1、1 ICH M7（ step4)：诱变性杂质评估和控制 （ 翻译： zhuyujiao1972） ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK 为限制潜在致癌风险而对药物中 DNA 活性（诱变性）杂质进行的评估和控制 M7 Current Step 4 version dated 23 June 2014 This Guideline has been developed by the appropriat
2、e ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 2 M7 Document History 文件历史 Code 文件代码 Hist
3、ory 历史 Date 日期 M7 Approval by the Steering Committee under Step 2 and release for public consultation. 第 2 阶段由筹委会批准，公开征求意见 6 February 2013 M7 Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies. 第 4 阶段由筹委会批准，推荐 ICH 三方药监局采用 5 June 2014 Cu
4、rrent Step 4 version 现行版本第 4 阶段 M7 Corrigendum to fix typographical errors and replace word “degradants” with “degradation products” throughout the document. 修正输入错误，将全文中“ degradants”替换成“ degradation products” . 23 June 2014 Legal Notice: This document is protected by copyright and may be used, repro
5、duced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICHs copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label,
6、demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided “as is“ without warranty of any kind. In n
7、o event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third par
8、ty, permission for reproduction must be obtained from this copyright holder. 3 ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK 为限制潜在致癌风险而对药物中 DNA 活性（诱变性）杂质进行的评估和控制 ICH Harmonised Tripartite Guideline ICH 三方协调指南 Having reached Step
9、 4 of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guideline is recommended for adoption to the three regulatory parties to ICH TABLE OF CONTENTS 目录 1. INTRODUCTION 概述 2. SCOPE OF GUIDELINE 指南范围 3. GENERAL PRINCIPLES 通用原则 4. CONSIDERATIONS FOR MARKETED PRODUCTS 上市产品应考虑的
10、问题 4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls 批准后原料药化学、生产和质量变更 4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls 批准后制剂的化学、生产和质量变更 4.3 Changes to the Clinical Use of Marketed Products 上市产品临床使用变更 4.4 Other Considerations fo
11、r Marketed Products 上市产品其它应考虑问题 5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT 原料药和制剂杂质评估 5.1 Synthetic Impurities 合成杂质 5.2 Degradation Products 降解产物 5.3 Considerations for Clinical Development 临床研发要考虑的问题 6. HAZARD ASSESSMENT ELEMENTS 危害性评估要素 4 7. RISK CHARACTERIZATION 风险特征 7.1 TTC-based Acc
12、eptable Intakes 根据 TTC 制订可接受摄入量 7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments 根据化合物特定风险评估制订的可接受摄入量 7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1) 致癌数据有利的诱变性杂质（表 1 中的第 1类） 7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold 具有实用阈
13、值证据的诱变性杂质 7.3 Acceptable Intakes in Relation to LTL Exposure 与 LTL 暴露相关的可接受摄入量 7.3.1 Clinical Development 临床研发 7.3.2 Marketed Products 已上市产品 7.4 Acceptable Intakes for Multiple Mutagenic Impurities 多个诱变性杂质的可接受摄入量 7.5 Exceptions and Flexibility in Approaches 方法例外情况和弹性 8. CONTROL 控制 8.1 Control of Pro
14、cess Related Impurities 工艺相关杂质的控制 8.2 Considerations for Control Approaches 控制方法要考虑的问题 8.3 Considerations for Periodic Testing 定期检查要考虑的问题 8.4 Control of Degradation Products 降解产物的控制 8.5 Lifecycle Management 生命周期管理 8.6 Considerations for Clinical Development 临床研发要考虑的问题 9. DOCUMENTATION 文件记录 9.1 Clini
15、cal Trial Applications 临床试验应用 9.2 Common Technical Document (Marketing Application) 通用技术文件（上市申报） NOTES 注解 GLOSSARY 术语 REFERENCES 参考文献 5 APPENDICES 附录 6 ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK 为限制潜在致癌风险而对药物中 DNA 活性（诱变性）杂质进行
16、的评估和控制 1. INTRODUCTION 概述 The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q
17、3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide
18、a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Co
19、nduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals (Ref. 3). 原料药合成牵涉到使用活性化学物质、试剂、溶剂、催化剂和其它工艺助剂，导致在所有原料药及其制剂中会残留有化学合成或其降解 产物、杂质。在 ICH Q3A(R2)新原料药中的杂质和 Q3B(R2)新制剂中的杂质（参考文献 1、 2）中提供了关于主要杂质定性和控制的指南，对 DNA 活性杂质给出了有限的指南。本指南的目的是提供实用框架，以应用于这些诱变杂质的鉴别、分类、定性和控制，对潜在致癌风险进行控制。本指南意在补充 I
20、CH Q3A(R2)、 Q3B(R2)（注解 1）和 ICH M3(R2)药物人用临床试验和上市许可中的非临床安全性研究（参考文献 3）。 This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment
21、and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use. 本指南强调在建立诱变性杂质水平时考虑安全性和质量风险管理两方面，该水平应该仅表现出可忽略不计的致癌风险。指南在考虑药物在人用时的条件下，给出了对原料药或制剂中残留或可能残留的诱变性杂质评估和控 制的建议。 2. SCOPE OF
22、GUIDELINE 指南适用范围 This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for 7 marketing. It also applies to post-approval submissions of marketed products, and to new marketing applications for product
23、s with a drug substance that is present in a previously approved product, in both cases only where: 本指南意在给研发期间和上市申报期间的新原料药和新制剂提供指南。它 也适用于已上市药物的批准后申报，以及之前已批准上市的制剂中的同样原料药生产的另一制剂新上市申报。当上述申报符合以下情形时： Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for exi
24、sting impurities; 原料药合成变更，导致产生新杂质或已有杂质可接受标准增加 Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products; 配方变更、组分变更或生产工艺变更，导致产生新的降解产物或已有降解产物可接受标准增加 Changes in indication or dosing regimen are
25、made which significantly affect the acceptable cancer risk level. 指征变更或给药方案变更，导致可接受癌症风险水平受到重大影响 Assessment of the mutagenic potential of impurities as described in this guideline is not intended for the following types of drug substances and drug products: biological/biotechnological, peptide, oligo
26、nucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin. 本指南中描述的杂质潜在诱变性评估不适用于以下类型的原料药和制剂：生物 /生物技术 制品、肽类、寡核苷酸、放射药物、发酵产品、草药制品和动物或植物来源的粗品。 This guideline does not apply to drug substances and drug products intended for advanced cancer indica
27、tions as defined in the scope of ICH S9 (Ref. 4). Additionally, there may be some cases where a drug substance intended for other indications is itself genotoxic at therapeutic concentrations and may be expected to be associated with an increased cancer risk. Exposure to a mutagenic impurity in thes
28、e cases would not significantly add to the cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable levels for non-mutagenic impurities. 本指南不适用于 ICH S9（参考文献 4）中所定义的晚期癌症指征用原料药和制剂。另外，可能会有些情况下，制剂用于其它治疗，而其自己本身在治疗浓度下就具有基因毒性，已知其会使癌症风险增加。这些情况下，暴露在具有诱变性的杂质下，不会显著增加原料药的癌症风险。因
29、此，杂质可以被控制在非诱变性杂质的可接受水平。 Assessment of the mutagenic potential of impurities as described in this guideline is not intended for excipients used in existing marketed products, flavoring agents, 8 colorants, and perfumes. Application of this guideline to leachables associated with drug product packagin
30、g is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted. The safety risk assessment principles of this guideline can be used if warranted for impurities in excipients that are used for the first time in
31、 a drug product and are chemically synthesized. 在本指南中所描述的对杂质潜在诱变性的评估不适用于已上市药物中使用的辅料、调味剂、着色剂和香料。本指南不适用于药物包材中的可浸出杂质，但指南中限制潜在致癌风险的安全风险评估原则在一定情况下是可以使用的。如果辅料是首次用于药物中，且是化学合成的，则本指南的安全风险评估原则可以适用于辅料中的杂质 。 3. GENERAL PRINCIPLES 通用原则 The focus of this guideline is on DNA reactive substances that have a potenti
32、al to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxicants that are non-mutagenic typically have th
33、reshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. Therefore to limit a possible human cancer risk associated with the exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutagenic pot
34、ential and the need for controls. Structure-based assessments are useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. There are a variety of approaches to conduct this evaluation including a review of the available literature, and/or computational toxicology a
35、ssessment. 本指南关注的 焦点为可与 DNA 反应的物质，这些物质在较低水平时也可能会直接引起DNA 损伤，导致 DNA 诱变，从而引发癌症。这类诱变性致癌作用常被细菌逆式突变（诱变）含量检出。其它类型不具有典型诱变性的基因毒性物质则有阈值进行控制，一般以常规水平杂质出现时对人类不具有致癌风险。因此，为了限制暴露于潜在诱变性杂质可能带来的人类癌症风险，我们使用细菌诱变含量来评估诱变可能性及控制的必要性。基于结构进行的评估有助于根据已有的知识来预测细菌诱变性测试结果。有很多方法可以用于实施该评估，包括对可获得的文献资料进行审核，和 /或采用计算方式进行毒性评估。 A Threshold
36、 of Toxicological Concern (TTC) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects. The methods upon which the TTC is based are generally considered to be very conservative since they involve a simple
37、 linear extrapolation from the dose giving a 50% tumor incidence (TD50) to a 1 in 106 incidence, using TD50 data for the most sensitive species and most sensitive site of tumor induction. For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and d
38、rug products, a value of 1.5 g/day corresponding to a theoretical 10-5 excess lifetime risk of cancer, can be justified. Some structural groups were identified to be of such high potency that 9 intakes even below the TTC would theoretically be associated with a potential for a significant carcinogen
39、ic risk. This group of high potency mutagenic carcinogens referred to as the “cohort of concern”, comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds. 已经建立了 TTC 概念，用于界定所有未经研究，但具有可忽略的致癌风险或其它毒性效果的化学品的可接受摄入量。基于 TTC 的方法一般被认为是非常保守的，因为它们牵涉到从给定的 50%肿瘤发生率（ TD50）简单线性外推到十万分之一发生率，且采用的数据是来自于最敏感物种和最
40、敏感肿瘤部位的 TD50 数据。在使用 TTC 评估原料药和制剂中诱变性杂质的可接爱标准时，可以采用 1.5g/天对应于十万 分之一生命时长患癌风险。有些结构基团被识别为具有较高的效价，因此即使摄入量低于 TTC 水平，从理论上来说仍会导致可能的显著癌症风险。这类具有较高效价的基团被称为“关注队列”，包括黄曲霉素类、 N-亚硝基化合物，以及烷基 -氧化偶氮基化合物。 During clinical development, it is expected that control strategies and approaches will be less developed in earlie
41、r phases where overall development experience is limited. This guideline bases acceptable intakes for mutagenic impurities on established risk assessment strategies. Acceptable risk during the early development phase is set at a theoretically calculated level of approximately one additional cancer p
42、er million. For later stages in development and for marketed products, acceptable increased cancer risk is set at a theoretically calculated level of approximately one in one hundred thousand. These risk levels represent a small theoretical increase in risk when compared to human overall lifetime in
43、cidence of developing any type of cancer, which is greater than 1 in 3. 在临床研发期间，如果整体研发经验有限，在早期临床阶段对控制策略和控制方法的要求会较低。本指南是在已建立的风险评估策略的基础上，制订诱变性杂质的可接受摄入量。在早期研发阶段，可接受风险是建立在患癌率约为百万分之一的理论计算水平上的。在研发 后期及上市后，可接受癌症增加风险是建立在患癌率约为十万分之一的理论计算水平上的。相较于人类整个生命周期罹患各类癌症的发生率（大于三分之一），这两个不同的风险水平在理论上风险稍有增加。 It is noted that
44、established cancer risk assessments are based on lifetime exposures. Less-Than-Lifetime (LTL) exposures both during development and marketing can have higher acceptable intakes of impurities and still maintain comparable risk levels. 已注意到所建立的患癌风险评估是根据生命周期内暴露情形的。在研发期间和上市期间低于生命周期（ LTL）暴露都可能允许摄入更多杂质，仍保
45、留一定的风险水平。 The use of a numerical cancer risk value (1 in 100,000) and its translation into risk-based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic indication of the actual risk. 使用量化患癌风险值（十万分之一），并将其转化为根据风险计算的剂量（ TTC 值）是一种高度假想的概念，不应作为真实风险的一种实际指标。 10 Neverthe
46、less, the TTC concept provides an estimate of safe exposures for any mutagenic compound. 不管怎样， TTC 概念提供了对诱变性化合物下安全暴露的一种估计方法。 However, exceeding the TTC is not necessarily associated with an increased cancer risk given the conservative assumptions employed in the derivation of the TTC value. 但是，假出在 T
47、TC 值计算时采用了保守假设，超出 TTC 值并不一定会伴随患癌风险增加。 The most likely increase in cancer incidence is actually much less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considera
48、tions, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be taken. 大多数患癌可能性实际远低于十万分之一，另外，如果有一个诱变性化合物在啮齿动物生物含量中
49、显示为非诱变性，则预测其致癌风险不会增加。基于上述这些原因，所有暴露在之后鉴定为诱变性杂质并不一定伴随已暴露于该杂质的患者癌症风险增加。应进行风险评估来决定是否需要采取进一步行动。 Where a potential risk has been identified for an impurity, an appropriate control strategy leveraging process understanding and/or analytical controls should be developed to ensure that the mutagenic impurity is at or below the acceptable cancer risk level. 如果一个杂质被鉴定为具有潜在风险，则需要采用一个适当的控制策略来平衡工艺知识和 /或分析控制，以保证诱变性杂质等于或低于可接受的癌症风险水平。 There may be cases when an impurity is also a metabolite of the drug substance. In such cases the risk assessment that addresses mutagenicity
