Evaluation of Starting Materials for PMIs (Potentially Mutagenic Impurities): A Vortioxetine Case Study,Organic Process Research & Development

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Evaluation of Starting Materials for PMIs (Potentially Mutagenic Impurities): A Vortioxetine Case Study
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-01-24 00:00:00 , DOI: 10.1021/acs.oprd.7b00239
Nevenka Kragelj Lapanja _{1,

2} , Borut Zupančič ₁ , Renata Toplak Časar ₁ , Sabina Jurca ₁ , Bojan Doljak ₂

Affiliation

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.

中文翻译：

PMI（潜在诱变杂质）原材料的评估：伏替西汀案例研究

起始材料（SM）的性质与（潜在）诱变杂质（PMI）的存在可以密切相关，因为许多合成过程都涉及使用可能诱变的亲电（烷基化）试剂作为SM。由于监管指南远非一目了然，因此，对于制药公司而言，选择合适的SM是一项非常具有挑战性的任务。在此，根据现有准则确定了选择SM的主要标准。在将伏替西汀原料药合成过程中，选择了三种SM，并根据它们是否已定义为API结构，是否已定义化学性质和结构，SM与API之间的合成步骤数为依据进行了论证。关于商业可得性和杂质的形成，和他们的控制。理论清除因子（TPF）的确定成功地评估了使用可能诱变的SM 1和SM 3及其相关杂质的风险，以及非诱变SM 2对API的质量和安全性的影响。这种方法可以证明使用选定的SM是合理的。

更新日期：2018-01-24

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