The environmental risk assessment of human pharmaceuticals in the overall EU regulatory affairs process.

The approval of new human pharmaceutical products in the EU requires an assessment of potential environmental risks related to the use by patients, besides the evaluation of the human safety, efficacy, and quality evaluation. The current guidance by the European Medicines Agency (EMEA), describing the process of the environmental risk assessment for human drugs, covers a two-tiered assessment programme with a modelling step for an environmental exposure scenario and a subsequent step of environmental fate and effects testing. The following paper describes ways how the requirements of the environmental risk assessment can be sensibly incorporated in the overall approval process of a pharmaceutical product including the risk/benefit analysis for the patient. The resources for environmental testing and assessment programmes can be employed economically, if the pharmacological, toxicological, and pharmacokinetic information obtained during the development programme of a human pharmaceutical is used to develop substance-specific test programmes and to evaluate the environmental risk assessment taking into account the pharmacodynamic properties and the use pattern by patients. Finally, we suggest that the environmental risk evaluation process as part of drug approvals should adhere to a focussed assessment strategy considering existing knowledge and the therapeutic needs.

A strategy to reduce the numbers of fish used in acute ecotoxicity testing of pharmaceuticals.

The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using > or = 42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (approximately 73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates.