In November 2018, the European Medicines Agency (EMA) published a revision to its guideline on the environmental risk assessment (ERA) of medicinal products for human use. The scope of the guidance remains the same, namely to evaluate the potential risks of any medicinal products to the environment and ensure risk mitigation measures are in place where required. Similarly, the situation remains that any potential adverse effects determined from the ERA does not constitute a criterion for refusal of a marketing authorisation of a medicinal product.
In brief, the revision of the guideline introduces a tiered decision tree approach to ERA and specifically outlines the relevant triggers for progressing through the tiers. It makes better utilisation of publicly available data, details expansive assessment approaches for persistent, bioaccumulative and toxic (PBT) substances and endocrine disruptors (ED) and provides updates on test systems/assays and the options for risk mitigation measures (Whomsley et al. 2019). The EMA website denotes that one of the most notable changes in the guideline is the introduction of the term ‘endocrine active substances’ (EAS) for all compounds that affect development or reproduction. In these cases, a tailored risk assessment will be necessary. It also states that another key introduction in the new guideline is for the estimation of exposure to predators through the food chain as secondary poisoning.
A major objective of the new guidance is to implement the 3Rs principles (Replacement, Reduction and Refinement) in the interests of animal welfare, and to that end encourages the sharing of data among applicants. However, every medicinal product submitted for marketing authorisation must have both an ERA and a specific hazard assessment for PBT properties.
The ERA consists of two parts: (i) a mandatory Phase I assessment based on environmental exposure and general characteristics of the HMP, concluding with the calculation of a PECsw, and (ii) a Phase II assessment outlining the experimental requirements for a detailed fate and effects assessment of the HMP.
The steps of Phase I are explicitly outlined in a decision tree, with the outcome being that either the risk assessment stops or that a Phase II assessment is required. The key criteria for entering the Phase II assessment is a PECsw of ≥ 0.01 μg/L., however, this does not apply to EAS. Where the evidence shows that endocrine adverse effects could occur at levels below 0.01 μg/L, the active substance should be further EAS assessed.
Phase II consists of two Tiers: Tier A requires studies on the physico-chemical properties, environmental fate and ecotoxicological effects of the active substance. It also details the trigger values that necessitate risk assessments for soil, groundwater and secondary poisoning. The PEC is then compared to the PNEC and, where risks are identified, a Tier B assessment is warranted, which includes PEC refinement options.
PBT and endocrine active substances
In the new guidance, ERA and PBT assessment have been separated, emphasizing that the PBT assessment is a hazard assessment and should not be based on the PEC since long term cumulative effects can lead to uncertainty in PEC calculations. Therefore, all active substances (apart from a few exceptions) must be assessed for PBT properties, regardless of their PEC. The PBT screening (octanol/water partitioning study) occurs in Phase I, with a definitive assessment in Phase II, if the trigger value of log Kow > 4.5 is met. If a definitive PBT assessment is required, it should follow the PBT and vPvB criteria defined under the REACH regulation. However, there are some small differences, for example QSARs are not appropriate and a stepwise assessment is not required as most of the data is available as part of the Phase II assessment.
Similarly, if a log Kow of > 3 is determined, the new guidance has introduced a secondary poisoning assessment. This assesses the potential of substances to accumulate through the food chain with an ultimate toxic effect on birds and mammals. This assessment is based on the data from the fish bioconcentration study combined with available, non-clinical, mammalian toxicity data. No further mammalian experimental data is requested and if no mammalian data is available further assessment can be waived.
As highlighted by the EMA, the terminology of EAS has been broadened and the risk assessment required is more comprehensive, mirroring the ECHA/ESFA guidance for the identification of endocrine disrupting chemicals (ECHA/EFSA 2018). While EAS which affect developmental and reproductive endpoints are of particular relevance in assessing environmental risk, assessment of thyroid hormone agonists and antagonists may also be required. For all EAS, the assessment is informed by the mechanism of action (MoA) of the compound. If the MoA indicates a potential EAS modality, the assessment can be tailored to specific groups of organisms and a tiered testing strategy should be followed.
If you have any questions on the revised guideline or would like some advice on how it may affect your products, feel free to contact Theresa Neely (Theresa.Neely@cea-res.co.uk) or Claire McMillan (Claire.McMillan@cea-res.co.uk).
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Original Guidance: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf
New guidance: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-environmental-risk-assessment-medicinal-products-human-use-revision-1_en.pdf
Whomsley et al. 2019 Commentary: https://enveurope.springeropen.com/articles/10.1186/s12302-019-0198-9
EMA website: https://www.ema.europa.eu/en/news/revised-guideline-assess-risk-human-medicines-environment
ECHA EFSA (2018) Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009: https://www.efsa.europa.eu/en/efsajournal/pub/5311