Every marketing authorization application to the European Medicines Agency or a national authority must demonstrate that the product does not pose an unacceptable environmental risk. The Environmental Risk Assessment (ERA) has become a significant scientific component, and inadequate planning can lead to submission delays, extra data requests, or unnecessary post-authorisation commitments.
This article discusses the European ERA framework for human and veterinary medicines, highlighting common scientific and procedural challenges for sponsors. It also presents the structured, expert-led strategy employed by regulatory partners like Zenovel to ensure that ERA workstreams align with submission timelines.
The Regulatory Basis for ERA in Europe
Environmental risk assessment for human medicinal products in the EU is primarily governed by the EMA’s Guideline on Environmental Risk Assessment of Medicinal Products for Human Use and Directive 2001/83/EC, while veterinary products follow Regulation (EU) 2019/6. Additionally, if an active substance requires REACH registration or involves exposure pathways to surface and groundwater, sponsors must align ERA data requirements with the EU Water Framework Directive and REACH obligations.
In contrast to the safety and efficacy dossier, an ERA primarily does not influence the granting of marketing authorization. Environmental grounds alone are insufficient for refusal. However, competent authorities may enforce risk mitigation measures, labeling requirements, and monitoring commitments based on ERA results. Incomplete or insufficiently justified ERA submissions often lead to clock-stop questions during procedural reviews.
Structure of a European ERA
The EMA framework consists of two sequential phases, each characterized by unique triggers and data requirements.
Phase I: Estimating Environmental Exposure
Phase I assesses the Predicted Environmental Concentration in surface water (PECsw) using the maximum daily dose, market penetration factor, and dilution assumptions. If PECsw is below the action limit and the substance is not a known endocrine disruptor or flagged for concern, no further testing is needed.
Phase II: Fate, Effects, and Risk Characterization
In cases where Phase I exposure estimates surpass the action limit, sponsors advance to Phase II, which consists of two tiers. Tier A focuses on establishing physicochemical properties, environmental fate (including biodegradation, sorption, and hydrolysis), and initial ecotoxicological data for aquatic and relevant terrestrial compartments. If specific outcomes from Tier A necessitate further investigation, Tier B requires more comprehensive fate and effects testing, which may involve chronic toxicity studies and assessments of sediment and soil compartments, especially for substances of persistence, bioaccumulation, or toxicity (PBT) concerns, in accordance with REACH methodology.
Common Pitfalls in ERA Planning and Execution
Sponsors preparing ERA packages for European submission often face a range of recurring and avoidable issues.
- When Phase II testing, especially Tier B ecotoxicology studies, is only planned after the clinical and CMC dossier is nearly complete, it can significantly delay submission readiness. Initiating early Phase I screening during late-stage clinical development enables sponsors to assess the need for Phase II testing and better plan study timelines.
- Inadequate justification of literature and read-across data in ecotoxicological studies can lead to regulatory inquiries. Sponsors must show that they have properly considered existing literature, structurally similar substances, or validated read-across data before initiating new studies.
- Inconsistent market penetration factors and dilution assumptions in PEC calculations across EU member states can lead to scientific credibility issues. Utilizing a uniform exposure calculation methodology across all markets minimizes this risk.
- Insufficient integration between CMC and Environmental, Health, and Safety (EHS) data leads to duplicated testing efforts and inconsistencies in data submissions across disconnected teams managing ERA studies and CMC characterisation work.
- Underestimating the complexity of PBT and vPvB screening often leads to late-stage timeline slippage for pharmaceutical sponsors, who typically lack sufficient in-house experience with REACH methodology and the associated data requirements and study durations.
Zenovel offers environmental risk assessment services tailored to the phased EMA framework, focusing on the integration of ERA workstreams with clinical and CMC development processes.
Figure 1: Zenovel’s ERA services
Early Phase I screening and gap analysis are conducted during late-stage clinical development to determine Phase II requirements before submission deadlines. This includes study design and CRO coordination for Phase II Tier A and Tier B fate and ecotoxicology testing, aligned with the sponsor’s regulatory timeline. Additionally, a literature and read-across assessment is performed to create a defensible scientific justification prior to commissioning new testing.
Multi-market PEC harmonization aims to maintain consistent and scientifically sound exposure calculations across EU jurisdictions. Additionally, regulatory authoring and dossier integration ensure that the ERA module meets the detailed expectations of both EMA and national authorities.
Zenovel assists sponsors in preventing late-stage delays in European marketing authorization submissions by initiating ERA planning early and integrating it with clinical and CMC development.
Here, Zenovel serves as a dedicated ERA partner by providing regulatory, scientific, and operational expertise to assist European pharmaceutical development in meeting environmental compliance requirements, ensuring that sponsors fulfill their obligations to regulators and the environment without causing unplanned delays in their development timelines.
Contact us at bd@zenovel.com.
