EMEA基因毒性杂质限度指南.docx

1、EMEA基因毒性杂质限度指南20060628 EMEA/CHMP/QWP/251344/2006基因毒性杂质限度指南（中英文对照）London, 28 June 2006CPMP/SWP/5199/02EMEA/CHMP/QWP/251344/2006The 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

2、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June 2002-October 2002TRANSMISSION TO CPMPCPMP传递December 2002RELEASE FOR CONSULTATION专家讨论December 2002DEADLINE FOR COMMENTS建议收集最后期限March 2003DISCUSSION 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June 2003-F

3、ebruary 2004TRANSMISSION TO CPMP转移给CPMPMarch 2004RE-RELEASE FOR CONSULTATION再次放行给顾问团June 2004DEADLINE FOR COMMENTS收集意见的最后期限December 2004DISCUSSION 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February 2005-May 2006ADOPTION BY CHMP被CHMP采用28 June 2006DATE FOR COMING INTO EFFECT

4、生效日期01January 2007KEYWORDS关键词Impurities; Genotoxicity; Threshold of toxicological concern (TTC); Structure activity relationship (SAR)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. 31. INTRODUCTION 介绍. 32. SCOPE 范围 . 33. LEGAL BASIS法 律依据. 34. TOXI

5、COLOGICAL BACKGROUND 毒理学背景. 45. RECOMMENDATIONS 建议. 45.1 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. 45.2 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. 55.2.1 Pharmaceutical Assess

6、ment药学评价. 55.2.2 Toxicological Assessment毒理学评价. 55.2.3 Application of a Threshold of Toxicological Concern 毒理学担忧阈值应用. 55.3 Decision Tree for Assessment of Acceptability of Genotoxic Impurities基因毒性杂质可接受性评价决策树. 7REFERENCES. 参考文献. 8EXECUTIVE SUMMARY 内容摘要The toxicological assessment of genotoxic impurit

7、ies 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 pr

8、ocess 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

9、generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed. A TTC value of 1.5 g/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 thi

10、s 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

11、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“1.5g/day”的TTC值，即相当于每天摄入1.5g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 i

12、mpurities 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 i

13、ndividual 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

14、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 activ

15、e 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 sa

16、me also applies to variations to existing Marketing Authorisations pertaining to the synthesis. The guideline does, however, not need to be applied retrospectively to authorised products unless there is a specific cause for concern.本指导原则阐述了如何处理新原料药中遗传毒性杂质的一般框架和实际方法。该指导原则也适用于已有原料药的新申请，如果其合成路线、过程控制和杂质

17、研究尚无法确保不会产生新的或更高含量的遗传毒性杂质（与EU目前批准的相同原料药相比）。该指导原则同样适用于已上市原料药有关合成方面的补充申请。除非有特殊原因，本指导原则不适用于已上市的产品。In the current context the classification of a compound (impurity) as genotoxic in general means that there are positive findings in established in vitro or in vivo genotoxicity tests with the main focus o

18、n DNA reactive substances that have a potential for direct DNA damage. Isolated in vitro findings may be assessed for in vivo relevance in adequate follow-up testing. In the absence of such information in vitro genotoxicants are usually considered as presumptive in vivo mutagens and carcinogens.目前对于

19、基因毒性杂质的分类主要是指：在以DNA反应物质为主要研究对象的体内体外试验中，如果发现它们对DNA有潜在的破坏性，那可称之为基因毒性。如果有足够的后续试验，可由单独的体外试验结果，对它的体内关联性进行评估。在缺乏这样的信息时，体外基因毒性物质经常被考虑为假定的体内诱变剂和致癌剂。3. LEGAL BASIS 法规依据This guideline has to be read in conjunction with Directive 2001/83/EC (as amended) and all relevant CHMP Guidance documents with special emp

20、hasis on:在阅读该指南时有必要参考“Directive 2001/83/EC”以及相关的CHMP指南文件，特别是以下几个指南：Impurities Testing Guideline: Impurities in New Drug Substances (CPMP/ICH/2737/99, ICHQ3A(R)Note for Guidance on Impurities in New Drug Products (CPMP/ICH/2738/99, ICHQ3B (R)Note for Guidance on Impurities: Residual Solvents (CPMP/IC

21、H/283/95)Note for Guidance on Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals (CPMP/ICH/141/95, ICHS2A)Note for Guidance on Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals (CPMP/ICH/174/95, ICHS2B)4. TOXICOLOGICAL BACKGROUN

22、D 毒理学背景According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development. Thus for genotoxic carcinogens it is prudent to assume that there is no discernib

23、le threshold and that any level of exposure carries a risk.根据目前的研究实践，具有（体内）遗传毒性的化合物在任何暴露量下都有可能对DNA产生损伤，而这种损伤可能会引发肿瘤。因此，对于遗传毒性致癌物质，应谨慎认为不存在明确的阈值，任何暴露量下都存在风险。However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events

24、. This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets. The regulatory approach to such chemicals can be based on the identification of a critical no-observed-effect

25、 level (NOEL) and use of uncertainty factors.然而，对于一些遗传毒性事件，其产生生物学意义的阈值效应的机理正越来越为人所了解。对于非DNA靶点的化合物和潜在致突变剂更是如此，因为它们在与关键靶点接触前就已经去毒化了。对于这些化合物，研究的基础可以是确定关键的未观察到影响的剂量（NOEL）和采用不确定因子。Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose

26、studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses. However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen. Thus, in the absence of a

27、ppropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.即使对能与DNA分子发生反应的化合物，由于低剂量时有多种有效的保护机制存在，而不能将高剂量下的影响以线性方式外推到很低的（人）暴露水平。不过，目前要用实验方法证明某诱

28、变剂的遗传毒性阈值仍然非常困难。所以，在缺乏恰当的证据支持遗传毒性阈值存在的情况下，确定安全剂量很困难，因此非常有必要采用一个可接受风险的暴露水平概念。5. RECOMMENDATIONS 建议As stated in the Q3A guideline, actual and potential impurities most likely to arise during synthesis, purification and storage of the new drug substance should be identified, based on a sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance, and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected