The great theme of the environmental risk assessment of medicinal products has been developed since the 1990s when some Institutions posed their attention to the possible impact of a number of active pharmaceutical substance into the environment. Residues of pharmaceutical active principles (APIs) and their potential toxic effects have been recognized as one of the emerging concerns in the scientific community as well as and, more and more, in the general public. The increasing attention on pharmaceuticals as potential pollutants is due to the fact that they can have similar physico-chemical behavior than other xenobiotics which are persistent and/or can produce adverse effects in environmental species. Additionally, we have to consider that APIs are continuously introduced into the environment as released by patients after use; this condition may lead to a huge persistence and/or bioccumulation in some cases.
The first piece of EU regulation is the 2006 guidance EMEA/CHMP/SWP/4447/00 followed by Q&A EMA/CHMP/SWP/44609/2010-2011. The guidance describes a tiered approach starting from a pre-screening approach up to an extended testing phase and a full Environmental Risk Assessment.
In all cases the ERA assessment must be prepared with robust scientific data generated by experimental studies carried out in recognized testing laboratories having long lasting experience in the ecotoxicological field. Data generated with prediction models (Q-SAR) or from literature are not easily accepted (or not at all); they can serve to support the selection of experimental studies but not for supporting the final calculation of the risk. This approach led, often, to prolong the testing and submission period up to 1-2 year from beginning and, particularly, to increase considerably the cost of the procedure.
Testing phases regarding eco-toxicological and environmental fate studies are requested on the basis of the different phases. All studies must be carried in GLP (Good Laboratory Practices) and under OECD study protocol. Studies, of course, need to be scientifically valid and signed by recognized Study Director.
The EMEA guidance (now EMA) has been recently replaced by an updated version released in March 2024 and going to be applied by September 1st, 2024. The document confirmed what already reported on the draft version (November 15, 2018) coming from the Concept Paper of 2016. It contains in brief:
- A review of the tiered approach strategy and triggers for further assessment and additional studies. This includes a review of the use of the consumption data.
- A review of the groups of medicinal products for which data are not currently required due to the nature of their constituents and clarification of the scientific conditions for such approaches.
- A review of possibilities for better utilization of data in the public domain to make a scientifically sound assessment of the environmental risk, with a special interest to avoid unnecessary repetition of animal studies (e.g. fish).
- A review of whether the approaches for substances with specific properties (e.g. PBT substances, endocrine disruptors, mixtures, substances highly toxic to specific taxonomic groups) are still adequate.
- A review of the applicability of the current test strategies to pharmaceuticals, considering their known pharmacodynamic and pharmacokinetic properties.
- An update of test systems recommended in the current guideline based on new scientific information and if possible, their validity for specific types of medicinal products.
- A consideration for recommendations of additional test systems/assays including areas not, or poorly, addressed in the present guideline.
- A review of possible options for risk mitigation measures, including discussion on how to monitor the potential impact of pharmaceuticals in the environment.Tu sum up, the most significant changes were the introduction of the specific assessment of Endocrine Disrupting Substances (EDS) and a strengthening of the PBT (Persistent, Bioaccumulative, Toxic) assessment. In particular, in the former case the EDS assessment will have to be carried out in parallel with the assessment of eco-toxicological properties. Thus, the need for such an assessment is emphasized given the problems that exist in many drugs (e.g., hormone-like) for this safety end-point. Furthermore, more requirements have been introduced regarding the Secondary Poisoning (in relation with PBT properties and biomagnification along the food chain) and, last but not least, for the Antibacterial Properties in relation with the antimicrobial resistance. This is a significant topic for antibiotic active principles which will be subjected to special environmental studies.
THE NEW EU DIRECTIVE ON MEDICINAL PRODUCT
The EU Directive on Medicinal Product was under discussion since years at EU Authority level but with a notable acceleration of the debate in the last two years. A draft document was released in 2023 and, at the end, approved by the EU Parliament on April 10, 2024.
From the scientific point of view, there is no relevant news compared with the updated guideline dated March 2024, which thus remains the main reference for the scientific approach!
On the other side, there are news, however, from the point of view of the impact of ERA evaluation on drug marketing authorization (MA). Up to now a simple principle was always followed “the evaluation of the potential environmental risk posed by medicinal product should be submitted, their environmental impact should be assessed and, on a case by case basis, specific arrangements to limit the impact should be considered; in any event this impact should not constitute a criterion for refusal of a marketing authorization (MA)”
Things have changed now!
A complete ERA assessment is required for each single API (and related pharmaceutical product) placed on the market with the rule action retroactive and extended to generic drugs as well. If the ERA is considered uncomplete by some EU Competent Authorities, the related pharmaceutical product may be withdrawn from the market. This is the strongest and amazing news!
Furthermore, emphasis is placed on the need for mandatory prescription for those drugs that show an environmental profile of concern (to be defined); we need to understand what is going to happen for over-the-counter drugs that are currently not subject to prescription but show such an environmental profile.
Other news concern increased and close cooperation between the three main European agencies EMA, ECHA EFSA (never happened before!!), the application of classification criteria according to Reg. CLP, and the possibility for Competent Authorities (EMA) to prepare specific ERA monographs.
DISCUSSION
The Environmental Risk Assessment of APIs used in drugs is becoming an important issue for the pharmaceutical industry, authorities and general public (citizens) as well. The challenges posed by PBT (Bioaccumulation and Persistence) and EDS (Endocrine Disrupting properties), Secondary Poisoning and Antimicrobial Resistance will require dedicated plans of action in the pharmaceutical industry. Some of them already started huge evaluation programs to understand the potential environmental impact of their APIs. PIE (Pharmaceutical into Environment) projects started to be adopted by some big pharmaceutical companies. On the other hand, progresses have been made in the evaluation of the problem by authorities (EU Commission); the final publication of the revised guidance is very useful to adopt the future criteria mainly for PBT and EDS substances but, on the other way, complicate the scientific approach to the assessment. EDS hazard assessment, of course, remains one of the crucial points.
Pharmaceutical companies are requested to submit complete ERA assessment otherwise they risk market withdrawal of their product.
But what does “complete”means?
Formally, a scientific work is considered complete when a robust conclusion can be reached on the basis of all data, studies, observation and evaluation done in the work. Hence, in terms of ERA, complete can mean when a clear idea of the environmental risk can be given. Is the studied API considered risky for the environment or for some environmental compartments or not? Is Risk Characterization ration lower or higher than 1?
As we all know, the ERA is a step-by-step procedure based on the need to continue to test/study the substance progressively on the results obtained in the different steps. Additionally, the scientific guideline is very restrictive and demanding; all this entails the fact that experimental packages could be very long (1-2 years) and not so cheap. The need to test an APIs for it environmental fate such as biodegradation or PBT properties may led to invest some hundred thousand Euros.
As said before, EMA may provide ERA Monographs on specific APIs. This could help a lot the pharmaceutical companies (mainly the smaller) to get an evaluation avoiding direct costs. But at this stage we do not know how and when EMA will proceed with such project.
CONCLUSION
Moving towards the conclusion I’d like to underline two other important points: data property and data sharing. The possibility to share experimental data on a specific API is mentioned in the new EU Directive on Medicines regarding the ERA dossier. This is a matter which was already crucial/central in other important and relatively recent EU regulations such as REACH, Biocides, Agrochemicals. Under the REACH regulation, mainly, the data sharing approach was strongly regulated under the principle of “non-discrimination”. “The data sharing must be non- discriminatory” intending that all costs should be distributed in the same way between all registrants. The REACH system works pretty well leading to have a huge number of so called joint registrations even from small companies.
Regarding ERA some questions are
still unanswered!
What will happen for ERA in the pharmaceutical world where economic interests are much stronger? Will originators share their data with others? Will the costs be distributed equally between all interested stakeholders? Will the small pharmaceutical companies and/or APIs manufacturers be able to create Task Forces to share experimental costs for new ERA dossiers?
As said, we do not have answers at the moment. 2025 will be crucial year to understand how companies will face such a big challenge posed to them by the new EU Directive and related scientific guidance.
