Incorrect Handling of OOS Results found in 10 FDA Warning Letters in 2011

A review of the 2011 FDA Warning Letters shows that the incorrect handling of OOS results is still a hot topic in FDA inspections and inspection follow up activities (483s, etc.). In total 10 companies (6 drug product manufacturers and 4 API manufacturers) received a FDA Warning Letter relating to OOS investigations in the calendar year 2011. Here are some examples of these citations:

  • Failure to investigate and document out-of-specification results obtained for … .
  • Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, and you failed to extend the investigation to other batches of the same drug product that may have been associated with the specific failure or discrepancy.
  • Your firm's out-of-specification (OOS) investigations did not include analysis of all available data.
  • Inadequate or lack of an investigation of critical deviations or a failure of a batch to meet its specifications or quality standards.
  • Your firm has failed to conduct an investigation for numerous OOS results (e.g., for colony forming units, conductivity, assay, etc.). Many of these OOS results were not reported to your client.
  • Your QCU approved and released a batch of … despite an initial OOS bulk assay result.  These results were later confirmed through repeat testing, but further testing of additional samples produced passing results.  Your QCU released the batch even though the investigation did not identify a discernable cause.
  • Your QCU failed to detect multiple discrepancies in sample weights and dilution factors between the analyst's notebook and the Calculation Sheet. As a result, incorrect data was recorded for multiple products and finished products not meeting specifications were released. Specifically, a lot of … was released and distributed even though it did not meet the established specification of … % label claim. The correct calculation would have reported a … % label claim.
  • Your QCU did not require a second, independent person to review the raw data, calculations and records before releasing these lots for distribution.
  • The inspection also found that your analyst did not record these out-of specification results in the OOS logbook as required by your SOP.
  • Your investigation failed to follow your procedures when your firm … initiated Phase 2 sample testing prior to completing Phase 1 of the investigation, and … only analyzed two samples as opposed to the required three samples

According to these citations, giving adequate attention to out-of-specification (OOS) results in batch release decision remained the dominant theme in 2011 in the FDA Warning Letters.

In order to assist the pharmaceutical industry in a FDA/GMP-compliant handling of OOS Results, the ECA Quality Control Working Group has established a general SOP for the handling of OOS results.

More than 100 members participated in a review team specifically formed for that purpose and gave their comments and feedback during the development process of this SOP. Version 01 of this OOS SOP has been finalised in the meantime and will be presented at ECA's OOS Forum, from 19-20 June 2012 in Prague, Czech Republic. Some of the review team members will also show different views or alternative approaches for handling OOS results at the OOS Forum.

Dr Günter Brendelberger

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