试论异常毒性作为药品质量控制指标的合理性

异常毒性最初是一种确保复杂成分制剂生产工艺一致性及安全性的辅助检测手段，后来成为针对外源性毒性污染物的通用安全性检测项，曾在世界范围内被各国药典收载。由于该检测与药品质量、安全性之间的关联性受到质疑，各国药典逐渐在各论及通则中删除该检测项，目前仅《中国药典》保留异常毒性。由于该检测存在设定限值难以统一、给药体积及给药剂量不合理、结果易受干扰且缺乏明确的判定标准等试验原理及设计上的缺陷，导致其试验结果没有实际参考意义。基于对历史数据的回顾分析，国际监管机构及卫生组织对异常毒性有了更为科学的认知，并已逐渐形成统一的监管共识：严格的生产控制措施和有效的质量检测手段，比异常毒性检测更为重要；异常毒性检测结果或与产品质量及污染不具相关性；在异常毒性检查中使用大量动物不符合动物福利和“3R”原则。本文从科学角度试论异常毒性作为药品质量控制指标的合理性，并总结异常毒性修订的科学原则，希望能为我国监管机构、制药行业修订异常毒性相关内容提供思考角度。

On the Rationality of Using Abnormal Toxicity as an Indicator of Drug Quality Control

Abnormal toxicity testing was initially considered as an auxiliary testing method to ensure the consistency and safety of the manufacturing processes for multiple-ingredients products, and subsequently recognized as a universally-accepted safety measure for exogenous toxic pollutants and was listed in the pharmacopoeia in various countries around the world. Due to the relevance of this testing result, the quality and/ or safety of the medication has been questioned, this method is gradually eliminated from the general guidance of pharmacopoeia in many countries, while it is still listed in Chinese Pharmacopoeia. Since the test has numerous limitations, such as the difficulty in unifying the setting limits, unreasonable administration volume and dosage, susceptible testing results and lack of clear evaluation standards and defects from experimental principles and design, the test results of abnormal toxicity have no significant practical reference. Based on the retrospective analysis of historical data, international regulatory agencies and the health organizations have an advanced scientific understanding of the abnormal toxicity, and have gradually formed a unified regulatory consensus, that is, strict manufacturing control measures and effective quality testing methods are more important than the abnormal toxicity testing; besides, no correlation between the abnormal toxicity testing results and quality of the product and contamination levels were found; furthermore, utilizing a large number of animals in the abnormal toxicity test does not comply with animal welfare and the "3R" principle. This article attempts to discuss the rationality of the abnormal toxicity test to be used as a standard quality control test from scientific perspectives, and summarizes the scientific principles for the revision of abnormal toxicitiy test, which will provide a consideration basis for Chinese regulatory agencies and the pharmaceutical industry to revise related guidance of abnormal toxicity testing.