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.

Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.

The nature of the starting material (SM) and the presence of (potentially) mutagenic impurities (PMIs) can correlate strongly, since many syntheses involve the use of potentially mutagenic electrophilic (alkylating) agents as SMs. Since the regulatory guidelines are far from clear and straightforward, selection of the appropriate SMs is a very challenging task for pharmaceutical companies. Here, the principal criteria for the selection of SMs have been identified based on the existing guidelines. Three SMs in the synthesis of vortioxetine drug substance were selected and justified on the basis of their incorporation into the structure of the API, on whether they have defined chemical properties and structure or not, on the number of synthetic steps between the SM and the API, on commercial availability and formation of impurities, and their control. Determination of a theoretical purge factor (TPF) was successful in evaluating the risk of using potentially mutagenic SM 1 and SM 3, with their related impurities, and the effect of a nonmutagenic SM 2 on the quality and safety of the API. This approach enables the use of selected SMs to be justified.