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
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
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
- "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.
- "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.