EMA：基因毒性杂质限度指南（中英文对照）.pdfVIP

EMA ：基因毒性杂质限度指南（中英⽂对照） EXECUTIVE SUMMARY 内容摘要 Thetoxicological assessment of genotoxic impurities and the determination ofacceptable limits for such impurities in active substances is a difficult issueand not addressed in sufficient detail in the existing ICH Q3X guidances. Thedata set usually available for genotoxic impurities is quite variable and isthe main factor that dictates the process used for the assessment of acceptablelimits. In the absence of data usually needed for the application of one of theestablished risk assessment methods, i.e. data from carcinogenicity long-termstudies or data providing evidence for a threshold mechanism of genotoxicity,implementation of a generally applicable approach as defined by the Thresholdof Toxicological Concern (TTC) is proposed. A TTC value of 1.5 µg/day intake ofa genotoxic impurity is considered to be associated with an acceptable risk(excess cancer risk of 1 in 100,000 over a lifetime) for mostpharmaceuticals. From this threshold value, a permitted level in the activesubstance can be calculated based on the expected daily dose. Higher limits maybe justified under certain conditions such as short-term exposure periods. 基因毒性杂质的毒理学评估和这些杂质在活性药物中的可接受标准的测定是⼀件困难的事情，并且在现 有的ICHQ3X指南中也没有详细的规定。现有的关于基因毒性杂质的相关数据是容易变化的，也是对杂 质可接受标准如何进⾏评价的主要影响因素。如果缺少风险评估⽅法所需要的数据，⽐如，致癌作⽤的 长期研究数据，或为基因毒性的阀值提供证据的数据，⼀般建议使⽤⼀般通⽤的被定义为毒理学关注的 阈值（TTC）的⽅法。⼀个“1.5µg/day”的TTC值，即相当于每天摄⼊1.5µg的基因毒性杂质，被认为对于 ⼤多数药品来说是可以接受的风险（⼀⽣中致癌的风险⼩于⼗万分之1）。按照这个阀值，可以根据这 个预期的每⽇摄⼊量计算出活性药物中可接受的杂质⽔平。较⾼的临界值可以在特定的条件下，如短期 暴露周期等，进⾏推算。 1. INTRODUCTION 介绍 A generalconcept of qualification of impurities is described in the guidelines foractive substances (Q3A, Impurities in New Active Substances) or medicinal products(Q3B, Impurities in New Medicinal Products), whereby qualification is definedas the process of acquiring and evaluating data that establishes the biologicalsafety of an individual impurity or a given impurity profile at the level(s)specified. In the case o