The Environmental Risk Assessment (ERA) play a key role in regulatory submissions for medicines in the European Union. The European Medicines Agency (EMA) requires a clear, evidence-based process to assess the potential environmental impact of active pharmaceutical ingredients (APIs) that enter the environment through patient use.
With the updated EMA guideline (EMEA/CHMP/SWP/4447/00 Rev. 1 – EMA 2024), applicants now need to follow a two-step approach that looks at both hazard and exposure. Moreover, a new change compared to the previous guideline is that generic drug manufacturers, who before could skip the ERA using a justification, are now required to carry out the assessment as well.
In this blog, we explore the ERA workflow set by EMA, enriched by real-world application insights drawn from our recent assessments. The focus is not on a specific product but on how we interpret and implement the guidelines in practice, especially under the constraints of limited data, tight timelines, and ever-evolving expectations.
Phase I: Screening and Preliminary Assessment
For this first step, a decision three must be followed, which also includes a preliminary screening to identify substances with endocrine activity and/or those that may be classified as Persistent, Bioaccumulative, and Toxic (PBT) or very Persistent and very Bioaccumulative (vPvB).
In particular, this step is focused solely on screening whether the pharmaceutical product could pose an environmental risk based on its Maximum Daily Dose (MDD), via the calculation of its Predicted Environmental Concentration Surface Water (PECSW). The assessment also relies on several conservative default assumptions, such as a fixed percentage of the population (typically 1%) using the product, a standard wastewater volume per person, and a set dilution factor.
In some cases, this step may not be necessary, such as for naturally occurring substances like vitamins, minerals, or proteins. In these instances, the ERA can be limited to a scientific justification explaining why a full Phase I assessment isn’t required, based on the drug’s physico-chemical properties. These substances are generally considered to be biodegradable in sewage treatment plants (STPs) and in the environment, and therefore are not expected to pose a significant environmental risk. A similar justification can apply to drugs made of non-natural proteins, given there is evidence that the substance is excreted unchanged at levels below 10%, or if an OECD 301 test demonstrates that it is readily biodegradable. In both cases, the ERA process can be concluded prior to the derivation of the PECSW.
If the calculated PECSW exceeds the action limit of 0.01 µg/L, or the API falls into one of the special categories (e.g., endocrine disruptor and antiparasitics), a Phase II risk assessment is triggered.
However, for drugs that don’t fall into the special categories, a further refinement step can be carried out, offering a final opportunity to avoid progressing to Phase II, which often involves experimental testing. This can be done by taking into account the prevalence of the disease in the regions where the product will be marketed, the posology (dosage regimen), or a combination of both.
Some of the most challenging aspects of the Phase I assessment include refining the exposure estimate and screening for potential endocrine activity.
- For exposure refinement, it is essential to conduct a comprehensive literature review to obtain reliable prevalence data, using reputable and independent sources such as peer-reviewed scientific journals or international organizations like the World Health Organization (WHO).
- When it comes to endocrine screening, a thorough literature review is equally important. However, accurately interpreting toxicological data is even more important, as some substances may show reproductive or developmental toxicity but not necessarily fall into the category of endocrine active substances (EAS). Literature reviews, mechanistic in vitro assays, and targeted in vivo studies help determine whether observed effects are due to endocrine disruption or secondary to other pharmacological actions. This distinction is crucial: if a compound is suspected to be an EAS, extensive testing is required to investigate its mode of action (MoA) during a Phase II assessment, studies that are not only costly but often involve animal testing. Therefore, relying on toxicologists for this delicate assessment is of primary importance, to ensure the correct interpretation of available data, and therefore avoid costly experimental studies.
Phase II Assessment
If a substance proceeds to Phase II, a more detailed hazard and exposure assessment is required. Phase II is divided into two tiers, A and B, both requiring the execution of experimental tests for different endpoints, if not already available in the literature. In fact, during this second step, the PECSW calculated during the Phase I assessment must be compared to the Predicted No Effect Concentration (PNEC) for each relevant endpoint, to determine the Risk Quotient (RQ) for that particular endpoint. Importantly, to obtain a PNEC, experimental studies on animals are needed.
In this step, data must be provided on the chemical-physical properties of the substance (specifically LogP, water solubility, and pKa) as well as its environmental fate, aquatic toxicity (covering three taxa: fish, invertebrates, and algae), and potential for secondary poisoning. Additionally, the chemical has to be screened to assess risks related to soil, groundwater, and secondary poisoning.
Importantly, a thorough literature search is also required at this stage, as some or all the data needed for the Phase II assessment may already be available in public sources. A key focus of the new EMA guideline is to avoid unnecessary repetition of animal studies, therefore, applicants are encouraged to include all existing data in their ERA and, whenever possible, share results from relevant tests already conducted by other Marketing Authorization Holders through a letter of access.
For studies sourced from the literature, a reliability assessment must be carried out. Literature studies used as substitutes for experimental data should have designs comparable to those recommended in this guideline, such as OECD technical guideline protocols. While Good Laboratory Practice (GLP) compliance is not mandatory for literature-based studies, any new studies conducted by the applicant must adhere to the latest OECD guidelines and comply with GLP standards.
NB: For all the endpoints for which no literature data were located, experimental studies must be conducted by the applicant.
Substances suspected or identified as EAS follow a separate track in Phase II, as their MoA has to be elucidated fully.
Labeling and Risk Mitigation
Even when an API is shown to pose minimal risk, risk mitigation through product labelling is advised. Regulatory guidelines recommend including disposal instructions in the Summary of Product Characteristics (SmPC) and Patient Leaflet (PL) such as:
- “Do not throw away any medicines via wastewater or household waste.“
- “Any unused medicinal product or waste material should be disposed of in accordance with local requirements.“
These measures, though not directly related to product formulation, are essential to minimize environmental release from unused or improperly discarded medicinal products.
Conclusions
Preparing an ERA for medicinal products can be a complex task. That’s why it’s essential for applicants to rely on experienced professionals, ideally with a strong background in toxicology and/or ecotoxicology, to ensure accurate evaluation of the product, proper interpretation of available data, and informed selection of any necessary experimental studies. If you start the ERA early, frame your data correctly, and take advantage of published knowledge, you can not only save time and cost, but also align your product with the growing demand for eco-responsibility in healthcare.
At ToxHub, our team of experienced toxicologists has prepared over 30 ERAs in the past seven months, supporting clients in their interactions with regulatory authorities and coordinating with laboratories for Phase II experimental studies. By choosing ToxHub, you’re not just getting technical expertise—you’re gaining a committed partner who understands your product’s journey, the importance of timelines, and the value of strategic, science-based decision-making.
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Article Issued by Chiara Gazerro