A Generic Industry Approach To Demonstrate Efficient Purification of Potential Mutagenic Impurities in the Synthesis of Drug Substances

Determination of theoretical purge factors for the evaluation of risk of carryover of potential mutagenic impurities (MIs) into the final active pharmaceutical ingredient (API) has been discussed as a possible approach to demonstrate efficient purification of potential MIs (Substances I, II, III, and IV) in the synthesis of the vortioxetine drug substance. Theoretical purge factors for the four potential MIs were determined based on the physicochemical properties of an MI in relation to processing conditions. Compared to depletion studies of I and III, the calculated purge factors were very conservative in predicting impurities reduction. However, even a conservatively calculated purge factor correctly predicted high purging capability of the process to eliminate substance I. This novel approach could help pharmaceutical companies to focus on those impurities that are more likely to be carried over into the final API, thus obviating the use of analytical testing where not necessary.