Straub Jürg Oliver
EurProBiol CBiol MIBiol, Corporate Safety and Environmental Protection, CSE, 49/2.033, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
Toxicol Lett. 2002 May 10;131(1-2):137-43. doi: 10.1016/s0378-4274(02)00049-8.
Since 1993, an environmental risk assessment (ERA) for a new drug application has been stipulated by EU Directive 93/39/EEC amending Directive 65/65/EEC. In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines Evaluation Agency (EMEA). The draft guideline describes a step-wise, tiered procedure for the ERA. The first tier consists of deriving a crude predicted environmental concentration (PEC) in the aquatic compartment for the active pharmaceutical ingredient (API) or its major metabolites, based on predicted amounts used and specific removal rates in sewage treatment or surface waters. If this crude PEC is <0.01 microg/l and no environmental concerns are apparent, no further assessment is deemed necessary. Else, in the second tier, a crude predicted no-effect level (PNEC) for the aquatic compartment is to be extrapolated by dividing the lowest 50%-effect concentration from acute ecotoxicity tests with algae, daphnia or fish (EC(50), LC(50)) by an assessment factor (usually 1000). If the ratio PEC/PNEC is <1, no further assessment is deemed necessary. Lastly, in the third tier, further considerations on a case-by-case basis are needed. This may encompass refining the environmental fate information and thereby the PEC, considering further environmental compartments and their respective PECs (up to and including field studies), but also refining the PNEC. While the ERA addresses mainly the API, excipients of the formulated drug should be considered as well. In the case of medicinal products, the benefit for patients has relative precedence over environmental risks, meaning that even in the case of an unacceptable residual risk for new drugs after third-tier considerations, prohibition of a new API is not taken into consideration. Instead, possible mitigating or precautionary safety measures may consist of specific product labelling (i.e. package leaflets for the patients regarding returning and proper disposal of unused medicines), restricted use through in-hospital or in-surgery administration under supervision only, or the recommendation of environmental analytical monitoring up to ecological field studies.
自1993年起，欧盟理事会指令93/39/EEC（修订指令65/65/EEC）规定了新药申请的环境风险评估（ERA）。2001年初，在发布了多个未公开的ERA指南草案版本之后，欧洲药品评估局（EMEA）发布了一份关于不含转基因成分药品的ERA指南草案/讨论文件。该指南草案描述了ERA的逐步分层程序。第一层包括根据预测使用量以及污水处理或地表水中的特定去除率，得出活性药物成分（API）或其主要代谢物在水相中的粗略预测环境浓度（PEC）。如果该粗略PEC<0.01微克/升且未发现明显环境问题，则无需进一步评估。否则，在第二层中，水相的粗略预测无效应水平（PNEC）应通过将藻类、水蚤或鱼类急性生态毒性试验中的最低50%效应浓度（EC(50)、LC(50)）除以评估因子（通常为1000）来推算。如果PEC/PNEC比值<1，则无需进一步评估。最后，在第三层中，需要根据具体情况进行进一步考虑。这可能包括完善环境归宿信息从而完善PEC，考虑其他环境介质及其各自的PEC（直至并包括实地研究），同时也包括完善PNEC。虽然ERA主要针对API，但也应考虑制剂药物的辅料。对于药品而言，患者的受益相对于环境风险具有相对优先权，这意味着即使在经过第三层考虑后新药仍存在不可接受的残留风险，也不会考虑禁止新的API。相反，可能的缓解或预防性安全措施可能包括特定的产品标签（即针对患者的包装说明书，说明未使用药品的返还和正确处置方法）、仅在监督下通过院内或手术中给药进行限制使用，或建议进行直至生态实地研究的环境分析监测。
