King's Centre for Risk management, King's College London, Strand, London WC2R 2LS, UK.
Expert Rev Clin Pharmacol. 2008 Mar;1(2):241-50. doi: 10.1586/17512433.1.2.241.
This paper explores the implications of the EMEA guideline EMEA/CHMP/QWP/251344/2006 for pharmaceutical risk decisions. The guidelines propose to consider the intake of 1.5 µg/day of a genotoxic impurity as a 'threshold of toxicological concern', and to treat this level as an acceptable risk (excess cancer risk of <10(-5) over a lifetime). The guidance document also introduces a specific decision-tree to assess the acceptability of genotoxic impurities. According to this decision-tree, when the presence of genotoxic impurities is unavoidable, their levels should be reduced 'as low as reasonably practicable' (ALARP). In the UK, the Health and Safety Executive has developed a 'tolerability of risk' (ToR) model to support ALARP requirements. The paper compares the EMEA risk-reduction requirements and the ToR model. EMEA/CHMP/QWP/251344/2006 introduces a risk-avoidance principle based on a controversial interpretation of 'pollution control'. The paper supports the view that this model is not optimal from a risk-management point of view. Using a ToR model could bring improvements to pharmaceutical risk decisions and would support a more practical and consensual approach to meeting the ALARP requirements.
本文探讨了 EMEA 指南 EMEA/CHMP/QWP/251344/2006 对药物风险决策的影响。该指南建议将每天摄入 1.5µg 的遗传毒性杂质视为“毒理学关注阈值”，并将此水平视为可接受的风险（终生超额癌症风险<10(-5)）。该指导文件还引入了一个特定的决策树来评估遗传毒性杂质的可接受性。根据该决策树，当遗传毒性杂质的存在不可避免时，应尽可能降低其水平（尽可能低）。在英国，健康与安全执行局开发了一个“风险可容忍性”（ToR）模型来支持尽可能低的原则要求。本文比较了 EMEA 的风险降低要求和 ToR 模型。EMEA/CHMP/QWP/251344/2006 基于对“污染控制”的有争议的解释，引入了一种风险规避原则。本文支持从风险管理角度来看，该模型并非最佳的观点。使用 ToR 模型可以改进药物风险决策，并支持采用更实际和更具共识的方法来满足尽可能低的原则要求。
