Evaluation of Starting Materials for PMIs (Potentially Mutagenic Impurities): A Vortioxetine Case Study

Abstract

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.

Transition-Metal-Free Thioamination of Arynes Using Sulfenamides

“…For example, the phenothiazine-containing drug chlorpromazine is used to treat psychotic disorders including schizophrenia (Figure ). Moreover, the FDA-approved antidepressant drug vortioxetine (sold as Trintellix) contains o -sulfanylaniline moiety, and the benzothiazole-derived drug riluzole (marketed as Rilutek and Teglutik) is used in the treatment of amyotrophic lateral sclerosis . In addition, the benzothiazepine-containing drug diltiazem (calcium channel blocker) is used in the treatment of hypertension and angina .…”

Leveraging ICH M7 Control Options 3 and 4: Discussion and Clarification Using Industrial Case Studies

“…There have been numerous publications discussing the use of ICH M7 Option 4 purge rationales to justify PMI purging through the application of process understanding on the fate and effect to specific impurities. − Additionally, a Lhasa Limited led industry consortium published a best practice paper to highlight the types of Supporting Information, which should accompany a regulatory submission to justify a proposed purge rationale . The later publication of the ICH M7 Questions and Answers (ICH M7 Q&A) document provided additional guidance for when the above control options can be applied .…”