基于杂质遗传毒性谈药物中5-羟甲基糠醛的质量控制

目的：对药物杂质5-羟甲基糠醛进行遗传毒性评价，并对其标准限度的合理性进行评价。方法：对中国药典2015年版收载5-羟甲基糠醛作为杂质的药物进行汇总分析，按照ICH M7指导原则的要求，采用基于专家知识规则的Derek和基于统计学的Sarah两类in silico评价系统，对5-羟甲基糠醛进行遗传毒性评价，并以葡萄糖和果糖作为母药对其进行分类。根据药物临床用量计算5-羟甲基糠醛的暴露量，并按照遗传毒性杂质相关指导原则的要求，对其标准限度进行评估。结果：5-羟甲基糠醛in silico遗传毒性预测结果为阳性，分类为2类。根据相关品种的临床用量计算的暴露量，5-羟甲基糠醛的标准限度远高于基于毒理学关注阈值的限度，存在安全隐患。结论：5-羟甲基糠醛为2类遗传毒性杂质，其标准限度应该进一步严格。

Objective: To assess the genotoxicity of 5-hydroxymethylfurfural(HMF)as an impurity in drugs,and to evaluate its limit.Methods: All the drugs in ChP 2015 which contained HMF as an impurity were listed.Two(Q)SAR prediction methodologies were applied(Derek is expert rule-based and Sarah is statistical-based)to assess the genotoxicity of HMF.And HMF was classified as an impurity in glucose or fructose.The potential exposure of HMF was calculated based on the dosages of drugs.Then the limit of an HMF was evaluated according to guidelines for genotoxic impurities.Results: In silico evaluation showed that HMF was positive and was classified as a class 2 genotoxic impurity.The limit of HMF,which was much higher than the TTC-based acceptable intake,was too high to ensure the drugs' safety.Conclusion: 5-hydroxymethylfurfural was a class 2 genotoxic impurity.The limit of it should be reduced.

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