Non-mutagenic, carcinogenic impurities

Non-mutagenic, carcinogenic impurities are negative in the bacterial reverse mutation assay and do not have a DNA reactive mechanism of carcinogenicity and are therefore not in the scope of ICH M7. Can non-mutagenic, carcinogenic impurities be controlled as per ICH Q3A?

In theory, yes, but ICH Q3A/B guidelines clearly state that if you have concerns over the safety of the threshold at ICHQ3A/B limits, specific thresholds should be derived

The exact wording of the ICH M7 guideline is the following:

Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. Therefore to limit a possible human cancer risk associated with the exposure to potentially mutagenic impurities, the
bacterial mutagenicity assay is used to assess the mutagenic potential and the need for controls.

In my opinion this means that non-mutagenic, carcinogenic impurities may be controlled according to ICH qualification thresholds only if their toxicology is well know and this will be accepted by the authorities. I do not think that you could omit to the authorities a carcinogen impurity (even if it is not mutagenic).

In any case this is totally excluded by EMA for any nitrosamine:

A negative result in an GLP-compliant enhanced Ames test (EAT, Appendix 3) allows control of the N-nitrosamine at 1.5 μg/day.
Only “A negative result in a relevant well-conducted in vivo mutagenicity study can allow control of the N-nitrosamine as a non-mutagenic impurity (NMI), i.e. according to ICH Q3A(R2) and ICH Q3B(R2) limits, irrespective of the limit calculated through option 1, 2 or 3.”

EMA Questions and answers for marketing authorisation holders/applicants


When a compound is positive in the rodent carcinogenicity study and negative in the bacterial mutagenicity study, for example, carcinogens that are negative in the bacterial mutation study may act through a non-mutagenic mechanism such as by causing hormonal imbalance or proliferative changes leading to cancer. When mechanisms are clearly demonstrated, these cases are considered outside the scope of ICH M7. When a genotoxic threshold is demonstrated per ICH M7 in an in vivo follow-up test e.g. rat micronucleus, a Permissible Daily Exposure (PDE) approach may be considered (