EMA Environmental Risk Assessment (ERA) Guideline 2024: Advanced Technical Requirements For EU Pharmaceutical Market Access

The European Medicines Agency (EMA) has implemented the revised Environmental Risk Assessment (ERA) Guideline in September 2024, establishing one of the most scientifically rigorous regulatory frameworks for assessing environmental impacts of human medicinal products in the EU. 
This update reflects a strategic shift toward evidence-based environmental protection, PBT/vPvB scrutiny, ecotoxicological robustness, and alignment with the EU Green Deal and Zero Pollution targets. 

The updated ERA integrates lifecycle environmental evaluation into pharmaceutical development, manufacturing, usage, and disposal—transforming environmental compliance into a critical prerequisite for Marketing Authorization Applications (MAAs) across all EU procedures. 

Expanded Regulatory Scope: Mandatory ERA for All Human Medicinal Products 

The 2024 guideline significantly broadens mandatory ERA applicability: 

Applies to: 

• New Chemical Entities (NCEs) 

• Generics, hybrid medicinal products 

• Biosimilars & fixed-dose combinations 

• Post-authorization variations increasing exposure 

• Line extensions & reformulations 

• High-prescription volume APIs 

Not eligible for simplified waivers: 

• APIs structurally like PBT/vPvB substances 

• Antibiotics, antiparasitic, endocrine-active substances 

• Poorly degradable compounds 

• Substances with complex metabolites 

The guideline now requires a complete ERA dossier (Module 1.6) for nearly all applications submitted via centralized, decentralized, mutual recognition, and national routes. 

Stepwise ERA Methodology: Advanced Phase I and Phase II Framework 

Phase I: Refined PEC Modelling & Environmental Exposure Screening 

Phase I now requires enhanced precision based on: 

Technical Inputs 

• API daily dose & regional consumption modelling 

• Excretion routes (renal, biliary, unchanged API) 

• Stability in STP influent/effluent 

• Physicochemical fate parameters (Koc, Kow, pKa) 

• Advanced simulation of environmental dilution factors 

Automatic Progression to Phase II When: 

• PECsw > 0.01 µg/L 

• Antibacterial, antiparasitic, or endocrine-active molecules 

• Poor biodegrades (e.g., DT50 > 120 days in soil/sediment) 

• APIs with high longbow or bioaccumulation alerts 

• APIs with endocrine or AMR-related structural motifs 

Phase II: Comprehensive Hazard Characterization & Environmental Fate Profiling 

Phase II requires a complete dataset to evaluate chronic ecotoxicity, bioaccumulation, degradation, and environmental persistence. 

Core Phase II Data Requirements 

Environmental Fate & Transformation 

• Ready biodegradation (OECD 301) 

• Inherent biodegradation (OECD 302) 

• Water–sediment simulation (OECD 308) 

• Aerobic/anaerobic transformation in soil (OECD 307) 

• Bioaccumulation in fish (OECD 305) 

• Transformation product identification using validated LC-MS/MS methods 

Ecotoxicological Endpoints 

• Algal growth inhibition (OECD 201) 

• Daphnia immobilization + chronic reproduction (OECD 202/211) 

• Fish acute toxicity & ELS studies (OECD 203/210) 

• Sediment organism studies (OECD 218/219) 

• Soil microorganism and microbial toxicity (OECD 216/222) 

• Activated sludge inhibition (OECD 209) 

All studies must follow GLP compliance, validated analytical methods, and comprehensive raw data traceability. 

Reinforced PBT/vPvB Evaluation: High Regulatory Priority 

The guideline introduces strict evaluation requirements for: 

• Persistent substances (P): DT50 > 120 days in sediment/soil 

• Bioaccumulative substances (B): BCF > 2,000 

• Toxic substances (T): chronic NOEC thresholds met 

• vP/vB substances: extremely slow degradation or high trophic magnification 

Regulators Now Expect: 

• Multi-compartment kinetic modelling 

• Metabolite persistence assessment 

• TMF (trophic magnification factor) calculation 

• Exposure mitigation strategies (SmPC Section 6.6) 

• Environmental monitoring proposals for high-risk APIs 

This aligns with the EU Chemicals Strategy for Sustainability (CSS) and REACH-level environmental expectations. 

Advanced Data Transparency, Systematic Reviews & Digital Traceability 

Applicants must now demonstrate: 

• Systematic literature reviews (SLR) compliant with PRISMA 

• Integration of global databases: ECHA, EPA, PubChem, ChEMBL 

• Justification for all waivers using scientific evidence 

• Clear audit trail for methodologies, raw data, and analytical validation 

• Structuring of ERA report per updated Module 1.6 eCTD format 

This ensures scientific defensibility and reduces regulatory queries. 

Strengthened 3Rs Framework: Modernized Ethical Environmental Testing 

The ERA guideline reinforces ethical testing principles: 

Replacement 

• QSAR/QSPR models 

• New Approach Methodologies (NAMs) 

• In-silico adsorption/degradation predictions 

Reduction 

• Study bridge 

• Read across for chemical analogues 

Refinement 

• Improved test design 

• Lower organism burden in chronic studies 

Applicants must justify every new animal study with regulatory need, aligning with EU animal welfare legislation. 

Table: Comparison of ERA Requirements — Previous vs. EMA 2024 Guideline 

Conclusion: Strategic ERA Integration is Now Critical for EU Regulatory Success 

The EMA ERA Guideline 2024 marks a substantial evolution in pharmaceutical environmental oversight. 
Companies must adopt: 

• Data-rich environmental fate models 

• Comprehensive ecotoxicology data packages 

• Robust PBT/vPvB assessments 

• Evidence-based systematic reviews 

• Lifecycle environmental risk mitigation 

Proactive alignment with the updated ERA expectations ensures: 

• Faster regulatory approval 

• Reduced deficiency letters 

• Stronger Environmental Governance 

• Enhanced ESG value and sustainability credentials