1、ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT 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M7Current Step 4 versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consu
2、ltation 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.M7Document History 文件历史Code 文件代码 History 历史 Date 日期M7 Approval by the Steering Committee under Ste
3、p 2 and release for public consultation.第 2 阶段由筹委会批准，公开征求意见6 February 2013M7 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 2014Current Step 4 version 现行版本第 4 阶段M7 Corrigendum to fix typographical e
4、rrors 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 2014Legal Notice: This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or dist
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8、SSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC 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 GuidelineICH 三方协调指南Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guid
9、eline is recommended for adoption to the three regulatory parties to ICHTABLE 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 上市产品应考虑的问题4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls批准
10、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 for 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
11、 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7. RISK CHARACTERIZATION 风险特征7.1 TTC-based Acceptable 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
12、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 Ma
13、rketed 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 Process Related 工艺相关杂质的控制Impurities8.2 Considerations for Control Approaches控制方法要考虑的问题8.3 Considerations for Periodic Testing 定期
14、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 Clinical 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APPENDI
15、CES 附录ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC 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1. INTRODUCTION 概述The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing
16、 aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provides guidance for qualification and control for
17、 the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit pote
18、ntial carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Conduct 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
19、、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 ICH 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 i
20、n establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the inte
21、nded 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 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 a
22、pplications for marketing. It also applies to post-approval submissions of marketed products, and to new marketing applications for products 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
23、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 existing 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 acce
24、ptance 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 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
25、this guideline is not intended for the following types of drug substances and drug products: biological/biotechnological, peptide, oligonucleotide, 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
26、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 indications 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 the
27、rapeutic concentrations and may be expected to be associated with an increased cancer risk. Exposure to a mutagenic impurity in these cases would not significantly add to the cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable levels for non-mutagenic impuritie
28、s.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 produc
29、ts, flavoring agents, colorants, and perfumes. Application of this guideline to leachables associated with drug product packaging 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 a
30、ssessment principles of this guideline can be used if warranted for impurities in excipients that are used for the first time in 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
31、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 potential 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
32、 in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxicants that are non-mutagenic typically have threshold 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
33、 with the exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutagenic potential and the need for controls. Structure-based assessments are useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. There are a variet
34、y of approaches to conduct this evaluation including a review of the available literature, and/or computational toxicology assessment.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
35、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 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
