ICH M7(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

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

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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 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

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 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 106incidence, 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”, co mprises 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