Out-of-Specification Results and Failure Investigations in current FDA Warning Letters

Even though the Final FDA Guidance for Industry for Out-of-Specification Results was published quite some time ago, in recent times there have increasingly been FDA warning letters dealing with this theme - improper dealing with OOS results and inadequate investigation of failures.

This is supported by examples of warning letters from 2008 and 2009, extracts of which can be read below.

In March 2008, the FDA wrote in a warning letter:

Investigations into out-of specification (OOS) results for Content Uniformity testing concluded that laboratory error had occurred and required test method changes and validation. However, drug products tested using the same method that caused the OOS results have not been evaluated to determine the lot quality using the newly-modified, valid method.

There is no assurance that any of the test results are accurate and reliable. Conclusions of error investigations are not specific enough to implement adequate corrections.... In addition, they are not always substantiated by sound scientific evidence.... Again, no rationale was provided to support the conclusions.

The test solution that generated the OOS result was discarded without explanation.

The Quality Control Unit allowed the reporting of only the passing results in the final certificate of analysis, thus disregarding the original failing results that could not be invalidated by the investigation. But the procedure stipulates that if the investigation is inconclusive, the original results and the retested results must be individually reported.

In another warning letter written in January 2009, the FDA stated:

Investigations into the failures of batches to meet specifications in response to out-of-specification (OOS) results were incomplete or not documented. In response to OOS results, the batches were remixed and then resampled to obtain passing results without performing adequate investigations into the root cause of your manufacturing problems. Further it was failed to expand investigations to determine if other batches were possibly affected. The OOS review stated only: "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained. The OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.

In the end the FDA underlined that it is the responsibility of the firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of such manufacturing problems.

And in a warning letter from February 2009, the following reference was found after a CBER (Center for Biologics Evaluation and Research) inspection:

Your SOP entitled "Procedure for the handling of Out of Specification Results (OOS) " is inadequate, in that it allows for repeat testing of OOS results before notifying Quality Assurance (QA) of nonconformities. Quality Assurance was not notified when a lot failed to meet the licensed final release specifications. These lots were retested without QA investigation and approval. The results of the retesting met the specification, and the lots were released for distribution.

Furthermore a current case from February 2009 concerns the manufacturer of topical application forms. The stability investigations into different lots of different products (ointments and creams) already on the market showed OOS results:


The frequency of discrepancies in stability investigations is significant. There is no evidence that the drug products meet the standard of strength, quality and purity at the time of their use within the expiration period. The necessary field alert reports for stability failures of distributed products were not always reported to the FDA within three working days. When a marketing authorisation holder becomes aware of any such information he is required to report it to the FDA within three working days.

A detailed analysis of all Warning Letters was published just recently. To find more details about the results, please see here. You can order the complete report as "FDA Navigator with Warning Letters Report" here.