ICHM7(step4)基因毒性杂质评估和控制◆中英解析

1、ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMITPOTENTIAL 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 M7 Curre 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 c

2、onsultation by the regulatory parties, in accordanee with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the Europea n Union, Japa n and USA. M7 Docume nt History 文件历史 Code文件代码 History 历史 Date 日期 M7 Approval by the Steeri ng Committe

3、e un der Step 2 and release for public con sultati on. 第2阶段由筹委会批准，公开征求意见 6 February 2013 M7 Approval by the Steeri ng Committee un der 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 2014 Current Step 4 version 现行版本第 4阶段 M7 Corrige ndum to f

4、ix 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 2014 Legal Notice: This document is protected by copyright and maybe used, reproduced, in corporated into other works, adapted,

5、 modified, tran slated or distributed un der a public lice nse provided that ICHs copyright in the docume nt is ack no wledged at all times. In case of any adaption, modification or translation of the document, reas on able steps must be take n to clearly label, demarcate or otherwise ide ntify that

6、 cha nges were made to or based on the origi nal docume nt. Any impressi on that the adapti on, modificati on or tran slati on of the origi nal docume nt is en dorsed or spon sored by the ICH must be avoided.The docume nt is provided as is without warra nty of any kind. In no eve nt shall the ICH or

7、 the authors of the origi nal docume nt 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 rep

8、roduct ion must be obta ined from this copyright holder.ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT POTENTIALCARCINOGENICRISK 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 Harmoni sed Tripartite Guideli ne ICH三方协调指南 Havi ng reached Step 4 of the ICH Process at

9、the ICH Steeri ng Committee meeti ng on 5 June 2014, this Guideli ne is recomme nded for adoptio n to the three regulatory parties to ICH TABLE 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 PRODUCT上 市产品应考虑的问题 4.1 Post-Approval

10、Changes to the Drug Substa nee Chemistry, Manu facturi ng, and Con trols 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, Manu facturi ng, and Con trols 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 Con siderati ons for Marketed P

11、roducts 上市产品其它应考虑问题 5. DRUG SUBSTANCE AND DRUG PRODUCT原料药和制齐U杂质评估 IMPURITY ASSESSMENT 5.1 Synthetic Impurities 合成杂质 5.2 Degradati on Products 降解产物 5.3 Con sideratio ns for Cli nical 临床研发要考虑的冋题 Developme nt 6. HAZARD ASSESSMENT ELEMENTS 危害性评估要素 7. RISK CHARACTERIZATION 风险特征 7.1 TTC-based Acceptable I

12、n takes 根据TTC制订可接受摄入量 7.2 Acceptable In takes Based on 根据化合物特定风险评估制订的可接受摄 Compo un d-Specific Risk Assessme nts 入量 7.2.1 Mutagenic Impurities with Positive 致癌数据有利的诱变性杂质（表 1中的第1 Carcinogenicity Data (Class 1 in Table 1) 类） 7.2.2 Mutagenic Impurities with Evidence 具有实用阈值证据的诱变性杂质 for a Practical Thresh

13、old 7.3 Acceptable In takes in Relati on to LTL 与LTL暴露相关的可接受摄入量 Exposure 7.3.1 Clinical Development 临床研发 7.3.2 Marketed Products 已上市产品 7.4 Acceptable In takes for Multiple 多个诱变性杂质的可接受摄入量 Mutagenic Impurities 7.5 Excepti ons and Flexibility in 方法例外情况和弹性 Approaches 8. CONTROL 控制 8.1 Control of Process

14、 Related Impurities 工艺相关杂质的控制 8.2 Considerations for Control Approaches 控制方法要考虑的冋题 8.3 Con siderati ons for Periodic Test ing 定期检查要考虑的冋题 8.4 Con trol of Degradati on Products 降解产物的控制 8.5 Lifecycle Man ageme nt 生命周期管理 8.6 Con sideratio ns for Cli nical 临床研发要考虑的冋题 Developme nt 9. DOCUMENTATION 文件记录 9.

15、1 Cli nical Trial Applicati ons 临床试验应用 9.2 Common Tech ni cal Docume nt (Market ing 通用技术文件（上市申报） Applicati on) NOTES 注解 GLOSSARY 术语 REFERENCES 参考文献 APPENDICES 附录 IN PHARMACEUTICALS TOLIMIT POTENTIALCARCINOGENICRISK 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 substanc

16、es involves the use of reactive chemicals, reagents, solve nts, catalysts, and other process ing aids. As a result of chemical syn thesis 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)

17、: Impurities in NewDrug Products (Ref. 1, 2) provides guidanee for qualification and control for the majority of the impurities, limited guidanee 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 identi

18、fication, 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 Authoriza

19、tions 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

20、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 mutage nic impurities that reside or are

21、 reas on ably expected to reside in final drug substa nee or product, tak ing into con siderati on the inten ded con diti ons of huma n use. ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES 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

22、估和控制的建议。 2. SCOPE OF GUIDELINE 指南适用范围 This document is intended to provide guidanee for new drug substances and new drug products during their clinical development and subsequent applications for marketi ng. It also applies to post-approval submissi ons of marketed products, and to new marketi ng ap

23、plicati ons for products with a drug substa nee that is prese nt 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： Chan ges to the drug substa nee syn thesis result in new impurities or in crea

24、sed accepta nce criteria for existi ng 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 Chan ges in the formulati on, compositi on or manu facturi ng process result in new degradati on products or in creased accepta nce criteria for existi ng degradati on 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

25、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 inten ded for the follow ing types of drug substa nces and drug produc

26、ts: biological/biotech no logical, peptide, oligo nu cleotide, radiopharmaceutical, ferme ntati on products, herbal products, and crude products of ani mal or pla nt origi n. 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 guideli ne does not apply to drug substa

27、nces and drug products inten ded for adva need cancer in dicati ons as defi ned in the scope of ICH S9 (Ref. 4). Additi on ally, there may be some cases where a drug substa nee inten ded for other in dicati ons is itself genotoxic at therapeutic concentrations and may be expected to be associated wi

28、th an in creased cancer risk. Exposure to a mutage nic impurity in these cases would not significantly add to the cancer risk of the drug substanee. Therefore, impurities could be con trolled at acceptable levels for non-m utage nic 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

29、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. App

30、lication 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

31、 if warranted for impurities in excipients that are used for the first time in a drug product and are chemically syn thesized. 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. GENERAL PRINCIPLE

32、S 通用原贝U 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, pote ntially caus ing cancer. This type of mutage nic carci nogen is usually detected in a bacterial reverse mutatio n (

33、mutage ni city) assay. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms and usually do not pose carci nogenic risk in huma ns at the level ordin arily prese nt as impurities. Therefore to limit a possible human cancer risk associated with the exposure to potent

34、ially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutage nic pote ntial and the n eed for con trols. Structure-based assessme nts are useful for predict ing bacterial mutage ni city outcomes based upon the established kno wledge. There are a variety of approaches to

35、con duct this evaluati on in clud ing a review of the available literature, an d/or computati onal toxicology assessme nt. 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

36、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) con cept was developed to defi ne an acceptable in take for any un studied chemical that poses a n egligible risk of carcinogenicity or other toxic e

37、ffects. The methods upon which the TTC is based are gen erally con sidered to be very con servative since they in volve a simple lin ear extrapolation from the dose giving a 50%tumor incidenee (TD50) to a 1 in 106incidenee, using TD50 data for the most sen sitive species and most sen sitive site of

38、tumor in duct ion. For applicati on of a TTC in the assessme nt of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 卩 g/day corresponding to a theoretical 10-5 excess lifetime risk of cancer, can be justified. Some structural groups were identified to be

39、 of such high potency that in takes even below the TTC would theoretically be associated with a pote ntial for a sig ni fica nt carci nogenic risk. This group of high pote ncy mutage nic carci nogens referred to as the “ cohort of concern ”，co mprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy com

40、po un ds. 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%中瘤发生率（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1.5卩g/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

41、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 guideli ne bases acceptable in takes for mutage nic impurities on established risk assessme nt

42、 strategies. Acceptable risk duri ng the early developme nt phase is set at a theoretically calculated level of approximately one additi onal cancer per milli on. For later stages in developme nt and for marketed products, acceptable in creased cancer risk is set at a theoretically calculated level

43、of approximately one in one hun dred thousa nd. These risk levels represe nt a small theoretical in crease in risk whe n compared to huma no verall lifetime in cide nce of develop ing any type of cancer, which is greater tha n 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，

44、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。 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 no ted that established cancer risk assessme nts are based on lifetime exposures. 相较 Less-Tha n-Lifetime (LTL) exposures both duri ng developm

45、e nt and marketi ng can have higher acceptable in takes 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 h

46、ighly 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 mutage nic compo und. 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

47、。 However, exceedi ng the TTC is not n ecessarily associated with an in creased 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 in crease in cancer in cide nee is actually muchless tha n 1 in 100,0

48、00. In additi on, in cases where a mutage nic compo und is a non-carci nogen in a rode nt bioassay, there would be no predicted in crease in can cer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not n ecessarily associated with an i

49、n creased cancer risk for patie nts already exposed to the impurity. A risk assessme nt would determ ine whether any further actions would be take n. 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 定是否需要采取进一步行动。 Where a potential risk has been identified for an

50、impurity, an appropriate control 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 strategy leveragi ng process un dersta nding an d/or an alytical con trols 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

51、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 whe n an impurity is also a metabolite of the drug substa nee. In such cases the risk assessme nt that addresses mutage nicity of the metabolite can qualify the impurity. 有时一种杂质可能也是药品的一种代谢产物， 这时，对代谢产物的诱变性风险评估可以用于 支持该杂质的质量水平。 4. CONSIDERATIONS FOR MARK

52、ETED PRODUCTS 已上市药品要考虑的问题 This guideli ne is not inten ded to be applied retrospectively (i.e., to products marketed prior to adoption of this guideline). However, sometypes of post-approval cha nges warra nt a reassessme nt of safety relative to mutage nic impurities. This sect ion applies to these

53、 post-approval cha nges for products marketed prior to, or after, the adoption of this guideline. Section 8.5 (Lifecycle Management) contains additional recommendations for products marketed after adoption of this guideline. 本指南无意回顾性地应用于在指南采纳前已上市的药物。 但是，有些类型的批准后变更需要 对有关的诱变性杂质安全性重新进行评估。 本部分适用于在指南被采纳前

54、后上市药品的该类 批准后的变更。第 8.5 (生命周期管理)包括了对采纳本指南后已上市药品的其它建议。 4.1 Post-Approval Chan ges to the Drug Substa nee Chemistry, Manu facturi ng, and Controls 上市后变更-原料药研发、生产和控制 Post-approval submissi ons in volvi ng the drug substa nee chemistry, manu facturi ng, and controls should include an evaluation of the pot

55、ential risk impact associated with mutagenic impurities from changes to the route of synthesis, reagents, solvents, or process conditions after the starting material. Specifically, changes should be evaluated to determine if the changes result in any new mutagenic impurities or higher accepta nee cr

56、iteria for exist ing mutage nic impurities. Reevaluati on of impurities not impacted by changes is not recommended. For example, when only a portion of the manufacturing process is changed, the assessment of risk from mutagenic impurities should be limited to whether any new mutagenic impurities res

57、ult from the change, whether any mutagenic impurities formed during the affected step are in creased, and whether any known mutage nic impurities from up-stream steps are in creased. Regulatory submissi ons associated with such cha nges should describe the assessment as outlined in Section 9.2. Chan

58、ging the site of manufacture of drug substa nee, in termediates, or start ing materials or cha nging raw materials supplier will not require a reassessment of mutagenic impurity risk. 批准后申报涉及原料药的研发、 生产和控制应包括起始物料后的合成路线、 试剂、溶剂或工 艺条件变更时，诱变性杂质对潜在风险影响的评估。 特别是，变更评估要确定其是否会导致 任何新的诱变性杂质或已知诱变性杂质会有更高的可接受标准。 不建

59、议对不受变更影响的杂 质重新进行评估。例如，如果只有一部分生产工艺发生变更， 则诱变性杂质的风险评估应局 限于该变更是否会产生新的诱变性杂质、 在受影响的步骤中是否有诱变性杂质含升高， 以及 上游步骤中的已知诱变性杂质是否升高。 该变更发生时提交的法规申报资料应描述 9.2中所 列的评估。对原料药、中间体或起始物料的生产场所的变更， 或变更原料供应商则不需要对 诱变性杂质风险重新进行评估。 When a new drug substa nee supplier is proposed, evide nee that the drug substa nee produced by this su

60、pplier using the same route of syn thesis as an existi ng drug product marketed in the assessor s region is considered to be sufficient evidenee of acceptable risk/benefit regarding mutagenic impurities and an assessment per this guideli ne is not required. If this is not the case, the n an assessme