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EXECUTIVESUAMMARY The toxicological assessment of genotoxic impuritiesand the determination of acceptable limits for suchimpurities in active substances is a difficult issue and not addressed insufficient detail in the existing ICH Q3X guidances. The data set usuallyavailable for genotoxic impurities is quite variable and is the main factorthat dictates the process used for the assessment of acceptable limits. In the absence of data usually needed for theapplication of one of the established 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 (excesscancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. Fromthis threshold value, a permitted level in the active substance can becalculated based on the expected daily dose. Higher limits may be justifiedunder certain conditions such as short-term exposure periods. 行政摘要 药物活性成分中基因毒性杂质的毒理学评估和这类杂质可接受限量的确定是一个复杂问题，在建立的ICH Q3X指南文件里没有对此进行详细说明。基因毒性杂质的现有数据集通常是相当易变的，且是决定可接受限量评估方法的重要因素。在缺少建立的风险评估方法需要的数据时，如；长期致癌性试验数据或基因毒性物质限量机理的支持数据，推荐实施基因毒性物质限量(TTC)规定的一种普通适用方法。多数药品中，基因杂质的摄取量为1.5 µg/天TTC值的风险被认为是可接受的（超过生命癌症风险的为<1/100,000）。由这个限量,药物活性成分中的允许限量可以根据预期日剂量计算。对于特定条件下（如短期暴露试验）的高限量，应该证明其合理性。 1. INTRODUCTION A general concept of qualification of impurities is described in theguidelines for active substances (Q3A, Impurities in New Active Substances) ormedicinal products (Q3B, Impurities in New Medicinal Products), wherebyqualification is defined as the process of acquiring and evaluating data thatestablishes the biological safety of an individual impurity or a given impurityprofile at the level(s) specified. In the case of impurities with a genotoxicpotential, determination of acceptable dose levels is generally considered as aparticularly critical issue, which is not specifically covered by the existingguidelines. 1. 简介 指南文件Q3A—新原料药中的杂质和Q3B—新制剂药品中的杂质分别对原料药和制剂药中杂质确认的一般概念进行了描述，杂质的确认被定义为获得或评估数据的方法，由此来获得并评估建立单个杂质或指定限量的特定杂质概况的生物安全性的数据。如果杂质有潜在的基因毒性，通常认为确定其可接受限量是尤其关键的问题，现有指南文件没有明确包括此内容。
基因毒性杂质的限定指南.zip
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发表于 2014-9-12 08:17:02
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