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Key within this section, (Section 3 of the guideline), is the reaffirmation of the specific focus of the guideline on mutagenic impurities. Indeed, the guideline goes further in making the specific statement that:

Other types of genotoxicants that are non‐mutagenic typically have thresholded mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities.

It also makes clear that in assessing mutagenic potential that this can be achieved through a combination of in silico SAR evaluation, and where required, with a bacterial reverse mutation assay (Ames test [10]). This is certainly useful in clarifying that in silico SAR assessments should focus specifically on mutagenicity. Other SAR models for other toxicological end points such as chromosomal activity and carcinogenicity exist within many of the in silico systems utilized; however, these do not need to be specifically applied in the evaluation of impurities; the primary focus is mutagenicity. It can be further concluded that in terms of in vitro/in vivo assays that no other test other than a reverse mutation assay is required, precluding in particular a mammalian cell assay defined as part of impurity qualification within ICH Q3A [6].

What is less clear is if there is evidence that an impurity is clastogenic/aneugenic, whether or not this can be ignored, or if limits should be based on an evaluation of the available data – i.e. a limit calculated based on an observed no observable effect level (NOEL) using the permitted daily exposure (PDE) calculation shown in ICH Q3C [11]. In practice it seems logical to use such safety data to set acceptable limits even though such impurities are effectively outside of the scope and would be defined as Class 5 (see Table 2.2).

Also reaffirmed within this section is the fact that the guideline remains, as per earlier regional EMA and FDA guidelines, based on the TTC principle [12–16], and a limit of 1.5 μg/day based on a 1 in 100 000 risk following lifetime exposure (70 years). While clear flaws within the TTC have been identified by Snodin [17] and Delaney [18], what is singularly lacking is any scientifically justified alternative. The TTC is without doubt an overtly conservative interpretation of the risk; one that employs multiple worst‐case scenarios, but to date an alternative to it remains elusive. This innate conservatism is even recognized within the guideline itself:

The use of a numerical cancer risk value (1 in 100,000) and its translation into risk‐based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic indication of the actual risk. Nevertheless, the TTC concept provides an estimate of safe exposures for any mutagenic compound. However, exceeding the TTC is not necessarily associated with an increased cancer risk given the conservative assumptions employed in the derivation of the TTC value. The most likely increase in cancer incidence is actually much less than 1 in 100,000.

Finally, within this section a passing reference is made to metabolites. The guideline simply states that where an impurity is also a metabolite its mutagenic potential should be addressed through evaluation of the metabolite. Again this was a specific area highlighted within the concept paper; however, it is difficult to see how this has been meaningfully addressed and sits as perhaps the one remaining area of uncertainty following publication of ICH M7. The issue is thoroughly examined in detail by Dobo et al. [19].