Genotoxic impurities in pharmaceutical products – regulatory, toxicological and pharmaceutical considerations

This article provides an overview of the most important aspects around the detecting and reporting of genotoxic impurities in the pharmaceutical industry. It focuses on relevant regulatory, toxicological, and pharmaceutical considerations. In this regard, the concept of Threshold of Toxicological Concern is explained and the most common genotoxic impurities are described. Furthermore, toxicological methods for genotoxic impurities screening are presented. Finally, the article emphasises several issues regarding further development. Genotoxicity is defined as any detrimental modification of the genetic material irrespective of its causative mechanism, as per ICH guidelines ICH (S2) R1 Genotoxicity testing and data interpretation for pharmaceuticals intended for human use [1]. Screening for the genotoxicity of pharmaceuticals intended for human use is crucial with regards to safety during therapy, and it is warranted during non-clinical development by ICH M3 (R2) Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals and ICH (S2) R1 guidelines [1,2]. Moreover, according to ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk guideline [3,4], the impurities present in a final drug formulation, including degradation products and reaction-related impurities (i.e. starting materials, reagents, intermediates, solvents, catalysts, etc.), also require genotoxicity profiling. Specifically, mutagenic impurities are DNA reactive substances with the potential to directly damage DNA even at low concentrations (equalling ppm level), causing mutations and thus potentially leading to neoplasia. The presence of unusually toxic (e.g. DNA reactive) impurities has been of significant con-