ICH-M7(step4)基因毒性杂质评估和控制◆中英.doc

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 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 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 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 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 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 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 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。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 in 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 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 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 acceptance 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 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 therapeutic concentrations and may be expected to be associated with an increased 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 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 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 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 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 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 variety 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 are generally considered to be very conservative since they involve a simple linear extrapolation from the dose giving a 50% tumor incidence (TD50) to a 1 in 106incidence, using TD50data for the most sensitive species and most sensitive site of tumor induction. For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 g/day corresponding to a theoretical 10-5excess lifetime risk of cancer, can be justified. Some structural groups were identified to be of such high potency that intakes even below the TTC would theoretically be associated with a potential for a significant carcinogenic risk. This group of high potency mutagenic carcinogens referred to as the “cohort of concern”, comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds.已经建立了TTC概念，用于界定所有未经研究，但具有可忽略的致癌风险或其它毒性效果的化学品的可接受摄入量。基于TTC的方法一般被认为是非常保守的，因为它们牵涉到从给定的50%肿瘤发生率（TD50）简单线性外推到十万分之一发生率，且采用的数据是来自于最敏感物种和最敏感肿瘤部位的TD50数据。在使用TTC评估原料药和制剂中诱变性杂质的可接爱标准时，可以采用1.5g/天对应于十万分之一生命时长患癌风险。有些结构基团被识别为具有较高的效价，因此即使摄入量低于TTC水平，从理论上来说仍会导致可能的显著癌症风险。这类具有较高效价的基团被称为“关注队列”，包括黄曲霉素类、N-亚硝基化合物，以及烷基-氧化偶氮基化合物。During clinical development, it is expected that control strategies and approaches will be less developed in earlier phases where overall development experience is limited. This guideline bases acceptable intakes for mutagenic impurities on established risk assessment strategies. Acceptable risk during the early development phase is set at a theoretically calculated level of approximately one additional cancer per million. For later stages in development and for marketed products, acceptable increased cancer risk is set at a theoretically calculated level of approximately one in one hundred thousand. These risk levels represent a small theoretical increase in risk when compared to human overall lifetime incidence of developing any type of cancer, which is greater than 1 in 3.在临床研发期间，如果整体研发经验有限，在早期临床阶段对控制策略和控制方法的要求会较低。本指南是在已建立的风险评估策略的基础上，制订诱变性杂质的可接受摄入量。在早期研发阶段，可接受风险是建立在患癌率约为百万分之一的理论计算水平上的。在研发后期及上市后，可接受癌症增加风险是建立在患癌率约为十万分之一的理论计算水平上的。相较于人类整个生命周期罹患各类癌症的发生率（大于三分之一），这两个不同的风险水平在理论上风险稍有增加。It is noted that established cancer risk assessments are based on lifetime exposures. Less-Than-Lifetime (LTL) exposures both during development and marketing can have higher acceptable intakes of impurities and still maintain comparable risk levels.已注意到所建立的患癌风险评估是根据生命周期内暴露情形的。在研发期间和上市期间低于生命周期（LTL）暴露都可能允许摄入更多杂质，仍保留一定的风险水平。The use of a numerical cancer risk value (1 in 100,000) and its translation into risk-based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic indication of the actual risk.使用量化患癌风险值（十万分之一），并将其转化为根据风险计算的剂量（TTC值）是一种高度假想的概念，不应作为真实风险的一种实际指标。Nevertheless, the TTC concept provides an estimate of safe exposures for any mutagenic compound.不管怎样，TTC概念提供了对诱变性化合物下安全暴露的一种估计方法。However, exceeding the TTC is not necessarily associated with an increased cancer risk given the conservative assumptions employed in the derivation of the TTC value.但是，假出在TTC值计算时采用了保守假设，超出TTC值并不一定会伴随患癌风险增加。The most likely increase in cancer incidence is actually much less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be taken.大多数患癌可能性实际远低于十万分之一，另外，如果有一个诱变性化合物在啮齿动物生物含量中显示为非诱变性，则预测其致癌风险不会增加。基于上述这些原因，所有暴露在之后鉴定为诱变性杂质并不一定伴随已暴露于该杂质的患者癌症风险增加。应进行风险评估来决定是否需要采取进一步行动。Where a potential risk has been identified for an impurity, an appropriate control strategy leveraging process understanding and/or analytical controls should be developed to ensure that the mutagenic impurity is at or below the acceptable cancer risk level.如果一个杂质被鉴定为具有潜在风险，则需要采用一个适当的控制策略来平衡工艺知识和/或分析控制，以保证诱变性杂质等于或低于可接受的癌症风险水平。There may be cases when an impurity is also a metabolite of the drug substance. In such cases the risk assessment that ad