In August 2005, the FDA published the draft for a
new guideline with the title
ANDAs: Impurities in Drug Products.
This guideline provides advice on the question which CMC (Chemistry,
Manufacturing and Control) information on the detection,
identification and qualification of impurities classified as degradation
products should be listed in an application for a marketing
authorisation. This refers both to ANDA (Abbreviated
New Drug Applications) applications for generics and
to changes in ANDA applications. This guideline will replace the
existing draft guidance of the same title dating back to 1998.
The revision of the draft guidance became necessary
in order to adapt it to the ICH Guideline Q3B(R) - Impurities in New
Drug Products revised in November 2003.
Even though the ICH Guideline Q3B(R) refers
primarily to impurities in new drug products (NDA applications), the FDA
assumes that many of the requirements laid down in this document should
also be applied to ANDAs.
Topics dealt with by the FDA Draft Guidance include:
- List of degradation products
- Acceptance criteria for degradation products
- Qualification of degradation products
A decision tree in the attachment to the draft
guidance describes considerations for the qualification of degradation
products in case the standard qualification thresholds mentioned in ICH
Q3B(R) are exceeded.
The document recommends three methods for the
qualification of degradation products:
- Comparison of the generic drug product's
analytical profiles with those of an approved human drug product using
the same validated stability-indicating analytical method.
- Scientific literature and significant
metabolites.
The degradation product does not need to be qualified if
its level is adequately justified by scientific literature. Furthermore,
a degradation product that represents a significant metabolite of the
drug product is generally considered qualified.
- Conduct of toxicity studies.
The text emphasises that this method should only be chosen if
qualification cannot be carried out by means of the procedures mentioned
above.
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