20060628 EMEA/CHMP/QWP/251344/2006 基因毒性杂质限度指南（中英文对照）

London, 28 June 2006 CPMP/SWP/5199/02

EMEA/CHMP/QWP/251344/2006

The European Agency for the Evaluation of Medicinal Products 欧洲共同体药物评审委员会 (EMEA) COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE 人用药品委员会 (CHMP) GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES 基因毒性杂质限度指南 DESCUSSION IN THE SAFETY WORKING PARTY 安全工作组之内的讨论 TRANSMISSION TO CPMP CPMP传递 RELEASE FOR CONSULTATION 专家讨论 DEADLINE FOR COMMENTS 建议收集最后期限 DISCUSSION IN THE SAFETY WORKING June 2003-February 2004 March 2003 December 2002 December 2002 June 2002-October 2002 PARTY AND QUALITY WORKING PARTY 安全工作组和质量工作组之间的讨论 TRANSMISSION TO CPMP 转移给CPMP RE-RELEASE FOR CONSULTATION 再次放行给顾问团 DEADLINE FOR COMMENTS 收集意见的最后期限 DISCUSSION IN THE SAFETY WORKING PARTY AND QUALITY WORKING PARTY 安全工作组和质量工作组之间的讨论 ADOPTION BY CHMP 被CHMP采用 DATE FOR COMING INTO EFFECT 生效日期 KEYWORDS 关键词 GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES 基因毒性杂质限度指南 TABLE OF CONTENTS 目录 EXECUTIVE SUMMARY 内容摘要.............................................................................................. 3 Impurities; Genotoxicity; Threshold of toxicological concern (TTC); Structure activity relationship (SAR) 01January 2007 28 June 2006 February 2005-May 2006 December 2004 June 2004 March 2004 1. INTRODUCTION 介绍............................................................................................................... 3 2. SCOPE 范围 ............................................................................................................................... 3 3. LEGAL BASIS法 律依据............................................................................................................ 3 4. TOXICOLOGICAL BACKGROUND 毒理学背景.................................................................... 4 5. RECOMMENDATIONS 建议..................................................................................................... 4 5.1 Genotoxic Compounds With Sufficient Evidence for a Threshold-Related Mechanism

具有充分证据证明其阈值相关机理的基因毒性化合物......................................................... 4 5.2 Genotoxic Compounds Without Sufficient Evidence for a Threshold-Related Mechanism

不具备充分证据支持其阈值相关机理的基因毒性化合物...................................................... 5 5.2.1 Pharmaceutical Assessment药学评价.................................................................................. 5 5.2.2 Toxicological Assessment毒理学评价................................................................................... 5 5.2.3 Application of a Threshold of Toxicological Concern 毒理学担忧阈值应用........................ 5 5.3 Decision Tree for Assessment of Acceptability of Genotoxic Impurities

基因毒性杂质可接受性评价决策树.......................................................................................... 7 REFERENCES. 参考文献................................................................................................................ 8

EXECUTIVE SUMMARY 内容摘要

The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances. The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits. In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed. A TTC value of 1.5 μg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer

risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be 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ICH Q3X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 general concept of qualification of impurities is described in the guidelines for active substances (Q3A, Impurities in New Active Substances) or medicinal products (Q3B, Impurities in New Medicinal Products), whereby qualification is defined as the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. In the case of impurities with a genotoxic potential, determination of acceptable dose levels is generally considered as a particularly critical issue, which is not specifically covered by the existing guidelines.

在原料药（Q3A）和药物制剂（Q3B）的杂质指导原则中，杂质限度确定的依据包括各个杂质的生物安全性数据或杂质在某特定含量水平的研究概况。而对于遗传毒性杂质限度的

确定，通常都认为是特别关键的问题，但目前尚无相关的指导原则。

2. SCOPE 范围

This Guideline describes a general framework and practical approaches on how to deal with genotoxic impurities in new active substances. It also relates to new applications for existing active substances, where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in the EU containing the same active substance. The same also applies to variations to existing Marketing Authorisations pertaining to the synthesis. The guideline does, however, not need to be applied retrospectively to authorised