wordASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性诱变性杂质进展的评估和控制M7CurrentStep 4versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is remended 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 mittee 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 mittee under Step 4 and remendation 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 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 2014Legal Notice:This document is protected by copyright and may be used, reproduced, 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, 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 no 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 party, permission for reproduction must be obtained from this copyright holder.ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性诱变性杂质进展的评估和控制ICH Harmonised Tripartite GuidelineICH三方协调指南Having reachedStep 4of the ICH Process at the ICH Steering mittee meeting on 5 June 2014, this Guideline is remended for adoption to the three regulatory parties to ICHTABLE OF CONTENTS目录1. INTRODUCTION概述2. SCOPE OF GUIDELINE指南X围3. GENERAL PRINCIPLES通用原如此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-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制订可承受摄入量7.2 Acceptable Intakes Based on pound-Specific Risk Assessments根据化合物特定风险评估制订的可承受摄入量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暴露相关的可承受摄入量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承受摄入量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 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 mon 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(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性诱变性杂质进展的评估和控制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 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, limi