March Frederick W. Blumenschein from the US Food & Drug Administration (FDA)
CDER Office of Compliance and member of the team that finalised the OOS
guidance, presented the final FDA Guidance for Industry on "Investigating
Out-of-Specification (OOS) Test Results for Pharmaceutical Production" from
October 2006 in a video presentation during a conference on
"Out-of-Specification Results" organised by the European Compliance Academy
In a subsequent Question and Answer Session he also
responded to questions from participants together with two colleagues: Paul
Haynie, Compliance Officer at the Division of Manufacturing & Product
Quality and principal author of the finalised OOS guidance document and John
Dietrick, team leader of the Foreign Inspection Team in the Division of
Manufacturing and Product Quality and also member of the team that finalised
the OOS Guidance. He was also the FDA Compliance Officer assigned to the
Barr Laboratories case.
Following are some of the questions and answers:
In the guidance it is mentioned that the manufacturing review should be done
prior to retesting. Can it be considered appropriate to go into retesting
first and then begin the manufacturing review?
It may be appropriate in some situations, but normally you should do the
manufacturing review first. Retesting, if done first, should not preclude a
manufacturing review or automatically eliminate the need for one.
There is a new General Chapter <1010> in the USP. Will the statistical
recommendations in <1010> be acceptable for the agency if they were part of
an internal procedure?
It would be OK for a firm to incorporate the procedures of <1010> except in
the cases where they are in conflict with the recommendations of our (FDA)
guidances. For instance, FDA guidance recommends that outlier testing has a
very limited role for chemical analysis, while USP <1010> gives quite an
extensive discussion of the use of outlier tests.
The principle in our guidance remains the same: a result that is identified
as a statistical outlier should not in itself lead to excluding it or
invalidating the result. It can be used as supporting evidence, along with
other evidence developed in the investigation, that the result is invalid.
What's the agency's position regarding the methodologies of <1010>?
FDA guidance makes no recommendations about the choice of statistical
outlier tests to be used. It only says that the use of outlier tests should
be specified in an SOP and should be scientifically sound.
European Compliance Academy (ECA) Conference: "Out of Specification Results"