Herein we document our evaluation of the oral toxicity of MeTHF and CPME as determined in three month repeat-dose toxicity studies in rats as well as a battery of tests conducted under Good Laboratory Practice (GLP) to assess induction of micronuclei, microbial mutagenicity, and chromosomal aberrations. Based on the studies performed, human permitted daily exposure limits of 6.2 and 7.4 mg/day for MeTHF and CPME respectively have been established, with both of these solvents also considered negative for genotoxicity and mutagenicity. In addition, for future standard repeat-dose GLP animal studies a general limit of 20 mg/kg/day and a maximum concentration of 2% of MeTHF or CPME would not be expected to contribute to any toxicity potentially exhibited by an active pharmaceutical ingredient containing these solvents. By sharing these data, we hope to facilitate the use of these ethereal solvents within the pharmaceutical chemical process development community and contribute to the path to their potential ICH classification.

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Potential genotoxic impurities (PGI) are chemical compounds that could potentially damage DNA and lead to mutation. Controlling the occurrence of PGIs in active pharmaceutical ingredients (APIs) poses a big challenge for chemists, as levels of these compounds must be reduced well below the amounts required for other types of less toxic impurities. In situations where formation of PGIs cannot be avoided, an ideal solution would allow the complete removal of PGIs after the synthesis is complete, for example, by recrystallization, preparative chromatography or other downstream processing approaches. Some disadvantages of using these approaches are potential high yield loss, high solvent consumption, and additional time and resources required for process development. In this work, we present a simple and rapid approach to remove electrophilic PGIs from APIs. A selected nucleophilic resin can be added to the final API solution to reduce or totally remove the PGI. Esters of methanesulfonic acid (MSA), benzenesulfonic acid (BSA), and p-toluenesulfonic acid (pTSA) were used as model electrophilic PGIs. Several nucleophilic resins were screened, and the resins with the highest efficiency of PGI removal were chosen. A recommended procedure is presented for the removal of MSA, BSA, and pTSA esters. The kinetics of PGI removal, resin loading capacity, solvent effects, and API matrix effects are demonstrated.

The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations to define the degree of "purge" of PMIs within a synthetic route to an active pharmaceutical ingredient (API) based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken. This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semiquantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent, and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from the published literature and experimental data is also discussed. Furthermore, this paper describes the application of Mirabilis software for the processes involved in the synthesis of verubecestat, naloxegol oxalate, and camicinal.