INTRODUCTION
The ICH Q3E guideline for Extractables and Leachables provides the international standard for evaluating chemical compounds that may migrate from pharmaceutical packaging or medical device components into drug products. It explains—in a harmonized format—how to design E&L studies, interpret results, and ensure patient safety.
ResolveMass Laboratories Inc. integrates the ICH Q3E guideline for Extractables and Leachables across all analytical programs to support compliant global submissions for pharmaceuticals, biologics, and combination products.
SUMMARY
- The ICH Q3E guideline for Extractables and Leachables establishes a global scientific and regulatory framework for managing chemical safety risks from packaging and medical devices.
- It clarifies expectations for study design, analytical strategy, toxicological evaluation, acceptance criteria, and lifecycle management.
- ResolveMass Laboratories Inc. provides full-spectrum E&L testing aligned with ICH Q3E, FDA, and EU MDR requirements.
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WHAT IS THE ICH Q3E GUIDELINE FOR EXTRACTABLES AND LEACHABLES?
The ICH Q3E guideline for Extractables and Leachables outlines regulatory expectations for identifying, quantifying, and assessing chemical migrants originating from materials that come in contact with drug products. It answers the fundamental question: How should manufacturers ensure that packaging and device components do not introduce harmful compounds?
Key Components
- Systematic risk assessment
- Comprehensive extractables profiling
- Real-world leachables evaluation
- Toxicological risk determination
- Analytical validation requirements
- Lifecycle of container/closure controls
WHY ICH Q3E MATTERS IN 2025: GLOBAL ALIGNMENT
The ICH Q3E guideline unifies the expectations of the FDA, EMA, PMDA, Health Canada, and other global agencies. In 2025, this harmonization enables organizations to submit one consistent E&L dataset across all major markets.
Benefits
- Reduces redundant testing
- Supports quicker regulatory approvals
- Improves scientific consistency
- Standardizes safety thresholds
Related Information (instead of links)
- ResolveMass provides dedicated guidance for E&L requirements in the United States, helping clients understand FDA expectations for packaging, container closure systems, and medical-device combination products.
- ResolveMass also provides detailed guidance on E&L regulatory requirements for medical devices, including polymer-specific risks and EU MDR compliance.
- ResolveMass publishes technical comparisons explaining extractables vs. leachables for medical devices, helping engineers and regulatory teams understand material interactions.
CORE PRINCIPLES OF THE ICH Q3E GUIDELINE FOR EXTRACTABLES AND LEACHABLES
1. Risk-Based E&L Assessment
ICH Q3E requires manufacturers to assess E&L risks based on material type, drug formulation, patient exposure, and contact conditions. The guideline provides clarity on how to set up worst-case scenarios supported by scientific justification.
Risk Elements to Consider
- Material chemistry (polymers, elastomers, metals, adhesives)
- Extractables knowledge during design
- Drug product characteristics (pH, polarity, viscosity)
- Exposure route (e.g., inhalation vs injection)
- Target patient group
- Contact time and storage temperature
2. Extractables Testing Requirements
Extractables testing under ICH Q3E uses aggressive solvents and forced conditions to extract potential migrating compounds from packaging or device components.
Steps in Extractables Studies
- Material characterization and selection
- Selection of extraction solvents (e.g., water, IPA, hexane)
- Use of exaggerated conditions (elevated temperature, extended time)
- Identification of organic and inorganic extractables
- Development of an analytical target list (ATL)
3. Leachables Testing Requirements
Leachables studies determine which compounds actually migrate into the drug product under real-time and accelerated conditions.
Components of Leachables Testing
- Monitoring predicted extractables
- Detecting unexpected leachables
- Quantifying leachables over stability timepoints
- Method validation per ICH Q2
- Final toxicological significance determination
TABLE — EXTRACTABLES VS LEACHABLES BASED ON ICH Q3E
| Factor | Extractables | Leachables |
|---|---|---|
| Test Medium | Solvents | Actual drug product |
| Conditions | Forced/exaggerated | Real-time/accelerated |
| Purpose | Identify potential migrants | Confirm actual migrants |
| Output | Analytical target list (ATL) | Final patient exposure profile |
| Regulatory Importance | High | Highest |
4. ANALYTICAL TECHNIQUES EXPECTED UNDER ICH Q3E
ICH Q3E emphasizes orthogonal methods to capture volatiles, semi-volatiles, organics, and inorganics.
Required Techniques
- GC-MS for volatile organics
- LC-HRMS for semi-volatile/non-volatiles
- ICP-MS for elemental impurities
- NMR for structural elucidation
- FTIR for polymer characterization
- Headspace GC for residual solvents
5. TOXICOLOGICAL RISK ASSESSMENT REQUIREMENTS
Toxicological evaluation under ICH Q3E is centered on the Analytical Evaluation Threshold (AET), Toxicological Concern Thresholds (TTC), and safety margins.
Toxicology Framework
- Identify compound type (organic/inorganic)
- Assess known toxicities and exposure limits
- Compare detected levels to PDE values
- Consider special populations
- Prepare toxicological qualification summaries
6. ACCEPTANCE CRITERIA IN ICH Q3E
ICH Q3E does not assign universal E&L limits. Instead, it requires scientifically justified thresholds.
Acceptance Criteria
- AET calculation
- Reporting and identification thresholds
- Compound qualification thresholds
- Safety margin justification
- Higher scrutiny for inhalation and parenteral products
7. DOCUMENTATION REQUIREMENTS
ICH Q3E demands structured documentation that supports regulatory review.
Required Documentation Includes
- Study design and risk assessment rationale
- Material selection justification
- Extractables and leachables data tables
- Method validation records
- Toxicology summaries
- Lifecycle monitoring plans
8. LIFECYCLE MANAGEMENT UNDER ICH Q3E
ICH Q3E requires E&L monitoring throughout the product lifecycle, especially when materials, formulations, suppliers, or manufacturing processes change.
Events Triggering Re-Assessment
- Material formulation changes
- Supplier changes
- Container closure redesign
- New sterilization or filling processes
- Shelf-life extension
9. HOW RESOLVEMASS LABORATORIES SUPPORTS ICH Q3E COMPLIANCE
ResolveMass Laboratories Inc. provides full analytical support aligned with the ICH Q3E guideline for Extractables and Leachables.
Capabilities Include
- Complete extractables profiling
- Leachables testing with real drug matrices
- Polymer & elastomer chemical characterization
- Orthogonal mass spectrometry workflows
- Detailed toxicology evaluation
- Submission-ready reports for FDA, EMA, Health Canada
- ResolveMass’ U.S. E&L guidance page explains differences between FDA expectations, drug-product classifications, and CCP requirements.
- Their medical-device regulatory guide outlines EU MDR risk categorization and device material testing rules.
- Their technical comparison page explains how extractables differ from leachables in real device systems such as tubing, connectors, pump components, and reservoirs.
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CONCLUSION
The ICH Q3E guideline for Extractables and Leachables establishes the global standard for designing, conducting, and interpreting E&L studies for pharmaceuticals and combination products. ResolveMass Laboratories Inc. delivers E&L programs that fully align with ICH Q3E to ensure patient safety, regulatory compliance, and global submission readiness.
FAQs on ICH Q3E Guideline for Extractables and Leachables
The primary purpose of the ICH Q3E guideline for Extractables and Leachables is to establish a globally harmonized scientific and regulatory framework for evaluating chemical substances that may migrate from pharmaceutical packaging, container closure systems, and device components into drug products.
ICH Q3E ensures that manufacturers follow standardized, risk-based, and reproducible methods for:
-Identifying potential chemical migrants (extractables)
-Detecting actual chemical migrants that enter the drug product during storage (leachables)
-Assessing toxicological risks
-Setting safe analytical thresholds
-Designing necessary analytical studies
By unifying expectations across major regulatory agencies (FDA, EMA, PMDA, Health Canada), ICH Q3E helps manufacturers avoid redundant testing, reduce regulatory uncertainty, and ensure consistent patient safety globally.
ICH Q3E applies to any pharmaceutical product that directly interacts with a material or system capable of releasing chemical compounds. This includes both traditional drug products and advanced therapy medicinal products.
Products requiring ICH Q3E-compliant E&L testing include:
1. Parenteral Products
-IV solutions, injectables, infusions, vials, cartridges, prefilled syringes
-High-risk due to direct bloodstream exposure
2. Ophthalmic Products
-Eye drops, gels, solutions
-Sensitive tissues require extremely low safety thresholds
3. Inhalation and Respiratory Products
-DPIs, nebulizers, nasal sprays
-High toxicity concern due to lung absorption
4. Drug–Device Combination Products
-Auto-injectors
-Inhalers with drug reservoirs
-Implantable drug-eluting systems
-E&L hazards must consider both drug and device components
5. Biologics, Cell & Gene Therapy Packaging
-Vials, stoppers, tubing, connectors
-Sensitive formulations increase risk of interaction with extractables
6. Medical Devices with Direct Drug Contact
-IV sets, administration kits, catheters, infusion pumps
-EU MDR and FDA combination product requirements overlap with ICH Q3E concepts
Any system where a material may leach into the drug product is covered by ICH Q3E expectations.
ICH Q3E requires a multi-platform, orthogonal analytical strategy because no single analytical method can detect all chemical classes.
Required Techniques Include:
1. GC-MS (Gas Chromatography—Mass Spectrometry)
-Detects volatile and semi-volatile organic compounds (VOCs/SVOCs)
-Identifies residual solvents, monomers, low-molecular-weight organics
2. LC-MS/MS or LC-HRMS (Liquid Chromatography—Mass Spectrometry)
-Detects non-volatile, polar, and high-molecular-weight organics
-Ideal for antioxidants, oligomers, polymer additives, degradation products
3. ICP-MS (Inductively Coupled Plasma—Mass Spectrometry)
-Detects trace metals and inorganic leachables
-Critical for evaluating catalysts, metal impurities, or corrosion-related contaminants
4. NMR (Nuclear Magnetic Resonance Spectroscopy)
-Provides definitive structural confirmation
-Essential for unknown compound identification
5. FTIR (Fourier Transform Infrared Spectroscopy)
-Supports polymer and elastomer characterization
-Useful for identifying chemical classes or matching material residues
6. Headspace GC
-Detects volatile organics that evaporate under heat
-Used for residual solvent analysis and screening elastomeric closures
ICH Q3E expects method selection justification and validation for all analytical platforms used.
E&L timelines depend on the product, material complexity, and regulatory pathway.
Extractables Studies
-Typically: 2–4 months
-Includes extraction, analytical profiling, identification, and reporting
-Faster because forced extraction accelerates chemical release
Leachables Studies
-Tied to product shelf life: 6–24 months
-Includes real-time and accelerated stability testing
-Requires testing at multiple timepoints
(e.g., 0, 1, 3, 6, 9, 12, 18, 24 months)
Full E&L Program Timeline Summary
-Minimum: 6 months (short shelf-life drugs)
-Typical: 12–18 months
-Extended: 24 months (biologics, inhalation, device-reservoir systems)
ICH Q3E emphasizes that real-time data is mandatory for submission, even if accelerated data is available earlier.
ICH Q3E was developed primarily for pharmaceutical products, but many principles directly apply to medical devices, especially:
-IV administration sets
-Tubing and infusion lines
-Catheters
-Implantable drug-delivery components
-Pump reservoirs
Regulatory bodies (EU MDR, FDA’s combination product requirements) already require:
-Material characterization
-Extractables/leachables studies
-Risk assessments
Therefore, for any device that interfaces with a drug or has patient-contact fluid pathways, ICH Q3E concepts are functionally required, even if not explicitly mandated.
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Reference
- ANSES, 2013. Évaluation des risques du bisphénol A (BPA) pour la santé
humaine. https://www.anses.fr/fr/system/files/CHIM2009sa0331Ra-0.pdf. Accessed April: 2025 - European Chemicals Agency (ECHA). 4,4′-isopropylidenediphenol. EC number: 201-245-8.
CAS number: 80-05-7. Bisphenol A; BPA. Eye irritation. https://echa.europa.eu/registrationdossier/-/registered-dossier/15752/7/4/3. Accessed: April 2024.
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