Testing into Compliance - FDA Warning Letter due to non-compliant GMP Invalidation of OOS results and Falsification of Data

The handling of out-of-specification analytical results should follow strict rules in the GMP-required quality control laboratory. FDA inspectors are sensitive when they find that a laboratory deviates in its approach from the procedure that corresponds to the FDA's common GMP understanding of OOS results and retesting, as described in the guidance "Investigaton Out-of-Specification (OOS) Test Results for Pharmaceutical Production."
This was precisely the experience Missouri Analytical Laboratories had when it received a Warning Letter for not invalidating OOS results in accordance with GMP after multiple testing. In addition, the FDA inspectors also found massive violations of the data integrity requirement and circumstantial evidence of intentional falsification or "disposal" of disagreeable data at this contract laboratory.

Citing Section 211.192 of the Code of Federal Regulations (CFR), the Warning Letter describes GMP violations that can be summarized as follows:

• A content determination and a retest were performed - the results were out of specification both times.
• Another content determination was performed, this time with reprocessed samples. The results were then within specification.
• The prior OOS results were invalidated; no investigation was made to determine the root cause of the OOS results.

This was apparently standard practice in this company's laboratory, as the Warning Letter describes this procedure for both finished product content determination and testing of the API. In any case, the invalidation of analytical results that do not comply with the specification without a well-founded scientific justification is completely unacceptable for FDA inspectors.

Section 211.68 of the CFR regulates the handling of electronic data in the GMP area and specifies the measures that must be taken to preserve the integrity of such data. Inspectors found the following violations of these regulations at Missouri Analytical Laboratories:

• Measurement system and analytical equipment accounts were not clearly assigned to specific authorised individuals. Several individuals were able to access raw data.
• One of the inspectors found that 36 electronic data had been deleted. He found additional print-outs with GMP-sensitive data in the trash.
• Some laboratory employees used non-validated Excel spreadsheets to calculate the content of API, impurities and other quality parameters relevant for release.

The standards that were violated here form the tough core of the GMP regulations that an analytical laboratory subject to GMP must comply with by all means. Accordingly, the FDA's requests for additional documents, which it usually requires within 15 days, are quite extensive.