Environmental Risk Assessment (ERA) for Medicinal Products: When Is It Required and What Are the Common Pitfalls?
Updated: 8 hours ago
Environmental considerations have become an established part of the regulatory development of human medicinal products in the European Union. Active pharmaceutical substances can enter the environment through the use and disposal of medicines, and their potential impact therefore needs to be assessed as part of the marketing authorisation process.
For pharmaceutical companies, however, an Environmental Risk Assessment (ERA) should not be viewed simply as another administrative document to complete before submission. It is a scientific assessment requiring an appropriate understanding of environmental exposure, ecotoxicology, environmental fate and the specific characteristics of the active substance.
Under the current European Medicines Agency (EMA) guideline, an ERA is mandatory for new marketing authorisation applications for human medicinal products. The revised guideline, which became effective on 1 September 2024, provides a more structured framework for determining the extent of the assessment and the data that may be required.
When is an Environmental Risk Assessment required?
An ERA is required for all new Marketing Authorisation Applications (MAAs) for human medicinal products submitted through centralised, mutual recognition, decentralised or national procedures.
Importantly, the requirement applies irrespective of the legal basis of the application, including applications submitted under Article 10 of Directive 2001/83/EC. In practical terms, an applicant should therefore not assume that an ERA can automatically be omitted simply because the active substance is already known or has previously been authorised.
The situation is different for post-authorisation activities. An ERA is not normally required for a marketing authorisation renewal. However, for certain Type II variations or extension applications, the existing ERA may need to be updated if the change is expected to increase environmental exposure. This can occur, for example, when a new indication leads to greater use of the medicinal product or when an extension changes the way the product is administered in a manner that affects environmental exposure.
The ERA should be submitted in Module 1.6 of the marketing authorisation dossier, together with the appropriate supporting documentation. Missing studies or data must be scientifically justified.
What does an ERA actually assess?
The ERA addresses environmental risks associated with the use, storage and disposal of the medicinal product. It does not assess environmental emissions resulting from the synthesis or manufacturing process, which are outside the scope of the ERA requirements established under Directive 2001/83/EC.
The assessment is performed for the pharmacologically active substance. Where a medicinal product contains several active substances, each active substance must be assessed separately. Excipients are outside the scope of the current EMA ERA guideline.
The objective is to determine whether exposure to the active substance could represent a risk to relevant environmental compartments or organisms, including surface water, groundwater, soil, sewage treatment plants and species potentially exposed through the food chain. The assessment also considers persistence, bioaccumulation and toxicity properties where relevant.
Phase I and Phase II: a stepwise approach
The ERA follows a stepwise approach, beginning with Phase I.
Phase I is primarily an exposure assessment. It considers the nature of the active substance and its intended use and calculates a Predicted Environmental Concentration in surface water (PECsw).
Under the current EMA guideline, a PECsw of 0.01 µg/L is generally used as the action limit. If the calculated PECsw is equal to or above this threshold, a Phase II environmental fate and effects assessment is normally required. When the PECsw is below the action limit and no other environmental concerns have been identified, further risk assessment may not be necessary.
However, the 0.01 µg/L threshold should not be treated as an automatic universal stop criterion.
Certain active substances may pose environmental concerns at concentrations below this value or have a mechanism of action requiring a specific assessment strategy. The EMA guideline notably identifies particular considerations for endocrine-active substances, antibacterials and antiparasitic substances. For example, endocrine-active substances and certain antiparasitics may need to enter Phase II regardless of the calculated PEC, while antibacterials require a tailored testing strategy when Phase II is triggered.
Phase II goes further by assessing relevant physicochemical properties, environmental fate and ecotoxicological effects. Predicted environmental concentrations are compared with concentrations at which effects are not expected, allowing the environmental risk for the relevant compartments to be characterised.
This is where careful study selection, data interpretation and scientific justification become particularly important.
Common ERA pitfalls
Assuming that an existing or generic active substance does not require an ERA
One of the first mistakes is determining the ERA strategy solely from the type of medicinal product or regulatory pathway.
A new MAA requires an ERA regardless of its legal basis. Existing environmental information may sometimes be used, but its relevance, accessibility and compliance with the current guideline need to be evaluated. Applicants should therefore establish the regulatory strategy early rather than assuming that an existing authorisation removes the requirement.
Treating the PEC threshold as the only decision criterion
A PECsw below 0.01 µg/L does not necessarily mean that the environmental assessment can always stop.
The pharmacological and toxicological profile of the active substance must also be considered. Substances with specific modes of action may require further assessment even at very low predicted environmental concentrations.
Failing to identify these characteristics early can lead to an inadequate testing strategy and, potentially, additional questions during regulatory review.
Refining exposure without sufficient justification
The default Phase I calculation is intentionally conservative. In some situations, the market penetration factor can be refined using information such as disease prevalence and the treatment regimen.
However, refinement must be scientifically supported. For products with several indications, the EMA guideline specifies that the overall exposure should consider all designated indications and their respective maximum prescribed doses. Prevalence data used for refinement should also come from reliable and independent sources.
Using an optimistic exposure scenario simply to remain below the Phase II trigger is therefore not an appropriate strategy.
Overlooking PBT/vPvB assessment
The environmental risk assessment and the assessment of Persistent, Bioaccumulative and Toxic (PBT) or very Persistent and very Bioaccumulative (vPvB) properties are related but distinct elements.
According to the revised EMA guideline, PBT/vPvB screening should be considered independently of the PEC-based risk assessment. As part of this screening, the octanol/water partition coefficient (log Kₒw) of the active substance is determined. If log Kₒw > 4.5, the trigger for a definitive PBT/vPvB assessment is met. If log Kₒw ≤ 4.5, a definitive assessment is generally not triggered at this screening stage, although further assessment may still be required if Phase II data indicate that relevant bioaccumulation and toxicity criteria, or the very bioaccumulative criterion, are met.
Focusing exclusively on the Phase I PEC calculation can therefore leave an important part of the ERA incomplete.
Relying on public regulatory summaries as a substitute for underlying data
Existing knowledge about an active substance can be extremely valuable, particularly for substances with a long regulatory history. But not every publicly available regulatory document can be used as supporting data.
The revised guideline specifically states that public assessment reports such as PARs or EPARs, as well as summary information from other regulatory frameworks, cannot simply replace the underlying studies in an ERA dossier. Where data owned by another company are relied upon, appropriate access to the underlying reports may be required.
A robust data-gap analysis at the beginning of the project can therefore prevent significant difficulties later in the submission process.
Why ERA planning should start early
An ERA can appear relatively straightforward when a project remains within Phase I. But it can become significantly more complex once Phase II studies, tailored assessments or additional environmental fate investigations are required. For this reason, ERA strategy is best considered early in pharmaceutical development or dossier preparation, rather than shortly before submission.
Early assessment makes it possible to identify the applicable regulatory pathway, review existing data, calculate preliminary environmental exposure, evaluate potential PBT/vPvB concerns and determine whether additional studies are likely to be necessary.
It can also help avoid unnecessary testing. The EMA guideline encourages the appropriate use of existing scientifically reliable information and application of the 3Rs principles where animal testing is concerned.
Building an ERA strategy adapted to your medicinal product
Environmental Risk Assessment sits at the intersection of pharmaceutical regulation, toxicology, ecotoxicology and environmental fate. A successful strategy therefore requires more than completing a standard regulatory template: it requires understanding how the properties and intended use of an active substance translate into the appropriate assessment and testing strategy.
At CEHTRA, our regulatory and scientific experts can support pharmaceutical companies throughout the ERA process, from an initial data-gap analysis and literature review to the Phase I assessment, definition of a Phase II strategy, evaluation of existing studies, PBT/vPvB assessment, coordination of additional testing where necessary, and preparation of the ERA documentation for submission.
Engaging ERA expertise early can help identify potential data requirements before they become a constraint on regulatory timelines and ensure that the assessment is scientifically justified and aligned with current EMA expectations.
Do you need to prepare, update or review an Environmental Risk Assessment for a medicinal product? Contact our experts to discuss your project and define the most appropriate ERA strategy.
