Eight years after the Draft OOS Guideline, the long-awaited FDA Guidance for Industry "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production" was published on 12 October 2006.

Compared to the draft version, now the steps of an OOS investigation are described more clearly. Phase I deals with the laboratory investigation. In this context, the guidance still distinguishes between the responsibility of the analyst and the responsibility of the laboratory supervisor.

When clear evidence of laboratory error exists, laboratory testing should be invalidated and the retest result would substitute for the original result. All original data should be retained, however, and an explanation recorded.

In case the investigation does not reveal a laboratory error, a full-scale OOS investigation has to be carried out.

Here, the guidance makes among others the following statements on retests:

1. "It is often important for the predefined retesting plan to include retests performed by an analyst other that the one who performed the original test. A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst."

Obviously, the FDA has taken into account industry comments saying that retests cannot always be performed by a second analyst, even if the second analyst is still considered very important.

2. "The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound principles. The number of retests should not be adjusted depending on the results obtained."

It is to be welcomed that the document does not require a fixed number of retests. However, an example given at the end of the guidance shows how, in the case of an inexplicable OOS result, seven retests help to prove that the first result did not reflect the true quality of the batch. This passage clearly refers back to the footnote of the Barr case of 1993!

Further important issues of the guidance are "averaging" and "outlier tests". Unfortunately, the final FDA guidance does not include a glossary of terms, nor does it illustrate the OOS investigation procedure by means of a flowchart.
  

Author:
Dr Günter Brendelberger
On behalf of ECA