are identified should include both pharmaceutical and toxicological evaluations. In general, pharmaceutical measurements should be guided by a policy of controlling levels to “as low as reasonably practicable” (ALARP principle), where avoiding is not possible. Levels considered being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view (see decision tree & following sections).
对于此类遗传毒性杂质，研究应包括药学和毒理学评估。总之，如果杂质无法避免，药学方面的控制应遵循“合理可行的最低限量”原则（ALARP原则）。符合ALARP原则的杂质水平再经毒理学方面的进一步评估，以验证其合理性（见决策树和以下章节）。
5.2.1 Pharmaceutical Assessment 药学评价
A specific discussion – as part of the overall discussion on impurities (see Q3A(R)) – should be provided in the application with regard to impurities with potential genotoxicity.
申请材料应提供关于潜在遗传毒性杂质的特别讨论资料（见Q3A（R））。 A rationale of the proposed formulation/manufacturing strategy should be provided based on available formulation options and technologies. The applicant should highlight, within the chemical process and impurity profile of active substance, all chemical substances, used as reagents or present as intermediates, or side-products, known as genotoxic and/or carcinogenic (e.g. alkylating agents).
需要根据现在的配方选择和技术，提供证明所选的配方/生产策略合理性的证据。申请人应在合成工艺和杂质研究部分重点指出所有的化学物质，包括用到的试剂、中间体、副产物，哪些是已知遗传毒性和/或致癌性物质（如烷化剂）。
More generally, reacting substances and substances which show “alerting structure” in terms of genotoxicity which are not shared with the active substance should be considered (see e.g. Dobo et al. 2006). Potential alternatives which do not lead to genotoxic residues in the final product, should be used if available.
值得关注的是，虽然有些含有“可能引起遗传毒性的结构” （alerting structure）的反应试剂与最终活性物质并没有共同结构，但也要考虑它们的遗传毒性(see e.g. Dobo et al. 2006).。如果有可能，应该对它们进行一些替代研究，以使最终产品中不会引入基因毒性残留。
A justification needs to be provided that no viable alternative exists, including alternative routes of synthesis or formulations, different starting materials. This might for instance include
cases where the structure, which is responsible for the genotoxic and/or carcinogenic potential is equivalent to that needed in chemical synthesis (e.g. alkylation reactions).
需要提供充分的论证来说明没有可行的替代方法存在，包括可替代的合成路线或配方，不同的起始物料等。比如，应证明具有遗传毒性和/或致癌性的结构在化学合成中（如烷化反应）是必需的。
If a genotoxic impurity is considered to be unavoidable in a drug substance, technical efforts (e.g. purification steps) should be undertaken to reduce the content of the genotoxic residues in the final product in compliance with safety needs or to a level as low as reasonably practicable (see safety assessment). Data on chemical stability of reactive intermediates, reactants, and other components should be included in this assessment.
如果遗传毒性杂质在原料中不可避免，则应该采取适当的技术（如纯化步骤）降低该杂质的含量，以满足安全性要求，或符合“合理可行的最低限量”原则（见安全评估）。药学评估还应包括反应中间体、反应物和其它组件等的化学稳定性研究。
Detection and/or quantification of these residues should be done by state-of-the-art analytical techniques.
应该使用比较先进的分析检测技术来检测和量化这些残留的杂质。 5.2.2 Toxicological Assessment 毒理学评价
The impossibility of defining a safe exposure level (zero risk concept) for genotoxic carcinogens without a threshold and the realization that complete elimination of genotoxic impurities from drug substances is often unachievable, requires implementation of a concept of an acceptable risk level, i.e. an estimate of daily human exposure at and below which there is a negligible risk to human health.
鉴于在没有明确阈值的前提下定义安全暴露水平（零风险）是不可能的，且从原料药中完全除去遗传毒性杂质经常是很难做到的，所以有必要提出一个“可接受风险水平”（acceptable risk level）的概念，比如估算一个“每日最大暴露量”值，低于该暴露量时就可以忽略其对人体健康的风险。
Procedures for the derivation of acceptable risk levels are considered in the Appendix 3 of the Q3C Note for Guidance on Impurities: Residual Solvents for Class 1 solvents. However, these approaches require availability of adequate data from long-term carcinogenicity studies.
对于可接受风险水平的推导过程请参见Q3C（杂质指南注释: 一类溶液残留）中的附件三。然而，应用这些方法必须有足够多的长期致癌性研究数据。
In most cases of toxicological assessment of genotoxic impurities only limited data from in vitro studies with the impurity (e.g. Ames test, chromosomal aberration test) are available and thus established approaches to determine acceptable intake levels cannot be applied. Calculation of “safety multiples” from in vitro data (e.g. Ames test) are considered inappropriate for justification of acceptable limits. Moreover, negative carcinogenicity and genotoxicity data with the drug substance containing the impurity at low ppm levels do not provide sufficient assurance for setting acceptable limits for the impurity due to the lack of sensitivity of this testing approach. Even potent mutagens and carcinogens are most likely to remain undetected when tested as part of the drug substance, i.e. at very low exposure levels. A pragmatic approach is therefore needed which recognises that the presence of very low levels of genotoxic impurities is not associated with an unacceptable risk.
大多数情况下，遗传毒性杂质的毒理学评估只是局限于杂质的体外研究（如Ames试验，染色体畸变试验），但这些方法并不适用于确定杂质可接受的摄入水平。也就是说，根据体外数据（如Ames试验）计算杂质的“安全倍数（safety multiples）”、进而确定可接受的限度，是不合适的。此外，用含有较低（ppm级）杂质水平的原料药研究其致癌性和遗传毒性，即使得出阴性结果也不足以确保该杂质限度的合理性，因为这种试验方法缺少必要的灵敏度。有些具有很强致突变性和致癌性物质与原料药一起进行试验时，因为在非常低的暴露水平情况下，很有可能因为低于检测限而无法检出。所以，如果认识到含量非常低的遗传毒性杂质不存在“不可接受的风险”（unacceptable risk），那么可以采取实用的方法来控制该杂质。
5.2.3 Application of a Threshold of Toxicological Concern 毒理学相关的阈值应用 A threshold of toxicological concern (TTC) has been developed to define a common exposure level for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects (Munro et al. 1999, Kroes and Kozianowski 2002). This TTC value was estimated to be 1.5 μg/person/day. The TTC, originally developed as a “threshold of regulation” at the FDA for food contact materials (Rulis 1989, FDA 1995) was established based on the analysis of 343 carcinogens from a carcinogenic potency database (Gold et al. 1984) and was repeatedly confirmed by evaluations expanding the database to more than 700 carcinogens (Munro 1990, Cheeseman et al. 1999, Kroes et al. 2004). The probability distribution of carcinogenic potencies has been used to derive an estimate of a daily exposure level (μg/person) of most carcinogens which would give rise
to less than a one in a million (1 x 10-6) upper bound lifetime risk of cancer (“virtually safe dose”). Further analysis of subsets of high potency carcinogens led to the suggestion of a 10-fold lower TTC (0.15 μg/day) for chemicals with structural alerts that raise concern for potential genotoxicity (Kroes et al. 2004).
“毒理学担忧阈值”用于定义那些不会产生显著致癌性或其他毒性作用、但又未明确研究的化合物的“常见暴露量”（common exposure level）(Munro et al. 1999, Kroes and Kozianowski 2002)。该TTC估计值是1.5μg/人/日。TTC概念最早来源于FDA关于食品接触材料的“规定阈值”（a threshold of regulation）（Rulis 1989, FDA 1995），该阈值根据对致癌能力数据库(Gold et al. 1984)中343种致癌物质的分析结果得出。随后该数据库扩大到700多个致癌性物质(Munro 1990, Cheeseman et al. 1999, Kroes et al. 2004)，这种分析结果不断得到重复验证。通过对致癌能力的概率分布进行评价，可以得到一个对大多数致癌物质适用的“日常摄入水平(μg/person)”，此水平造成的一生中患癌症的风险小于正常风险水平的上限1 x 10-6（真实的安全剂量）。对于含有“可能引起遗传毒性结构” 的化合物，其TTC应严格10倍（0.15?g/日）（Kroes et al. 2004）。
However, for application of a TTC in the assessment of acceptable limits of genotoxic impurities in drug substances a value of 1.5 μg/day, corresponding to a 10-5 lifetime risk of cancer can be justified as for pharmaceuticals a benefit exists. It should be recognized in this context that the methods on which the TTC value is based, are generally considered very conservative since they involved a simple linear extrapolation from the dose giving a 50% tumour incidence (TD50) to a 1 in 106 incidence, using TD50 data for the most sensitive species and most sensitive site (several “worst case” assumptions) (Munro et al. 1999).
然而，用TTC评估原料药中的遗传毒性杂质限度，1.5?g/日（相当于10万分之一的患癌风险）是可以接受的。应该承认，基于TTC值控制遗传毒性杂质是非常保守的，因为这只是根据从产生50%肿瘤发生率（TD50）到百万分之一致癌率的剂量线性推导得到的，而且TD50数据是用最敏感的动物和最敏感的部位研究得到的（几个“最坏条件”假设）（Munro et al. 1999）。
Some structural groups were identified to be of such high potency that intakes even below the TTC would be associated with a high probability of a significant carcinogenic risk (Cheeseman et al. 1999, Kroes et al. 2004). This group of high potency genotoxic carcinogens comprises aflatoxin-like-, nitroso-, and azoxy-compounds that have to be excluded from the TTC approach. Risk assessment of members of such groups requires compound-specific toxicity data.
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