S-IN Soluzioni Informatiche SRL, Vicenza, Italy.
Methods Mol Biol. 2022;2425:537-560. doi: 10.1007/978-1-0716-1960-5_21.
The use of novel non-testing methodologies to support the toxicological assessment of drug impurities is having a growing impact in the regulatory framework for pharmaceutical development and marketed products. For DNA reactive (mutagenic) impurities specific recommendations for the use of in silico structure-based approaches (namely (Q)SAR methodologies) are provided in the ICH M7 guideline. In 2018 a draft reflection paper has been published by EMA addressing open issues in the qualification approach of non-genotoxic impurities (NGI) according to the ICH Q3A/Q3B guidelines, and proposing the use of alternative testing strategies, including TTC, (Q)SAR, read-across, and in vitro approaches, to gather impurity-specific safety information.In the present chapter we describe a workflow to perform the safety assessment of drug impurities based on non-testing in silico methodologies. The proposed approach consists of a stepwise decision scheme including three key phases: PHASE 1: assessment of bacterial mutagenicity and consequent classification of impurities according to ICH M7; PHASE 2: risk characterization of mutagenic impurities (Classes 1, 2 or 3); PHASE 3: qualification of non-mutagenic impurities (Classes 4 or 5). The proposed decision scheme offers the possibility to acquire impurity-specific data, also if testing is not feasible, and to decide on further in vitro testing, besides meeting 3R's principle.
新型非测试方法学在药物杂质毒理学评估中的应用，对药物开发和上市产品的监管框架产生了越来越大的影响。对于 DNA 反应性（致突变性）杂质，ICH M7 指南中为基于计算机的结构方法（即（Q）SAR 方法）的使用提供了具体建议。2018 年，EMA 发布了一份草案反馈文件，针对根据 ICH Q3A/Q3B 指南对非遗传毒性杂质（NGI）的资格方法的开放性问题进行了探讨，并提出了使用替代测试策略的建议，包括 TTC、（Q）SAR、数据外推和体外方法，以收集杂质特异性安全性信息。在本章中，我们描述了一种基于非测试计算机模拟方法学来进行药物杂质安全性评估的工作流程。所提出的方法包括一个逐步决策方案，包括三个关键阶段：PHASE 1：评估细菌致突变性，并根据 ICH M7 对杂质进行分类；PHASE 2：对致突变杂质（类别 1、2 或 3）进行风险特征描述；PHASE 3：对非致突变杂质（类别 4 或 5）进行资格认定。所提出的决策方案提供了一种可能性，即使无法进行测试，也可以获得杂质特异性数据，并决定进一步进行体外测试，同时满足 3R 原则。
