针对所拟的商业包装进行试验，在开始长期稳定性试验前确定降解途径相关性。这类研究对于知晓根据潜在降解途径知识，但在产品中未发现的潜在降解产物的相关性尤其有用。 Based on the result of these accelerated studies, if it is anticipated that the degradation product will form at levels approaching the acceptable limit under the proposed packaging and storage conditions, then efforts to control formation of the degradation product is expected. In these cases, monitoring for the drug substance or drug product degradation product in long term primary stability studies at the proposed storage conditions (in the proposed commercial pack) is expected unless otherwise justified. Whether or not a specification limit for the mutagenic degradation product is appropriate will generally depend on the results from these stability studies.
根据这些加速试验的结果，如果所预料的降解产物在所拟包装和存贮条件下形成，且接近可接受限度，则应采取措施控制降解产物的形成。这种情况下，除另有论述外，应监控采用所拟存贮条件（采用所拟商业包装）长期稳定性试验中原料药或制剂的质量。该诱变性降解产物的质量标准限度是否适当一般是取决于这些稳定性研究的结果。
If it is anticipated that formulation development and packaging design options are unable to control mutagenic degradation product levels to less than the acceptable limit and levels are as low as reasonably practicable, a higher limit can be justified based on a risk/benefit analysis.
如果预料制剂研发和包装设计选择不能控制诱变性降解产物水平低于可接受限度，而处于ALARP水平，则可以根据风险/利益分析确定一个更高的限度。 8.5 Lifecycle Management 生命周期管理
This section is intended to apply to those products approved after the issuance of this guideline.
本部分适用于本指南颁发后批准的药品。
The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each
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lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. 在ICH Q10中所述的质量体系要素和管理职责意在鼓励在生命周期各阶段使用基于科学和基于风险的方法，从而在整个产品生命周期中促进持续改进。产品和工艺知识应从研发阶段开始进行管理，贯穿产品的整个商业化生命期间，直到产品退市。
The development and improvement of a drug substance or drug product manufacturing process usually continues over its lifecycle. Manufacturing process performance, including the effectiveness of the control strategy, should be periodically evaluated. Knowledge gained from commercial manufacturing can be used to further improve process understanding and process performance and to adjust the control strategy.
对原料药和制剂的生产工艺的研发和改进一般会在其整个生命周期中持续。生产工艺性能，包括控制策略的有效性，应定期进行评估。在商业化生产中所获得的知识可以用于进一步促进对工艺的了解，改进工艺表现，以及调整控制策略。
Any proposed change to the manufacturing process should be evaluated for the impact on the quality of drug substance and drug product. This evaluation should be based on understanding of the manufacturing process and should determine if appropriate testing to analyze the impact of the proposed changes is required. Additionally, improvements in analytical procedures may lead to structural identification of an impurity. In those cases the new structure would be assessed for mutagenicity as described in this guideline.
对生产工艺拟定任何变更时，均应评估其对原料药和制剂质量产生的影响。该评估应根据对生产工艺的理解，决定是否需要对所拟变更进行分析测试。另外，分析方法的改进可能会引起对杂质结构的鉴别。在这种情况下，对新结构需要按本指南的要求进行诱变性评估。 Throughout the lifecycle of the product, it will be important to reassess if testing is recommended when intended or unintended changes occur in the process. This applies when there is no routine monitoring at the acceptable limit (Option 3 or Option 4
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control approaches), or when applying periodic rather than batch-by-batch testing. This testing should be performed at an appropriate point in the manufacturing process.
在药品的整个生命周期中，如果对工艺进行了计划内或计划外的变更，对检测是否适当进行再次评估是很重要的。这适用于未进行可接受限度常规监控的情况（第3种或第4种控制方法），以及采用定期测试而不是每批测试时。该测试应在生产过程中适当的工艺点实施。 In some cases, the use of statistical process control and trending of process measurements can be useful for continued suitability and capability of processes to provide adequate control on the impurity. Statistical process control can be based on process parameters that influence impurity formation or clearance, even when that impurity is not routinely monitored (e.g., Option 4).
在有些情况下，使用统计学过程控制和趋势分析可能会对工艺的持续性和产能有用，它可以对杂质进行充分的控制。即使并没有对杂质进行常规监控（例如方法4），统计学工艺控制也可以基于对杂质形成或清除有影响的工艺参数进行。
All changes should be subject to internal change management processes as part of the quality system (ICH Q10). Changes to information filed and approved in a dossier should be reported to regulatory authorities in accordance with regional regulations and guidelines.
所有变更均应按质量体系（ICH Q10）中内部变更管理流程进行控制。对被批准的申报资料中的内容进行的变更应根据当地法规和指南要求向法规当局进行报告。 8.6 Considerations for Clinical Development 临床研发要考虑的问题
It is recognized that product and process knowledge increases over the course of development and therefore it is expected that data to support control strategies in the clinical development trial phases will be less than at the marketing registration phase. A risk-based approach based on process chemistry fundamentals is encouraged to prioritize analytical efforts on those impurities with the highest likelihood of being present in the drug substance or drug product. Analytical data
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may not be expected to support early clinical development when the likelihood of an impurity being present is low, but in a similar situation analytical data may be appropriate to support the control approach for the marketing application. It is also recognized that commercial formulation design occurs later in clinical development and therefore efforts associated with drug product degradation products will be limited in the earlier phases.
大家都认识到，产品和工艺知识是随着研发进程而增长的，因此，在临床研发试验阶段用于支持控制策略的数据肯定会比上市注册阶段要少。在此鼓励根据化学工艺基础知识来建立一种基于风险的方法，将最可能出现在原料药或制剂中的杂质进行优先分析。如果一种杂质出现的可能性很低的话，分析数据可能无法用于支持早期临床研发，但在类似情形下，分析数据可以用于支持上市申报的控制方法。大家也认识到，商业化配方是在临床研发后期才设计的，因此在早期对原料药的降解产物的研究会比较有限。 9. DOCUMENTATION 文件记录
Information relevant to the application of this guideline should be provided at the following stages:
本指南中与申报相关的资料应在以下阶段提供： 9.1 Clinical Trial Applications 临床试验申报
? It is expected that the number of structures assessed for mutagenicity, and the collection of analytical data will both increase throughout the clinical development period.
预期诱变性的结构评估数量、分析数据均会在临床研发期间不断增加。
? For Phase 1 studies of 14 days or less a description of efforts to mitigate risks of mutagenic impurities focused on Class 1, and Class 2 impurities and those in the cohort of concern as outlined in Section 7 should be included. For Phase 1 clinical trials greater than 14 days and for Phase 2a clinical trials additionally Class 3 impurities that require analytical controls should be included.
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14天或更短的一期临床中，要包括努力降低诱变杂质，主要是1类和2类杂质及第7部分所列的关注队列中杂质的风险所采取的措施的描述。在长于14天的一期临床试验，和2a期临床试验中，要求包括对需要进行分析控制的第3类杂质。
? For Phase 2b and Phase 3 clinical development trials, a list of the impurities assessed by (Q)SAR should be included, and any Class 1, 2 or 3 actual and potential impurities should be described along with plans for control. The in silico (Q)SAR systems used to perform the assessments should be described. The results of bacterial mutagenicity tests of actual impurities should be reported.
对于2b期和3期临床试验，要包括一份（Q）SAR评估的杂质清单，所有1类、2类和3类急笥和潜在杂质要与控制计划一起提交。要描述用于评估的电子（Q）SAR系统。要报告实际杂质细菌诱变测试的结果。
? Chemistry arguments may be appropriate instead of analytical data for potential impurities that present a low likelihood of being present as described in Section 8.6.
对于存在可能性很低的潜在杂质，如第8.6所述采用化学讨论来替代分析数据也是可以的。 9.2 Common Technical Document (Marketing Application) 上市申报CTD文件 ? For actual and potential process related impurities and degradation products where assessments according to this guideline are conducted, the mutagenic impurity classification and rationale for this classification should be provided: 如果根据本指南对实际和可能的工艺相关杂质和降解产物进行了评估，则应提供诱变性杂质分类及该分类的理由：
? This would include the results and description of in silico (Q)SAR systems used, and as appropriate, supporting information to
arrive at the overall conclusion for Class 4 and 5 impurities.
? 应包括所采用的电子(Q)SAR系统的结果和描述，适当时，还要提交
支持性资料以得出4类和5类杂质的总体结论。
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