ICH M7step4基因毒性杂质评估和控制中英解析.docx

1、ICH M7step4基因毒性杂质评估和控制中英解析ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK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M7CurrentStep 4versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been

2、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.M7Document History文件历史Code文件代码History历史Date日期M7Approval by the Steering Committee

3、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 2013M7Approval 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M7Corrigendum to fix typographical err

4、ors 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 distrib

5、uted 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, demarcate or otherwise identify that changes were made to or based on the orig

6、inal 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 no event shall the ICH or the authors of the original document be liable for any c

7、laim, 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 party, permission for reproduction must be obtained from this copyright holder.ASSESS

8、MENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK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 reachedStep 4of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guideline is recommen

9、ded 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批准后原料药化学、生产和质量变更4.2 Post

10、-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 Synthetic Impurities合

11、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订的可接受摄入量7.2.1 Mutagenic Impur

12、ities 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 Marketed Products已上市产品7.4 Acceptable

13、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 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 Pro

14、ducts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APPENDICES附录ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUT

15、AGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK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 aids. As a result of chemical synthesis or subsequent d

16、egradation, 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 the majority of the impurities, limited guidance is pro

17、vided 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 potential carcinogenic risk. This guideline is intended to c

18、omplement 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、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

19、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 in establishing levels of mutagenic impurities that are expected t

20、o 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 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

21、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 OFGUIDELINE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 marketing. It also applies to post-approval submiss

22、ions 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 synthe

23、sis 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 acceptance criteria for existing degradation products;配方变更、组分变更或生产工艺变更，导致产

24、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 this guideline is not intended for the following types of drug substances

25、 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 subst

26、ances 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 therapeutic concentrations and may be expected to be associated with an incr

27、eased cancer risk. Exposure to a mutagenic impurity in these cases would notsignificantly 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

28、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 products,flavoring agents, colorants, and perfumes. Application of this guideline

29、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 assessment principles of this guideline can be used if warranted for impuritie

30、s 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，则本指南的安全风险评估原则可以适用于辅料中的杂质。3. GENERALPRINCIPLES通用原则The focus of this guideline is o

31、n 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 in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxic

32、ants 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 with the exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to