The ICH Q3E Extractables & Leachables (E&L) Risk Assessment provides a global structure to ensure that materials, components, and manufacturing systems used in pharmaceuticals, biologics, and medical devices do not release harmful chemicals into final products. This guideline helps companies identify, assess, and control extractables and leachables in a clear, science-based manner. By following this standard, manufacturers improve product safety, avoid regulatory issues, and maintain consistent quality across markets.
ResolveMass Laboratories Inc., a trusted analytical partner in Canada, supports this full process with validated testing platforms, strong toxicology input, and regulatory-aligned workflows. Their team helps companies anticipate regulatory expectations, shorten project timelines, and maintain patient safety from development through submission.
Summary of This Article
- What the ICH Q3E guideline covers and why it matters
- Stepwise approach for ICH Q3E Extractables & Leachables (E&L) Risk Assessment
- Safety thresholds used: AET, TTC, PDE
- How to calculate and apply Threshold of Toxicological Concern
- Material characterization needs
- E&L study design expectations
- Best practices for ICH Q3E compliance
- Links to ResolveMass E&L services and resources
1. What Is ICH Q3E and Why It Matters for Extractables & Leachables?
The ICH Q3E Extractables & Leachables (E&L) Risk Assessment guideline describes global expectations for identifying chemicals that may migrate from manufacturing and packaging materials into drug products. It explains how companies should decide which compounds are relevant, how to assess their risks, and what controls are required. This creates a consistent global approach and removes confusion caused by region-specific requirements.
This guideline is important because unseen leachables may harm patient safety, affect drug stability, or reduce product performance. By following ICH Q3E, manufacturers show that they understand their materials and processes, which increases regulatory confidence and protects product quality.
ICH Q3E applies to:
- Pharmaceutical packaging materials
- Biologic manufacturing components
- Single-use systems
- Medical device–drug combination products
- Container closure systems
ResolveMass Laboratories supports compliance through:
Extractable and Leachable EL Services
2. Stepwise Approach in ICH Q3E Extractables & Leachables (E&L) Risk Assessment
The ICH Q3E framework uses a structured five-step method for conducting a full ICH Q3E Extractables & Leachables (E&L) Risk Assessment. This approach ensures that every decision is supported by scientific data rather than assumptions. It also prevents unnecessary testing and helps companies justify study scope to regulators.
Step 1: Material Characterization and Chemistry Knowledge
The first step involves listing all materials that contact the drug product. This includes polymers, additives, manufacturing aids, and any known impurities. Companies also collect vendor data and compare past studies to understand which materials may pose higher risk.
This early review forms the foundation of the E&L program and helps identify materials that require deeper study.
Helpful resources from ResolveMass:
ISO 10993-18 and E&L Testing
Analytical Techniques Used in E&L Testing for Medical Devices
Step 2: Controlled Extractables Study
Controlled extraction studies show which compounds may migrate from materials when exposed to exaggerated conditions such as strong solvents, increased temperature, or extended extraction time. These studies give early insight into possible risks long before real-time data is available.
ResolveMass supports this requirement:
Controlled Extractables Study (CES)
Step 3: Migration (Leachables) Study
Leachables studies identify which extractables actually enter the drug product during real storage and use. This includes testing with actual formulations, real-time aging, and realistic storage conditions. This step provides true patient exposure information and is essential for determining final safety risks.
Step 4: Safety Assessment / Toxicological Qualification
Each detected compound must be evaluated using TTC, PDE, and AET thresholds. These values help determine whether a compound may pose health risks. ResolveMass supports this step with toxicology reports, AET calculations, and regulatory-aligned evaluation.
Step 5: Final Risk Documentation
The final step is preparing complete documentation for FDA, EMA, Health Canada, and PMDA. This includes detailed methods, justification, results, and toxicology conclusions. ResolveMass also supports clients during regulatory submissions.
ICH Q3E stresses strong scientific justification and well-structured evidence at each step.
3. Safety Thresholds in ICH Q3E: AET, TTC & PDE Explained
A strong ICH Q3E Extractables & Leachables (E&L) Risk Assessment relies on correctly understanding key thresholds. These thresholds help decide which compounds require deeper study or toxicology review.
Analytical Evaluation Threshold (AET)
The AET defines the lowest level at which compounds must be reported in an analytical study. ICH Q3E requires that AET values be scientifically justified and based on safety thresholds, dosage, and sample conditions.
AET formula:
AET = (Safety Threshold × Dose) / Sample Volume or Surface Area
This ensures that analytical methods are sensitive enough to detect compounds of concern.
More details:
Analytical Evaluation Threshold (AET)
Threshold of Toxicological Concern (TTC)
TTC provides a safe exposure limit when toxicology data for a compound is not available.
Common TTC values include:
- 1.5 µg/day for lifetime exposure
- 5 µg/day for short-term exposure
- Special TTC values for genotoxic compounds
TTC helps with risk screening when the structure or toxicology data is limited.
ResolveMass supports carcinogenicity evaluation:
Extractables and Leachables (E&L) in Carcinogenicity Risk
Permitted Daily Exposure (PDE)
PDE is used when compound-specific toxicology data exists. It is derived from factors such as NOAEL, human variability, interspecies differences, and exposure duration. PDE values give the most conservative and accurate safety limits.
4. Applying TTC & PDE in ICH Q3E E&L Risk Assessments
The ICH Q3E Extractables & Leachables (E&L) Risk Assessment requires that every detected leachable be evaluated using TTC and PDE values. These safety thresholds help determine whether a compound poses low risk or needs a deeper toxicological review. By applying these values correctly, manufacturers create a consistent and predictable safety strategy that regulators understand and trust.
TTC is commonly used for compounds with unknown structures or where toxicology data is limited. It serves as a quick screening tool to separate negligible risks from areas where more data is needed. PDE, on the other hand, is applied when compound-specific toxicology information is available, offering a stronger and more data-driven safety margin. Together, TTC and PDE create a balanced approach to E&L toxicological qualification.
Summary Table
| Compound Type | Threshold Used | Purpose |
|---|---|---|
| Unknown structure | TTC | Initial risk screening |
| Known, non-toxic | PDE | Final qualification |
| Genotoxic | Lower TTC values | Highest level of control |
| Highly potent compounds | PDE | Strong toxicology evaluation |
This decision-making framework ensures that every compound is judged fairly and scientifically, allowing companies to avoid unnecessary work while still protecting patient safety.
5. E&L Study Design for ICH Q3E Compliance
ResolveMass Laboratories develops E&L study designs that follow ICH Q3E, USP <1663>/<1664>, and ISO 10993-18. A strong study design ensures that the right conditions, solvents, and analytical methods are selected. This leads to better compound detection, clearer data, and smoother regulatory review.
A proper E&L study starts with identifying all materials that contact the product. Then, solvents are selected to represent realistic and worst-case conditions. Analytical methods are chosen to detect a broad range of chemical classes, and worst-case extraction conditions are applied to reveal potential risks. By using a structured plan, companies can build a complete E&L profile that meets global regulatory expectations.
Helpful links from ResolveMass:
How an E&L Study is Conducted
Custom E&L Study Design and Method Development
Rapid Turnaround E&L Testing for Time-Sensitive Projects
Multi-Matrix E&L Testing
This careful planning ensures that the ICH Q3E Extractables & Leachables (E&L) Risk Assessment process is thorough, efficient, and aligned with regulatory needs.
6. Analytical Techniques Required Under ICH Q3E
To fully characterize extractables and leachables, ICH Q3E encourages the use of several complementary analytical techniques. No single instrument can detect every type of compound, so orthogonal methods are essential. ResolveMass uses a wide set of platforms to ensure nothing important is missed.
Common Techniques Include:
- GC-MS for volatile and semi-volatile compounds
- LC-MS/MS for non-volatile and polar compounds
- ICP-MS for detecting elemental impurities
- FT-IR and NMR for structural confirmation
These tools work together to create a complete chemical picture of materials. Because E&L profiles can be complex, using multiple techniques increases accuracy and confidence in the final results.
More details:
Analytical Techniques Used in E&L Testing for Medical Devices
Orthogonal detection is a key requirement in a reliable ICH Q3E Extractables & Leachables (E&L) Risk Assessment because it ensures full coverage across chemical classes.
7. Extractables & Leachables in Medical Devices and Biopharma
Medical devices, combination products, and biologics often have higher E&L risks due to their extensive use of polymers, adhesives, tubing, filters, and single-use components. These materials interact closely with formulations, which increases the chance of chemical migration. A strong E&L strategy is essential to protect product quality and patient safety.
ResolveMass Laboratories provides specialized E&L support for these complex systems. Their services help identify extractables early, monitor leachables under real conditions, and evaluate risks based on ICH Q3E, ISO 10993-18, and FDA expectations. This approach ensures that devices and biologics maintain stability, potency, and sterility, even when exposed to challenging materials.
Helpful resources:
E&L Testing for Medical Devices
Choosing the Right CRO for E&L Testing in Medical Devices
Extractables and Leachables (E&L) Testing in Biopharma
Because these products contact patient tissues, blood, or injectable formulations, ICH Q3E plays a major role in ensuring that all risks are well understood and controlled.
8. FDA, USP, and ISO Alignment with ICH Q3E
ICH Q3E aligns with major international standards, including FDA guidance, USP <1663>/<1664>, and ISO 10993-18. This alignment gives companies one unified E&L approach instead of needing separate strategies for different regions. As a result, development timelines become shorter, documentation becomes clearer, and regulatory communication improves.
Manufacturers can also avoid repeating tests when moving products between markets, which saves time and reduces cost. This global harmony simplifies compliance without lowering safety or scientific expectations.
Useful resources:
Extractables and Leachables FDA Guidance
USP Guidelines for Extractables and Leachables Testing
A harmonized framework ensures that the ICH Q3E Extractables & Leachables (E&L) Risk Assessment matches global expectations from the start of development.
9. Conclusion
The ICH Q3E Extractables & Leachables (E&L) Risk Assessment offers a dependable, science-driven, and patient-focused approach for evaluating chemical risks from materials used in pharmaceuticals, biologics, and medical devices. By following the stepwise process—material characterization, extractables studies, leachables evaluation, AET/TTC/PDE safety thresholds, and final qualification—manufacturers can achieve full control over E&L risks and meet global regulatory expectations.
ResolveMass Laboratories Inc. supports the entire journey with advanced analytics, toxicological expertise, and regulatory-ready reporting. Their support helps teams move efficiently from planning to submission while maintaining high safety and quality standards.
For project support or consultations:
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Frequently Asked Questions
ICH Q3E provides the global foundation for evaluating chemical compounds that migrate from materials into drug products. It sets expectations for extractables and leachables identification, risk ranking, and safety threshold application. This unified approach improves consistency across regulatory submissions and strengthens patient protection. The guideline also encourages manufacturers to use validated data instead of assumptions, improving the reliability of safety decisions.
TTC is used when compound specific toxicology data are unavailable. It provides a conservative exposure limit for unknown or minimally characterized compounds. TTC values differ by compound class, such as 1.5 µg/day for general unknowns and lower limits for genotoxic species. TTC supports rapid, protective screening within ICH Q3E Extractables & Leachables (E&L) Risk Assessment.
AET is an analytical threshold that determines method sensitivity based on safety limits.
TTC is a generic toxicology value for compounds lacking toxicology data.
PDE is a compound specific safe exposure limit derived from NOAEL or LOAEL data.
ICH Q3E requires all three thresholds to be applied consistently to ensure robust risk management.
Yes. Leachables studies are essential whenever drug products contact materials such as polymers, adhesives, elastomers, coatings, or tubing. Real time leachables data provide the most accurate picture of patient exposure, even when extractables studies suggest minimal risk. Migrant formation cannot be assumed and must be verified experimentally.
Worst case conditions must be scientifically justified and represent maximum realistic patient exposure. This may include high temperatures, aggressive solvents, or extended extraction times. The choice depends on the material type, product formulation, and expected contact conditions.
Yes. Biologics frequently use single use systems and polymeric materials that interact with the product during culture, purification, and storage. Temperature, pH, and long contact times can increase E&L risk. Therefore, E&L evaluation is critical for bioreactors, bags, filters, and tubing used in biologic manufacturing.
ICH Q3E expects orthogonal analytical coverage because no single technique can detect all compound classes. GC MS, LC MS, and ICP MS are core platforms, with NMR and FT IR used for structural confirmation. Orthogonal testing improves identification confidence and reduces the risk of missing critical leachables.
Any unknown peak above the AET must be identified or at least structurally classified. If identification is not possible, the compound must be treated conservatively using TTC or similar safety thresholds. Regulators expect transparent reporting, justified decisions, and documented analytical attempts.
A full ICH Q3E submission includes:
Material characterization summary
Extractables study report
Leachables study report
Toxicological assessment
Analytical method validation
Risk control justification
ResolveMass provides complete, submission ready documentation packages.
Yes. CROs like ResolveMass can manage the entire process, from study design to toxicology evaluation and regulatory support. End to end services reduce internal workload, shorten timelines, and improve compliance across all ICH Q3E Extractables & Leachables (E&L) requirements.
References
- United States Pharmacopeial Convention. (n.d.). Extractables and leachables. Retrieved October 10, 2025, from https://www.usp.org/impurities/extractables-and-leachables
- Balfour, H. (2022, April 29). Advancing extractables and leachables testing. European Pharmaceutical Review. https://www.europeanpharmaceuticalreview.com/article/170814/advancing-extractables-and-leachables-testing/
- Rozio, M. G. (2025). Correcting detection and quantitation bias in extractables and leachables testing. Journal of Pharmaceutical Analysis, 15(2), 123–134. https://doi.org/10.1016/j.jpha.2025.04.004
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