Environmental risk assessment for new human pharmaceuticals in the European Union according to the draft guideline/discussion paper of January 2001.

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 In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines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.