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
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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
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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
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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.
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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
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