By Alice Marshall, PhD researcher in Environmental Toxicology at University of York & contributor of PREMIER WP2.1; and Caroline Moermond, Sr Policy Advisor at the National Institute for Public Health and the Environment (RIVM), lead of PREMIER WP4 and contributor of WP3.
With the continuous development of new and existing pharmaceuticals, investigation into the environmental legacy of active pharmaceutical ingredients (APIs) is a rapidly growing area of research. Following manufacture, testing and consumption, APIs may be released into aquatic and terrestrial environments, with cocktails of API residues now routinely detected in surface waters, soils and sediments across the world. Ecotoxicity testing of APIs has been part of the environmental risk assessment (ERA) within the marketing authorisation procedure since 2006. This ERA dossier is lacking for pharmaceutical products authorised before 2006. However, even if an ERA has been performed, data may not always be publicly available. Thus, for many APIs the only information available is present in public literature, where the quality of testing may be highly variable in quality. During a PREMIER Masterclass, testing guidelines and quality evaluation of data were discussed.
Before approval, APIs that are used in amounts higher than the threshold of 10 µg/L generally are subject to environmental testing through standardised tests required by regulatory authorities around the world. However, for older (legacy) APIs marketed before 2006 these standard studies often have not been conducted. Besides this, information from the ERA dossier is not always publicly available and thus not transparent to some stakeholders. Thus, for risk evaluation by stakeholders like water managers, only academic scientific literature is available, where data collection and reporting is often unstandardised and more often unreliable than formal guideline study reports. PREMIER therefore aims to fill existing data gaps for at least 25 priority APIs that lack information. This will be done using standard study protocols, but if necessary due to the mode of action, also non-standardized studies may be performed. In addition, the work from WP2 on QSARs and in vitro tests will also be focused on these APIs. If there is some data for these prioritized APIs in public literature or databases, reliability and relevance of these studies will be assessed.
The PREMIER project will therefore apply a suite of guidelines and evaluative tools to achieve this. Where applicable, testing procedures of chemicals within regulatory frameworks according to OECD guidelines will be followed. Use of these guidelines aims to standardise laboratory testing techniques for environmental safety testing of chemicals to generate reliable, comparable, traceable, and reproducible data. They usually contain a very detailed description of the test design, including exposure scenarios, test species, test systems, and environmental conditions. OECD guidelines also contain a description of the data to be recorded, statistical analysis and how to report the results. Thus, they require highly transparent and detailed reporting of raw data to ensure full transparency. Alongside this, regulatory tests also need to be performed under Good Laboratory Practice (GLP), which is a quality system providing guidelines on the organisational process, providing information on the planning, performance, monitoring, recording, archiving, and reporting of results. OECD and GLP guidelines set a high standard for scientific protocols when performing environmental risk assessments, but also facilitate sharing of data between regulatory frameworks.
OECD study protocols were developed and generally tested across multiple laboratories before being agreed and accepted; in this sense following these study protocols should ensure that studies are reliable and can be replicated. However, also studies performed according to OECD protocols may lack clarity in reporting which will affect the evaluation of its reliability. If a study is clearly reported in a way that would enable it to be exactly repeated then one can have more confidence in the result, and expect the same result if it were repeated. There may also have been flaws in OECD study setup and performance and interpretation of results. Thus, also OECD/GLP studies should be assessed for reliability.
The quality or reliability of all data, including OECD GLP studies, should be assessed in a transparent and systematic way. Within PREMIER, the CRED method will be used for this. The CRED method contains 20 evaluation criteria (e.g., on test design, species, exposure conditions, statistics, availability of raw data) with guidance on how to apply these. The assessment results in a reliability score from 1 to 4, where a reliability of 1 means the study is reliable without restrictions, 2 means the study is reliable with restrictions, 3 indicates the study is not reliable, and 4 means there is not enough information to complete the reliability assessment. Studies with reliability 1 and 2 will be used for further assessment, in regulatory contexts and also within PREMIER.
With increasing pressure on natural resources and rapid pharmaceutical innovation, thorough environmental safety testing is an essential component in developing sustainable APIs. The PREMIER project involves prioritisation and screening of current and emerging APIs in various environmental systems with the ultimate aim of generating a good-quality, large, accessible and transparent environmental dataset. Through use of the standardisation tools outlined here, such data can be used to help accurately evaluate potential environmental risk.
