ICH M7 GUIDELINE. From in silico to in vivo assessment for mutageniciy of impurities

2021 Qepler Genotoxic Impurities in Pharmaceuticals. Virtual Summit 2021

ICH M7 guideline on assessment and control of mutagenic impurities in pharmaceuticals provides a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk.

The integrated genotoxicity assessment encompasses 4 main phases from the literature search to the execution of in vivo follow-up testing passing through in silico evaluation, classification, and in vitro tests.

Positive results in the Ames test mean a significant hurdle for the development of new drugs and as a result, most companies drop mutagenic ingredients from further development.

In recent years a number of questions have been posed regarding the most appropriate in vivo tests to use to follow up on positive genotoxicity results in vitro, which tissues to sample, what constitutes convincing evidence of target tissue exposure and what does one do if exposure seems too low, and the potential of new in vivo assays for which OECD guidelines do not currently exist.

In particular, the following question has to be addressed in the selection of appropriate in vivo tests:

  1. Which is the most appropriate animal model?
  2. Which tissues should be sampled, and under what circumstances, in an in vivo comet assay?
  3. What is considered acceptable evidence of target tissue exposure, in particular with the blood or bone marrow micronucleus (MNviv) test?
  4. Appropriateness of intraperitoneal (i.p.) versus oral routes of administration
  5. Which is the current status of validation of MN assays in non-hematopoietic tissues such as the liver, GI tract, and lung?
  6. Can I use the Pig-a assay?

M7 guideline suggests which tests can be performed to investigate the in vivo relevance of in vitro mutagens resulted positive in a Bacterial Mutagenicity Assay. However, the selection of the model to be used and the protocol to follow are crucial points on which to pay extreme attention in order not to obtain results that cannot be used for regulatory purposes.








Kirkland D, Uno Y, Luijten M, Beevers C, van Benthem J, Burlinson B, Dertinger S, Douglas GR, Hamada S, Horibata K, Lovell DP, Manjanatha M, Martus HJ, Mei N, Morita T, Ohyama W, Williams A. In vivo genotoxicity testing strategies: Report from the 7th International workshop on genotoxicity testing (IWGT). Mutat Res. 2019 Nov;847:403035. doi: 10.1016/j.mrgentox.2019.03.008. Epub 2019 Apr 25. PMID: 31699340.