According to the Code of Federal Regulations (21 CFR 211.192 Production Record Review), the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated. A written record of the investigation shall be made and shall include the conclusions and follow-up.
A company recently received the following observation:
….. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.
Specifically, investigation reports into out-of-specification (OOS) results lack sufficient detail in describing and recording OOS results, confirmation testing, hypothesis testing, root cause determinations, and/or follow-up. For example, Investigation … for … lot ….. was missing standard and sample preparatory documentation and the original OOS result generated for … via … analysis (overwritten). Root cause determination and corrective/ preventative actions were also not included.
According to GMP Trends® Annual Reports, over the last 5 years the observations pertaining to laboratory investigations, including OOS investigations (21 CFR 211.192) have been in the top 10 observations cited by the FDA each year.
When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigations using a predefined procedure should be conducted. This investigation may consist of a production process review and/or additional laboratory work. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action. A full-scale investigation should include a review of production and sampling procedures, and will often include additional laboratory testing. Such investigations should be given the highest priority. Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches.
For more information on conducting an Out of Specification (OOS) investigation, refer to the FDA Guidance Document, Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production Issued October 2006.
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