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1、ASSESSMENTASSESSMENT ANDAND CONTROLCONTROL OFOF DNADNA REACTIVE(MUTAGENIC)REACTIVE(MUTAGENIC) IMPURITIESIMPURITIES ININ PHARMACEUTICALSPHARMACEUTICALS TOLIMITTOLIMIT POTENTIALPOTENTIAL CARCINOGENICCARCINOGENIC RISKRISK 为限制潜在致癌风险而对药物中为限制潜在致癌风险而对药物中 DNADNA 活性（诱变性）杂质进行的评估和控制活性（诱变性）杂质进行的评估和控制 M7M7 Curre
2、nt Step 4 version dated 23 June 2014 This 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 recommended for adoption to the regulator
3、y bodies of the European Union, Japan and USA. M7 Document History 文件历史 Code 文件代码History 历史Date 日期 M7Approval 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 M7Approval by the Steering Committee under Step 4 and recommendation for adopt
4、ion 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 Current 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 20
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7、he 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 s
8、upplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. ASSESSMENTASSESSMENT ANDAND CONTROLCONTROL OFOF DNADNA REACTIVEREACTIVE (MUTAGENIC)(MUTAGENIC) IMPURITIESIMPURITIES ININ PHARMACEUTI
9、CALSPHARMACEUTICALS TOTO LIMITLIMIT POTENTIALCARCINOGENICPOTENTIALCARCINOGENIC RISKRISK 为限制潜在致癌风险而对药物中为限制潜在致癌风险而对药物中 DNADNA 活性（诱变性）杂质进行的评估和控制活性（诱变性）杂质进行的评估和控制 ICHICH HarmonisedHarmonised TripartiteTripartite GuidelineGuideline ICHICH 三方协调指南三方协调指南 Having reached Step 4 of the ICH Process at the ICH S
10、teering Committee meeting on 5 June 2014, this Guideline is recommended for adoption to the three regulatory parties to ICH TABLETABLE OFOF CONTENTSCONTENTS 目录 1.1. INTRODUCTIONINTRODUCTION 概述 2.2. SCOPESCOPE OFOF GUIDELINEGUIDELINE 指南范围 3.3. GENERALGENERAL PRINCIPLESPRINCIPLES 通用原则 4.4. CONSIDERATI
11、ONSCONSIDERATIONS FORFOR MARKETEDMARKETED PRODUCTSPRODUCTS 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 Clini
12、cal 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 5.5. DRUGDRUG SUBSTANCESUBSTANCE ANDAND DRUGDRUG PRODUCTPRODUCT IMPURITYIMPURITY ASSESSMENTASSESSMENT 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 Clini
13、cal Development 临床研发要考虑的问题 6.6. HAZARDHAZARD ASSESSMENTASSESSMENT ELEMENTSELEMENTS 危害性评估要素 7.7. RISKRISK CHARACTERIZATIONCHARACTERIZATION 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 Imp
14、urities 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
15、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 8.8. CONTROLCONTROL 控制 8.1 Control of Process Related 工艺相关杂质的控制 Impurities 8.2 Considerations for Control Approaches 控制方法要考虑的问题 8.3 Considerations for Periodic Testing 定期
16、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 9.9. DOCUMENTATIONDOCUMENTATION 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） NOTESNOTES 注解 GLOSSARYGLOSSARY 术语 REFERENCESREFERENCES 参考文献 APPENDICESAPPENDICES 附录附录 ASSESSMENTASSESSMENT ANDAND CONTROLCONTROL OFOF DNADNA REACTIVEREACTIVE (MUTAGENIC)(MUTAGENIC) IMPURITIESIMPURITIES ININ PHARM
