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When bacterial mutagenicity assays were performed on impurities, study reports should be provided for bacterial mutagenicity assays on impurities.
如果对杂质进行了细菌诱变测试，要提交该测试研究报告。 ? Justification for the proposed specification and the approach to control should be provided (e.g., ICH Q11 example 5b, Ref. 12). For example, this information could include the acceptable intake, the location and sensitivity of relevant routine monitoring. For Option 3 and Option 4 control approaches, a summary of knowledge of the purge factor, and identification of factors providing control (e.g., process steps, solubility in wash solutions, etc.) is important.
要提交所拟质量标准的论证，及用以控制杂质的方法（例如，ICH Q11例5b，参考文件12）。例如，该信息可以包括可接受摄入量、相关常规监控的位置和灵敏度。对于第3种控制方法和第4种控制方法，挤压系数和提供控制的因素的识别（例如，工艺步骤、洗液中的溶解度等）的知识总结很重要。 NOTES 注
Note 1 The ICH M7 Guideline recommendations provide a state-of-the-art approach
for assessing the potential of impurities to induce point mutations and ensure that such impurities are controlled to safe levels so that below or above the ICH Q3A/B qualification threshold no further qualification for mutagenic potential is required. This includes the initial use of (Q)SAR tools to predict bacterial mutagenicity. In cases where the amount of the impurity exceeds 1 mg daily dose for chronic administration, evaluation of genotoxic potential as recommended in ICH Q3A/B could be considered. In cases where the amount of the impurity is less than 1 mg, no further genotoxicity testing is required regardless of other qualification thresholds.
注1 ICH M7指南中的建议提供了一种理想的方法来评估杂质诱发点诱变的可能性，
保证这样的杂质被控制在安全水平，这样在低于或高于ICH Q3A/B定性阈时不需
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要进一步对诱变可能性进行确证。这包括了开始时使用（Q）SAR工具预测细菌诱变性。如果在长期摄入时杂质日摄入量超出1mg，则要考虑ICH Q3A/B中建议的潜在基因毒性评估。如果杂质量量少小1mg，即使超出定性阈，也不需要进行进一步的基因毒性测试。
Note 2 To assess the mutagenic potential of impurities, a single bacterial
mutagenicity assay can be carried out with a fully adequate protocol according to ICH S2(R1) and OECD 471 guidelines (Ref. 13 and 14). The assays are expected to be performed in compliance with Good Laboratory Practices (GLP) regulations; however, lack of full GLP compliance does not necessarily mean that the data cannot be used to support clinical trials and marketing authorizations. Such deviations should be described in the study report. For example, the test article may not be prepared or analyzed in compliance with GLP regulations. In some cases, the selection of bacterial tester strains may be limited to those proven to be sensitive to the identified alert. For impurities that are not feasible to isolate or synthesize or when compound quantity is limited, it may not be possible to achieve the highest test concentrations recommended for an ICH-compliant bacterial mutagenicity assay according to the current testing guidelines. In this case, bacterial mutagenicity testing could be carried out using a miniaturized assay format with proven high concordance to the ICH-compliant assay to enable testing at higher concentrations with justification.
注2 为了对杂质的潜在诱变性进行评估，要根据ICH S2(R1)和OECD 471指南（参考文
献 13和14）制订全面充分的方案实施单一细菌诱变性测试。测试应符合GLP规范，但是，没有完全符合GLP并不一定表示数据不能用于支持临床试验和上市许可。该偏差可以在研究报告中进行描述。例如，测试对象的制备和分析可能不符合GLP规范要求。在有些情况下，对检测用细菌菌株的选择可能受到限制，只能使用那些经证明对鉴别出的警示敏感的菌。对于不易分离或合成的杂质，或化合物数量有限时，可能无法达到符合ICH推荐的根据目前测试指南所要求的最高测
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试浓度。这种情况下，细菌诱变性测试可以采用小型测试方式，被证实能较好符合ICH测试要求的方法在较高的浓度下进行测试，并同时进行论证。
Note 3 Tests to Investigate the in vivo Relevance of in vitro Mutagens
(Positive Bacterial Mutagenicity) In vivo test Transgenic mutation assays Pig-a assay (blood) Factors to justify choice of test as fit-for-purpose For any bacterial mutagenicity positive. Justify selection of assay tissue/organ. For directly acting mutagents (bacterial mutagenicity positive without S9)* Micronucleus (blood marrow) Rat Unscheduled liver DNA or test bone For directly acting mutagens (bacterial mutagenicity positive without S9) and compounds known to be clastogenic* In particular for bacterial mutagenicity positive with S9 only Responsible liver metabolite known To be generated in test species used To induce bulky adducts Synthesis (UDS) test Comet assay Justification needed (chemical class specific mode of action to form alkaline labile sites or single-strand breaks as preceding DNA damage that can potentially lead to mutations Justify selection of assay tissue/organ Others With convincing justification *For indirect acting mutagens (requiring metabolic activation), adequate exposure to metabolite(s) should be demonstrated. 注3：调查体外诱变的体内相关性的测试（阳性细菌诱变） 体内试验 基因突变检测 文案大全
讨论所选测试是否达到目的的论述 对所有细菌诱变阳性，论述测定组织/器官选实用标准文档
择的理由 Pig-a测试（血液） 对于直接作用突变剂（无S9时细菌诱变阳性）* 微核测定（血液或骨髓） 大鼠肝计划外DNA合成（UDS）测试 对于直接作用突变剂（S9细菌诱变阳性）和已知致畸化合物* 尤其是只有在采用S9时对细菌诱变阳性 已知有关肝代谢物会 在测试所用特种时会产生 减少加合物 单细胞凝胶电泳 需要做出论述（形成容易发生碱性反应的位置的措施的化学类别特定模式，或对DNA形成损坏时单链断裂可能会导致诱变） 对测试组织/器官的选择做出论述 其它 具有很强说服力的论述 *对于非直接作用诱变（需要代谢激活），要证明在代谢物中在充分的暴露。 Note 4 Example of linear extrapolation from the TD50 It is possible to calculate a compound-specific acceptable intake based on rodent carcinogenicity potency data such as TD50 values (doses giving a 50% tumor incidence equivalent to a cancer risk probability level of 1:2). Linear extrapolation to a probability of 1 in 100,000 (i.e., the accepted lifetime risk level used) is achieved by simply dividing the TD50 by 50,000. This procedure is similar to that employed for derivation of the TTC.
注4：从TD50线性外推举例 可以根据啮齿动物致癌效应数据，例如TD50值（导致50%肿瘤发生率的给药剂量相当于患癌风险可能性水平为1：2）计算化合物的可接受摄入值。线性外推至可能性为十万分之一（即，所用的已接受的生命周期风险水平），简单采用TD50值除以五万（50,000）。该方法类似于TTC计算方法。 Calculation example: Ethylene oxide
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TD50 values for ethylene oxide according to the Carcinogenic Potency Database are 21.3 mg/kg body weight/day (rat) and 63.7 mg/kg body weight/day (mouse). For the calculation of an acceptable intake, the lower (i.e., more conservative) value of the rat is used.
To derive a dose to cause tumors in 1 in 100,000 animals, divide by 50,000: 21.3 mg/kg ? 50,000 = 0.42 μg/kg To derive a total human daily dose:
0.42 μg/kg/day x 50 kg body weight = 21.3 μg/person/day
Hence, a daily life-long intake of 21.3 μg ethylene oxide would correspond to a theoretical cancer risk of 10-5 and therefore be an acceptable intake when present as an impurity in a drug substance. 计算举例：环氧乙烷
根据致癌效应数据库，环氧乙烷的TD50为21.3mg/kg体重/天（大鼠）和63.7mg/kg体重/天（小鼠）。在计算可接受摄入量时，采用了较低的大鼠值（即更保守）。 计算十万分之一概率致癌剂量，将该值除以50,000：21.3mg/kg÷50,000 = 0.42μg/kg.
计算人类每日总摄入量：0.42μg/kg×50kg体重 = 21.3μg/人/天。
因此，永久性每日服用21.3μg环氧乙烷对应理论致癌风险为十万分之一是环氧乙烷作为药品中的杂质时可接受的摄入值。
Alternative methods and published regulatory limits for cancer risk assessment
As an alternative of using the most conservative TD50 value from rodent carcinogenicity studies irrespective of its relevance to humans, an in-depth toxicological expert assessment of the available carcinogenicity data can be done in order to initially identify the findings (species, organ,
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ICHM7(step4)基因毒性杂质评估和控制中英
