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Prioritisation and Risk Evaluation of Medicines in the EnviRonment

Periodic Reporting for period 1 - PREMIER (Prioritisation and Risk Evaluation of Medicines in the EnviRonment)

Reporting period: 2020-09-01 to 2021-08-31

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. In the EU, since 2006 new medicines are required to undergo an environmental risk assessment (ERA). However, few of the approximately 1900 active pharmaceutical ingredients (APIs) marketed before 2006 have been assessed for their environmental impact.
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: The universe of APIs available on the European Market was mapped, and easily accessible data of (authorization) studies relevant for environmental risk assessment (e.g. identifiers, physico-chemical characteristics, toxicity data) were collated in spreadsheets. From this list, the first test candidates were selected after grouping the APIs based on working mechanism and selecting those groups with the lowest number of toxicity data. In order to minimize fish testing, a decision tree was developed to determine whether toxicity testing in fish is likely to result in new and useful information.
WP2: Two computer models have been developed: a physiologically-based pharmacokinetic model (PBK model) for fish, and a model to predict API levels in European surface waters, called ePiE. The fish PBK model serves to predict the uptake, distribution, metabolism and excretion (ADME) of APIs in fish. Unique features of the model are its generic nature and easy parameterisation (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. We are currently preparing publications on the expanded ePiE model and the fish PBK model so these become available to the broader scientific community.
WP3: The PREMIER database architecture and digital assessment system (DAS; the software that lets us analyse the data) have been created and established. Two planned update releases have already taken place this year which are available to all consortium members. The first collection of data was loaded to the database and is now available to all partners to be utilized for scientific purposes. 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. The database and DAS will be open and publicly accessible to all stakeholders by March 2023 (M30).
WP4: Interviews were held with stakeholders (WP4.1) and industry drug discovery and development experts (WP4.2). Results of these interviews were analysed and used as input for two sets of separate workshops for these WPs. A background paper on ‘Pharmaceuticals in the Environment – Understanding the Feasibility of Designing Greener Drugs’ was written. Results of an internal workshop on criteria how to identify more environmentally friendly APIs were integrated in a draft scientific paper.
WP5: Efforts have concentrated on establishing the project governance and management structure to optimally coordinate from the scientific and operational point of view all the project activities. This included the strategic scientific coordination, the formation of the scientific advisory board, the planning and support of regular project meetings, the monitoring and of the progression of tasks, deliverables, milestones and potential risks. From the communication side, WP5 established an editorial team, developed a project communication plan (D5.2) as well as various communication materials and platforms. Also, a sustainability group was set up and the first draft of the sustainability principles were defined.
The project has gained a lot of experience with the collection, extraction, selection and curation of ERA data on APIs and making these available; for now, mainly within the consortium. One of the lessons learnt is that APIs can be referred to using different identifiers, e.g. their common name, CAS number, chemical structure, ATC code, medicinal product, etcetera. All these identifiers refer to products that can have slightly different specifications such as salts, enantiomers, prodrugs and mixtures. From an environmental risk perspective, it is the active moiety (or moieties) in the environment that is of main interest and this active moiety is not always adequately covered by traditional identifiers. One recommendation of PREMIER to the stakeholder community, and particularly regulatory authorities such as EMA, OECD and WHO, is to introduce a unique identifier for environmentally active moieties in order to facilitate the management of ERA data and the subsequent risk assessment process. The introduction of such an identifier would for example facilitate the extraction of API consumption data from sales data on medicinal products. This recommendation is now actively propagated towards stakeholders, e.g. during EMA's Veterinary Big Data stakeholder forum which was held online on June 1-2, 2021.
Another example of an early impact of the PREMIER work is the application of the expanded ePiE model in two ongoing studies, i.e. one on the antidepressant amitriptyline and one on the NSAID drug ibuprofen; both initiated by industry. In both cases, the ePiE model was used to predict API concentrations across European surface waters in order to obtain an impression of the exposure and associated risks, including the identification of hotspots. Two manuscripts are currently being prepared. Regarding ibuprofen, a follow-up study is being considered focussing on identifying optimal locations for the installation of tertiary treatment facilities to reduce environmental risks, underlining the potential of ePiE as a tool for scenario study and the optimisation of interventions. Both examples illustrate that the tools developed in PREMIER are already being used by stakeholders to determine the extent to which APIs pose a risk to the environment and to identify cost effective measures along the development-production-use-emission-effect chain.
Other tools and initiatives being developed include a decision tree for performing fish testing in WP1.3 (with the aim to avoid these vertebrate studies where possible and reduce it to the absolute minimum where necessary), the public release of the PREMIER database (anticipated for March 2023), 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.
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