WP1
Prioritisation and Environmental Assessment of APIs
In this WP, we define the basis of the PREMIER project by determining the “universe of APIs”. We will work with a wide range of stakeholders, including environmental regulators, water managers and policy makers, to identify and make relevant data available and to develop decision trees for prioritisation and further testing of APIs. The decision trees will allow users to iteratively refine an assessment by adding new data, e.g. from experiments or extensive literature searches (WP3), and by applying the appropriate exposure and effect tools (WP2) accordingly.
The decision trees, including the tools of WP2 and the integrated API information and assessment system of WP3, will be demonstrated and tested in practice by performing case studies on 25 APIs which will be selected based on the prioritisation exercises in WP1.1 and WP1.2, and in consultation and agreement with key stakeholders. The case study APIs will be selected to optimize and test different components of our decision trees and will include APIs identified of concern due to a lack of data on their therapeutic MoA (MoA-driven selection), due to predicted off-target effects, APIs identified during prioritisation as potential high-risk compounds but with insufficient data for a full ERA (data gap-driven selection) and relevant human metabolites or environmental transformation products. The experimental testing to support the case studies is assembled in a separate work package, i.e. WP1.3.
WP2
Exposure and effect tools
WP2 will generate new in silico and in vitro tools to close the key knowledge gaps which currently hamper an optimal prioritisation and environmental risk assessment of legacy APIs, as well as of APIs in the drug development pipeline. The ultimate aim of WP2 is to deliver an optimized set of tools for testing and assessing the environmental exposure, effects and risks of APIs. The tools will be used in the decision trees developed in WP1 and the guidance developed in WP4. Part of the tools will be selected based on reviewing existing tools (WP1.2). Where needed, these existing tools will be extended, or new tools will be developed. Examples include:
- Experimental-based screening methods and in silico methods (including read-across techniques based on structural alerts and machine learning-based approaches; Miller et al., 2019) for estimating key environmental fate properties (e.g., degradation, sorption and bioaccumulation) required for establishing exposure in different environmental media and for PBT classification (Pizzo et al., 2016; ChemicalWatch, 2016);
- Expansion of a high spatial resolution aquatic exposure modelling framework (Oldenkamp et al., 2018) to estimate concentrations of APIs, metabolites and other transformation products in surface waters, sediments, soils, biota and ground waters across the European landscape and subsequent food chain exposure;
- In vitro (including fish 3D cultures) and in silico (including machine learning-based methods, an advanced fish plasma model and species read-across) approaches for predicting the potential for uptake and metabolism, target conservation and off-target effects of APIs, including relevant human metabolites and environmental transformation products, on a range of environmental taxa (microbes, primary producers, invertebrates, fish, and birds and mammals) for a range of environmental compartments (surface water, sediment, soils; Khan et al., 2019).
The tools and models developed in WP2 will span different levels of complexity, extending from simple, conservative tools using limited data to more environmentally realistic tools using more extensive data.
WP3
PREMIER ERA Database and Digital Assessment System (DAS)
The decision trees for prioritisation and targeted testing (WP1) and the exposure and effect tools (WP2) will be integrated into a flexible, user-friendly, and publicly accessible API information and assessment system for prioritisation and assessment of environmental risks of APIs in Europe and to support greener API design for use by diverse stakeholders. At the heart of the system is a database that captures relevant data on API physicochemical properties, fate, exposure, and effects. This database will be populated with data from high quality databases (WP1.1), European and national public assessment reports (EPARs; WP3) and industry studies used in marketing applications (WP3.1). Scientific literature and new data from experiments and monitoring campaigns performed in WP1.3 and WP2 will be uploaded into the database after appropriate quality control and assurance; this includes quality assessment of data on the 25 case study APIs (WP3.2). The system will be accompanied by graphical user interfaces, prompts and digital paper trails (WP3.3; for a demo movie see Simomics EPV), facilitating the use of the system and its underlying decision trees, tools and data to meet a range of stakeholder requirements and functionality.
WP4
Guidance and Application
The consortium strives to increase the use of the decision trees and tools developed in PREMIER by all stakeholders. This implies a stakeholder-driven strategy. In this WP, we will work with industry, regulators, water companies, NGOs, intergovernmental bodies such as OECD and UN Environment, and health organisations. In consultation with these stakeholder organisations, we will identify relevant issues and requirements that could be addressed by the PREMIER products (WP4.1). Possible examples include the prioritisation of APIs based on environmental risks in different management contexts, the identification of suitable risk management options along the development-production-use-emission-effect chain, the development of monitoring and assessment strategies for APIs, and the derivation of safe discharge targets for API manufacturing sites on a local scale. For a selected number of these stakeholder issues, we will draft guidance together with relevant stakeholders, integrating the tools and decision trees developed in PREMIER and taking other considerations into account where relevant, e.g. risk/benefit ratios, patient safety and socio-economic analysis.
An issue that will be specifically addressed in a targeted effort by the PREMIER project is the feasibility of greener drugs (WP4.2). We will identify key decision points where environmental considerations (API design and green chemistry) are currently made within drug development and identify potential opportunities to integrate the environmental tools and models developed in PREMIER earlier in drug development, should appropriate assays be available. The potential of emerging innovative therapies (e.g., precision or personalised medicines, biologics, nano-based medicines and antibody drug conjugates) to reduce environmental exposure and risk will be reviewed.
Industry partners will provide critical insights into the design principles commonly used in the development of new molecular entities to (i) increase biological stability such that the API can be delivered to the drug target, (ii) maximise oral adsorption, and (iii) minimise safety concerns and off-target effects, while other stakeholders and environmental experts will provide insights into their needs and wishes. Industry partners will engage with environmental chemists and environmental toxicologists to determine the feasibility of greener drug design.
WP5
Project management, Communication and Dissemination
- Optimally coordinate all project activities, implement strategic direction, alignment and assure achievement of the project goals. Provide project leadership and coordination through the application of the best scientific knowledge, vision and collaborative work.
- Establish a governance and management structure to both steer the efforts optimally towards the desired results and to provide an efficient structure for decision making across different WPs.
- Guarantee that the project is appropriately implemented according to the work plan, and that scientific activities are managed efficiently, with special attention to cross WP activities, dependencies and budget assignments, implementing
mechanisms for capturing the full potential of the assembled expertise. - Manage resources, procedures and tools for ensuring that all expected results are delivered on time, to a high-quality level and within cost, including quality control and risk management procedures on deliverables.
