Identifying the Risk of Formation of Nitrosamines and Other Potentially Mutagenic Impurities during API Manufacture Using In Silico Risk Assessment

Synthetic routes to drug products typically introduceseveral potentiallymutagenic impurities (PMIs) which require controlling to a safe levelin the final drug substance, generally directed by the control optionswithin the ICH M7 guideline. These impurities are most commonly introduceddue to their specific synthetic utility; however, the formation ofa PMI can also occur indirectly from a combination of otherwise nonmutagenicsources, as was the case for NDMA within valsartan. Identifying theseformation risks currently relies on manually assessing the syntheticroute, a process requiring extensive knowledge and potentially liableto oversight. Herein we report on the development of functionalitywithin an in silico risk assessment tool to facilitatethe identification of synthetic stages which introduce the risk offormation of PMIs for industrial and/or regulatory users.

Automated summary

Synthetic routes to drug products often introduce potentially mutagenic impurities (PMIs) that need to be controlled to safe levels. Current methods of identifying the formation risks of these impurities rely on manual assessment, which can be time-consuming and prone to oversight. In this study, an in silico risk assessment tool was developed to facilitate the identification of synthetic stages that introduce the risk of PMI formation.