Mutagenic impurities in pharmaceuticals: A critical assessment of the cohort of concern with a focus on N-nitrosamines

Dr. Snodin published a new paper related to CoC in ICH M7. This paper includes a list of non carcinogenic nitrosamines with structual features such as hydroxyl or carboxyl; steric hindrance at the second α-carbon; aryl group at the second α-carbon. It will be helpful to consider read-across method for NDSRIs.
He stresses the current CoC definition is considered inadequate in relation to protection of human health since it relies entirely on simple structural alerts rather than compound-specific data on mutagenicity and carcinogenicity. And I think non CoC should be clearly separated from CoC.


That is a good paper indeed. However, as of now as much we can get is to control Non CoC at the TTC until tox studies are widely available. And 150 ng/day or the 10% is still realistically possible when the API si a secondary amine as LTL is not accepted completelly and there is still some molecules that are for chronic use and would not apply.

  • Not an easy way out for a complex topic.

Additionally, the ICH M7 is now on revision 2 (R2) recently approved. Trying to eliminate or similar the CoC term would take quite a bit of time. Nevertheless, evidence is starting to acummulate recently and hopefully we see some changes later on.


All these just show how we let these topics slip in the last few decades. I think it is an interesting and thought-provoking paper.