Pharmaceuticals within the EU are regulated by the European Medicines Agency (EMA). The current regulatory guideline covering the environmental risk assessment of medicines for human use was published by the EMA in 2006.
“It’s fair to say that our knowledge of the occurrence, behaviour and potential risks of pharmaceuticals in the environment has evolved significantly since then,” suggests Dr. Sam Harrison, an environmental modeller at the United Kingdom’s Centre for Ecology and Hydrology (UKCEH) and leader of ETERNAL’s Work Package 4 in Environmental Assessment and Ecotoxicity Studies.
In part influenced by that evolution, in 2020 the European Commission (EC) launched its Pharmaceuticals Strategy for Europe with a view to updating EU pharmaceutical legislation, and in April this year (2023), the first draft directive and regulation was adopted by the EC and opened for public consultation. That consultation is currently ongoing as of October 2023, and to date has received over 170 responses from a broad range of sources.
Whilst the scope of the new legislation is not limited to making pharmaceuticals more environmentally sustainable (for example, equitable access to medicines and security of supply are key themes), there is significant focus on the environment. According to Sam Harrison, “The new legislation takes a more holistic, ‘One Health’ approach, and addresses several weaknesses of the existing regulations.”
Some notable changes include:
The proposed regulation includes, for the first time, a requirement to assess the environmental impact of the entire lifecycle of a product, from manufacturing, through use, to disposal. The current regulatory guideline focuses largely on use and disposal.
Whilst completing an environmental risk assessment is mandatory for new products under the current regulation, evidence of potential environmental risk cannot be used as a basis for refusal of authorisation. Under the proposed regulation, European authorities can, for the first time, refuse, suspend or vary an authorisation on the basis of environmental harm without sufficient risk mitigation measures.
Under the current rules, products that entered the market before its implementation do not need to have undergone an environmental risk assessment, meaning many longstanding pharmaceutical products have never had any assessment of their potential harm to the environment. The proposed regulation will include post-authorisation requirements meaning that environmental risk assessments must be performed on products authorised prior to the current regulation. It is proposed that these environmental risk assessments must be completed within thirty months of the regulation coming into force.
Environmental risk assessments should be continuously updated with new information that might affect the outcome of the assessments, and this new information should be added “without undue delay”. This is a significant departure from the current requirement for an environmental risk assessment only prior to market authorisation.
“The proposed regulation strengthens the requirements for reporting on substances based on a range of their characteristics,” explains Catherine Barnett, a radioecologist at the UKCEH. “Manufacturers will need to consider the mobility of their substances (how they move around the environment), their persistence (whether they degrade or not), their toxicity (to what extent they may affect non-target organisms), any tendency to bioaccumulate, and whether they are identified as endocrine disruptors (substances which interfere with different parts of the hormone system).”
That’s not all. Substances that are identified as PBT (persistent, bio-accumulative, toxic), vPvB (very persistent, very bio-accumulative), PMT (persistent, mobile, toxic), vPvM (very persistent, very mobile) or endocrine disrupting must be identified in environmental risk assessments, and risk mitigation measures should be included that limit their emissions to air, water and soil. In addition, risk assessments for genetically modified organisms (GMOs) must identify risks to the environment.
It is worth commenting separately on antimicrobial resistance (AMR), which is a topic not addressed in the current regulation. Tackling AMR is a key theme within the Pharmaceuticals Strategy for Europe, and the EC has pledged complementary measures within a so-called One Health approach that combats AMR in human health, animal health and the environment. These measures include promoting the prudent use of antimicrobials (including raising public awareness of AMR and adapted packaging and prescription requirements), targeted measures to enable this that take into account national situations, and incentivising the development of AMR countermeasures such as vaccines, rapid diagnostics and novel antimicrobials to avoid the development of antimicrobial resistant pathogens.
Catherine Barnett points out, “These measures introduce the requirement to assess the potential risk of AMR to human health and the environment, covering the entire product lifecycle within and outside of the EU. New antimicrobials are required to submit a “stewardship plan” that includes monitoring the development of AMR.”
Not all measures included in the proposed regulation have been received warmly by industry. Notable objections revolve around the added burden placed on pharmaceutical companies and potential impacts on innovation from rules around equitable access to medicines. Perhaps the most controversial change is that two years have been shaved off the period of exclusivity which new branded medicines have to themselves on the market before generic competitors can launch (eight years instead of ten). Companies can only regain these two years if they launch in all twenty-seven EU markets.
Another longstanding issue not tackled directly by the new regulation is that it is products, rather than active pharmaceutical ingredients, that must be risk assessed. If multiple products containing the same pharmaceutical ingredients enter the market, this might lead to replication of effort in performing multiple risk assessments. Whilst this isn’t explicitly addressed, there are requirements that completed environmental risk assessments must be included in a public register. This, alongside a proposed database of the environmental properties of active substances, could reduce the burden of new market authorisations through the re-use of previously published data.
Whether it is professionally or personally, pharmaceutical - and environmental - legislation affects us all one way or another. Comparison and review of this landscape forms a critical part of the work being done in ETERNAL WP4.
Sam Harrison says, “We are currently performing a gap analysis to identify where existing regulation could and should be improved upon to help protect the environment. We will soon be publishing an open report detailing our findings.”
Watch this space!