Run a dual-methodology hazard assessment — expert-rule alerts plus a statistical QSAR model — with dynamic nitrosamine CPCA scoring and acceptable-intake limits.
ICH M7 controls DNA-reactive (mutagenic) impurities that could be carcinogenic at very low levels. Because these act without a threshold, the guideline uses a Threshold of Toxicological Concern (TTC) rather than a percentage limit.
For a single mutagenic impurity, the default lifetime acceptable intake is 1.5 µg/day. That intake is turned into a product concentration with the daily dose:
Concentration limit (ppm) = Acceptable intake (µg/day) / maximum daily dose (g/day)Shorter (less-than-lifetime) exposures allow proportionally higher intakes under the M7 LTL framework.
M7 asks for a hazard assessment using two independent methodologies: an expert rule-based analysis and a statistical (Q)SAR model. If both find no structural alert, the impurity is treated as non-mutagenic (Class 5). Conflicts are resolved by expert review.
For N-nitrosamines, the FDA/ICH Carcinogenic Potency Categorisation Approach (CPCA) assigns an acceptable intake (commonly 18, 100, 400 or 1500 ng/day) from structural features — chiefly the number of α-hydrogens next to the N-nitroso group and potency-modifying substituents. More α-hydrogens generally means higher potency and a lower limit.
A drug with a maximum daily dose of 500 mg/day contains one mutagenic impurity at the default TTC:
Reference: ICH M7(R2); FDA guidance on N-nitrosamine impurities (CPCA).
A small group of exceptionally potent carcinogens — aflatoxin-like, N-nitroso, and alkyl-azoxy compounds — that are not covered by the generic 1.5 µg/day TTC and require compound-specific limits (for nitrosamines, via CPCA or substance-specific data).
The two methodologies have complementary strengths and error modes; agreement between a knowledge-based expert system and a statistical model gives a more robust mutagenicity call than either alone.
It scores structural features that modulate carcinogenic potency (notably the count of α-hydrogens and deactivating groups) and maps the result to a categorical acceptable intake in ng/day.