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At the concept stage of the ICH M7 guideline, a series of critical areas were identified, these included:

1 Use of in silico SAR tools for the assessment of mutagenic potential.

2 What are acceptable levels of genotoxic impurities during drug development?

3 What are acceptable levels of genotoxic impurities for marketing?

4 Should those impurities be regulated differently that are likely to have threshold effects?

5 Should levels of genotoxic impurities be regulated using a TTC approach?

6 Structurally related genotoxic impurities are likely to have similar mechanisms of action. Should these be summed in calculating a TTC?

7 What process of qualification testing should be followed for impurities that are metabolites?

8 What additional data are needed to support having no special restrictions, or a higher ADI than the TTC, for a genotoxic impurity?

Does ICH M7 adequately address these points? Yes. Certainly most, if not all, of the ambiguity present in earlier guidelines is addressed. Some areas of ambiguity do remain though. Certainly, management of mutagenic metabolites remains an area of uncertainty and some new areas added within the guideline may also prove challenging to interpret; this includes periodic testing and some of the documentation requirements.