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
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