P09-35 An alternative approach to evaluate PECSW in the Environmental Risk Assessment: [GB1] – A case-study of a pharmaceutical product with emergencial indication

The Environmental Risk Assessment (ERA), topic of the 2024-revised guideline, evaluates the environmental impact of Human Medicinal Products (HMPs) based on their release into the environment after therapeutic use and disposal by patients. ERA is required for all new Marketing Authorization (MA) applications, but its results do not currently hinder product approval. The guideline provides a step-by-step process for assessing environmental exposure, considering worst-case scenarios for dosage and posology. Phase I involves evaluating the drug's physical-chemical properties and calculating the Predicted Environmental Concentration for Surface Water (PEC SW ). If PEC SW exceeds 0.1 μg/L, Phase II is triggered, where adjustments are made based on real life data on market penetration fraction (F PEN ) or worstcase treatment regimens. However, assessing sporadically used HMPs, such as those used in surgeries, is challenging due to their unpredictable usage. This scenario, not addressed by the guideline, requires clarification from health authorities on how to refine the F PEN . Alternative approaches, like reasoning by absurdity, may be needed for such cases. Here we present the case study of a drug used in adults for cardiac arrest, anaphylactic shock, and as a vasoconstrictor additive to local anaesthetics. Since these conditions occur in emergency settings or sporadic surgeries, predicting a specific dose regimen in advance is impossible, making it challenging to estimate a reasonable PEC SW . Therefore, in this particular case, the PEC SW was set at 0.01 μg/L, the EMA guideline's threshold for Phase II triggering, to derive the theoretical number of days of treatment for one year, (n treatment× t treatment ), assuming a homogeneous P region . Given the drug's sporadic use in mainly emergency cases, it was presumed sufficiently conservatively to assume that at most one person out of 100 would be treated daily with the drug, thus setting P region at 0.01 (ERA guideline default factor). With the highest daily dose for the reference product set at 3 mg, calculations indicated that each patient (1% of the entire population) would receive treatment for 243 days per year. However, considering the primary use of this drug in emergency situations, the likelihood of 243 treatment days per year is deemed improbable and therefore sufficiently conservative to state that the product poses no significant environmental risk. Although this approach and its conclusions align with the ERA's goal of ensuring environmental protection from drugrelated risks, it is not explicitly addressed in the guideline. This could lead to varying European authorities’ outcomes on ERA evaluation. The lack of specific guidance for such unique cases underscores the need for clarification from health authorities to standardize assessment procedures. Furthermore, it would be beneficial if ERA evaluators were open to considering alternative, well-justified approaches.