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Previous guidelines, especially the EMA [2] guideline, have struggled to address the thorny question of the potential retrospective application of the guideline to existing products. This had led to variable interpretation, often resulting in requests for application to existing products triggered by apparent trivial changes (in the context of effect on levels of mutagenic impurities within the DS/DP) such as change in dose size or formulation volume. A lot of the uncertainty is related to the inclusion within the original EMA guideline of a catchall phrase of “cause for concern.” Attempts to resolve these uncertainties made via the EMA Q&A process [3] proved only partially successful.

In contrast ICH M7 is clear and concise. Existing products are only in scope where:

1 changes to the DS synthesis result in new impurities or increased acceptance criteria for existing impurities;

2 changes in the formulation, composition, or manufacturing process result in new degradants or increased acceptance criteria for existing degradants;

3 changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

It is hoped that this addresses much, if not all, of the uncertainty that has existed previously. One remaining area is how this applies to products marketed after the introduction of regional guidelines, particularly the EMA guideline, as this was formally issued and became effective in January 2007. Although not stated directly, many have assumed such products, marketed after the introduction of earlier regional guidelines, to be in scope.