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Prioritisation and Risk Evaluation of Medicines in the EnviRonment

Periodic Reporting for period 2 - PREMIER (Prioritisation and Risk Evaluation of Medicines in the EnviRonment)

Reporting period: 2021-09-01 to 2022-08-31

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, especially since many of these APIs were already marketed before 2006.
The aim of PREMIER is to deliver a framework for assessing and characterising the environmental risks of APIs. This framework 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 major achievements within this reporting period are listed below:
WP1: All readily-available and relevant data on chemical identifiers, fundamental physicochemical properties, consumption and ecotoxicty for the European inventory of APIs have now been collated and made available for all PREMIER partners through the project’s Sharepoint site. Following the first set of test candidates approved during RP1, a second set was compiled and approved, completing the set of 10 MoA-based and 15 risk-based test candidates. The first test study has been placed with an external CRO. The fish decision tree developed during RP1 is currently being put into practice for the first case study API (Disulfiram).
WP2: Work has focused on the selection of APIs for study in different components, establishment and optimization of test methodologies, collation of data from the literature and other studies, generation of preliminary data on selected APIs and the initial development of a range of modelling approaches.
WP3: Version 4 of the DAS was released, containing further API data and various additional functionalities and query options as outlined in the WP specific chapter below. It was agreed to conduct the reliability assessment of literature and new data generated within PREMIER using the existing CRED reliability assessment spreadsheet as published by Moermond et al., 2016. The partner Fraunhofer conducted literature searches for the 11 agreed case study compounds and EFPIA partners are now to conduct CRED assessments.
WP4: A workshop with stakeholders, combined with results from an online survey and previous results of interviews, resulted in a plan for further guidance work. This work has now started (WP4.1). In WP4.2 a paper on GREENER criteria for active pharmaceutical ingredients was drafted, which was published as a Global Perspective in Environmental Science and Technology Letters. Although this paper was not part of the work plan, it did help further collaboration and work in WP4.2. In this work package, a workshop was held with industry discovery and development experts, leading to report D4.5. Author groups have been working on the next report on incorporating environmental parameters in drug discovery and development.
WP5: Efforts have concentrated on maintaining the project governance and management structure to optimally coordinate all the project activities from the scientific and operational point of view. This included the strategic scientific coordination, scientific advisory board engagement, planning and support of regular project management office (PMO), Executive Committee (ExCom) and General Assembly Meetings (GAM), the monitoring and of the progression of tasks, deliverables, milestones and potential risks, preparation of all the documentation to process the grant agreement Amendment #1 (AMD#1), which is currently open. From the communication side, two newsletters and various campaigns in social media have been launched to promote the project awareness and to maximise the dissemination of the project results. Also, the sustainability group has continued their work to draft the project sustainability principles.
During the first two years, the project compiled large data sets relevant for the environmental risk assessment of pharmaceuticals. These data sets include chemical identifiers, physicochemical properties, fate parameters and ecotoxicity data. Most data have now been made available to all project partners through the project’s Sharepoint. This has stimulated the consistent and transparent use of data throughout the project and boosted the exchange of ideas to use these data for innovative purposes such as prioritisation approaches, selection of case study compounds for various types of experiments, QSAR development and initial risk assessments. The intention is to make these data publicly available through the PREMIER DAS.

An important activity during RP2 was the determination of stakeholders’ guidance needs in WP4.1. To further optimize the projected impact of these guidance documents, the drafts will be subjected to proof reading by a group of key stakeholders. In this way, we aim to optimize the societal impact of the guidance documents.

A key milestone during RP2 was the publication of a science-based opinion paper entitled GREENER Pharmaceuticals for More Sustainable Healthcare. Within the context of WP4.2 on Greener Drug Design, several PREMIER partners covering a diversity of perspectives (i.e. government, industry and academics) contributed to this seminal paper. The paper describes an approach to identify and meet important environmental criteria, which will help reduce the impact of medicinal residues on the environment. The paper received the accolade of Editor’s choice due to its broad public interest.

Further dissemination activities included various presentations of PREMIER initial results in SETAC Europe meeting in May 2022 (e.g: fish PBK model, a decision tree for fish toxicity testing and application of the expanded ePiE model). Additionally, the project leader (AZ) presented PREMIER during an EFPIA meeting, resulting in several industry parties expressing their interest to join PREMIER. The negotiations with one partner have been completed successfully and has joined PREMIER in September 2022. The negotiations with two other interested partners are currently ongoing. The project coordinator (RU) presented PREMIER during the Dutch networking day on medicinal residues in the environment which resulted in several interested responses and an invitation to present the scientific work on medicines during a regional meeting on the environmental risks of pharmaceuticals for water managers and the health sector.

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. Examples include the work on EnviPath, in vitro assays, the merger between the Ecodrug and DrupMapper databases, read-across approaches, QSAR models and other tools to describe and predict sorption, biodegradation, bioaccumulation and ecotoxicity. However, it is currently too early to demonstrate the impact of these developments.