EMEA基因毒性杂质限度指南

1 18 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 June 2002 October 2002 TRANSMISSION TO CPMP CPMP 传递 December 2002 RELEASE FOR CONSULTATION 专家讨论 December 2002 DEADLINE FOR COMMENTS 建议收集最后期限 March 2003 DISCUSSION IN THE SAFETY WORKING June 2003 February 2004 2 18 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 March 2004 RE RELEASE FOR CONSULTATION 再次放行给顾问团 June 2004 DEADLINE FOR COMMENTS 收集意见的最后期限 December 2004 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 February 2005 May 2006 ADOPTION BY CHMP 被 CHMP 采用 28 June 2006 DATE FOR COMING INTO EFFECT 生效日期 01January 2007 KEYWORDS 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 3 3 18 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 4 18 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 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 5 g day 的 TTC 值 即相当于每天摄入1 5 g 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 5 18 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 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 on 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 emphasis 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 ICH 283 95 Note for Guidance on Genotoxicity Guidance on Specific Aspects of Regulatory Genotoxicity 6 18 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 BACKGROUND 毒理学背景毒理学背景 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 discernible 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 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 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 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 appropriate 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 7 18 方法证明某诱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 based on knowledge of the chemical reactions and conditions involved Guided by existing genotoxicity data or the presence of structural alerts potential genotoxic impurities should be identified When a potential impurity contains structural alerts additional genotoxicity testing of the impurity typically in a bacterial reverse mutation assay should be considered Dobo et al 2006 M ller et al 2006 While according to the Q3A guideline such studies can usually be conducted on the drug substance containing the impurity to be controlled studies using isolated impurities are much more appropriate for this purpose and highly recommended 正如 Q3A 指导原则所述 根据合理的化学反应机理分析 在新的原料药合成 纯化和 贮存过程中很有可能产生实际的和潜在的杂质 依据现有的 可能引起遗传毒性的结构 数 据库 潜在的遗传毒性杂质应能被确认 如果潜在的杂质含有可引起遗传毒性的结构单元 该杂质应考虑进行遗传毒性试验 一般是细菌回复突变试验 Dobo 等 2006 虽然 Q3A 指导原则认为这些研究采用含有那些需控制杂质的原料药进行是可行的 但用分离出来的 杂质进行这些研究更恰当 也是高度推荐的方法 For determination of acceptable levels of exposure to genotoxic carcinogens considerations of possible mechanisms of action and of the dose response relationship are important components Based on the above considerations genotoxic impurities may be distinguished into the following two classes 根据以上论述 遗传毒性杂质可以归纳成以下两类 Genotoxic compounds with sufficient experimental evidence for a threshold related mechanism 8 18 有充分阈值相关机理证据 实验 的遗传毒性化合物 Genotoxic compounds without sufficient experimental evidence for a threshold related mechanism 无充分阈值相关机理证据 实验 的遗传毒性化合物 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具有充分证据证明其阈值相关机理的基因毒性化合物 Examples of mechanisms of genotoxicity that may be demonstrated to lead to non linear or thresholded dose response relationships include interaction with the spindle apparatus of cell division leading to aneuploidy topoisomerase inhibition inhibition of DNA synthesis overloading of defence mechanisms metabolic overload and physiological perturbations e g induction of erythropoeisis hyper or hypothermia 非线性或阈值明确的剂量效应关系的遗传毒性机理包括 与细胞分化过程中纺锤体相互 作用 拓扑异构酶抑制 DNA 合成抑制 过度的防御机制 代谢过度和生理性干扰 如诱 导红血球生成 高体温和低体温 For classes of compounds with clear evidence for a thresholded genotoxicity exposure levels which are without appreciable risk of genotoxicity can be established according to the procedure as outlined for class 2 solvents in the Q3C Note for Guidance on Impurities Residual Solvents This approach calculates a Permitted Daily Exposure PDE which is derived from the NOEL or the lowestobserved effect level LOEL in the most relevant animal study using uncertainty factors UF 有明确遗传毒性阈值的化合物 不产生遗传毒性风险的暴露水平可以被确定 方法可参 照 Q3C 杂质指导原则 中二类溶剂的限度确定方法 该方法可计算 每日最大允许暴露量 PDE 数据来源于 不确定因数 动物研究中的 NOEL 未观察到效果的最低水平 或观 察到效果的最低水平 LOEL 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不具备充分证据支持其阈值相关机理的基因毒性化合物 The assessment of acceptability of genotoxic impurities for which no threshold mechanisms are identified should include both pharmaceutical and toxicological evaluations In general pharmaceutical measurements should be guided by a policy of controlling levels to as low as reasonably practicable ALARP principle where avoiding is not possible Levels considered 9 18 being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view see decision tree following sections 对于此类遗传毒性杂质 研究应包括药学和毒理学评估 总之 如果杂质无法避免 药 学方面的控制应遵循 合理可行的最低限量 原则 ALARP 原则 符合 ALARP 原则的杂质 水平再经毒理学方面的进一步评估 以验证其合理性 见决策树和以下章节 5 2 1 Pharmaceutical Assessment 药学评价药学评价 A specific discussion as part of the overall discussion on impurities see Q3A R should be provided in the application with regard to impurities with potential genotoxicity 申请材料应提供关于潜在遗传毒性杂质的特别讨论资料 见 Q3A R A rationale of the proposed formulation manufacturing strategy should be provided based on available formulation options and technologies The applicant should highlight within the chemical process and impurity profile of active substance all chemical substances used as reagents or present as intermediates or side products known as genotoxic and or carcinogenic e g alkylating agents 需要根据现在的配方选择和技术 提供证明所选的配方 生产策略合理性的证据 申请 人应在合成工艺和杂质研究部分重点指出所有的化学物质 包括用到的试剂 中间体 副 产物 哪些是已知遗传毒性和 或致癌性物质 如烷化剂 More generally reacting substances and substances which show alerting structure in terms of genotoxicity which are not shared with the active substance should be considered see e g Dobo et al 2006 Potential alternatives which do not lead to genotoxic residues in the final product should be used if available 值得关注的是 虽然有些含有 可能引起遗传毒性的结构 alerting structure 的反应 试剂与最终活性物质并没有共同结构 但也要考虑它们的遗传毒性 see e g Dobo et al 2006 如果有可能 应该对它们进行一些替代研究 以使最终产品中不会引入基因毒性残留 A justification needs to be provided that no viable alternative exists including alternative routes of synthesis or formulations different starting materials This might for instance include cases where the structure which is responsible for the genotoxic and or carcinogenic potential is equivalent to that needed in chemical synthesis e g alkylation reactions 10 18 需要提供充分的论证来说明没有可行的替代方法存在 包括可替代的合成路线或配方 不同的起始物料等 比如 应证明具有遗传毒性和 或致癌性的结构在化学合成中 如烷化 反应 是必需的 If a genotoxic impurity is considered to be unavoidable in a drug substance technical efforts e g purification steps should be undertaken to reduce the content of the genotoxic residues in the final product in compliance with safety needs or to a level as low as reasonably practicable see safety assessment Data on chemical stability of reactive intermediates reactants and other components should be included in this assessment 如果遗传毒性杂质在原料中不可避免 则应该采取适当的技术 如纯化步骤 降低该杂 质的含量 以满足安全性要求 或符合 合理可行的最低限量 原则 见安全评估 药学评 估还应包括反应中间体 反应物和其它组件等的化学稳定性研究 Detection and or quantification of these residues should be done by state of the art analytical techniques 应该使用比较先进的分析检测技术来检测和量化这些残留的杂质 5 2 2 Toxicological Assessment 毒理学评价毒理学评价 The impossibility of defining a safe exposure level zero risk concept for genotoxic carcinogens without a threshold and the realization that complete elimination of genotoxic impurities from drug substances is often unachievable requires implementation of a concept of an acceptable risk level i e an estimate of daily human exposure at and below which there is a negligible risk to human health 鉴于在没有明确阈值的前提下定义安全暴露水平 零风险 是不可能的 且从原料药中 完全除去遗传毒性杂质经常是很难做到的 所以有必要提出一个 可接受风险水平 acceptable risk level 的概念 比如估算一个 每日最大暴露量 值 低于该暴露量时就可 以忽略其对人体健康的风险 Procedures for the derivation of acceptable risk levels are considered in the Appendix 3 of the Q3C Note for Guidance on Impurities Residual Solvents for Class 1 solvents However these approaches require availability of adequate data from long term carcinogenicity studies 对于可接受风险水平的推导过程请参见 Q3C 杂质指南注释 一类溶液残留 中的附件 三 然而 应用这些方法必须有足够多的长期致癌性研究数据 11 18 In most cases of toxicological assessment of genotoxic impurities only limited data from in vitro studies with the impurity e g Ames test chromosomal aberration test are available and thus established approaches to determine acceptable intake levels cannot be applied Calculation of safety multiples from in vitro data e g Ames test are considered inappropriate for justification of acceptable limits Moreover negative carcinogenicity and genotoxicity data with the drug substance containing the impurity at low ppm levels do not provide sufficient assurance for setting acceptable limits for the impurity due to the lack of sensitivity of this testing approach Even potent mutagens and carcinogens are most likely to remain undetected when tested as part of the drug substance i e at very low exposure levels A pragmatic approach is therefore needed which recognises that the presence of very low levels of genotoxic impurities is not associated with an unacceptable risk 大多数情况下 遗传毒性杂质的毒理学评估只是局限于杂质的体外研究 如 Ames 试验 染色体畸变试验 但这些方法并不适用于确定杂质可接受的摄入水平 也就是说 根据体 外数据 如 Ames 试验 计算杂质的 安全倍数 safety multiples 进而确定可接受的限度 是不合适的 此外 用含有较低 ppm 级 杂质水平的原料药研究其致癌性和遗传毒性 即使得出阴性结果也不足以确保该杂质限度的合理性 因为这种试验方法缺少必要的灵敏 度 有些具有很强致突变性和致癌性物质与原料药一起进行试验时 因为在非常低的暴露 水平情况下 很有可能因为低于检测限而无法检出 所以 如果认识到含量非常低的遗传 毒性杂质不存在 不可接受的风险 unacceptable risk 那么可以采取实用的方法来控制该 杂质 5 2 3 Application of a Threshold of Toxicological Concern 毒理学相关的阈值应用毒理学相关的阈值应用 A threshold of toxicological concern TTC has been developed to define a common exposure level for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects Munro et al 1999 Kroes and Kozianowski 2002 This TTC value was estimated to be 1 5 g person day The TTC originally developed as a threshold of regulation at the FDA for food contact materials Rulis 1989 FDA 1995 was established based on the analysis of 343 carcinogens from a carcinogenic potency database Gold et al 1984 and was repeatedly confirmed by evaluations expanding the database to more than 700 carcinogens Munro 1990 Cheeseman et al 1999 Kroes et al 2004 The probability distribution of carcinogenic potencies has been used to derive an estimate of a daily exposure level g person of most carcinogens which would give rise to less than a one in a million 1 x 10 6 upper bound lifetime risk of cancer virtually safe dose Further analysis of subsets of high potency carcinogens led to the suggestion of a 10 fold lower 12 18 TTC 0 15 g day for chemicals with structural alerts that raise concern for potential genotoxicit