Genotoxic Impurities in Pharmaceuticals

Genotoxic compounds induce genetic mutations and/or chromosomal rearrangements and can therefore act as carcinogenic compounds (McGovern and Jacobson-Kram, 2006). These compounds cause damage to DNA by different mechanisms such as alkylation or other interactions that can lead to mutation of the genetic codes. In general, chemists employ the terms "genotoxic" and "mutagenic" synonymously; however, there is a subtle distinction. Genotoxicity pertains to all types of DNA damage (including mutagenicity), whereas mutagenicity pertains specifically to mutation induction at the gene and chromosome levels. Thus, the term “genotoxic” is applied to agents that interact with DNA and/or its associated cellular components (e.g. the spindle apparatus) or enzymes (e.g. topoisomerases) (Dearfield et al., 2002; Robinson, 2010). Irrespective of the mechanism by which cancer is induced, it is now well agreed that it involves a change in the integrity or expression of genomic DNA. The majority of chemical carcinogens are capable of causing DNA damage, i.e., are "genotoxic" (Ashby, 1990). Moreover, a genotoxic compound also carries with it the carcinogenic effect which causes additional concern from the safety viewpoint. Drug substances and their relative compounds such as impurities constitute an important group of genotoxic compounds. Thus, these compounds pose an additive concern to clinical subjects and patients (Müller et al., 2006). Considering the importance of this problem, the challenge for regulatory agencies is to form guidelines and standards for the identification and control of genotoxic compounds and their impurities especially in pharmaceuticals. In this article, genotoxicity profiles of the main group of genotoxic compounds are discussed. The article throws light on the challenges in analyzing and predicting for these groups and also deals with the different management problems of genotoxic impurities in pharmaceuticals.