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 Hazard assessment involves an initial analysis of actual and potential impurities by conducting database and literature searches for carcinogenicity and bacterial mutagenicity data in order to classify them as Class 1, 2, or 5 according to Table 1. If data for such a classification are not available, an assessment of Structure-Activity Relationships (SAR) that focuses on bacterial mutagenicity predictions should be performed. This could lead to a classification into Class 3, 4, or 5. 危害性分析会涉及采用数据库和诱变和细菌诱变数据文献检索启动对实际和可能杂质的分析，以根据表1将其分类为第1类、第2类或第5类。如果无法获得这样的分类数据，则应进行结构-活性关系（SAR）评估，该评估应着重关注细菌诱变性预期。这时可能会使得该杂质被分入第3类、第4类或第5类。 Table 1: Impurities Classification with Respect to Mutagenic and Carcinogenic Potential and Resulting Control Actions Class Definition Proposed action for control (details in Section 7 and 8) 1 Known mutagenic carcinogens Control at or below compound-specific acceptable limit 2 Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive*, no rodent carcinogenicity data) 3 Alerting structure, unrelated to the structure of the drug substance: no mutagenicity data Control at or below acceptable limits (appropriate TTC) or conduct bacterial mutagenicity assay: If non-mutagenic = Class 5 If mutagenic = Class 2 4 Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenic 5 No structural alerts, or alerting Treat as non-mutagenic impurity Treat as non-mutagenic impurity Control at or below acceptable limits (appropriate TTC) structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity *Or other relevant positive mutagenicity data indicative of DNA-reactivity related induction of gene mutations (e.g., positive findings in in vivo gene mutation studies) 表1：根据诱变性和致癌性及其控制措施对杂质分类 分类 1 2 定义 已知诱变致癌性 已知具有诱变性，致癌效应未知（细菌诱变呈阳性*，无啮齿动物致癌数据） 3 警示结构，与原料药结构无关，无诱变性数据 控制不高于可接受限度（适当的TTC）或检测细菌诱变含量： 如果非诱变性 = 第5类 如果具有诱变性 = 第2类 4 警示结构，与原料药或有关物质有相同警示（例如，工艺中间体），经测试为无诱变性 5 无警示结构，或警示结果具有充分的数据证明其不具备诱变性和致癌性 *或其它相关阳性诱变数据，说明与诱导基因变性的DNA反应活性（例如，体内基因诱变研究显示阳性） 拟定控制措施（详见第7和8部分） 控制不高于化合物可接受限度 控制不高于可接受限度（适当的TTC） 与非诱变性杂质同等对待 与非诱变性杂质同等对待 A computational toxicology assessment should be performed using (Q)SAR methodologies that predict the outcome of a bacterial mutagenicity assay (Ref. 6). Two (Q)SAR prediction methodologies that complement each other should be applied. One methodology should be expert rule-based and the second methodology should be statistical-based. (Q)SAR models utilizing these prediction methodologies should follow the general validation principles set forth by the Organisation for Economic Co-operation and Development (OECD). 应采用（Q）SAR方法进行计算学毒性评估，预测细菌诱变含量（参考文献6）的结果。要使用两个相互补充的（Q）SAR预测方法。一个方法应是依据专家规则的，另一个方法则应该是统计方式的。(Q)SAR模式采用的这些预测方法应服从OECD制订的通用验证原则。 The absence of structural alerts from two complementary (Q)SAR methodologies (expert rule-based and statistical) is sufficient to conclude that the impurity is of no mutagenic concern, and no further testing is recommended (Class 5 in Table 1).
两个互补的（Q）SAR方法（专家规则和统计学）如果没有发现结构警示，则足以得出结论该杂质没有诱变可能，不需要做进一步的检测（表1中第5类）。
If warranted, the outcome of any computer system-based analysis can be reviewed with the use of expert knowledge in order to provide additional supportive evidence on relevance of any positive, negative, conflicting or inconclusive prediction and provide a rationale to support the final conclusion.
如果可以得到保证的话，所有基于计算机系统的分析均可以使用专家知识进行审核，以对所有阳性、阴性、相互矛盾或无法得出结论的预期之间的相关性提供额外的支持性证据，从而支持最终结论的合理性。
To follow up on a relevant structural alert (Class 3 in Table 1), either adequate control measures could be applied or a bacterial mutagenicity assay with the impurity alone can be conducted. An appropriately conducted negative bacterial mutagenicity assay (Note 2) would overrule any structure-based concern, and no further genotoxicity assessments would be recommended (Note 1). These impurities should be considered non-mutagenic (Class 5 in Table 1). A positive bacterial mutagenicity result would warrant further hazard assessment and/or control measures (Class 2 in Table 1). For instance, when levels of the impurity cannot be controlled at an appropriate acceptable limit, it is recommended that the impurity be tested in an in vivo gene mutation assay in order to understand the relevance of the bacterial
mutagenicity assay result under in vivo conditions. The selection of other in vivo genotoxicity assays should be scientifically justified based on knowledge of the mechanism of action of the impurity and expected target tissue exposure (Note 3). In vivo studies should be designed taking into consideration existing ICH genotoxicity Guidelines. Results in the appropriate in vivo assay may support setting compound specific impurity limits.
在对有关的警示结构（表1第3类）进行确认之后，可以采用充分的控制措施，或者对该杂质单独进行细菌诱变测试。如果所得的细菌诱变测试（注2）结果为阴性，则可以推翻基于结构的疑虑，这时不建议进行进一步的基因毒性评估（注1）。这些杂质应被当作非诱变性杂质（表1中第5类）。如果细菌诱变测试为阳性，则要进行进一步的危害性分析和/或采取控制措施（表1中第2类）。例如，如果杂质的水平不能被控制在一个适当的可接受水平，则建议进行体内基因诱变测试，以搞清楚在体内环境下细菌诱变测试结果。其它体内基因毒性测试的选择也应根据杂质的反应机理和预期标靶组织
暴露（注3）的知识进行科学论述。体内研究的设计应考虑已有的ICH基因毒性指南。恰当的体内测试结果可以用于支持设定特定化合物杂质的限度。
An impurity with a structural alert that is shared (e.g., same structural alert in the same position and chemical environment) with the drug substance or related compounds can be considered as non-mutagenic (Class 4 in Table 1) if the testing of such material in the bacterial mutagenicity assay was negative.
如果一种杂质具有与药用物质或相关化合物具有相似的警示结构（例如，在相同位置和相同化学环境下具有相同警示结构），且该物料的细菌诱变测试为阴性，则该杂质可以被认为是非诱变性的（表1第4类）。
7. RISK CHARACTERIZATION 风险定性
As a result of hazard assessment described in Section 6, each impurity will be assigned to one of the five classes in Table 1. For impurities belonging in Classes 1, 2, and 3 the principles of risk characterization used to derive acceptable intakes are described in this section.
作为第6部分所述的危害性评估的结果，每个杂质会按表1中分在5类中。本部分描述的是用于1、2、3类杂质计算可接受摄入量的风险定性原则。
7.1 TTC-based Acceptable Intakes 根据TTC计算可接受摄入量
A TTC-based acceptable intake of a mutagenic impurity of 1.5 μg per person per day is considered to be associated with a negligible risk (theoretical excess cancer risk of <1 in 100,000 over a lifetime of exposure) and can in general be used for most pharmaceuticals as a default to derive an acceptable limit for control. This approach would usually be used for mutagenic impurities present in pharmaceuticals for long-term treatment (> 10 years) and where no carcinogenicity data are available (Classes 2 and 3).
根据TTC计算可接受摄入量时，一个具有诱变性的杂质每天每人摄入1.5μg时其风险被认为是可以忽略的（终生暴露情况下理论的患癌风险小于十万分之一），可以通用于大部分药物，作为默认的可接受限度控制标准。该方法一般用于长期治疗用药物中的诱变性杂质（>10年），且没有致癌数据时（第2类和3类）。
7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments 根据化合物特定风险评估计算的可接受摄入量
7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1) 具有阳性致癌数据的诱变杂质（表1第1类）
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