Despite the Barr verdict from 1993 – in which the US Food & Drug Administration concentrated on OOS results – the appropriate handling of deviant analysis results is still an important issue in FDA inspections. A 483 form from an inspection in spring 2006 shows many findings with regard to OOS.

Following are some examples from the inspection report:

• Your firm failed to perform adequate investigations with scientifically justifiable conclusions to incidents of out-of-specification results or production deviations and/or failed to implement appropriate corrective actions for the root cause determination.

• The Quality Control Unit failed to ensure that Phase I Laboratory Investigations were adequately investigated, documented, and trended after they were removed from the … system in September 2005 and transferred to a manual logbook.

• The investigation report TWR #1540 for finished product testing of Metformin HCl Extended-release (XT) Tablets, 1000 mg Lot No. F575F0620 Sublot C was specifically for related compounds testing. The unknown related compound in this sample was OOS. With-in specification results were obtained upon retest of the sample and the firm concluded that the OOS result was due to contaminated glassware. … This statement indicates that there is no definitive assignable cause for the OOS result since they state that the contamination could have come from glassware or sample handling. The investigation does not explain how glassware contamination or sample handling may have increased the unknown related compound for this sample. If in fact the contamination was due to sample handling then the proposed corrective action of additional glassware cleaning would not be appropriate. In this case, the investigation indicated that the current glassware cleaning procedure may not be adequate for this particular product but does not explain why. The corrective action does not address training for all analysts on the required glassware procedure nor does it state if this will be incorporated into the analytical procedure for this product. Furthermore, the investigation was inconclusive and the results were invalidated without extending the investigation into the manufacturing area.

• There is no scientific justification for invalidating the OOS results. … the laboratory practices shown in this investigation were inadequate.

These examples show that FDA investigators set a great value on the effort to find out what caused the OOS result. The determination of the real cause for an OOS result is also a central request in the FDA Guidance for Industry “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production” from October 2006. It is pointed out there that “The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action.”

The examples from the 483 form further show that many companies not only find it difficult to identify the cause for an OOS result, but also to take appropriate corrective and preventive actions. As the quote shows, though, the guideline does request exactly these actions.