On April 26, 2023, the European Commission proposed a new directive and regulation to revise and replace current pharmaceutical legislation. The proposed reform of the EU's pharmaceutical sector brings significant changes to product lifecycles, from launch to decline. The new legislation will impact all stages in the pharmaceutical product life cycle and will cover all provisions except for advertising, falsified medical products, homeopathic and traditional herbal medicinal products.

The proposed reform is currently in its preparatory stage in the European Parliament, and it is waiting for the opinions of the rapporteurs and the submission of amendments by the committees, including the Committee responsible for the Environment, Public Health, and Food Safety.

The new regulations will come into effect 18 months after their entry into force, on the 20th day following their entry into force.

Objectives of the Reform

The reform aims at simplifying and adapting the framework to scientific and technological changes while reducing the environmental impact of medicinal products. The intended outcome of these changes is to ensure a high level of public health by harmonizing the internal market, providing timely and equitable access to safe, effective, and affordable medicines, increasing the security of supply, promoting innovation and competitiveness, and making medicines more environmentally sustainable.

According to scientific evidence, the environment is negatively impacted by the production, usage, and incorrect disposal of pharmaceuticals. This has resulted in a growing concern regarding the increasing levels of pharmaceuticals and their metabolites found in raw and treated wastewater, as well as surface waters. This poses a significant risk of contamination of the environment by these substances. Additionally, the development of antimicrobial resistance (AMR) in microorganisms is an alarming issue that must be addressed.

In line with earlier commitments in the Strategic Approach to Pharmaceuticals in the Environment, the reform aims at promoting environmentally sustainable production of medicines. The new regulations are also designed to reinforce the mandatory environmental risk assessment (ERA) for all pharmaceutical companies introducing medical products into the EU market. Failure of a pharmaceutical company to accurately present an environmental risk assessment, and undertake appropriate measures to mitigate any risks, may result in the denial of marketing authorization for the drug in accordance with the new regulations.

Reinforcing Environmental Risk Assessment (ERA)

One major aspect of this reform is the reinforcement of the environmental risk assessment (ERA) of medicines to limit the potential adverse impact of pharmaceuticals on the environment and public health.

The newly introduced legislation mandates that medicinal products containing or consisting of genetically modified organisms (GMOs) must undergo an environmental risk assessment (ERA) to identify and evaluate their potential negative impact on human health and the environment before they can be placed on the EU market. The requirement is stated in Article 2(2) of Directive 2001/18/EC, with its implementation details provided in Directive 2001/83/EC, as amended.

In accordance with the revised Directive and Regulation, the ERA should consist of:

1. Identification of potential risks: Medicinal products or any of its ingredientsor other constituents should be identified if they are PBT, vPvB, PMT, vPvM or Endocrine-disrupting chemicals (EDCs).
2. Proposed risk mitigation measures to avoid or limit emissions to air, water, and soil of pollutants listed in EU Directives.
3. Evaluation of risk for antimicrobial resistance selection in the environment which covers the use and disposal of the product for the entire manufacturing supply chain inside and outside the EU.

The ERA should also be updated with new information without undue delay to the relevant competent authorities on any relevant information from environmental monitoring, eco-toxicity studies, new or updated risk assessments under other EU legislation, and environmental exposure data.

The new legislation will also introduce obligations for medicinal products authorized prior to 30 October 2005 for which an environmental risk assessment program will be established. Marketing Authorization Holder (MAH) of such medicinal products will be responsible for complying with the new requirement to submit ERA as part of the established program.

For the medicinal products that contain GMOs, ERA should consist of:

• descriptions of the GMOs and their modifications,
• identification and characterization of hazards for the environment, animals, and human health,
• exposure characterization,
• risk characterization, and risk minimization strategies, including containment measures to limit contact with medicinal products,
• environmental risk assessment reports based on the information specified in Directive 2001/18/EC and,
• appropriate measures to inform the public.

Some new obligations will also be established for the marketing authorization holder, who might be obliged, at the European Medicines Agency’s request, to conduct a post-authorization ERA study to further investigate the risks to the environment or public health due to the release of the medicinal product in the environment.

Consequences for Non-Compliance

Failure to meet the above requirements will result in a refusal of authorization or a ban on marketing the medicinal product within the European Union. Rejection of a centralized marketing authorization can occur if the product fails to meet the requirements described above, or if there is an unfavorable balance between the benefits and risks, insufficient documentation of the product's quality, safety, or efficacy, an incomplete or inadequate ERA, or if the labeling and packaging does not adhere to EU standards. Moreover, marketing authorization may be suspended or revoked if there is a serious public health or environmental risk. If any of the issues mentioned above are detected or if production or control standards are not met, the competent authorities may also prohibit the supply or remove the product from the market. However, in exceptional situations, the competent authority may allow the supply of the product to patients who are already undergoing treatment with it during a transitional period.

Impact on Pharmaceutical Companies

Overall, these legislative changes will require pharmaceutical companies to conduct ERAs for their products and implement environmental risk mitigation measures. Failure to comply with the new Directive and Regulation could result in penalties and reputational damage. However, these changes will also help protect the environment and public health by ensuring that medicinal products are safe for use and do not have adverse effects on the environment.

Manufacturers and pharmaceutical companies may face additional expenses and a longer timeline to develop and introduce medicines to the EU market that meet these requirements. This can also be illustrated in the following examples:

• Companies that produce medication containing PBT ingredients may be required to conduct ERAs to identify potential risks to the environment and human health. To achieve this, companies will need to invest in research and development to find less harmful alternative ingredients or implement risk mitigation measures to limit emissions of pollutants to air, water, and soil.
• For GMO-based medication and biopharmacy, companies may need to invest in containment measures to limit contact with the medication, implement risk minimization strategies, and produce environment risk assessment reports to inform the public.
• Antibiotics manufacturers may need to evaluate the risk for antimicrobial resistance of microorganisms in the environment through the use and disposal of their products for the entire manufacturing supply chain inside and outside the EU. Some companies may need to implement measures to limit the impact of their products on the environment and public health, such as proper disposal protocols and wastewater treatment.

Recommendations

To be better prepared for the future legislative changes, pharmaceutical companies should:

• Conduct internal assessments of their current practices and procedures to determine if they are following the new EU law.
• Ensure that the ERA processes are reinforced, and risk mitigation measures are implemented, to avoid any negative impact on the environment and public health.
• Conduct post-authorization environmental risk assessment studies to further investigate the environmental or public health risks due to the release of their medicinal products into the environment.
• Ensure that their documentation, labeling, and packaging complies with the new legislation to avoid any refusal or prohibition of marketing authorization.
• Be prepared to comply with any potential suspension or revocation of their marketing authorizations if there is a serious risk to the environment or public health.