Pharmaceutical companies take note: the EU plans to refuse marketing authorizations for environmentally-unfriendly medicines.  

The EU has published a package of revisions to the bloc’s common pharmaceutical regime.  Many revisions aim to reduce the environmental impact of human medicinal products.  The key environmental measures include:

• Pre-authorization — Environment-related refusals:  The European authorities will be able to refuse a marketing authorization application where the accompanying Environmental Risk Assessment (“ERA”) is not adequate, or if the environmental risks have not been sufficiently addressed.  
• Post-authorization — Environment-related monitoring and conditions of use:  The European authorities will be able to impose environment‑related conditions of use on authorized medicines, including limiting the product to prescription-only or requiring additional post-authorization ERAs.  They will also be able to suspend, revoke or vary marketing authorizations where a medicine presents a serious risk to the environment.
• Awareness and knowledge building — Warnings and environmental risk databases:  Companies will be required to include additional information on environmental impact in a medicine’s EPAR, and additional awareness‑raising information in the product packaging of antimicrobials. 

In this post, we lay out what pharmaceutical companies need to know about the key environmental measures.

The Commission’s environmental programme

There is mounting evidence that when pharmaceuticals are manufactured or used, residues of medicines can end up in the environment.  The residues are most commonly emitted either in the water used in manufacturing, or in household wastewater, when users of medicines excrete consumable medicines, or wash off topical medicines.  Due in part to the chemical/metabolic stability of many medicines, these residues are often not effectively removed by wastewater treatment.

According to the Commission, two, overlapping problems ensue:

• Definite harm to human health through the development of antimicrobial resistance (“AMR”) — When antimicrobial pharmaceuticals enter the environment and come into contact with microbes, many microbes will be killed off, but some may survive.  Those “resistant” survivors may replicate and create a strain of a disease that is resistant to, or even unaffected by, existing antimicrobial pharmaceuticals.  This is a serious risk — without effective antimicrobials, an infection following a comparatively minor injury, or a complication from a mild disease can be fatal.  The Commission is very clear regarding these risks, and the specific measures it wants to take to tackle them.  The proposals set out a two‑pronged approach: (i) encourage companies to develop new antimicrobials by offering incentives such as attractive data exclusivity packages; and (ii) increase environmental scrutiny of pharmaceuticals to try to slow the development of AMR.  This blog addresses the second set of measures; for more on the first set, please see this blog.
• Potential harm to human health, and to flora/fauna, and to the environment in general — The proposals require marketing authorization applications to include an ERA that covers, among other things; (i) whether the product, or any of its constituents, is an endocrine disruptor, or falls into specified chemical hazard classes relevant to human health and the environment; [1] (ii) measures to limit the risk of emissions of pollutants to the air, water and soil.

The Commission also warns that these problems will get worse over time.  The EU’s use of medicines is growing, and the pace of that growth is accelerating, as the EU population grows larger, gets older, and increases its appetite for pharmaceuticals in general.  As a result, the Commission argues, more and more medicines will end up in the environment.

The Commission sets out a specific (and ambitious) objective for its environmental proposals: to “limit the environmental impact [of medicines] without affecting the appropriate therapeutic use.”  The Commission also hopes that its measures will have a positive “domino effect” across other markets, noting that “the introduction of new rules at an EU level has been known to be a trigger for other regions, leveraging EU actions.”

The Commission highlights that the proposals support various initiatives under the European Green Deal and align with the EU Strategic Approach to Pharmaceuticals in the Environment.  

Pre-authorization measures

Under the proposals, the EMA and national competent authorities (“European Authorities”) will have increased powers to refuse a marketing authorization application (“MAA”) for a medicine for environmental reasons.  The European Authorities will be able to exercise this power in one of two ways.

• Risk of anti‑microbial resistance:  The European competent authorities could refuse an MAA on the basis that the medicine’s “benefit-risk” profile is not favourable; the proposals expand the existing definition of “benefit‑risk” profile, adding that “undesirable effects on public health due to the release of the medicinal product in the environment including anti-microbial resistance” are also a good reason to refuse.
• Inadequate ERA:  The proposals empower European Authorities to refuse an MAA on the basis that the ERA is incomplete or insufficiently substantiated, or if the environmental risks have not been sufficiently addressed.  The MA Applicant must prepare the ERAs in accordance with specifications in Annex II of the proposed Directive, and with scientific guidelines to be drawn up by the EMA (in collaboration with the European Chemical Agency (“ECHA”), the European Food Safety Authority (“EFSA”), and the European Environmental Agency (“EEA”)).  As noted above, the ERA will also have to specify whether the product is classed as hazardous to human health or the environment under EU chemicals legislation, and propose risk mitigation measures to reduce discharges and emissions into the environment. 

These proposals represent a significant change to the existing regime.  Applicants for a marketing authorization (“MA Applicants”) have been required to submit an ERA with their application since 2006.  However, there has been little associated risk for MA Applicants.  Currently, if the ERA is incomplete at the time of the application, European competent authorities can request that the MA Applicant follow up with more information, but the request is not enforceable.  Further, a recent publication from the German Environment Agency found that even a “scientifically unacceptable” ERA is not grounds for refusing a marketing authorization.  Currently, the only consequence for a medicine with clear environmental risks is a non-binding recommendation from the relevant competent authority that the medicine be sold with clear disposal instructions. 

Furthermore, holders of pre-2006 marketing authorizations can no longer rest easy without an ERA.  The proposals set out that holders of MAs granted before October 2005 — who did not originally need to submit an ERA — will have to evaluate their existing products and submit data on environmental risk.  The EMA will prioritize its requests for assessment based on the risk posed by the particular product or active substance.

Post-authorization measures

The Commission has also proposed a number of post‑authorization measures, which mean that companies will need to remain aware of the environmental risk posed by their products, even after they receive marketing authorization.  

• Marking authorization holders (“MAHs”) will need to update their ERA if new information becomes available — through environmental monitoring, eco‑toxicity studies, environmental exposure data, etc. — that could lead to a change in the ERA’s conclusions.
• The EMA and/or Member State competent authorities may “suspend, revoke or vary a marketing authorisation if a serious risk to the environment or public health has been identified and not sufficiently addressed by the marketing authorisation holder”.
• The EMA, and/or national competent authorities may — when granting an authorization — impose conditions of use designed to reduce the medicine’s environmental impact.  Crucially, the proposals empower the authorities to designate a medicine as prescription‑only where the medicine is an antimicrobial product, or is classed as hazardous to human health or the environment under EU chemicals legislation.  
• The EMA, and/or national competent authorities may require the MAH to conduct further environmental risk studies or even another post‑authorization ERA.  Interestingly, where an authority wants more information on several, presumably related products, the EMA can also “encourage” the MAHs to work together on the study.
• Of all the environmental issues flagged by the Commission, there is a clear focus on AMR.  Under the proposals, a developer of a new antibiotic will have to submit a “stewardship plan” that includes a plan to monitor the development of AMR as a result of the drug’s manufacture and use, and measures to limit that risk.  Developers will also be required to ensure that packs for antibiotics are an appropriate size for a course of treatment, and to include an “awareness card” in the product packaging that warns users about the dangers of AMR, and supplies information about the best means to address it.

On top of post-authorization risk management for medicines on the market, the Commission may include measures to combat AMR in future GMP assessments.  The proposals do not set out those plans in detail, but empower the Commission to adopt implementing acts specifying the principles of GMP and GDP.  The Commission also plans to establish a “Joint Audit Scheme” to bolster the capacity of Member States to conduct GMP (and GDP) inspections.  The proposals make clear that manufacturing of products for the EU market will be subject to the oversight of European competent authorities, whether or not the manufacturing takes place in the EU.  In other words, they will have the power to conduct inspections of manufacturing sites in third countries.

Awareness and knowledge-building

Finally, the proposals set out a number of measures to increase information-sharing about environmental issues, and to build public awareness of the environmental impact of medicines.

• When a medicine is granted marketing authorization, the EMA publishes a European public assessment report (“EPAR”).  The EPAR provides information about the product (and its assessment) to the public, in a transparent and comprehensible way.  The proposals will increase the environmental content of the EPAR, and require a section on the conditions of use of the medicine and summaries of the ERAs.
• The Commission plans to establish a “register” via which ERAs will be made publicly available.  The proposals suggest that “commercially confidential information” will be protected, although it is not yet clear what exactly the Commission will consider “confidential”: specific information about the product only, or also information about environmental test techniques.
• The Commission has also proposed the establishment of a “monograph” system for the environmental properties of active substances — a database of information and risk assessments.

This blog is based on the wording of the EU’s proposal published on 26 April 2023.  This wording could significantly change during the legislative process.  Our Dublin, Brussels, Frankfurt and London teams will continue to monitor this legislation.  We will be hosting a webinar to discuss the impact on 9 May. To sign up for the webinar please click here.

---

[1] Specifically, the following hazard classes, as defined in Annex I to CLP Regulation (EC) No 1272/2008: (a) persistent, bioaccumulative and toxic (PBT); (b) very persistent and very bioaccumulative (vPvB); and (c) persistent, mobile and toxic (PMT) and, very persistent and very mobile (vPvM).