Periodic Reporting for period 5 - PREMIER (Prioritisation and Risk Evaluation of Medicines in the EnviRonment)
Okres sprawozdawczy: 2024-09-01 do 2025-08-31
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: In collaboration with EMA and WP1 partners, RU developed a decision tree to prioritise legacy APIs for environmental risk assessment (ERA), now being finalised. EFPIA and public partners scheduled and began experimental tests for 25 case study APIs, with results enabling final ERA in RP6.
WP2: Major advances were made, including a new approach to experimentally measure and predict half—lives in soil and water-sediment systems through read-across has been developed. Simplified machine learning-based approach was developed and applied for assessing sorption mobility of APIs in the environment. An aquatic secondary poisoning model was developed and validated for aquatic food webs. The ePiE model (https://shoeks.github.io/ePiE_desktopApp/(odnośnik otworzy się w nowym oknie)) was expanded and evaluated using an extensive European monitoring set. The EcoDrug+ database (https://ecodrugplus.helsinki.fi/(odnośnik otworzy się w nowym oknie)) is finalised. The VERA model (https://www.vegahub.eu/download/(odnośnik otworzy się w nowym oknie)) was improved for acute/chronic fish toxicity, and new QSAR models were developed to assess the acute toxicity of earthworms. Integration of effect modelling tools into the DAS progressed, with new data generated for API uptake and clearance, and predictive methods for API effects in fish. Multiple journal articles resulted from WP2.
WP3: WP3 enhance the PREMIER ERA Database and Digital Assessment System (DAS) across three sub-WPs. WP3.1 focused on database design and population, adapting based on partner feedback and DAS testing, including an EU-wide API inventory and GLP study data. WP3.2 systematically extracted and assessed literature and regulatory data for case study compounds, evaluating data reliability and conducting comprehensive assessments for 25 APIs. WP3.3 defined and improved DAS functionalities, enhancing search capabilities and refining ERA tool architecture per EMA guidelines, preparing DAS for public access in RP6.
WP4: Guidance documents 1–4 are in advanced draft stages, with annexed example calculations for clozapine and metoprolol. Guidance 4 addresses selecting environmental threshold concentrations, with a scientific article nearly ready for review. Guidance 8 for drug R&D experts will be published as a brochure. Guidance 1, 3, and 4 are slightly delayed (D4.4) while guidance 2 on exposure assessment will be delivered as D4.3. D4.8 with conclusions on greener drug design, has been submitted, and an interview-based article is nearing completion. D4.7 and its manuscript, covering new drug modalities and their environmental impact, are delayed.
WP5: RP5 focused on robust project governance and management, coordinating all scientific and operational activities. This included strategic oversight, engaging the SAB, supporting the PMO, ExCom, and GAMs. Virtual GAM#10 and onsite GAM#11 in Barcelona (September 2025) were organised. WP5 maintained oversight of deliverables, milestones, and risk management, with regular meetings and continuous editorial communication. Efforts enhanced internal/external communications, including two newsletters and targeted social media posts. Commitment to open-source development ensures long-term PREMIER outcomes, especially the DAS. Increasing EMA involvement supports EU platform compatibility, strengthening DAS relevance and accessibility.
WP2: Major advances were made, including a new approach to experimentally measure and predict half—lives in soil and water-sediment systems through read-across has been developed. Simplified machine learning-based approach was developed and applied for assessing sorption mobility of APIs in the environment. An aquatic secondary poisoning model was developed and validated for aquatic food webs. The ePiE model (https://shoeks.github.io/ePiE_desktopApp/(odnośnik otworzy się w nowym oknie)) was expanded and evaluated using an extensive European monitoring set. The EcoDrug+ database (https://ecodrugplus.helsinki.fi/(odnośnik otworzy się w nowym oknie)) is finalised. The VERA model (https://www.vegahub.eu/download/(odnośnik otworzy się w nowym oknie)) was improved for acute/chronic fish toxicity, and new QSAR models were developed to assess the acute toxicity of earthworms. Integration of effect modelling tools into the DAS progressed, with new data generated for API uptake and clearance, and predictive methods for API effects in fish. Multiple journal articles resulted from WP2.
WP3: WP3 enhance the PREMIER ERA Database and Digital Assessment System (DAS) across three sub-WPs. WP3.1 focused on database design and population, adapting based on partner feedback and DAS testing, including an EU-wide API inventory and GLP study data. WP3.2 systematically extracted and assessed literature and regulatory data for case study compounds, evaluating data reliability and conducting comprehensive assessments for 25 APIs. WP3.3 defined and improved DAS functionalities, enhancing search capabilities and refining ERA tool architecture per EMA guidelines, preparing DAS for public access in RP6.
WP4: Guidance documents 1–4 are in advanced draft stages, with annexed example calculations for clozapine and metoprolol. Guidance 4 addresses selecting environmental threshold concentrations, with a scientific article nearly ready for review. Guidance 8 for drug R&D experts will be published as a brochure. Guidance 1, 3, and 4 are slightly delayed (D4.4) while guidance 2 on exposure assessment will be delivered as D4.3. D4.8 with conclusions on greener drug design, has been submitted, and an interview-based article is nearing completion. D4.7 and its manuscript, covering new drug modalities and their environmental impact, are delayed.
WP5: RP5 focused on robust project governance and management, coordinating all scientific and operational activities. This included strategic oversight, engaging the SAB, supporting the PMO, ExCom, and GAMs. Virtual GAM#10 and onsite GAM#11 in Barcelona (September 2025) were organised. WP5 maintained oversight of deliverables, milestones, and risk management, with regular meetings and continuous editorial communication. Efforts enhanced internal/external communications, including two newsletters and targeted social media posts. Commitment to open-source development ensures long-term PREMIER outcomes, especially the DAS. Increasing EMA involvement supports EU platform compatibility, strengthening DAS relevance and accessibility.
RP1: PREMIER developed and established the database architecture and DAS, releasing two updates. Initial data input included a preliminary list of APIs on the EU market and partial ERA data from iPiE. The final API inventory is now accessible to partners for scientific use.
RP2: Additional datasets were integrated and two more database updates released. The Fish PBK model, published in "Environmental Science and Technology", predicts API uptake, distribution, metabolism, and excretion, and was validated with five APIs. The ePiE model is used to predict concentrations of APIs in European waters and supports risk identification. The PBK model will be further applied to case study compounds.
RP3: Biodegradation studies yielded initial results. The database and DAS work resumed with IRFMN as new lead. Literature data for 23 of 25 case study APIs were extracted, with first experimental results available. Stakeholder engagement was enhanced through a workshop with TransPharm and presentations at EFPIA, boosting collaboration and awareness.
RP4: New tools were developed: a QSAR model for sorption prediction, VERA for acute fish toxicity, and the EcoDrug+ website for API analysis. Extensive testing of APIs was conducted, especially the 25 case studies. The internal DAS version was launched, with the first public release planned for autumn 2025, expected to make valuable data accessible and stimulate ERA of legacy APIs. Guidance documents on ERA and green drug design are forthcoming.
RP5: All experimental tests were commissioned, with results arriving for use in RP6. A decision tree for prioritising legacy APIs was created and will be finalised. Several exposure and effect tools for ERA were completed or are near completion. The database (https://premier.marionegri.it/(odnośnik otworzy się w nowym oknie)) now filled with industry and literature data and verified by data owners, will be public in autumn 2025 and expanded in RP6, significantly advancing environmental risk assessment of APIs.
RP2: Additional datasets were integrated and two more database updates released. The Fish PBK model, published in "Environmental Science and Technology", predicts API uptake, distribution, metabolism, and excretion, and was validated with five APIs. The ePiE model is used to predict concentrations of APIs in European waters and supports risk identification. The PBK model will be further applied to case study compounds.
RP3: Biodegradation studies yielded initial results. The database and DAS work resumed with IRFMN as new lead. Literature data for 23 of 25 case study APIs were extracted, with first experimental results available. Stakeholder engagement was enhanced through a workshop with TransPharm and presentations at EFPIA, boosting collaboration and awareness.
RP4: New tools were developed: a QSAR model for sorption prediction, VERA for acute fish toxicity, and the EcoDrug+ website for API analysis. Extensive testing of APIs was conducted, especially the 25 case studies. The internal DAS version was launched, with the first public release planned for autumn 2025, expected to make valuable data accessible and stimulate ERA of legacy APIs. Guidance documents on ERA and green drug design are forthcoming.
RP5: All experimental tests were commissioned, with results arriving for use in RP6. A decision tree for prioritising legacy APIs was created and will be finalised. Several exposure and effect tools for ERA were completed or are near completion. The database (https://premier.marionegri.it/(odnośnik otworzy się w nowym oknie)) now filled with industry and literature data and verified by data owners, will be public in autumn 2025 and expanded in RP6, significantly advancing environmental risk assessment of APIs.