ICHM7step4基因毒性杂质评估和控制中英(8)

在原料、起始物料或中间体的质量标准中包括对杂质的检测，或作为中控检测，同时制订一个高于原料药中可接受限度的质量标准，采用适当的分析方法，配合经过证明杂质致命知识，杂质在后续工艺中被清除的知识，并对后续工艺进行控制，保证原料药中的该杂质残留水平低于可接受限度，而不需要在后续工艺中再行检测。

This option can be justified when the level of the impurity in the drug substance will be less than 30% of the acceptable limit by review of data from laboratory scale experiments (spiking experiments are encouraged) and where necessary supported by data from pilot scale or commercial scale batches. See Case Examples 1 and 2. Alternative approaches can be used to justify Option 3.

当实验室级试验（鼓励采用加样试验）数据，必要时可以采用中试生产或商业批次数据加以支持，显示原料药中杂质水平低于可接受限度的30%时，可以采用该方法。 Option 4 第4种方法

Understand process parameters and impact on residual impurity levels (including fate and purge knowledge) with sufficient confidence that the level of the impurity in the drug substance will be below the acceptable limit such that no analytical testing is recommended for this impurity. (i.e., the impurity does not need to be listed on any specification).

对工艺参数和残留杂质水平（包括致命性和清除知识）影响有了解，确信原料药中的杂质一定会低于可接受限度，此时，建议该杂质不需要进行分析测试（例如，不需要将杂质列在任何质量标准中）。

A control strategy that relies on process controls in lieu of analytical testing can be appropriate if the process chemistry and process parameters that impact levels of mutagenic impurities are understood and the risk of an impurity residing in the final drug substance above the acceptable limit is determined to be negligible. In many cases justification of this control approach based on scientific principles alone is sufficient. Elements of a scientific risk assessment can be used to justify an option 4 approach. The risk assessment can be based on physicochemical properties and process factors that influence the fate and purge of an impurity including

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chemical reactivity, solubility, volatility, ionizability and any physical process steps designed to remove impurities. The result of this risk assessment might be shown as an estimated purge factor for clearance of the impurity by the process (Ref. 11). Option 4 is especially useful for those impurities that are inherently unstable (e.g., thionyl chloride that reacts rapidly and completely with water) or for those impurities that are introduced early in the synthesis and are effectively purged.

如果生产工艺的化学特性和工艺参数对诱变杂质的影响水平是已知的，并且最终原料药中杂质残留超出可接受限度的风险已经评估并认为是可以忽略的，那么可以采用对工艺的控制来取代采用分析方法控制。在很多情况下，只需要根据科学原理对该控制方法进行论述就可以了。科学风险评估要素可以用来论证第4种方法。可以根据对杂质去向和消除产生影响的理化特性和工艺因素，包括化学反应性、溶解性、挥发性、离解性和所有用于去除杂质的物理处理步骤进行风险评估。该风险评估的结果可以用来作为杂质被工艺所清除的预估因子（参考文献 11）。第4种方法特别适用于那些本质上来说就不稳定的杂质（例如 ，亚硫酰氯，与水迅速完全反应），以及那些在合成路线早期引入，但已被有效清除的杂质。

In some cases an Option 4 approach can be appropriate when the impurity is known to form, or is introduced late in the synthesis, however process-specific data should then be provided to justify this approach.

有些情况下，如果已经知道杂质是在合成后期引入或形成的，则也可以采用第4种方法，但这时，需要提交与工艺相关的数据来论述该方法的合理性。

8.2 Considerations for Control Approaches 控制方法要考虑的问题

For Option 4 approaches where justification based on scientific principles alone is not considered sufficient, as well as for Option 3 approaches, analytical data to support the control approach is expected. This could include as appropriate information on the structural changes to the impurity caused by downstream chemistry (“fate”), analytical data on pilot scale batches, and in some cases, laboratory scale studies with intentional addition of the impurity (“spiking studies”). In these cases, it is important to demonstrate that the fate/purge argument for the

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impurity is robust and will consistently assure a negligible probability of an impurity residing in the final drug substance above the acceptable limit. Where the purge factor is based on developmental data, it is important to address the expected scale-dependence or independence. In the case that the small scale model used in the development stage is considered to not represent the commercial scale, confirmation of suitable control in pilot scale and/or initial commercial batches is generally appropriate. The need for data from pilot/commercial batches is influenced by the magnitude of the purge factor calculated from laboratory or pilot scale data, point of entry of the impurity, and knowledge of downstream process purge points.

采用第4种方法时，如果与第3种方法一样仅仅根据科学原理来进行论述是不够充分的，这时需要提交分析数据来支持控制方法。提交的资料可以包括在后续化学反应中杂质的结构变化（去向）、中试批次分析数据，以及有些情况下可以包括实验室级别研究中有意加入杂质（加标研究）。在这些情况中，重点是要证明该杂质的去向/清除论证是严谨的，能够持续地保证杂质在最终原料药中残留量超过可接受限度的可能性可以忽略。如果清除因子是根据研发数据来计算的，则重点需要说明所期望的放大效应或与放大不相关。如果用于研发阶段的小规模模型被认为不能代表商业规模，则一般需要确认中试规模和/或初始商业批次中所用的控制是适当的。所需提交的中试/商业批次数据根据实验室级别或中试级别数据、杂质产生点和后续工艺清除点计算所得的清除因子的级别不同而不同，

If Options 3 and 4 cannot be justified, then a test for the impurity on the specification for a raw material, starting material or intermediate, or as an in-process control (Option 2) or drug substance (Option 1) at the acceptable limit should be included. For impurities introduced in the last synthetic step, an Option 1 control approach would be expected unless otherwise justified.

如果不能采用第3种和第4种方法，则申报资料中应包括根据原料、起始物料或中间体质量标准对杂质进行的检测，或中控（第2种方法）或原料药（第4种方法）在可接受限度水平所进行的测试。对于在较后合成步骤中引入的杂质，除另有论述外，应采用第1种控制方法。

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The application of “As Low As Reasonably Practicable” (ALARP) is not necessary if the level of the mutagenic impurity is below acceptable limits. Similarly, it is not necessary to demonstrate that alternate routes of synthesis have been explored.

如果诱变性杂质的水平低于可接受限度，则不需要应用“与合理并可行水平一样低（ALARP）”原则。类似地，也不需要证明已摸索过可替代的合成路线。

In cases where control efforts cannot reduce the level of the mutagenic impurity to below the acceptable limit and levels are ALARP, a higher limit may be justified based on a risk/benefit analysis.

如果各种控制的努力仍不能将诱变性杂质的水平降低至可接受限度以下，而杂质水平是ALARP，可以根据风险/利益分析来制订一个更高的限度。

8.3 Considerations for Periodic Testing 定期检测要考虑的问题

The above options include situations where a test is recommended to be included in the specification, but where routine measurement for release of every batch may not be necessary. This approach, referred to as periodic or skip testing in ICH Q6A could also be called “Periodic Verification Testing.” This approach may be appropriate when it can be demonstrated that processing subsequent to impurity formation/introduction clears the impurity. It should be noted that allowance of Periodic Verification Testing is contingent upon use of a process that is under a state of control (i.e., produces a quality product that consistently meets specifications and conforms to an appropriately established facility, equipment, processing, and operational control regimen). If upon testing, the level of the mutagenic impurity fails to meet the acceptance criteria established for the periodic test, the drug producer should immediately commence full testing (i.e., testing of every batch for the attribute specified) until the cause of the failure has been conclusively determined, corrective action has been implemented, and the process is again documented to be in a state of control. As noted in ICH Q6A,

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regulatory authorities should be notified of a periodic verification test failure to evaluate the risk/benefit of previously released batches that were not tested. 上述这些方法包括了在质量标准中要包含推荐方法的情形，但不一定需要对每批均进行放行例行测试。这种方法在ICH Q6A中被称为定期检测或间隔检测，也可以称为“定期确认性测试”。如果能证明杂质形成/引入之后的工艺能清除杂质的话，该方法也是恰当的。要注意的是，是否允许使用定期确认性测试依控制状态下的工艺使用而不同（即，生产出的产品质量能持续满足质量标准，采用适当的设施、设备、工艺和操作控制方案）。如果检测结果显示，诱变性杂质的水平无法符合定期测试所建立的可接受标准，则药品生产商要立即实施全检（即，对每个批次的所指属性进行检测）直至找出超标的原因、实施了纠正措施，并且所记录的工艺重新处于受控状态。正如ICH Q6A中所注，如果定期确认性测试失败，则要通知法规当局，以对之前未进行检测的批次进行风险/利益评估。 8.4 Control of Degradation Products 降解产物的控制

For a potential degradation product that has been characterized as mutagenic, it is important to understand if the degradation pathway is relevant to the drug substance and drug product manufacturing processes and/or their proposed packaging and storage conditions. A well-designed accelerated stability study (e.g., 40°C/75% relative humidity, 6 months) in the proposed packaging, with appropriate analytical procedures is recommended to determine the relevance of the potential degradation product. Alternatively, well designed kinetically equivalent shorter term stability studies at higher temperatures in the proposed commercial package may be used to determine the relevance of the degradation pathway prior to initiating longer term stability studies. This type of study would be especially useful to understand the relevance of those potential degradation products that are based on knowledge of potential degradation pathways but not yet observed in the product. 对于已经定性为具有诱变性的潜在降解杂质，一定要知晓该降解途径是否与原料药和制剂的生产工艺和/或其所拟的包装和存贮条件有关。建议采用一个设计良好的加速稳定性试验（例如，40℃/75%，6个月），采用所拟的包装形式、采用适当的分析方法来确定潜在降解产物的相关性。也可以采用一个设计良好的动力学等效，但时间更短温度更高的稳定性试验，来

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