Environmental hazard and risk assessment
Between us and our expert partners, we can assist in conducting Environmental risk assessments (ERAs) for various purposes, including REACH registrations, PPP active dossier submissions, and for human medicines [see below for details]. This could involve:
- Searching for existing physico-chemical (e.g. water solubility and Log Kow), environmental fate and behaviour (e.g. biodegradation and bioaccumulation), and ecotoxicity (e.g. aquatic toxicity) studies
- Assessing and summarising the existing data
- Use of QSAR and read-across to fill identified gaps and justifying their use
- Commissioning and monitoring new studies, and commenting on study plans and draft reports
- Proposing Predicted Environmental Concentrations (PECs) and conducting an environmental exposure assessment
- Calculating Predicted No Effects Concentrations (PNECs) from the underlying ecotoxicity dataset and with application of suitable uncertainty factors (e.g. REACH Assessment Factors)
- Concluding on the ERA
- Conducting an assessment of the substance’s Persistent, Bioaccumulative and Toxic (PBT) and vPvB properties
For example, in the EU, an ERA is required for all new pharmaceutical product marketing authorisation applications for human medicines (Article 8(3) of Directive 2001/83/EC). An (updated) ERA is also needed where a potential increase in environmental exposure is likely, including for type II variations (e.g. new indication) and extension applications (e.g. new route of human exposure) to existing marketing authorisations.
EMA guidance sets out a phased approach for the ERA. Phase I (pre-screening) involves two key tasks. The first involves a preliminary screen for potential PBT properties using the (ideally experimentally-determined) partition co-efficient (Log Kow value). If the Log Kow value exceeds 4.5, a full PBT assessment maybe needed as described in REACH guidance. Indeed, this may involve the generation of new test data. Bibra and its partners have experience of searching for and calculating (using (Q)SAR) Log Kow values for a large number of substances, for commissioning and monitoring OECD/ISO-compliant GLP Log Kow studies at suitably experienced EU CRO’s, and for carrying out PBT/vPvB assessments. The second task involves conducting a preliminary exposure assessment (based on proposed dosage). For this, the default value for the fraction of the overall market penetration (Fpen) within the range of existing medicinal products can be used. However, a refinement of the Fpen based on treatment regime or prevalence data (e.g. recent epidemiology data) maybe appropriate (and will be needed for each indication; assuming 100% market share). We have experience of refining the Fpen, based on recent and robust publically-available disease prevalence data from various EU countries. If the subsequently determined surface-water Predicted Environmental Concentration (PECsw) equals or exceeds the default action limit (of 0.01 μg/L), a more thorough investigation of the environmental fate and effects of the API is required (i.e. the ERA proceeds to Phase II). This may also be true of APIs of environmental concern (e.g. endocrine disruptors), with adverse effect levels potentially below the action limit. A specific, tailoured, testing strategy maybe required for this cohort of concern.
Between ourselves, and our expert partners, we have extensive experience of searching for and assessing the existing environmental fate and behaviour and ecotoxicity studies required in Phase II (e.g. aquatic and terrestrial ecotoxicity, biodegradation and bioaccumulation studies), in commissioning and monitoring new studies (where needed) and peer-reviewing/commenting on study plans and draft reports, in conducting comprehensive exposure assessments (e.g. groundwater PECs), in calculating PNECs, and in concluding on the ERA. We can also assess the endocrine disrupting properties (if the mode-of-action indicates a need) and assess key metabolite(s) where appropriate. The ERA, or justification for its absence (which maybe the case for generics and certain substances, including vitamins, amino acids and lipids), should be provided (as an Expert Report) along with the study reports in Module 1.6 of the marketing authorisation application. Although the outcome of the ERA will not “constitute a criterion for refusal of a marketing authorisation”, risk mitigation measures should be considered where appropriate (e.g. labelling).
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