Determination of compound-specific acceptable daily intakes for 11 mutagenic carcinogens used in pharmaceutical synthesis

The synthesis of pharmaceutical products often involves the use of reactive starting materials and intermediates. Low levels may be present in the final product as impurities and of particular concern are impurities that have mutagenic and carcinogenic potential. Regulatory guidance documents provide a general framework to minimise human exposure to these impurities; however, compound-specific recommendations are limited. Our practical experience with 11 pharmaceutical impurities is presented. The genotoxicity and carcinogenicity data are summarised and the approach used to derive an acceptable daily intake (ADI) is described for each chemical. We have highlighted the considerations and challenges associated with calculating ADIs based on available carcinogenicity data. This may provide a useful reference to others in the pharmaceutical industry regarding impurity control, where the weight of evidence indicates the chemical is a mutagenic carcinogen.