发布时间 : 星期三 文章基因毒性杂质限度指南（转载中英文）更新完毕开始阅读cef4192a52d380eb62946dd3
有几个结构基团被认定为具有非常高的基因毒性，它们即使被摄入低于TTC值的量也会面临非常高的基因毒性风险(Cheeseman et al. 1999, Kroes et al. 2004)。这些高致癌性物质包括黄曲霉素类、N-亚硝基物和偶氮类化合物，不适用TTC方法。这类化合物的风险评估需采用专门的毒性数据。
There may be reasons to deviate from the TTC value based on the profile of genotoxicity results.
根据基因杂质概况，有些情况下会偏离TTC值。
Positive result from in vitro studies only may allow to exempt an impurity from limitation at TTC level if lack of in vivo relevance of the findings is convincingly demonstrated based on a weight-ofevidence approach (see ICH S2 guidelines). This approach will usually need negative results with the impurity from some additional in vitro and/or appropriate in vivo testing.
假如按照证据权衡法能充分证明“结果缺乏体内相关性”，体外试验的阳性结果也仅能在TTC水平上排除一个杂质(参见 ICH 指南S2)。这种方法经常需要在额外的体外试验和/或合理的体内试验，并且得到杂质的阴性结果。
A TTC value higher than 1.5 μg/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites.
某些情况下TTC值高于1.5?g/日也是可以接受的，如短期用药；用于治疗威胁生命疾病的药物；或人的存活期少于5年；或该杂质是已知物质，人体从其他途经（如食物）获得的暴露量远远高于药物途经。如果遗传毒性杂质本身就是重要的代谢物，那么该杂质可以根据代谢物的可接受限度进行控制。
The concentration limits in ppm of genotoxic impurity in drug substance derived from the TTC can be calculated based on the expected daily dose to the patient using equation (1).
采用下列公式，从TTC值和日服用剂量，可以计算出原料药中的基因毒性杂质的浓度限度。
(1) Concentration limit (ppm) = TTC [μg/day]/dose (g/day] 浓度限度（ppm） = TTC [μg/day]/剂量(g/day]
The TTC concept should not be applied to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compound-specific risk assessment.
对于有确切毒性数据（长期毒性研究）的致癌性物质不宜使用TTC概念，应进行特定化合物风险评估。
It has to be emphasized that the TTC is a pragmatic risk management tool using a probabilistic methodology, i.e. there is a high probability that a 10-5 lifetime cancer risk will not be exceeded if the daily intake of a genotoxic impurity with unknown carcinogenic potential/potency is below the TTC value. The TTC concept should not be interpreted as providing absolute certainty of no risk.
应强调，TTC是一个实用性的风险管理方法，是按概率方法学估算的。比如按这一概念，如果某未知致癌性遗传毒性杂质的摄入量低于TTC值，那么就可以保证患癌风险控制在十万分之一之内。但TTC概念不能被理解为确保绝对无风险。
5.3 Decision Tree for Assessment of Acceptability of Genotoxic Impurities 基因毒性可接受性评价决策树
(shaded boxes = pharmaceutical assessment, white boxes = toxicological assessment) （阴影框 = 药学评价，白框 = 毒理学评价）
1) Impurities with structural relationship to high potency carcinogens (see text) are to be excluded from the TTC approach
1)结构上与高致癌性物质有关的杂质（见正文）不能采用TTC法。
2) If carcinogenicity data available: Does intake exceed calculated 10-5 cancer lifetime risk? 2)如果有致癌性数据：摄入量超过10-5患癌风险吗？
3) Case-by-case assessment should include duration of treatment, indication, patient population etc (see text)
3)具体情况具体分析，包括用药时间长短、适应症、患者人群等（见正文）。 *) Abbreviations: 缩写