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The final area covered in Section 7 of the guideline addresses various further scenarios where modified limits may apply. Areas include:

1 Where substantive exposure to the impurity may occur either exogenously or endogenously. Perhaps the clearest example of this is formaldehyde.

2 Exceptions to the use of the appropriate AI can be justified in cases of severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives. In practice this is likely to be applicable where effective control has not been possible, in such instances levels will likely be controlled to as low as reasonably practical (ALARP) and justified following subsequent consultation with regulatory authorities.

3 Where the mutagenic impurity, based on its structure, is considered to likely be a potent carcinogen (cohort of concern), i.e. aflatoxin‐like‐, N‐nitroso‐, and alkyl‐azoxy structures, the guideline states that if these compounds are found as impurities in pharmaceuticals, AIs would likely be significantly lower than the AIs defined in this guideline. This area has of course been brought sharply into focus by issues surrounding N‐nitrosamines, this being examined from both a quality and safety perspective in Chapters 10 and 7, respectively.