shall include testing for compliance with the specifications of the finished product including identity and strength of the active ingredient, manufacturers have released their drug products on the basis of incomplete testing (such as odour, appearance or other physical parameters). In single cases the product was even released prior to the receipt of the test results.
The lack of testing of the batches of the finished product for impurities is also described several times in the Warning Letters.
No Acceptance of Responsibility for the Release Testing
Several contract companies finishing the product for instance by only filling it up have transferred the responsibility for release testing to the customer. But according to the FDA the production site carrying out the last manufacturing step immediately prior to the release of the drug product is obliged to carry out the batch release. FDA considers the transferral of responsibility to be a GMP violation.
Figure 1: Percentage of Warning Letters with notifications of deficiencies associated with the testing of the finished product according to 21 CFR 211.165 for the fiscal years 2019 - 2023
No Rejection of the Batch in Case of a Failed Release Testing
In several cases the quality control unit did not reject a batch or place a hold on it after the final testing failed.
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Use of Non-validated Methods for the Release Testing
According to 211.165(e) only validated methods may be used for release testing. In some cases, FDA inspectors discovered that the quality control units released batches of the finished product after testing with non-validated methods.
Follow-up Requests from the FDA
Usually Warning Letters contain a follow-up request for documents/evidence in respect to each GMP deficiency associated with one of the paragraphs of CFR 211. In the case of 211.165 the FDA demands the following:
- A list of chemical and microbial specifications of the finished product, including the relevant test methods.
- An action plan and timelines for conducting full chemical and microbiological testing of retain samples of all batches distributed to the United States that are within expiry as of the date of the Warning Letter.
- A summary of the results obtained from testing retain samples.
- A comprehensive independent assessment of the methods, procedures, equipment, documentation of the quality control unit, and analyst competencies. Based on this review, provision of a detailed plan to remediate the deficiencies and evaluation of the effectiveness of the laboratory system.
If these proofs can be provided in the course of an FDA inspection the topic „release testing“ shouldn‘t pose a problem.
| Note: You can find the complete analyses of the Warning Letters of the fiscal years 2022 and 2023 as well as further documents relevant in this context in the members’ area of the ECA website. |
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.
