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The EMA’s 2024 ERA guideline revision tightened the roles beyond screening and how applicants must structure and evidence their ERA in Module 1.6 for initial MAAs and exposure-increasing variations. The update separated risk assessment from Persistent, Bioaccumulative, and Toxic (substance classification) (PBT )hazard identification and clarified the Phase I decision process, expanded Tier A requirements, and formalized a transparent report format for clear tracing of assumptions, data, and conclusions. Lets understand it in more detail.
What changed in 2024
The revised guideline was adopted on 15 February 2024 and entered into force on 1 September 2024, replacing the 2006 approach with a harmonized, more explicit framework that applicants must follow across centralized, MRP/DCP, and national routes for human medicinal products. A minor revision on 22 August 2024 clarified wording in Section 3.1 for excipients and applied editorial corrections, underscoring the EMA’s intent to remove interpretive gray zones that previously led to uneven dossiers and review questions.
The update kept the tiered concept but operationalized it with a practical decision tree, clearer triggers, and detailed study expectations, reducing variability in how sponsors characterize exposure and effects across relevant environmental compartments. The guidance also formalized the independent PBT hazard determination alongside the exposure-based risk assessment, ensuring that persistence and bioaccumulation concerns are addressed even when risk quotients might appear acceptable on exposure grounds alone. The following phases highlights the guidelines importance.
Phase I: Exposure first, but better justified
Phase I retains the 0.01 µg/L surface-water action limit as the screening threshold but now requires clearer justification for refinements and cumulative exposure across indications before decision-making. The default PEC is conservative, but refinements are allowed with robust, transparent data on prevalence and regimens. When sponsors refine parameters, they must document data sources, assumptions, and cumulative PEC to ensure traceability, making Phase I a transparent, reproducible process estimates.
Phase II: Tier A first, then refine
Phase II expectations are more prescriptive, moving core fate and effect studies to Tier A for a consistent baseline across compartments like surface water, sediment, sewage, soil, groundwater, and secondary poisoning when triggers are met. Tier B refines and adds studies based on initial risk quotients or compartment triggers, focusing resources on data gaps instead of exploratory testing. This guidance aligns test methods with OECD practice and GLP, recognizing the 3Rs, and clarifies when tailored strategies are needed to capture population-relevant endpoints at realistic concentrations. By codifying triggers and endpoints, the EMA reduces delays and post-approval complications related to study necessity and design.
PBT/vPvB and literature: Independent and Rigorous
A stronger, independent PBT/vPvB screening and assessment are now part of the dossier, with clear criteria and decision points separate from exposure-based risk quotients. This means minimizing environmental exposure might be necessary for substances labelled PBT/vPvB, even if traditional risk ratios don’t suggest controls. These outcomes should be reflected in labeling and risk mitigation.
This guideline also sets expectations for literature search methods, data reliability, and conditions for using existing studies through data sharing or access letters. This improves the quality and transparency of third-party evidence, reduces duplication, and makes literature a structured evidence source that influences assessment components.
Revisions to Module 1.6 Contents
- Substance identity and pharmacological profile for each active, including identifiers and attributes signaling tailored assessment needs in testing and interpretation.
- A complete Phase I record showing default calculations, any refined
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with robust epidemiology and regimen justification, and an aggregate PEC across all approved or proposed indications to support the stop/go decision. - Phase II Tier A dataset covering physicochemical properties, environmental fate, and ecotoxicity across relevant compartments, with Tier B refinements where triggers and risk quotients indicate remaining uncertainty or concern.
- An independent PBT/vPvB screening and, if applicable, a full assessment against P, B, and T criteria, with conclusions tied to exposure minimization and product information where appropriate.
- Literature search strategy, data selection and reliability appraisal, and documentation of access to any prior studies used to support the dossier to ensure Regulatory reusability and traceability.
- Risk characterization by compartment with PEC, PNEC, and RQ values, integrated conclusions, and explicit SmPC/PL statements plus feasible risk‑mitigation measures aligned to guideline Section 7 and reflected in the product information.
- Report structure per the guideline’s reporting section, with any deviations or missing data explicitly justified so assessors can understand limitations and proposed mitigations without delay.
with robust epidemiology and regimen justification, and an aggregate PEC across all approved or proposed indications to support the stop/go decision.What MAHs should do or follow going forward?
Confirm alignment with the dates and clarifications then quickly assess gaps using the decision tree, Tier A list, and PBT/vPvB screening to see if older ERAs support current labeling and plans. When using legacy studies, verify OECD/GLP compliance, obtain access letters, and update literature reviews with new ecotoxicology and fate data that might alter triggers or risks.
Recalculate PECSW using current epidemiology, aggregate across indications, and plan Tier B updates only when risk quotients or triggers require, to shorten timelines and focus spending. Pre-draft SmPC/PL environmental statements and risk mitigation measures to align Module 1.6 conclusions and product info during assessment stages.
Our experts at Freyr’s Non-Clinical Team can partner with sponsors to ensure an ERA readiness audit, benchmarking Module 1.6 against the 2024 guidelines. This helps close evidence gaps early and de-risks reviews with a defensible, transparent environmental narrative, thereby accelerating approvals and protecting your launch plans.
