可提取物与浸出物的毒理学风险评价策略

生产用一次性组件与容器密闭系统中的可提取物和浸出物（extractable&leachable,E&L）安全性评估是药品上市申报的重要环节之一。E&L的毒理学评价是其安全性评估的重点内容,目前尚未有E&L毒理学评价的系统性指导法规,特别是多个毒理数据来源的合理选择,以及毒理数据缺乏的问题,是E&L安全性评估的难点。基于E&L安全性评估,重点介绍了安全阈值的确定策略,包括每日允许最大暴露量和日摄入量计算、多层次毒理学关注阈值的选择;相关毒理数据的选择和评价,包括毒理学观测指标和试验选择,以及关键毒性效应的选择。并结合实际事例,为解决E&L研究中安全性评估问题提供新思路,为药品研发及生产企业提供借鉴。

Toxicological risk evaluation strategy of extractable and leachable

The safety assessment of extractable & leachable (E&L) in single use system, applied in manufacturing process and container closure system for drug product, is a vital part of new drug application or biologic license application. Toxicological evaluation of E&L is of importance in E&L safety evaluation. There are no systematic guidelines for E&L toxicological evaluation, especially for toxicological data selection, which poses a great challenge for E&L safety evaluation. Based on the E&L safety assessment, this paper focuses on the establishment strategy of safety threshold, including permitted daily exposure and acceptable intake calculation, the selection of multi-level threshold toxicological concern; the selection and evaluation of key toxicological data, including toxicological observation indicators and rational assay selection, and the identification of "critical effects". Here, we combined the systematic introduction of E&L toxicology evaluation with actual cases, which provides a new insight to solve the problem in E&L research and gives recommends and assistance for drug development and production enterprises.