Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances.

Controlling the quality of medicines is just as important as demonstrating efficacy. The International Conference on Harmonisation has published general guidance on the quality and safety assessment of impurities in pharmaceutical drug substances and drug products. More recently, the European Medicines Evaluation Agency has published a guideline focusing on limits for genotoxic impurities. This is based on a Threshold of Toxicological Concern (TTC) derived from animal carcinogenicity data using multiple worst case assumptions to estimate a daily dose (1.5 microg/day) associated with a lifetime cancer risk of 1 in 100,000, a risk level considered acceptable for genotoxic impurities in human medicines. Based on these assumptions, presentation of the TTC as a single figure infers an unwarranted level of precision and supports the adoption of a more flexible approach by regulatory authorities when evaluating new drug products; a range within fivefold of the TTC limit would seem sensible. Furthermore, the limit is based on 70 years continuous daily exposure, a scenario that is uncommon for most medicines and irrelevant to the preregistration clinical development phase. To address this latter point, a staged TTC has been developed that proposes limits based on shorter durations of treatment, e.g., up to 1 year. Based on recent history, this approach has been acceptable to some authorities but not to others, and it is imperative that steps are taken to reach a common agreement between the pharmaceutical industry and regulatory authorities globally in order that new medicines can continue to be developed and delivered to benefit patients in a safe and timely manner.