基因毒性杂质的评估与控制

ichm7基因毒性杂质评估和控制◆中英

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 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Current Step 4 version 现行版本第4阶段Legal 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 ICH's 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 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 Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT 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 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, 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 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 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。

【医药】如何控制基因毒性杂质

01、何为基因毒性杂质基因毒性杂质（或遗传毒性杂质，Genotoxic Impurity，GTI）是指能直接或间接损害DNA，引起DNA突变、染色体断裂、DNA重组及DNA 复制过程中共价键结合或插入，导致基因突变或癌症的物质（如卤代烷烃、烷基磺酸酯类等）。

潜在基因毒性杂质（Potential Genotoxic Impurity ，PGI）结构中含有与基因毒性杂质反应活性相似的基团（如肼类、环氧化合物、N-亚硝胺类等），通常也作为基因毒性杂质来评估。

基因毒性杂质主要来源于原料药合成过程中的起始物料、中间体、试剂和反应副产物。

此外，药物在合成、储存或者制剂过程中也可能会降解产生基因毒性杂质。

除此之外，有些药物通过激活正常细胞而产生基因毒性物质导致突变，如化疗药物顺铂等。

02、何为基因毒性杂质“警示结构”由于杂质结构的多样性，一般很难进行归类，因此，在缺乏安全性数据支持的情况下，法规和指导原则采用“警示结构”用来区分普通杂质和基因毒性杂质。

所谓“警示结构”，是指杂质中的特殊基团可能与遗传物质发生化学反应，诱导基因突变或者染色体断裂，因此具有潜在的致癌风险。

对于含有警示结构的杂质，应当进行（Q）SAR预测和体内外遗传毒性和致癌性研究，或者将杂质水平控制在毒理学关注阈值（TTC）之下。

但是含有警示结构并不能说明该杂质一定具有遗传毒性，而确认有遗传毒性的物质也不一定会产生致癌作用。

杂质自身性质和结构特点会对其毒性产生抑制或调节作用。

警示结构的重要性在于它提示了可能存在的遗传毒性和致癌性，为进一步的杂质安全性评价与控制指明方向。

（关于基因毒杂质警示结构的详细信息可参考欧盟发布的警示结构《Development ofstructure alerts for the in vivo micronucleus assay in rodents》）。

03、基因毒性杂质严格控制的必要性基因毒性杂质最主要的特点是在极低浓度时即可造成人体遗传物质的损伤，导致基因突变并促使肿瘤发生。

基因毒性杂质的评估与控制

6. Istituto Superiore di Sanita (Italy) 7. Prous Institute (Spain) 8. Swedish Toxicology Science Research Center(Sweden)
1.临床使用剂量增加 2.用药时长显著增加 3.病情严重或危及生命的病患状态下采用较高可接受摄入量，变为不那么严重的病患情况后，原有的杂质可接受摄入量不再适当 4.使用新的给药途径 5.扩大使用患者群包括孕妇和（或）小儿
◆新的杂质被确知属于第一类或第二类诱变性杂
质
THREE
基因毒性杂质的评估
一、评估内容
五、杂质残留风险评估考量
基毒杂质清除因子计算表
代码
GTI
到API 步骤
3 2 1
反应活性
1-100 X X
溶解性
1-10(100) X X
挥发性
1-10 X X
电离性
5 X X
消除因子/步
XXX
总消除因子
清除原理
Xx,xxx,xxx
参考文献： Teasdale A, Elder D, Chang S-J, et al. Risk assessment of genotoxic impurities in new chemical entities: strategies to demonstrate control[J]. Org Process Res Dev, 2013, 17: 221-230.
FDA
2008 年签发《原料药和成品药中遗传毒性和致癌性杂质，推荐方法》
内容和EMA指南基本一致，主要包括： ◆ 原料药和制剂中的基因毒性杂质生成的预防办法

ICH M7step4基因毒性杂质评估和控制◆中英

请联系网站删除只供学习与交流资料收集于网络，如有侵权IMPURITIESCONTROL OF DNA REACTIVE(MUTAGENIC) ASSESSMENT ANDPOTENTIAL RISKCARCINOGENIC IN PHARMACEUTICALS TOLIMITDNA为限制潜在致癌风险而对药物中活性（诱变性）杂质进行的评估和控制 M7Step 4 version Currentdated 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 recommended for adoption to the regulatory bodies of the European Union, Japan and USA.只供学习与交流．资料收集于网络，如有侵权请联系网站删除只供学习与交流M7Document History 文件历史阶段Current Step 4 version 现行版本第4reproduced, be used, copyright is protected by and may document Notice: Legal This incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's 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 thatthe adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.只供学习与交流．请联系网站删除只供学习与交流资料收集于网络，如有侵权The document is provided as is without warranty of any kind. In no event shallthe ICH or the authors of the original document be liable for any claim, damagesor other liability arising from the use of the document.parties. third content supplied by apply above-mentioned The permissions do not to for party, permission third in copyright where for Therefore, documents the vests a reproduction must be obtained from this copyright holder.只供学习与交流．请联系网站删除只供学习与交流资料收集于网络，如有侵权IMPURITIES(MUTAGENIC) OF DNA REACTIVE ASSESSMENT AND CONTROLRISKLIMIT IN PHARMACEUTICALS TO POTENTIALCARCINOGENIC活性（诱变性）杂质进行的评估和控制为限制潜在致癌风险而对药物中DNA ICH Harmonised Tripartite Guideline 三方协调指南ICH Step 4 of the ICH Process at the ICH Steering Committee meeting Having reachedregulatory three on 5 June 2014, this Guideline is recommended for adoption to the parties to ICH资料收集于网络，如有侵权请联系网站删除只供学习与交流只供学习与交流．资料收集于网络，如有侵权请联系网站删除只供学习与交流IMPURITIESDNA REACTIVE (MUTAGENIC) ASSESSMENT AND CONTROL OFRISKPHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC IN活性（诱变性）杂质进行的评估和控制为限制潜在致癌风险而对药物中DNA概述1. INTRODUCTIONreagents, chemicals, of reactive drug substances involves the use of The synthesis solvents, catalysts, and other processing aids. As a result of chemical synthesis associated and drug substances degradation, impurities reside in all or subsequent drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): and for qualification guidance (Ref. 1, 2) provides Impurities in New Drug Products those provided for impurities, limited guidance is control for the majority of the impurities that are DNA reactive. The purpose of this guideline is to provide a categorization, the identification, is applicable to practical framework that potential limit mutagenic these impurities to qualification, and control of 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 HumanClinical Trials and Marketing Authorizations for Pharmaceuticals (Ref. 3).导致在所有原催化剂和其它工艺助剂，原料药合成牵涉到使用活性化学物质、试剂、溶剂、新原料药中的杂质Q3A(R2)料药及其制剂中会残留有化学合成或其降解产物、杂质。

基因毒性杂质研究方案

基因毒性杂质研究方案基因毒性杂质研究是一种评估化学物质的潜在基因毒性的方法。

基因毒性杂质可以通过直接损害DNA或干扰DNA复制和修复过程来引发基因突变。

这些基因突变可能导致细胞死亡、肿瘤形成和遗传疾病。

为了研究基因毒性杂质，我们可以采用以下研究方案：1. 确定研究对象：选择一种潜在的基因毒性杂质，如化学物质或药物。

根据已有的文献和实验证据，确定该物质可能对基因产生毒性影响。

2. 毒性评估：使用细胞培养模型对潜在的基因毒性杂质进行毒性评估。

选择常用的细胞系，如人类肝细胞或小鼠胚胎细胞。

暴露这些细胞系于不同浓度的基因毒性杂质，并评估其对细胞的毒性效应，如细胞死亡率、增殖能力和DNA损伤。

通过比较不同浓度下的效应，可以确定该基因毒性杂质的剂量依赖性。

3. 潜在的基因突变：通过分析细胞培养后的DNA样本，使用一系列分子生物学技术来检测潜在的基因突变。

例如，可以使用聚合酶链式反应（PCR）来扩增特定基因区域，并使用DNA测序来鉴定突变位点。

还可以利用单细胞凝胶电泳（COMET）分析来检测DNA损伤和碱基修复的能力。

这些技术可以帮助确定基因毒性杂质对DNA的直接损害以及细胞的修复能力。

4. 基因表达分析：使用转录组测序技术来评估基因毒性杂质对基因表达的影响。

通过比较暴露于基因毒性杂质的细胞和未暴露的对照细胞，可以鉴定潜在的差异表达基因。

这些差异表达基因可能与基因毒性杂质相关的毒性途径和生物学效应有关。

5. 分析结果的解释：根据实验数据，进行数据统计和生物信息学分析，以解释实验结果。

这可能涉及到寻找共同受影响的信号通路、寻找注释基因和分析基因表达调控网络。

通过以上研究方案，我们可以全面地评估基因毒性杂质的作用机制和潜在的风险。

这些研究结果可以为药物开发和环境毒理学领域提供重要的参考，帮助保护人类和环境健康。

ICHM7(step4)基因毒性杂质评估和控制◆中英

ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT P OTENTIAL 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 andhas been subject to consultation by the regulatory parties, in accordance with theICH Process. At Step 4 of the Process the final draft is recommended for adoptionto 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6 February 2013 M7 Approval by the Steering Committee under Step 2and release for public consultation.第2阶段由筹委会批准，公开征求意见5 June 2014M7 Approval by the Steering Committee under Step 4and recommendation for adoption to the three ICHregulatory bodies.第4阶段由筹委会批准，推荐ICH三方药监局采用Current Step 4 version 现行版本第4阶段23 June 2014M7 Corrigendum to fix typographical errors andreplace word “degradants” with “degradationproducts” throughout the document.修正输入错误，将全文中“degradants”替换成“degradation products”.Legal Notice: This document is protected by copyright and may b e used, reproduced, incorporated into other works, adapted, modified, translated or distributed undera public license provided that ICH's copyright in the document is acknowledged atall times. In case of any adaption, modification or translation of the document,reasonable steps must be taken to clearly label, demarcate or otherwise identifythat changes were made to or based on the original document. Any impression thatthe adaption, modification or translation of the original document is endorsed orsponsored by the ICH must be avoided.The document is provided "as is" without warranty of any kind. In no event shallthe ICH or the authors of the original document be liable for any claim, damagesor 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 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 meetingon 5 June 2014, this Guideline 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批准后原料药化学、生产和质量变更4.1 Post-Approval Changes to the DrugSubstance Chemistry, Manufacturing, andControls4.2 Post-Approval Changes to the Drug批准后制剂的化学、生产和质量变更Product Chemistry, Manufacturing, andControls上市产品临床使用变更4.3 Changes to the Clinical Use ofMarketed Products4.4 Other Considerations for Marketed上市产品其它应考虑问题Products原料药和制剂杂质评估5. DRUG SUBSTANCE A ND DRUG PRODUCTIMPURITY ASSESSMENT5.1 Synthetic Impurities 合成杂质5.2 Degradation Products 降解产物5.3 Considerations for ClinicalDevelopment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 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 Evidencefor a Practical Threshold具有实用阈值证据的诱变性杂质7.3 Acceptable Intakes in Relation to LTLExposure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 MultipleMutagenic Impurities多个诱变性杂质的可接受摄入量7.5 Exceptions and Flexibility inApproaches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生命周期管理临床研发要考虑的问题8.6 Considerations for ClinicalDevelopment9. DOCUMENTATION文件记录9.1 Clinical Trial Applications临床试验应用9.2 Common Technical Document (Marketing通用技术文件（上市申报）Application)NOTES注解GLOSSARY术语REFERENCES参考文献APPENDICES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 aids. As a result of chemical synthesisor 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 D rug 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 apractical 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 Conduct of HumanClinical 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。

ICH M7(step4)基因毒性杂质评估和控制◆中英剖析

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 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 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 Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT 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 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, 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 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 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。

(完整版)基因毒性杂质的评估与控制

杂质来源
降解杂质
加速试验、长期试验、光降解、强制降解试验
环境污染
三、基因毒性杂质识别
工艺杂质
实际杂质
潜在杂质
API中实际观察到>ICH Q3A 报告限（0.05%）工艺杂质
1）合成API过程：起始物料，中间体，化学试剂 2）风险评估可能带入API中的，存在于起始物料，中间体中已识别的杂质，以及合理机理预测产生的副产物（对于工艺早期杂质携带入API的风险可忽略，但要提供基于风险论证的表明哪步后应该评估杂质的潜在突变性） 3）对后工艺引入的起始物料，评价起始物料合成最后一步的潜在基因毒性杂质
2018年
华海药业生产的缬沙坦原料药中含有微量基因毒性杂质N,N-二甲基亚硝胺（NDMA），缬沙坦及其相关制剂从欧洲、美国和中国市场被召回。
2018年
印度Torrent制药生产的缬沙坦片剂中也检测出含有NDMA，该公司也从美国市场上自愿召回了14批相关药品。
二、相关概念
何为基因毒性杂质？
基因毒性杂质，也称遗传毒性杂质，通常指较低水平可直接造成DNA损伤，进而导致DNA突变，因此可能引发癌症的DNA反应性物质。
EMA
2006年颁布《基因毒性杂质限度指南》
2010年发布《遗传毒性杂质限度指导原则问答》 ◆为限制新活性物质中的基因毒性杂质提供了解决问题的框架和具体方案。
◆新药必须进行基因毒性杂质分析
◆对于现有药品，不强制进行基因毒性杂质分析评估
◆对已上市产品进行化学合成变更或仿制药上市前，需对合成路线、过程控制、杂质概括评价并与现有产品对比，以确定未引入新的或更高水平的基因毒性杂质
降解杂质
长期稳定性试验， API 中观察到>ICH Q3A报告限降解产物

ICHM7(step4)基因毒性杂质评估和控制◆中英

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 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 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 Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT 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 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, 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 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 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。

基因杂质的评估和控制 ICH M7

（细菌诱变呈阳性*，无啮齿动物 TTC）
rodents》。或进入 The Carcinogenic Potency
致癌数据
Database (CPDB)，里面有 1547 种致癌物质的列
3
警示结构，与原料药结构无关，无控制不高于可接受限度（适当的
诱变数据
TTC）或检测细菌诱变含量：
表，结构式，CAS 号，作用部位，TTC 值等一系
基因杂质的评估和控制 ICH M7
1 概述
1 概述
ICH Q3A(R2) 新原料药中的杂质 ICH Q3B(R2) 新制剂中的杂质
关于主要杂质定性和控制的指南
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
EMA《遗传毒性杂质限度指导原则》
ICH M7 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目的：提供使用框架，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了控制。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人用条件下，给出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
➢ 如果有足够后续试验，可由单独的体外试验结果，可以对它的体内关联性进行评估。
➢ 若缺乏这些信息时，体外基因毒性物质经常被考虑为假定的体内诱变剂和致癌剂。
----摘自EMA《毒性杂质限度
指南》
✓ 为何重点研究基因毒性杂质？基毒杂质特点：很低浓度时即可造成人体遗传物质的损伤，进而导致基因突变并可能促使肿瘤发生。
补充
1 概述
✓ 何为基因毒性杂质、诱变杂质（Genotoxic Impurities，Mutagenic Impurities）？
基因毒性杂质（或遗传毒性杂质，Genotoxic Impurity ，GTI）是指化合物本身直接或间接损伤细胞DNA，产生基因突变或体内

ICH M7(step4)基因毒性杂质评估和控制◆中英解析

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 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 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 Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT 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 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, 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 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 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。

基因毒性杂质控制

2
因毒性杂质检测技术。
研究制定更有效的基因毒性杂质控制策
略，减少其对人体健康的潜在危害。
3
教育和宣传
加强公众对基因毒性杂质问题的认识，提高风险意识，并促进相关领域的交流和合作。
基因毒性杂质对健康的影响
基因毒性杂质的长期暴露可能导致诸多健康问题，包括癌症、生殖问题和遗传突变等。因此，控制和管理这些杂质对人体健康至关重要。
科学家使用显微镜来观察细胞和基因毒性物质之间的相互环境样本中存在着复杂的混合物，使得基因毒性杂质的检测和控制变得困难。
2 影响难以预测
不同基因毒性杂质对不同个体的影响各不相同，因此控制策略难以确定。
3 长期效应
一些基因毒性杂质对人体的影响可能需要长时间才能显现，给控制工作带来挑战。
芳香胺类化合物 (Aromatic Amines)
这些化合物常用于染料和塑料制造中，可导致诸如膀胱癌等严重健康问题。
基因毒性杂质的检测方法
试管实验
在实验室中，科学家使用试管等工具来鉴定和分析样本中的基因毒性杂质。
DNA测序
通过检测DNA序列的改变来确定基因毒性杂质对基因组的影响。
显微镜观察
基因毒性杂质控制
基因毒性杂质控制在生物领域中扮演着重要角色。本演示将介绍其背景、重要性以及对健康的影响。
常见基因毒性杂质
多环芳烃 (PAHs)
PAHs是常见的基因毒性杂质，可通过燃烧、柴油排放和烟草烟雾中获得。
硝基多环芳烃 (NPAHs)
NPAHs通常存在于排放源的烟雾中，与许多疾病的发展有关。
行业对基因毒性杂质控制的要求
食品和饮料
强调对原材料和成品的基因毒性杂质控制，确保产品安全。

基因杂质的评估和控制 ICH M7

计算十万分之一概率单致个癌杂质剂的可量接，受日将总摄该入量值除以50,000：
21.治3m疗期g/kg÷50,0≤10月0 = 0.42μ＞g1-/1k2g月.
＞1-10年
＞10年到终生
日计总摄算入量人（类μg/天每）日总摄120入量：0.422μ0g/kg×50kg1体0 重 = 21.3μ1.5g/
----摘自EMA《毒性杂质限度指南》
2
第 5 诱变杂质的评估
页
和控制
适用范围
研发期间和上市申报期间的新原料药和新制剂的杂质
已上市药物的批准后申报，已经之前已批准上市的制剂中同原料药生产的另一制剂的
新上市申报
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
生配物方变/更生、物组分技变更术或制生产品工艺、变更肽，类导致、产生寡新核的降苷解产酸物或、已有
为在何以重DN点A研反究应基物因质毒为性主杂要质研？究对象的体内体外试验中，如果基发毒现杂它质们特对点D：NA很具低有浓潜度在时的即破可坏造性成，人及体可遗称传之物为质基的因损毒伤，
性进。而导致基因突变并可能促使肿瘤发生。
如果有足够后续试验，可由单独的体外试验结果，可以对它的体内关联性进行评估。若缺乏这些信息时，体外基因毒性物质经常被考虑为假定的体内诱变剂和致癌剂。
步骤中的潜在诱变性杂质
已知结构和这些潜在杂质均按照第6部分要求评估其潜在诱变性
5.2 降解产物
原料药和制剂中的潜在降解产物是指经过合理推测，在长期存储
6
第 12 诱变杂质的评估
页
和控制
危害性评估要素
采用数据库和诱变以及细菌诱变数据文献检索对实际和可能杂质进行分析，根据分类表将其分类为1类、2类或5类；若无法获得这样的分类数据，则应进行结构-活性关系（SAR未以）发得现出评警结示论估结无构诱。，变足可

基因毒性杂质控制

杂质的检测水平及拟定限度有充分的科学文献依据；
(4) The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies. 杂质的检测水平及拟定限度不超过经过充分的毒理学研究的水平。
（2）特定限度控制策略
• 计算：已知致癌活性（如半数致癌剂量TD50），线性外推可接受限度，按十万分之一风险计算，TD50/50000，据此计算限度(见第16页，note4,环氧乙烷)；
• 参考：如有化学结构相似，且特定限度已确定的化合物，在提供结构相似合理性及支持数据前提下，可参考计算限度；
• 计算：如前例，已知NOEL，计算杂质的PDE，结合每日最大用药剂量计算限度；
➢ 方法3：起始原料或中间体标准或中控过程中控制在可接受限度以上；
明确杂质的去向及清除过程；根据实验室研究，成品残留在可接受限度的30%以下（推荐加标试验）；必要时有中试或商业化批数据支持。
➢ 方法4：充分理解工艺参数和影响杂质残留因素，有足够信心保证原料药中残留在可接受限度以下，不需检测（不定入任何标准）。
结论：按一般杂质控制。
三、基因毒性杂质的分类
需充分检索和对比文献后，确定控制策略！
三、基因毒性杂质的控制
4、基因毒性杂质（分类1、2和3）的限度
（Risk characterization M7 第7页）
（1）基于TTC的控制
一般为长期用药（＞10年）、杂质无致癌性数据（分类2和3）；杂质控制水平为1.5μg/日；
摘自：FDA Guidance for Industry ANDAs: Impurities in Drug Substances 第4页