The document – the current version of which was updated last Friday – is designed to support the advice set out in USP Chapters 85 and 161 and AAMI ST72:2002/R2010 and provide guidance for the submission of such information.
Topics covered in the Q&A include the development of sampling plans, retesting requirements, guidance on storage, suggested alternative assays and a description of how manufacturers can pool product samples for analysis.
The FDA also reiterated why it withdrew its old guidelines on endotoxin testing in July last year, explaining that it was out of date due to the increase in numbers of dosage regimes and drug strengths since the publication of the 1987 Guidance.
“The appropriate way to establish the endotoxins limit is to use the calculation methods provided in the USP or AAMI standards. Monograph limits may also not account for current product strengths or dosage regimes; these should also be checked using the calculations recommended in the standards.”
Endotoxin: A toxin that forms an integral part of the cell wall of certain bacteria and is only released upon destruction of the bacterial cell.
Exogenous pyrogen: A fever-producing agent of external origin, includes bacterial endotoxins and other microbial products, antigen-antibody complexes, viruses and synthetic polynucleotides, incompatible blood and blood products, and androgen breakdown products.
QbD and ‘limits’
Another core part of the Q&A is the discussion of how endotoxin and pyrogen testing should be conducted in accordance with quality by design (QBD) concepts.
The agency advises that testing should be based on detailed knowledge of the product in question and the production processes and focus on areas at risk of endotoxins formation or incursion, which it believes is already an approach taken by manufacturers.
“Many firms already have programs for monitoring incoming ingredients and components, including the processing water, for endotoxins contamination. The finished product release specification should be considered when determining in-process limits for each phase of manufacturing tested.”
However, rather than setting limits for endotoxins and pyrogens, the FDA would prefer that manufacturers adopt a quantitative approach to testing.
“For purposes of evaluating the relative risk of product contamination, quantitative testing may be preferable to limit testing to facilitate product quality trending and to identify and correct excursions before they exceed the specification and cause product failure. An endotoxins limit should be justified on a case-by-case basis, and will be evaluated as a part of each relevant marketing application or supplement.”