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One of the questions posed within the original ICH M7 concept paper relates to potential synergistic effect of multiple mutagenic impurities, especially where they are closely related. Based on the work of Bercu [29], the guideline concludes that such effects are unlikely at the low levels potentially present and hence permits the presence of up to three mutagenic impurities, to give a total AI as defined in Table 2.5.

Table 2.5 Acceptable total daily intakes for multiple impurities.

Source: Reproduced from ICH M7.

Duration of treatment	≤1 month	>1–12 months	>1–10 years	>10 years to lifetime
Total daily intake (μg/day)	120	60	30	5

It is important to note that this total only applies to specified Class 2 and Class 3 impurities. In reality most synthetic routes will utilize multiple mutagenic reagents/intermediates; however, due to the innate reactivity of the reagents in question and the downstream process conditions, few actually pose a substantive risk in terms of potential carryover. This is discussed in detail in the control section.