Periodic Reporting for period 3 - PREMIER (Prioritisation and Risk Evaluation of Medicines in the EnviRonment)
Reporting period: 2022-09-01 to 2023-08-31
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). However, few of the approximately 1900 active pharmaceutical ingredients (APIs) have been assessed for their environmental impact, since many of these APIs were already marketed before 2006.
The aim of PREMIER 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 may also be used to pick up potential environmental risks of new APIs that are still under development, thereby contributing to greener drug design. PREMIER will make environmental data gathered within the context of the project visible and publicly accessible to all stakeholders.
The aim of PREMIER 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 may also be used to pick up potential environmental risks of new APIs that are still under development, thereby contributing to greener drug design. PREMIER will make environmental data gathered within the context of the project visible and publicly accessible to all stakeholders.
The collaboration within the Consortium has been productive and efficient during the third year of PREMIER and the project has progressed according to plan. The major achievements of this reporting period are summerized below:
WP1: The selection of the 25 case study APIs was completed, with the exception of 2 MoA-specific APIs (i.e. an antifungal and an immunosuppressant API) which will be selected over the next two months (before M39). The experimental testing of the case study compounds has been divided among the partners and literature searches have been completed in collaboration with WP3.2. Initial risk assessments were performed for two case study APIs, i.e. Clozapine and Disulfiram. Testing of case study APIs has continued, and the first testing results have been reported in D1.6.
WP2: Work in Year 3 has been focused on the establishment and optimization of test methodologies, collation of data from the literature and our studies, generation of preliminary data on selected APIs and the initial development of a range of modelling approaches. 3 APIs for testing uptake in fish to further improve and validate the FPM have been selected, experimental designs have been extensively discussed and testing has started in RP3.
WP3: In order to replace the former project partner and DAS developer Simomics, the project made good progress, identified and prepared the onboarding of a new DAS developer (existing project partner Mario Negri Institute). At this point in time (end of RP3), the onboarding is however not yet finalized. This shall be completed by the end of 2023 in RP4. WP3 and the project are well prepared to get started with the new DAS developer and we anticipate rapid progress in RP4.
WP4: A draft of the Exposure modelling guidance was sent to the key user group to obtain feedback on language use, level of detail, wording, etc. All key users were very positive. Thus, all other guidance documents will be written with the same level of information. In April 2023, a three-day workshop was held in Nijmegen (NL) together with the EU TransPharm project. During this workshop, results of the project were presented to drug R&D specialists and other stakeholders. In a special session during this workshop, a discussion was held on the needs of R&D experts regarding tools and assays, and how to incorporate this in their daily practice. A report has been written on environmental parameters and the way these may be tested and incorporated into drug R&D. Work has started on an overview of new drug modalities and what would be their environmental impact.
WP5: the primary focus has been on maintaining the project's governance and management structure, which is crucial for effectively coordinating all project activities from both scientific and operational perspectives. Managing the departure of Simomics and identifying a viable solution were significant challenges in terms of additional time and administartion. Project governance has included several key aspects, including strategic scientific coordination, engagement with the Scientific Advisory Board, planning and regular support for the project management office (PMO), Executive Committee (ExCom), and General Assembly Meetings (GAM).
WP1: The selection of the 25 case study APIs was completed, with the exception of 2 MoA-specific APIs (i.e. an antifungal and an immunosuppressant API) which will be selected over the next two months (before M39). The experimental testing of the case study compounds has been divided among the partners and literature searches have been completed in collaboration with WP3.2. Initial risk assessments were performed for two case study APIs, i.e. Clozapine and Disulfiram. Testing of case study APIs has continued, and the first testing results have been reported in D1.6.
WP2: Work in Year 3 has been focused on the establishment and optimization of test methodologies, collation of data from the literature and our studies, generation of preliminary data on selected APIs and the initial development of a range of modelling approaches. 3 APIs for testing uptake in fish to further improve and validate the FPM have been selected, experimental designs have been extensively discussed and testing has started in RP3.
WP3: In order to replace the former project partner and DAS developer Simomics, the project made good progress, identified and prepared the onboarding of a new DAS developer (existing project partner Mario Negri Institute). At this point in time (end of RP3), the onboarding is however not yet finalized. This shall be completed by the end of 2023 in RP4. WP3 and the project are well prepared to get started with the new DAS developer and we anticipate rapid progress in RP4.
WP4: A draft of the Exposure modelling guidance was sent to the key user group to obtain feedback on language use, level of detail, wording, etc. All key users were very positive. Thus, all other guidance documents will be written with the same level of information. In April 2023, a three-day workshop was held in Nijmegen (NL) together with the EU TransPharm project. During this workshop, results of the project were presented to drug R&D specialists and other stakeholders. In a special session during this workshop, a discussion was held on the needs of R&D experts regarding tools and assays, and how to incorporate this in their daily practice. A report has been written on environmental parameters and the way these may be tested and incorporated into drug R&D. Work has started on an overview of new drug modalities and what would be their environmental impact.
WP5: the primary focus has been on maintaining the project's governance and management structure, which is crucial for effectively coordinating all project activities from both scientific and operational perspectives. Managing the departure of Simomics and identifying a viable solution were significant challenges in terms of additional time and administartion. Project governance has included several key aspects, including strategic scientific coordination, engagement with the Scientific Advisory Board, planning and regular support for the project management office (PMO), Executive Committee (ExCom), and General Assembly Meetings (GAM).
During RP1, the PREMIER database architecture and digital assessment system have been created an established and two update releases took place. The first collection of data was input in the database, this includes a preliminary list of APIs on the European market (based on EMA's Article 57 database) and part of the ERA data from the iPiE database. In parallel, the ultimate inventory of API in the European market has been completed and is now available to all partners to be utilized for scientific purposes. During RP2 we continued inputting the remaining existing datasets in the database and two more updated database versions were released, which are available to all consortium members.
The Fish PBK model serves to predict API uptake, distribution, metabolism and excretion (ADME). Unique features of the model are its generic nature and easy parameterization (making it very useful for risk assessment purposes), and the fact that it accounts for ionization of APIs. The expanded ePiE model is being used internally (i.e. by consortium members) 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. During RP2, the PBK model was published in "Environmental Science and technology" journal. The model was applied to five 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).
During 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 responsible partner (Mario Negri). Literature data on 23 of the 25 case study compounds were extracted and the first experimental test results became available.
PREMIER continued its active engagement with external stakeholders, building upon the interactions established in previous years. We maintained our approach of inviting these stakeholders, in WP3 for the workshop that was held together with the TransPharm project in Nijmegen, to seek their valuable advice and expert opinions. The insights gathered from these interactions played a crucial role in shaping the development of the PREMIER project, including the database and DAS, the uptake of environmental criteria in drug R&D processes, as well as the formulation of guidelines to address pharmaceuticals in the environment. Additionally, consortium partners seized various opportunities to engage with external stakeholders, strengthening awareness and collaboration: EFPIA meeting presentation.
There are many other tools and initiatives being developed in PREMIER which are likely to have a substantial impact on the stakeholder community, European policy, the scientific community and society in general.
The Fish PBK model serves to predict API uptake, distribution, metabolism and excretion (ADME). Unique features of the model are its generic nature and easy parameterization (making it very useful for risk assessment purposes), and the fact that it accounts for ionization of APIs. The expanded ePiE model is being used internally (i.e. by consortium members) 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. During RP2, the PBK model was published in "Environmental Science and technology" journal. The model was applied to five 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).
During 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 responsible partner (Mario Negri). Literature data on 23 of the 25 case study compounds were extracted and the first experimental test results became available.
PREMIER continued its active engagement with external stakeholders, building upon the interactions established in previous years. We maintained our approach of inviting these stakeholders, in WP3 for the workshop that was held together with the TransPharm project in Nijmegen, to seek their valuable advice and expert opinions. The insights gathered from these interactions played a crucial role in shaping the development of the PREMIER project, including the database and DAS, the uptake of environmental criteria in drug R&D processes, as well as the formulation of guidelines to address pharmaceuticals in the environment. Additionally, consortium partners seized various opportunities to engage with external stakeholders, strengthening awareness and collaboration: EFPIA meeting presentation.
There are many other tools and initiatives being developed in PREMIER which are likely to have a substantial impact on the stakeholder community, European policy, the scientific community and society in general.