Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance.

ABSTRACT

In pharmaceutical development, significant effort is made to minimize the carcinogenic potential of new drug substances (NDS). This involves appropriate genotoxicity and carcinogenicity testing of the NDS, and understanding the genotoxic potential of its impurities. Current available guidance recommends the use of the threshold of toxicological concern (TTC) for a single impurity where mutagenicity but no carcinogenicity information exists. Despite best efforts, the presence of more than one genotoxic impurity in an NDS may occur at trace levels. This paper repeats the analysis performed by others for a single genotoxic compound, but also uses statistical simulations to assess the impact on cancer risk for a mixture of genotoxic compounds. In summary, with the addition of multiple impurities all controlled to the TTC, an increase in cancer risk was observed. This increase is relatively small when considering the conservative assumptions of the TTC. If structurally similar compounds had an assumed strong correlation (+/-10-fold from the first randomly selected impurity) in cancer potency, the resulting cancer risk was not negatively impacted. Findings based on probabilistic analysis here can be very useful in making appropriate decisions about risk management of multiple genotoxic impurities measured in the final drug substance.