European Union to introduce stricter rules on Environmental Risk Assessments for pharmaceuticals

Residues of pharmaceutical products can enter the environment during their manufacture, use and disposal and have been found in surface and ground waters, soils and animal tissues across the EU. The European Union Strategic Approach to Pharmaceuticals in the Environment observed that, for example, male fish exposed to low concentrations of the main ingredient in the contraceptive pill may become feminised as a result of its effects on the endocrine system, affecting the capacity of the population to reproduce. Several antibiotic and antifungal pharmaceuticals from the treatment of humans and animals have also been found in water and soil, potentially accelerating the development, maintenance and spread of resistant bacteria and fungi.

The current pharmaceutical legislation already requires companies to include an Environmental Risk Assessment (ERA) in the marketing authorisation (MA) application for all new medicinal products, whether through a centralised, mutual recognition, decentralised or national procedure (with the exception of renewals or Type IA/IB variations). However, the current ERA requirement was considered insufficient to address environmental concerns, as (i) the ERA was a one-time snapshot at the time of the MA application and (ii) there were no real consequences associated with the (lack of) quality of the ERA or (non-)compliance with the identified risk measures. 

Following the GPL package, the existing requirements on the ERA will be supplemented with additional information obligations and responsibilities for pharmaceutical companies, including extending the scope of the ERA to manufacturing and antimicrobial resistance. In addition, the ERA requirements will have more teeth and non-compliance can lead to serious consequences with respect to a company’s MA (application) and its products already on the market.

The European Commission hopes that strengthening the requirements of the ERA in the MA will drive pharmaceutical companies to better evaluate and limit the potential adverse effects to the environment and to public health.

Medicinal products in-scope of the ERA requirement

All MA applications are still required to include an ERA. As with other studies and data, applications for medicinal products following the generic, biosimilar or (bio-)hybrid route may rely on studies conducted for the reference product when preparing their ERA, but may need to provide additional data relating to their own specific manufacturing processes (Article 22(7) Directive).

With respect to medicinal products authorised before 30 October 2005, the European Medicines Agency (EMA) will set up a programme within 30 months after the entry into force of the Directive to require an ERA for products that have not been subject to an ERA and that are identified by the EMA as potentially harmful to the environment. For this identification as “potentially harmful to the environment”, the EMA shall set scientific criteria used a risk-based approach (Article 23 Directive).

Content of the ERA

In the ERA, MA applicants will be required to evaluate possible risks to the environment or public health due to the use and disposal of the medicinal product, and identify appropriate risk prevention, limitation and mitigation measures. The ERA should take account of the scientific guidelines prepared by the EMA as well as risk mitigation measures under existing EU standards and ERAs performed under such legislation, for example, the Groundwater Directive (2006/118/EC15) and the Industrial Emissions Directive (2010/75/EU18) (Articles 4(33), 22(1) and 22(3) Directive). Furthermore, based on the ERA, the applicant should make proposals for appropriate labelling provisions in the MA application. More specific technical details on the content of an ERA are still to be identified by the EMA in scientific guidelines.

In addition, special ERA requirements will attach to medicinal products with an antimicrobial mode of action. The ERA will have to (i) indicate whether the medicinal product or any of its ingredients or other constituents is an antimicrobial and (ii) include an evaluation of the risk for antimicrobial resistance selection in the environment caused by the entire manufacturing supply chain both inside and outside the EU, the use and the disposal of the medicinal product (Articles 4(33), 22(2) and 22(4) Directive).

Sanctions

The proposed Directive contains several far-reaching measures that the competent authorities can take when companies either do not provide adequate evidence that environmental risks were evaluated or that risk mitigation measures were taken:

• Withdrawal of MA application: where the competent authorities consider the MA to be incomplete – and that includes any matters that should be dealt with in the ERA – it will set a time limit for submitting the missing information. If the missing information is not provided within the time limit, the application will be considered to have been withdrawn (Article 29(3) Directive);

• Refusal of the MA: an MA can be refused in its entirety if the competent authorities consider that (i) the ERA is incomplete or insufficiently substantiated or (ii) if the identified risks have not been sufficiently addressed by appropriate mitigation measures (Article 47(1)(d) Directive and Article 15(1)(d) Regulation). A risk mitigation measure could be, for example, a medical prescription;

• Conditional MA: the granting of a national MA can be made conditional upon conducting additional post-authorisation ERA studies and collecting monitoring data or information on use, where identified or potential concerns need to be further investigated after the medicinal product has been marketed (Article 44(1)(h) Directive). Even after the granting of a national or centralised MA, the competent authorities may still impose obligations to conduct additional post-authorisation ERA studies and collect further monitoring data or information on use. The MA will then be modified to include the obligation as a condition of the MA (Article 87(1)(c) Directive and Article 20(1)(c) Regulation);

• Revocation, suspension or variation of the terms of the MA: a granted MA may be suspended, revoked or varied if a serious environmental risk or public health risk has been identified and not sufficiently addressed by the MA holder (Article 195(2) Directive); and

• Prohibition of supply or withdrawal of products from the market: in addition to the sanction included in the previous bullet point, the competent authorities may take measures to prohibit the supply or withdraw the relevant medicinal products from the market if a serious environmental risk or public health risk has been identified and not sufficiently addressed by the MA holder (Article 196(1)(f) Directive).

Post-authorisation

Once an MA has been granted, the MA holder will be responsible for continuously updating the ERA if new information emerges that could change the conclusions. This includes information on environmental monitoring, new or updates ERAs under other EU legislation, eco-toxicity studies and environmental exposure data. Moreover, for an ERA conducted at any time prior to 18 months after the entry into force of the proposed Directive, the competent authorities can request an update of the ERA if missing information has been identified for medicinal products that are potentially harmful to the environment (Article 22(6) Directive).

As regards publicity measures, (i) the European public assessment report (EPAR) will include a summary of the ERA studies and their results as submitted by the MA holder and the assessment of the ERA by the EMA (Article 16(3) Regulation) and (ii) the EMA shall set up a public register containing previously conducted ERA studies (Article 104(3) Regulation).