Читать книгу Mutagenic Impurities - Группа авторов - Страница 25

Given the complex multistep nature of the synthesis of many synthetic Active Pharmaceutical Ingredient (APIs), it is possible for a product to contain more than one potentially MI. Indeed, a study published in 2016 [11] showed that multiple reagents of mutagenic potential are used in a “typical” synthesis. The EMA guidance [9] was not clear on what control expectations would exist when more than one potential MI was likely to be present in the active substance on product. Would each be simply controlled on the basis of individual TTC limits?²

This would seem reasonable given the conservative nature of the derivation of the general 1.5 μg/day TTC limit. Or would there be an expectation that the total genotoxic impurity load would be controlled to a total level of 1.5 μg/day or other limit? There might be some scientific basis for implementing such a cumulative control if the impurities were known to be (or likely to be) toxicologically similar, but far less need to do so if the impurities were known to be (or likely to be) toxicologically distinct. These are all interesting and potentially important considerations, but the published guideline provided no detailed guidance on these questions. In terms of the toxicological risk, Bercu et al. reviewed the supporting evidence and demonstrated that with the addition of one to two MIs, a slight but insignificant increase in cancer risk was observed. There was not an increase in cancer risk when comparing structurally related impurities with structurally unrelated impurities. They therefore concluded that there was little evidence to support a view that effect was cumulative at low levels, <5 μg/day [12].