Inadequate OOS Investigations lead to FDA Warning Letter

Recently the U.S. Food and Drug Administration (FDA) issued a warning letter dated January 7, 2022, due to inadequate investigations into out-of-specification (OOS) test results.

In May and June 2021, the FDA inspected the drug manufacturing facility Professional Disposables International, Inc, located in Orangeburg, New York. During that inspection, the FDA investigators observed specific GMP violations.

Legal background

According to the Code of Federal Regulations, Sec. 211.192 (Production record review), the following applies:

"All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup."

Investigations into Out-of-Specification (OOS) Test Results

The FDA considers the firm's OOS investigations as inadequate for the following reasons:

  • the investigations were not performed in a timely manner
  • root causes were not appropriately identified
  • the investigations were not expanded to all potentially affected batches
  • corrective action and preventive action (CAPA) was not implemented
  • the CAPA effectiveness was not evaluated.

In the warning letter, different examples are mentioned. According to the FDA, in all of these examples, the quality unit (QU) "concluded, without adequate scientific justification, that analytical error was the most probable root cause for the original OOS results." The company also failed to initiate a "production review or CAPA at the conclusion of the investigations, including a comprehensive evaluation of the product development, manufacturing validation, previous failing results obtained, and analytical test method."

In response to the warning letter, the FDA now expects the following:

  • a comprehensive, independent assessment of the overall system for investigating deviations, discrepancies, complaints, OOS results, and failures
  • a revised OOS procedure
  • a retrospective, independent review of all invalidated OOS
  • a summary of results from testing retain samples of all drug product batches within expiry

Please see the FDA Warning Letter to Professional Disposables International, Inc. for more information.

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