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Prioritisation and Risk Evaluation of Medicines in the EnviRonment

Periodic Reporting for period 4 - PREMIER (Prioritisation and Risk Evaluation of Medicines in the EnviRonment)

Berichtszeitraum: 2023-09-01 bis 2024-08-31

Active ingredients from medicines can be released into the environment through a variety of routes, and once there, they may prove harmful to wildlife and ecosystems. Since 2006, new medicines introduced into the EU are required to undergo an environmental risk assessment (ERA). Few of the approx. 1900 active pharmaceutical ingredients (APIs) that are currently on the market have been assessed for their environmental impact, since many of these APIs were already marketed before 2006. The aim is to deliver data, methods and tools for assessing and characterising the environmental risks of APIs, and combine these in a digital assessment system. This system will be used to prioritise and screen older (‘legacy’) APIs that have never been evaluated in an ERA. The assessment tools developed in PREMIER can be used to pick up potential environmental risks of new APIs that are still under development, thereby contributing to greener drug design.
WP1: Selection of case study APIs was completed with the addition of 2 immunosuppressants. The initial hazard and risk assessments in fresh surface water were completed for all case study APIs. In consultation with the ethics committee, the fish decision tree (RP2) was applied to reach decisions on chronic fish testing for several case study APIs. For the remaining APIs, data are being generated that will soon allow taking decisions on chronic fish testing. Preparations were made for the development of an iterative decision tree on legacy APIs with the aim to reach policy-relevant conclusions on their environmental risk for fresh surface water based on minimal testing needs and making optimal use of the in vitro and in silico techniques available in literature or developed within the PREMIER project.
WP2: Significant progress on the development of new approaches for assessing exposure and effects of APIs. A new machine-learning based model for estimating the sorption behaviour of APIs in sludge, soil and sediment was developed. A draft desktop application of the ePiE model was developed for end users and is now available for testing. A large-scale study was performed to determine the spatial and temporal variability of concentrations of 56 APIs in river systems across Europe. The EcoDrug+ website was launched enabling user to determine the conservation of drug targets across species. A new tool ‘Virtual Extensive Read-Across’ (VERA) was developed and assessed for read-across for APIs. In-vitro effect models were applied to determine the uptake, hepatic clearance and pharmacological effects of APIs in a range of model systems. Work on the integrated effects models (WP2.3) has involved the curation and standardization of data on the toxicity and bioavailability of APIs in mammalian systems for use in the MAMTOX approach for deriving critical environmental concentrations for APIs. Ecotoxicity data has also been collated to support the development of the approach. Work on the development of an improved fish plasma model has involved the development of in-vivo data on two APIs in different fish species and the quantification of plasma protein binding for 16 APIs.
WP3: Focus on the design and development of the DAS. 1st internal version of the DAS was shared with the consortium. Data retrieval, check and assessment proceeded during RP4, so the data can later be imported and made available within the DAS. Connection with EMA was established, to discuss their possible role as maintainer of the DAS after the project.
WP4: Mature drafts of 3 guidance documents were generated and sent to the key user group to obtain feedback. D4.2 submitted-provides an overview of the overall guidance and includes the mature drafts as annexes. D4.6 was summarized into a scientific paper for wider outreach. Efforts were invested to provide an overview of new drug modalities and what would be their environmental impact (D4.7). A round of interviews with relevant stakeholders from the healthcare sector was conducted to evaluate the feasibility to incorporate environmental risks/hazards into procurement and/or prescription processes.
WP5: Maintaining the governance and management structure to effectively coordinate scientific and operational activities, including engagement with the SAB, planning and support for meetings (PMO, ExCom and GAMs). Organized virtual GAM#8 and prepared GAM#9. Diligently monitored task progress, deliverables, milestones, and risks while preparing for the Mid-term review. 2 newsletters and multiple social media campaigns were launched. Sustainability of project outcomes, especially the DAS, was reinforced by adopting an open-source approach and involving the EMA to ensure compatibility with EU systems.
RP1: PREMIER database architecture and DAS have been created an established and 2 update releases took place. The first collection of data was input in the database, including a preliminary list of APIs on the EU market (based on EMA's Article 57 database) and part of the ERA data from the iPiE database. Ultimate inventory of API in the EU market has been completed and is available to all partners for scientific purposes. RP2: continued inputting the remaining existing datasets in the database and 2 more updated database versions were released. The Fish PBK model serves to predict API uptake, distribution, metabolism and excretion (ADME). The expanded ePiE model is being used internally to predict the concentrations of specific APIs in European surface waters in order to establish the validity of the model predictions and to identify potential environmental risks of specific compounds. The PBK model was published in "Environmental Science and Technology" journal. The model was applied to 5 APIs in order to test its performance. The model will be further improved and applied to the PREMIER case study compounds in the project (D2.8). RP3: the work on biodegradation of pharmaceuticals resulted in the first products and the work on database and DAS was re-initiated with a new lead (IRFMN). Literature data on 23 of the 25 case study compounds were extracted and the 1st experimental test results are available. PREMIER continued its active engagement with external stakeholders. In WP3 the workshop was held together with the TransPharm project, to seek their valuable advice and expert opinions. Consortium seized various opportunities to engage with external stakeholders, strengthening awareness and collaboration: EFPIA meeting presentation. RP4: new tools were developed, published and/or made available (1) a QSAR model to predict sorption of APIs to sludge, sediment and soil, (2) a tool to predict the acute fish toxicity of APIs based on chemically-related compounds (VERA) and (3) EcoDrug+ website to support the analysis of APIs, their targets and the conservation of these targets in wildlife species. Extensive testing of APIs, and particularly the 25 case study APIs, was performed. Internal version of the DAS was launched. 1st public version of the DAS is planned in spring 2025. It's expected to have significant impact on the ERA community since this will make available a significant amount of data previously inaccessible, thereby stimulating the ERA of legacy APIs. Planned to launch guidance documents on ERA of APIs and green drug design.
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