Genotoxic Impurities in Pharmaceuticals

Reliable quality is one of the key attributes of drugs nowadays. Patients deserve the highest quality and are expecting to not be put at risk for health effects especially related to impurities in drug substances or drug products. While ICH guidelines for “ordinary” impurities have been available for many years, a harmonized guideline on how to assess, limit and control potential health effects of low levels of genotoxic/carcinogenic impurities was lacking and only regional (draft) guidelines existed. With the ICH M7 guideline entitled “Assessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”, this gap in the internationally harmonized regulatory framework has been filled. This chapter deals with the history of the guideline and concepts of risk assessment with a focus on the Threshold of Toxicological Concern (TTC) principle. Further, a few examples are given on how to deal with potential impurities with mutagenic/carcinogenic potential or for compounds for such a potential is assumed but not demonstrated. Hence, in the following chapter, the reader can expect some background information about the ICH M7 guideline and tips how to use it in practice. Regulatory precedence of the use of evidence of non-linear dose–response for genotoxic carcinogens such as EMS is also referred to.

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