By Cristiana Cannata, PhD researcher in Environmental Science at Radboud University (Nijmegen, The Netherlands) & contributor of PREMIER WP1.2
There are more than 1500 active pharmaceutical ingredients (APIs) on the European market. Residues of these APIs can eventually reach the environment and given the enormous number of human medicines being used, it is unclear which APIs cause the highest environmental risk and require mitigation. Although an environmental risk assessment (ERA) for marketing authorization applications of medicinal products is mandatory in the European Union since 2006, a comprehensive ERA is lacking for most medicines approved prior to 2006. Since it is unfeasible to collect ERA data on all these APIs, there is a need to prioritize them based on limited available information and further investigate the top-ranking APIs to establish their true environmental risk. The main aim of our work is to propose 15 APIs from the “universe of APIs” on the European market, lacking a reliable ERA but suspected to trigger a substantial environmental risk, so these APIs can be considered for further investigation and environmental risk assessment in the IMI PREMIER project (2020-2026). To realize this aim, a prioritization procedure was developed and applied to APIs of human medicinal products authorized in Europe.
Different approaches can be adopted to prioritize APIs. Work Package 1.2 of the IMI PREMIER project followed a risk-based prioritization approach, which implies that an environmental exposure concentration (measured or predicted environmental concentration; MEC or PEC, respectively) is combined with an ecotoxicology-based threshold, typically represented by the Predicted No Effect Concentration (PNEC). The ratio between the environmental exposure and the PNEC forms the basis of the prioritization: the higher this ratio, the higher the potential risk.
We developed various risk-based ranking procedures making use of both empirical and predicted data. The ranking that is based on empirical data only is used as the “Golden Standard” and it includes the lowest number of APIs because of high data demands. The other rankings, based on predicted environmental concentrations and/or predicted ecotoxicity data, are subsequently compared to this Golden Standard. A ranking based on predicted data is called robust if the APIs appear in the same order of the Golden Standard list. The idea behind this is simple: an API ranking high in a robust ranking but lacking in the Golden Standard qualifies for further investigation since it is likely to pose an environmental risk but is lacking a comprehensive ERA data set. We identified three robust lists and we took the 25 top-ranking APIs from these rankings. The top-ranking compounds were screened for availability of ecotoxicity and fate data in data repositories (i.e., public literature, PREMIER EFPIA partners and EMA) and subsequently reviewed by key PREMIER partners. This ultimately resulted in a list of 15 APIs that are proposed for further investigation in the PREMIER project, i.e., Diflunisal, Disulfiram, Dosulepin, Eprosartan, Felbinac, Flecainide, Melperone, Mesalazine, Nevirapine, Orphenadrine, Prazosin, Repaglinide, Sulfasalazine, Sulpiride and Trimebutine. The current list of test candidates is not the final list, but will be subject to changes as the PREMIER project evolves. In the near future, the relevance and suitability of each of these proposed test candidates will be analysed in detail within the context of Work Packages 1.3 and 3.1, based on an in-depth screening of the available data, identified data gaps, mode-of-action considerations, availability of analytical grade preparations, analytical techniques, etc. If this detailed assessment results in the rejection of a test candidate, new candidates will be selected from the three risk-based rankings.
The prioritization conducted within Work Package 1.2 of the IMI PREMIER project represents a novel approach that is mainly driven by data gaps and subsequent relevant data needs. Thanks to the fruitful collaboration with PREMIER partners, the large amount of information collected in the frame of this prioritisation will ultimately contribute to the creation of a user-friendly and publicly available database, making consistent ERA data visible and accessible to the public.