ich m7(step4)诱变性杂质评估和控制-2016_图文

ich m7(step4)诱变性杂质评估和控制-2016_图文 20140623 ICH M7，step4):诱变性杂质评估和控制 ，中英文1/3， ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES INPHARMACEUTICALS TO LIMIT 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 M7 Current 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 regulatory 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 M7 Approval by the Steering Committee under Step 2 and release for 6 February 2013 public consultation. 第2阶段由筹委会批准，公开征求意见 M7 Approval by the Steering Committee under Step 4 and 5 June 2014 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 Current Step 4 version 现行版本第4阶段 M7 Corrigendum to fix typographical errors and replace word 23 June 2014 “degradants” with “degradation products” 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 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 INPHARMACEUTICALS TO LIMIT 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 ICH Harmonised Tripartite Guideline ICH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 ICH 目录 TABLE OF CONTENTS 概述 1. INTRODUCTION 指南范围 2. SCOPE OF GUIDELINE 通用原则 3. GENERAL PRINCIPLES 上市产品应考虑的问题 4. CONSIDERATIONS FOR MARKETED PRODUCTS 批准后原料药化学、生产和质量变更 4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls 批准后制剂的化学、生产和质量变更 4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls 上市产品临床使用变更 4.3 Changes to the Clinical Use of Marketed Products 上市产品其它应考虑问题 4.4 Other Considerations for Marketed Products 原料药和制剂杂质评估 5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT 合成杂质 5.1 Synthetic Impurities 降解产物 5.2 Degradation Products 临床研发要考虑的问题 5.3 Considerations for Clinical Development 危害性评估要素 6. HAZARD ASSESSMENT ELEMENTS 风险特征 7. RISK CHARACTERIZATION 根据TTC制订可接受摄入量 7.1 TTC-based Acceptable Intakes 根据化合物特定风险评估制订的可接受摄入量 7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments 致癌数据有利的诱变性杂质(表1中的第1类) 7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1) 具有实用阈值证据的诱变性杂质 7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold 与LTL暴露相关的可接受摄入量 7.3 Acceptable Intakes in Relation to LTL Exposure 临床研发 7.3.1 Clinical Development 已上市产品 7.3.2 Marketed Products 多个诱变性杂质的可接受摄入量 7.4 Acceptable Intakes for Multiple Mutagenic Impurities 方法例外情况和弹性 7.5 Exceptions and Flexibility in Approaches 控制 8. CONTROL 工艺 钢结构制作工艺流程车尿素生产工艺流程自动玻璃钢生产工艺2工艺纪律检查制度q345焊接工艺规程 相关杂质的控制 8.1 Control of Process Related Impurities 控制方法要考虑的问题 8.2 Considerations for Control Approaches 定期检查要考虑的问题 8.3 Considerations for Periodic Testing 降解产物的控制 8.4 Control of Degradation Products 生命周期管理 8.5 Lifecycle Management 临床研发要考虑的问题 8.6 Considerations for Clinical Development 文件记录 9. DOCUMENTATION 临床试验应用 9.1 Clinical Trial Applications 通用技术文件(上市申报) 9.2 Common Technical Document (Marketing Application) 注解 NOTES 术语 GLOSSARY 参考文献 REFERENCES APPENDICES 附录 ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES INPHARMACEUTICALS TO LIMIT 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 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 OF GUIDELINE 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 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 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 not significantly 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. GENERAL PRINCIPLES 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 106 incidence, using TD50 data 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 μg/day corresponding to a theoretical 10-5 excess 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1.5μg/ 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 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 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 addresses mutagenicity 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 MARKETED PRODUCTS 已上市药品要考虑的问题 This guideline is not intended to be applied retrospectively (i.e., to products marketed prior to adoption of this guideline). However, some types of post-approval changes warrant a reassessment of safety relative to mutagenic impurities. This section applies to these post-approval changes 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 Changes to the Drug Substance Chemistry, Manufacturing, and Controls 上市后变更---原料药研发、生产和控制 Post-approval submissions involving the drug substance chemistry, manufacturing, and controls should include an evaluation of the potential 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 acceptance criteria for existing mutagenic impurities. Reevaluation 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 result from the change, whether any mutagenic impurities formed during the affected step are increased, and whether any known mutagenic impurities from up-stream steps are increased. Regulatory submissions associated with such changes should describe the assessment as outlined in Section 9.2. Changing the site of manufacture of drug substance, intermediates, or starting materials or changing 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 substance supplier is proposed, evidence that the drug substance produced by this supplier using the same route of synthesis as an existing drug product marketed in the assessor’s region is considered to be sufficient evidence of acceptable risk/benefit regarding mutagenic impurities and an assessment per this guideline is not required. If this is not the case, then an assessment per this guideline is expected. 如果拟提交一个新的原料药供应商，如有证据证明该供应商生产的原料药采用了与审评区域 内已上市制剂中所用的原料药具有相同的合成路线，则足以说明关于诱变性杂质其风险/利益 是可以接受的，不需要根据本指南进行评估。如果不同这样，则需要根据本指南进行评估。 4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls 上市后变更---制剂研发、生产和控制 Post-approval submissions involving the drug product (e.g., change in composition, manufacturing process, dosage form) should include an evaluation of the potential risk associated with any new mutagenic degradation products or higher acceptance criteria for existing mutagenic degradation products. If appropriate, the regulatory submission would include an updated control strategy. Reevaluation of the drug substance associated with drug products is not recommended or expected provided there are no changes to the drug substance. Changing the site of manufacture of drug product will not require a reassessment of mutagenic impurity risk. 上市后申报如果涉及制剂(例如、成分、生产工艺、剂型)，则应包括对所有新的诱变性降解产物或 已有诱变性降解产物更高的可接受标准进行评估。适当时，法规申报资料应包括对控制策略的更新。 如果原料药并没有发生变更，则不建议，也不期望对制剂相关的原料药重新进行评估，制剂生产场所 变更不需要对诱变性杂质风险重新进行评估。 4.3 Changes to the Clinical Use of Marketed Products 上市后药品临床使用变更 Changes to the clinical use of marketed products that can warrant a reevaluation of the mutagenic impurity limits include a significant increase in clinical dose, an increase in duration of use (in particular when a mutagenic impurity was controlled above the lifetime acceptable intake for a previous indication that may no longer be appropriate for the longer treatment duration associated with the new indication), or for a change in indication from a serious or life threatening condition where higher acceptable intakes were justified (Section 7.5) to an indication for a less serious condition where the existing impurity acceptable intakes may no longer be appropriate. Changes to the clinical use of marketed products associated with new routes of administration or expansion into patient populations that include pregnant women and/or pediatrics will not warrant a reevaluation, assuming no increases in daily dose or duration of treatment. 已上市药品的临床应用变更拒收情节包括，变更所引起的对诱变杂质限度的重新评估中会包括临床使 用剂量的显著增加、用药时长的增加(特别是当根据之前的指征，将诱变性杂质控制在超出生命全程 使用时可接受摄入量时，可能采用新的指征，其原定摄入量已不再适用于更长的治疗时长。)或者是 指征变更是从已论述的在病情较严重或危及生命的病患状态下采用较高可接受摄入量的情况，变成不 那么严重的病患情况，原有的杂质可接受摄入量可能不再适当了。如果已上市药品的临床应用变更包 涵有使用新的给药途径，或扩大使用患者群，从而包括孕妇和/或小儿，假定日剂量或用药时长不增加， 则无法保证重新评估符合要求。 4.4 Other Considerations for Marketed Products 已上市药物的其它需考虑问题 Application of this guideline may be warranted to marketed products if there is specific cause for concern. The existence of impurity structural alerts alone is considered insufficient to trigger follow-up measures, unless it is a structure in the cohort of concern (Section 3). However a specific cause for concern would be new relevant impurity hazard data (classified as Class 1 or 2, Section 6) generated after the overall control strategy and specifications for market authorization were established. This new relevant impurity hazard data should be derived from high-quality scientific studies consistent with relevant regulatory testing guidelines, with data records or reports readily available. Similarly, a newly discovered impurity that is a known Class 1 or Class 2 mutagen that is present in a marketed product could also be a cause for concern. In both of these cases when the applicant becomes aware of this new information, an evaluation per this guideline should be conducted. 本指南在某些特殊原因考虑时可以适用于已上市的药品。仅凭杂质存在警示结构是无法启动后续措施 的，除非该结构具有队列方面的担忧(第3部分)。所谓的一种特殊顾虑原因可以是在上市产品已建 立其总体控制策略和质量标准后所获得的新的相关杂质危害数据(分类为第1或和2类，第6部分)。 这些新的相关杂质危害性数据所采用的研究方法应具有高质量科学性，且与相关的法规测试指南相一 致，其数据记录或 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 应易于获得。类似地，在已上市药品中发现一个新的杂质，且被确知属于第1 类或第2类诱变性，则也属于一种特殊顾虑原因。上述两种情形下，一旦申报人知晓这些新的信息， 则需要实施本指南所要求的评估。 5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT 原料药和制剂杂质评估 Actual and potential impurities that are likely to arise during the synthesis and storage of a new drug substance, and during manufacturing and storage of a new drug product should be assessed. 实际存在和可能存在的杂质是可能在新原料药合成和存贮过程、生产过程中生成。对新制剂的存贮条 件应进行评估。 The impurity assessment is a two-stage process: 杂质评估可以分为两个阶段: — Actual impurities that have been identified should be considered for their mutagenic potential. — 已被鉴定的实际存在的杂质应考虑其潜在诱变性 — An assessment of potential impurities likely to be present in the final drug substance is carried out to determine if further evaluation of their mutagenic potential is required. — 对可能存在于原料药中的潜在杂质进行评估，以确定是否需要对其潜在诱变性进行进一步评估 The steps as applied to synthetic impurities and degradation products are described in Sections 5.1 and 5.2, respectively. 适用于合成杂质和降解产物的方法分别在第5.1和5.2部分进行了描述。 5.1 Synthetic Impurities 合成杂质 Actual impurities include those observed in the drug substance above the ICH Q3A reporting thresholds. Identification of actual impurities is expected when the levels exceed the identification thresholds outlined by ICH Q3A. It is acknowledged that some impurities below the identification threshold may also have been identified. 实际杂质包括原料药中超出ICH Q3A报告阈的杂质。如果杂质水平超过了ICH Q3A中所述的鉴别 阈，则需要进行鉴别。有些低于鉴别阈的杂质可能也是经过鉴别的。 Potential impurities in the drug substance can include starting materials, reagents and intermediates in the route of synthesis from the starting material to the drug substance. 原料药中潜在杂质可以包括起始物料、试剂和从起始物料到原料药合成路线中的中间体， The risk of carryover into the drug substance should be assessed for identified impurities that are present in starting materials and intermediates, and impurities that are reasonably expected by-products in the route of synthesis from the starting material to the drug substance. As the risk of carryover may be negligible for some impurities (e.g., those impurities in early synthetic steps of long routes of synthesis), a risk-based justification could be provided for the point in the synthesis after which these types of impurities should be evaluated for mutagenic potential. 应评估起始物料和中间体中的杂质，以及从起始物料到原料药的合成路线中会生成的副产物被带入原 料药的风险。由于有些杂质被带入原料药的风险可以忽略(例如，很长的合成路线中较早的合成步骤 中的杂质)，可以提交对这些杂质在合成路线某一点时基于风险的论述。在合成路线该点之后，此类 杂质需要评估其诱变可能性。 For starting materials that are introduced late in the synthesis of the drug substance (and where the synthetic route of the starting material is known) the final steps of the starting material synthesis should be evaluated for potential mutagenic impurities. 对于在原料药合成路线后期才引入的起始物料(以及如果已知起始物料的合成路线)，需要评估起始 物料合成的最终步骤中的潜在诱变性杂质。 Actual impurities where the structures are known and potential impurities as defined above should be evaluated for mutagenic potential as described in Section 6. 已知其结构的实际杂质和如上所述的潜在杂质应按第6部分要求评估其潜在诱变性。 5.2 Degradation Products 降解产物 Actual drug substance degradation products include those observed above the ICH Q3A reporting threshold during storage of the drug substance in the proposed long-term storage conditions and primary and secondary packaging. Actual degradation products in the drug product include those observed above the ICH Q3B reporting threshold during storage of the drug product in the proposed long-term storage conditions and primary and secondary packaging, and also include those impurities that arise during the manufacture of the drug product. Identification of actual degradation products is expected when the levels exceed the identification thresholds outlined by ICH Q3A/Q3B. It is acknowledged that some degradation products below the identification threshold may also have been identified. 原料药实际降解产物包括原料药在内包装和外包装内，在拟定的长期存贮条件下原料药存贮期间观察 到的高于ICH Q3A报告阈值的物质。制剂中实际降解产物包括制剂在内包装和外包装内，在拟定的 长期存贮条件下原料药存贮期间观察到的高于ICH Q3B报告阈值的物质，还包括在制剂生产过程中 产生的那些杂质。如果降解产物的含量水平超过ICH Q3A/Q3B的鉴别阈，则应进行鉴别。有些低于 鉴别阈值的降解产物可能也是经过鉴别的。 Potential degradation products in the drug substance and drug product are those that may be reasonably expected to form during long term storage conditions. Potential degradation products include those that form above the ICH Q3A/B identification threshold during accelerated stability studies (e.g., 40?C/75% relative humidity for 6 months) and confirmatory photo-stability studies as described in ICH Q1B (Ref. 5), but are yet to be confirmed in the drug substance or drug product under long-term storage conditions in the primary packaging. 原料药和制剂中潜在的降解产物是指经过合理推测，在长期存贮条件下可能会形成的物质。潜在降解 产物包括在加速稳定性试验中(例如 40?C/75%下6个月)和ICH Q1B(参考文献5)光照稳定性试验 中形成的超出ICH Q3A/B的鉴别限，但在原料药和制剂内包装长期存贮条件下尚未确认的物质。 Knowledge of relevant degradation pathways can be used to help guide decisions on the selection of potential degradation products to be evaluated for mutagenicity e.g., from degradation chemistry principles, relevant stress testing studies, and development stability studies. 相关降解途径的知识有助于指导选择性地评估潜在降解产物的诱变性，例如，从降解化学原理、相关 强降解试验和研发稳定性研究。 Actual and potential degradation products likely to be present in the final drug substance or drug product and where the structure is known should be evaluated for mutagenic potential as described in Section 6. 实际存在和可能存在于最终原料药或制剂中的降解产物只要知道结构，均应根据第6部分要 求评估其诱变可能性。 5.3 Considerations for Clinical Development 临床研发中要考虑的问题 It is expected that the impurity assessment described in Sections 5.1 and 5.2 applies to products in clinical development. However, it is acknowledged that the available information is limited. For example, information from long term stability studies and photo-stability studies may not be available during clinical development and thus information on potential degradation products may be limited. Additionally, the thresholds outlined in ICH Q3A/B do not apply to products in clinical development and consequently fewer impurities will be identified. 要求在临床阶段应用第5.1和5.2部分对杂质进行评估。但是，众所周知可能获得的信息会比较有限。 例如，在临床阶段可能还没有长期稳定性研究和光照稳定性试验数据，因此关于潜在降解杂质的资料 可能比较有限。另外，在ICH Q3A/B中列出的阈值不适用于临床阶段的药品，因此被鉴别出的杂质 会很少。 6. HAZARD ASSESSMENT ELEMENTS 危害性评估要素 Hazard assessment involves an initial analysis of actual and potential impurities by conducting database and literature searches for carcinogenicity and bacterial mutagenicity data in order to classify them as Class 1, 2, or 5 according to Table 1. If data for such a classification are not available, an assessment of Structure-Activity Relationships (SAR) that focuses on bacterial mutagenicity predictions should be performed. This could lead to a classification into Class 3, 4, or 5. 危害性分析会涉及采用数据库和诱变和细菌诱变数据文献检索启动对实际和可能杂质的分析，以根据 表1将其分类为第1类、第2类或第5类。如果无法获得这样的分类数据，则应进行结构-活性关系 (SAR)评估，该评估应着重关注细菌诱变性预期。这时可能会使得该杂质被分入第3类、第4类或 第5类。 Table 1: Impurities Classification with Respect to Mutagenic and Carcinogenic Potential and Resulting Control Actions Class Definition Proposed action for control (details in Section 7 and 8) 1 Known mutagenic carcinogens Control at or below compound-specific acceptable limit 2 Known mutagens with unknown Control at or below acceptable limits (appropriate carcinogenic potential (bacterial TTC) mutagenicity positive*, no rodent carcinogenicity data) 3 Alerting structure, unrelated to the Control at or below acceptable limits (appropriate structure of the drug substance: no TTC) or conduct bacterial mutagenicity assay: mutagenicity data If non-mutagenic = Class 5 If mutagenic = Class 2 4 Alerting structure, same alert in drug Treat as non-mutagenic impurity substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenic 5 No structural alerts, or alerting Treat as non-mutagenic impurity structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity *Or other relevant positive mutagenicity data indicative of DNA-reactivity related induction of gene mutations (e.g., positive findings in in vivo gene mutation studies) 表1:根据诱变性和致癌性及其控制措施对杂质分类 分类 定义 拟定控制措施(详见第7和8部分) 已知诱变致癌性 控制不高于化合物可接受限度 1 已知具有诱变性，致癌效应未知(细菌控制不高于可接受限度(适当的TTC) 2 诱变呈阳性*，无啮齿动物致癌数据) 警示结构，与原料药结构无关，无诱变控制不高于可接受限度(适当的TTC)或检测细菌诱3 性数据 变含量: 如果非诱变性 = 第5类 如果具有诱变性 = 第2类 警示结构，与原料药或有关物质有相同与非诱变性杂质同等对待 4 警示(例如，工艺中间体)，经测试为 无诱变性 无警示结构，或警示结果具有充分的数与非诱变性杂质同等对待 5 据证明其不具备诱变性和致癌性 *或其它相关阳性诱变数据，说明与诱导基因变性的DNA反应活性(例如，体内基因诱变研究显示阳性) A computational toxicology assessment should be performed using (Q)SAR methodologies that predict the outcome of a bacterial mutagenicity assay (Ref. 6). Two (Q)SAR prediction methodologies that complement each other should be applied. One methodology should be expert rule-based and the second methodology should be statistical-based. (Q)SAR models utilizing these prediction methodologies should follow the general validation principles set forth by the Organisation for Economic Co-operation and Development (OECD). 应采用(Q)SAR方法进行计算学毒性评估，预测细菌诱变含量(参考文献6)的结果。要使用两个 相互补充的(Q)SAR预测方法。一个方法应是依据专家规则的，另一个方法则应该是统计方式的。 (Q)SAR模式采用的这些预测方法应服从OECD制订的通用验证原则。 The absence of structural alerts from two complementary (Q)SAR methodologies (expert rule-based and statistical) is sufficient to conclude that the impurity is of no mutagenic concern, and no further testing is recommended (Class 5 in Table 1). 两个互补的(Q)SAR方法(专家规则和统计学)如果没有发现结构警示，则足以得出结论该杂质没 有诱变可能，不需要做进一步的检测(表1中第5类)。 If warranted, the outcome of any computer system-based analysis can be reviewed with the use of expert knowledge in order to provide additional supportive evidence on relevance of any positive, negative, conflicting or inconclusive prediction and provide a rationale to support the final conclusion. 如果可以得到保证的话，所有基于计算机系统的分析均可以使用专家知识进行审核，以对所有阳性、 阴性、相互矛盾或无法得出结论的预期之间的相关性提供额外的支持性证据，从而支持最终结论的合 理性。 To follow up on a relevant structural alert (Class 3 in Table 1), either adequate control measures could be applied or a bacterial mutagenicity assay with the impurity alone can be conducted. An appropriately conducted negative bacterial mutagenicity assay (Note 2) would overrule any structure-based concern, and no further genotoxicity assessments would be recommended (Note 1). These impurities should be considered non-mutagenic (Class 5 in Table 1). A positive bacterial mutagenicity result would warrant further hazard assessment and/or control measures (Class 2 in Table 1). For instance, when levels of the impurity cannot be controlled at an appropriate acceptable limit, it is recommended that the impurity be tested in an in vivo gene mutation assay in order to understand the relevance of the bacterial mutagenicity assay result under in vivo conditions. The selection of other in vivo genotoxicity assays should be scientifically justified based on knowledge of the mechanism of action of the impurity and expected target tissue exposure (Note 3). In vivo studies should be designed taking into consideration existing ICH genotoxicity Guidelines. Results in the appropriate in vivo assay may support setting compound specific impurity limits. 在对有关的警示结构(表1第3类)进行确认之后，可以采用充分的控制措施，或者对该杂质单独进 行细菌诱变测试。如果所得的细菌诱变测试(注2)结果为阴性，则可以推翻基于结构的疑虑，这时 不建议进行进一步的基因毒性评估(注1)。这些杂质应被当作非诱变性杂质(表1中第5类)。如 果细菌诱变测试为阳性，则要进行进一步的危害性分析和/或采取控制措施(表1中第2类)。例如， 如果杂质的水平不能被控制在一个适当的可接受水平，则建议进行体内基因诱变测试，以搞清楚在体 内环境下细菌诱变测试结果。其它体内基因毒性测试的选择也应根据杂质的反应机理和预期标靶组织 暴露(注3)的知识进行科学论述。体内研究的 设计 领导形象设计圆作业设计ao工艺污水处理厂设计附属工程施工组织设计清扫机器人结构设计 应考虑已有的ICH基因毒性指南。恰当的体内测 试结果可以用于支持设定特定化合物杂质的限度。 An impurity with a structural alert that is shared (e.g., same structural alert in the same position and chemical environment) with the drug substance or related compounds can be considered as non-mutagenic (Class 4 in Table 1) if the testing of such material in the bacterial mutagenicity assay was negative. 如果一种杂质具有与药用物质或相关化合物具有相似的警示结构(例如，在相同位置和相同化学环境 下具有相同警示结构)，且该物料的细菌诱变测试为阴性，则该杂质可以被认为是非诱变性的(表1 第4类)。 7. RISK CHARACTERIZATION 风险定性 As a result of hazard assessment described in Section 6, each impurity will be assigned to one of the five classes in Table 1. For impurities belonging in Classes 1, 2, and 3 the principles of risk characterization used to derive acceptable intakes are described in this section. 作为第6部分所述的危害性评估的结果，每个杂质会按表1中分在5类中。本部分描述的是用于1、 2、3类杂质计算可接受摄入量的风险定性原则。 7.1 TTC-based Acceptable Intakes 根据TTC计算可接受摄入量 A TTC-based acceptable intake of a mutagenic impurity of 1.5 μg per person per day is considered to be associated with a negligible risk (theoretical excess cancer risk of <1 in 100,000 over a lifetime of exposure) and can in general be used for most pharmaceuticals as a default to derive an acceptable limit for control. This approach would usually be used for mutagenic impurities present in pharmaceuticals for long-term treatment (> 10 years) and where no carcinogenicity data are available (Classes 2 and 3). 根据TTC计算可接受摄入量时，一个具有诱变性的杂质每天每人摄入1.5μg时其风险被认为是可以 忽略的(终生暴露情况下理论的患癌风险小于十万分之一)，可以通用于大部分药物，作为默认的可 接受限度控制标准。该方法一般用于长期治疗用药物中的诱变性杂质(>10年)，且没有致癌数据时 (第2类和3类)。 7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments 根据化合物特定 风险评估计算的可接受摄入量 7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1) 具 1第1类) 有阳性致癌数据的诱变杂质(表 Compound-specific risk assessments to derive acceptable intakes should be applied instead of the TTC-based acceptable intakes where sufficient carcinogenicity data exist. For a known mutagenic carcinogen, a compound-specific acceptable intake can be calculated based on carcinogenic potency and linear extrapolation as a default approach. Alternatively, other established risk assessment practices such as those used by international regulatory bodies may be applied either to calculate acceptable intakes or to use already existing values published by regulatory authorities (Note 4). 如果具备足够的基因致癌性数据，则应采用对特定化合物进行风险评估的方式计算可接受摄入量，取 代根据TTC所计算的可接受摄入量。对于已知具有突变致癌性的化合物，可以根据致癌可能性和线 性计算可接受摄入量，这时默认采用线性外推法。对应地，其它已实施的风险评估经验，例如，被国 际法规实体采用的经验，也可以用于计算可接受摄入量，或采用已由法规当局公布的值(注4)。 Compound-specific calculations for acceptable intakes can be applied case-by-case for impurities which are chemically similar to a known carcinogen compound class (class-specific acceptable intakes) provided that a rationale for chemical similarity and supporting data can be demonstrated (Note 5). 对特定化合物的可接受摄入量的计算方法可以根据实际情况应用于与已知致癌化合物在化学结构上 类别较相似的杂质(按类别制订的可接受摄入量)，但前提是必须证明该杂质与已知化合物化学结构 相似性的合理性及具备支持性数据。 7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold 有实际阈值证据的诱 变性杂质 The existence of mechanisms leading to a dose response that is non-linear or has a practical threshold is increasingly recognized, not only for compounds that interact with non-DNA targets but also for DNA-reactive compounds, whose effects may be modulated by, for example, rapid detoxification before coming into contact with DNA, or by effective repair of induced damage. The regulatory approach to such compounds can be based on the identification of a No-Observed Effect Level (NOEL) and use of uncertainty factors (ICH Q3C(R5), Ref. 7) to calculate a Permissible Daily Exposure (PDE) when data are available. 大家现在越来越认识到，有一些机理说明对剂量的反应并非线性或实用阈值，不仅仅是与非DNA靶 标产生作用的化合物，也包括与DNA有活性反应的化合物，其影响可能会，例如，在与DNA接触 前其毒性即被快速清除，或对产生的损伤进行有效修复。针对该类化合物的合规方法可以是根据对无 明显反应水平(NOEL)的鉴别，在可以获得数据的情况下，使用不确定性因子(ICH Q3C(R5) 参考文献7)计算允许日暴露量(PDE)。 The acceptable intakes derived from compound-specific risk assessments (Section 7.2) can be adjusted for shorter duration of use in the same proportions as defined in the following sections (Section 7.3.1 and 7.3.2) or should be limited to not more than 0.5%, whichever is lower. For example, if the compound specific acceptable intake is 15 μg/day for lifetime exposure, the less than lifetime limits (Table 2) can be increased to a daily intake of 100 μg (> 1-10 years treatment duration), 200 μg (> 1-12 months) or 1200 μg (< 1 month). However, for a drug with a maximum daily dose of, for instance, 100 mg the acceptable daily intake for the < 1 month duration would be limited to 0.5% (500 μg) rather than 1200 μg. 在短期服用时，特定化合物风险分析所获得的可接受服用量(第7.2部分)可以按以下部分所指定的 比例进行调整(第7.3.1和7.3.2部分)，或限制不超过0.1%，取低者。例如，如果一个特定化合物 的可接受服用量为终生暴露期15μg/天，在短于终生时长暴露时的限度(表2)可以增加至100μg (>1-10年治疗进长)，200μg(>1-12月)或1200μg(<1个月)。但是，对于具有最大日服用剂 量的药物，例如，100mg，则<1个月时长的可接受日服用剂量应受限于0.1%(500μg)，而不是1200μg。 7.3 Acceptable Intakes in Relation to LTL Exposure 与LTL暴露有关的可接受摄入量 Standard risk assessments of known carcinogens assume that cancer risk increases as a function of cumulative dose. Thus, cancer risk of a continuous low dose over a lifetime would be equivalent to the cancer risk associated with an identical cumulative exposure averaged over a shorter duration. 对已知致癌物的标准风险评估假定癌症风险随着给药量的累积而增加，这样，终生以低剂量持续给药 时癌症风险则与在短期内大量给药具有相同的累积暴露平均值。 The TTC-based acceptable intake of 1.5μg/day is considered to be protective for a lifetime of daily exposure. To address LTL exposures to mutagenic impurities in pharmaceuticals, an approach is applied in which the acceptable cumulative lifetime dose (1.5μg/day x 25,550 days = 38.3 mg) is uniformly distributed over the total number of exposure days during LTL exposure. This would allow higher daily intake of mutagenic impurities than would be the case for lifetime exposure and still maintain comparable risk levels for daily and non-daily treatment regimens. Table 2 is derived from the above concepts and illustrates the acceptable intakes for LTL to lifetime exposures for clinical development and marketing. In the case of intermittent dosing, the acceptable daily intake should be based on the total number of dosing days instead of the time interval over which the doses were administered and that number of dosing days should be related to the relevant duration category in Table 2. For example, a drug administered once per week for 2 years (i.e., 104 dosing days) would have an acceptable intake per dose of 20μg. 基于TTC计算的可接受日摄入量1.5μg/天被认为是在终生每日暴露情况下可以受到保护的量。在说 明药品中诱变性杂质的LTL暴露量时，所采用的方法是假定可接受的累积终生剂量(1.5μg/天 X25,550天=38.3mg)在终生摄入期间是均匀分布在这些天数中的，这样诱变性杂质的日摄入量可以 高于平均终生日暴露量，而其风险水平仍与每日或非每日治疗方案相持平。表2是从上述概念得到的 数据，其中写出了临床研发阶段和上市阶段终生暴露LTL下可接受摄入量数值。如果给药是间歇性 的，则可接受日摄入量应根据给药总天数计算，而不是服用药物的总时间长度计算，给药天数与表2 中相关时长分类有关。例如，2年期间每周服用一次的药物(即104个服药天数)，其可接受摄入剂 量为每剂20μg。 Table 2: Acceptable Intakes for an Individual Impurity ?1month Duration of >1-12months >1-10years >10 years to treatment lifetime Total Daily intake 120 20 10 1.5 (μg/day) 表2:单个杂质的可接受摄入量 治疗期 ?1月 >1-12月 >1-10年 >10 年到终生 日总摄入量 120 20 10 1.5 (μg/天) 7.3.1 Clinical Development 临床研发 Using this LTL concept, acceptable intakes of mutagenic impurities are recommended for limited treatment periods during clinical development of up to 1 month, 1 to 12 months and more than one year up to completion of Phase 3 clinical trials (Table 2). These adjusted acceptable intake values maintain a 10-6 risk level in early clinical development when benefit has not yet been established and a 10-5 risk level for later stages in development (Note 6). 采用LTL概念，诱变性杂质的可接受摄入量在临床研究中的治疗期限最高为1个月、1-12个月及长 于1年直到完成3期临床试验(表2)。对可接受摄入值的调节在其受益水平尚未不可知时，保持早 期临床风险水平为百万分之一，后期临床为十万分之一。 An alternative approach to the strict use of an adjusted acceptable intake for any mutagenic impurity could be applied for Phase 1 clinical trials for dosing up to 14 days. For this approach, only impurities that are known mutagenic carcinogens (Class 1) and known mutagens of unknown carcinogenic potential (Class 2), as well as impurities in the cohort of concern chemical class, should be controlled (see Section 8) to acceptable limits as described in Section 7. All other impurities would be treated as non-mutagenic impurities. This includes impurities which contain structural alerts (Class 3), which alone would not trigger action for an assessment for this limited Phase 1 duration. 所有诱变性杂质经过调整的可接受摄入量严格用法的替代方式可以应用于长达14天的一期临床试验 阶段。采用该方法时，只有已知诱变性致癌(1类)杂质和致癌性未知的已知诱变物(2类)，以及 被列入关注化学类别中的杂质要控制(参见第8部分)在第7部分的可接受限度内。所有其它杂质可 以作为非诱变性杂质对待，其中包括含有警示结构(3类)的杂质。仅仅只是含有警示结构不需要在 一期临床试验期间进行评估。 7.3.2 Marketed Products 已上市药物 The treatment duration categories with acceptable intakes in Table 2 for marketed products are intended to be applied to anticipated exposure durations for the great majority of patients. The proposed intakes along with various scenarios for applying those intakes are described in Table 4, Note 7. In some cases, a subset of the population of patients may extend treatment beyond the marketed drugs categorical upper limit (e.g., treatment exceeding 10 years for an acceptable intake of 10 μg/day, perhaps receiving 15 years of treatment). This would result in a negligible increase (in the example given, a fractional increase to 1.5/100,000) compared to the overall calculated risk for the majority of patients treated for 10 years. 已上市药品的治疗时长分类与可接受摄入量在表2中列中。它可以用来预计绝大部分患者的暴露时长。 所拟的摄入量与使用这些摄入量的不同情景在表4注7中已有说明。在有些情况下，患者中一部分人 群可能会延长治疗时长，超出上市药物分类的上限(例如，可接受摄入量为10μg/天的药物治疗超出 10年，可能会接受15年治疗)。与按绝大部分患者治疗10年计算出的整体风险相比，延长治疗时 长导致的风险增加(如上例，增加比例为1.5/100000)可以忽略。 7.4 Acceptable Intakes for Multiple Mutagenic Impurities 多个诱变性杂质可接受摄入量 The TTC-based acceptable intakes should be applied to each individual impurity. When there are two Class 2 or Class 3 impurities, individual limits apply. When there are three or more Class 2 or Class 3 impurities specified on the drug substance specification, total mutagenic impurities should be limited as described in Table 3 for clinical development and marketed products. 根据TTC制订的可接受摄入量要用单独应用于各个杂质。如果有两个2类或3类杂质，则限度是针 对单个杂质的。如果原料药质量标准中有3个或更多3类或3类杂质，临床研发和已上市药品中的总 诱变性杂质应根据表3所列进行限制。 For combination products each active ingredient should be regulated separately. 对于复方药品，每个活性成分要分别规定。 Table 3: Acceptable Total Daily Intakes for Multiple Impurities ?1month Duration of >1-12months >1-10years >10 years to treatment lifetime Total Daily intake 120 60 30 5 (μg/day) 表 3: 多个杂质的可接受日总摄入量 治疗期 ?1月 >1-12月 >1-10年 >10 年到终生 日总摄入量 120 60 30 5 (μg/天) Only specified Class 2 and 3 impurities on the drug substance specification are included in the calculation of the total limit. However, impurities with compound-specific or class-related acceptable intake limits (Class 1) should not be included in the total limits of Class 2 and Class 3 impurities. Also, degradation products which form in the drug product would be controlled individually and a total limit would not be applied. 在原料药质量标准中，只有列出的2类和3类杂质才会被包括在总限度计算中，而特定化合物或按可 接受摄入限度分类(第1类)的杂质不应计入第2类和第3类杂质总限度。还有，原料药中形成的降 解产物要单独控制，不能计入总限度。 7.5 Exceptions and Flexibility in Approaches 方法特例和灵活性 ? Higher acceptable intakes may be justified when human exposure to the impurity will be much greater from other sources e.g., food, or endogenous metabolism (e.g., formaldehyde). 如果人们暴露于其它杂质其它来源，如，食品或内源性代谢物(例如甲醛) 的可能性非常大，则可以 考虑判定较高的可接受摄入量。 ? Case-by-case exceptions to the use of the appropriate acceptable intake can be justified in cases of severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives. 使用适当的可接受摄入量可以用于以下各案例外情况:病情严重、降低生命期望、发病迟但长期疾病， 或其它治疗方法有限的情况。 ? Compounds from some structural classes of mutagens can display extremely high carcinogenic potency (cohort of concern), i.e., aflatoxin-like-, N-nitroso-, and alkyl-azoxy structures. If these compounds are found as impurities in pharmaceuticals, acceptable intakes for these high-potency carcinogens would likely be significantly lower than the acceptable intakes defined in this guideline. Although the principles of this guideline can be used, a case-by-case approach using e.g., carcinogenicity data from closely related structures, if available, should usually be developed to justify acceptable intakes for pharmaceutical development and marketed products. 有些诱变结构类别的化合物可能会显示出非常高的诱变性(关注的队列)，例如，黄曲霉毒素类、 N-亚硝基化合物、以及烷基-氧化偶氮结构。如果在药物的杂质中存在杂质是这样的化合物，则这些 高效价诱变物的可接受摄入量很可能要显著低于本指南中定义的可接受摄入量。尽管如果，也还是能 使用本指南的原则，一般要研究一种针对各案采用，例如，已有的近似的相关结构的基因致癌数据， 的方法来判定药品研发和上市药品中的可接受摄入量。 The above risk approaches described in Section 7 are applicable to all routes of administration and no corrections to acceptable intakes are generally warranted. Exceptions to consider may include situations where data justify route-specific concerns that should be evaluated case-by-case. These approaches are also applicable to all patient populations based upon the conservative nature of the risk approaches being applied. 在第7部分中所描述的上述风险方法可以应用于所有摄入途径，不需要修正可接受摄入量。对例外情 况的考虑可能包括需要各案评价的特定摄入途径数据判定。由于所采用的风险方法是较为保守的，因 此这些方法也适用于所有患者人群，