INTRODUCTION
Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences is one of the most crucial topics for manufacturers seeking approval for pharmaceuticals, biologics, combination products, and medical devices. The focus keyword is included here because companies often struggle to understand why E&L USA requirements differ so significantly from European expectations.
ResolveMass Laboratories Inc. supports global manufacturers with comprehensive E&L programs—offering U.S.-aligned, European-aligned, and harmonized E&L strategies to ensure global E&L compliance without costly delays.
SUMMARY
- The article includes a comparison table, bullet points, and integrated ResolveMass expertise information.
- Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences mainly lie in regulatory philosophy, data depth, toxicology requirements, and documentation expectations.
- USA follows flexible, science-driven guidelines (USP, FDA), while Europe adopts stricter, more prescriptive frameworks (EMA, Ph. Eur., MDR).
- Manufacturers seeking global E&L compliance must understand both markets to avoid repeat studies.
- ResolveMass Laboratories Inc. provides end-to-end E&L testing aligned with U.S. and European regulatory expectations.
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1: What Is Extractables & Leachables Testing?
Extractables and Leachables testing identifies harmful chemicals that may migrate from packaging, container closure systems, and medical devices. It is essential in both regions, but Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences affects how testing is designed and documented.
Key Concepts
- Extractables: Compounds released under aggressive, forced laboratory conditions.
- Leachables: Compounds that actually migrate into the drug or patient-contact environment during real use.
ResolveMass performs both extractables profiling and leachables simulation using advanced analytical science.
2: Why the USA vs. Europe Differences Matter?
These differences matter because FDA and EMA/MDR submissions require different levels of evidence. A study accepted by FDA may be insufficient for European reviewers. Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences can determine whether a product achieves global approval without re-testing.
Potential Risks if Differences Aren’t Understood
- Duplicate studies
- Regulatory delays
- Rejections or questions
- Missed market timelines
3: USA Regulatory Framework for E&L Testing
In the USA, Extractables and Leachables (E&L) Testing follows a flexible, science-based approach guided by USP, FDA expectations, and ISO standards.
Core U.S. Standards
- USP <1663> – Extractables
- USP <1664> – Leachables
- USP <661.1>/<661.2> – Plastic and polymeric systems
- FDA container closure guidelines
- ISO 10993-18 for medical devices
ResolveMass E&L Expertise in the USA
ResolveMass Laboratories provides U.S.-focused E&L services built on:
- Strong regulatory alignment with USP and FDA expectations
- Custom study designs based on dosage forms (inhalation, injectable, ophthalmic, oral)
- Risk-based AET calculations
- Advanced analytical platforms: LC-MS/MS, GC-MS, ICP-MS, FTIR, high-resolution MS
- Submission-ready reports including chromatograms, toxicology summaries, and method details
Their U.S. E&L workflows ensure that pharmaceutical and medical device companies meet all FDA expectations.
4: European Regulatory Framework for E&L Testing
Europe requires more prescriptive, detailed, and toxicology-heavy E&L documentation. Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences is most obvious here.
Core European Standards
- EMA Guidance for Veterinary & Human Medicines
- Ph. Eur. 3.1 standards for materials
- ISO 10993-18 (chemical characterization)
- ISO 10993-17 (toxicological risk)
- EU MDR 2017/745
European Requirements Are Stricter Because:
- Toxicology assessments must be more detailed
- Complete chemical identification is expected
- All extractables must be risk-assessed
- Analytical justification must be fully documented
5: Table – Comparison of Extractables and Leachables (E&L) Testing in the USA vs. Europe
| Parameter | USA | Europe |
|---|---|---|
| Regulatory Style | Flexible, guidance-based | Strict, prescriptive |
| Key Standards | USP, FDA, ISO | EMA, Ph. Eur., MDR |
| Toxicology Depth | Moderate | Very high |
| Expectation for Medical Devices | ISO 10993 driven | MDR + extensive ISO |
| Study Design | Justification accepted | Extensive justification needed |
| Submission Expectations | Summary acceptable | Full analytical package |
| Overall Strictness | Medium | High |
6: Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences Explained
The main differences come from regulatory philosophy:
1. Data Depth
- USA: Accepts risk justification, reducing unnecessary testing.
- Europe: Requires complete, often exhaustive profiling.
2. AET & Toxicology
- USA: AET approach is flexible.
- Europe: AET must be justified with deep toxicology and patient exposure calculations.
3. Medical Devices
- USA: ISO 10993-18 is the main reference.
- Europe: MDR demands chemical characterization + toxicology + leachables data even for low-risk devices.
7: ResolveMass Expertise in U.S. E&L Testing
ResolveMass provides comprehensive E&L testing services customized for the U.S. regulatory landscape.
Capabilities Include:
- Extractables studies following USP <1663>
- Leachables studies using USP <1664> principles
- Full analytical platform: LC-MS/MS, GC-MS, ICP-MS, FTIR, HR-MS
- Customized protocols based on risk, formulation, and packaging
- Toxicological support to justify safety and thresholds
- Detailed reporting for FDA submissions
ResolveMass is recognized for fast turnaround, transparent costing, and multidisciplinary expertise.
8: Extractables vs. Leachables in Medical Devices – ResolveMass Approach
This section replaces your second link.
ResolveMass Defines E&L for Medical Devices as Follows:
Extractables
Compounds forced out of device materials under exaggerated conditions to determine the chemical profile and potential risks.
Leachables
Compounds that migrate during real patient use. This determines actual exposure.
E&L Standards for Devices
ResolveMass follows:
- ISO 10993-18 (extractables)
- ISO 10993-17 (toxicology)
- ISO 10993-1 (biological evaluation)
- FDA & MDR expectations
Analytical Techniques
- LC-MS/MS for non-volatiles
- GC-MS for volatiles
- ICP-MS for metals
- FTIR/Raman for polymer identification
- High-resolution MS for unknown screening
Toxicology & Risk Assessment
ResolveMass performs toxicological risk assessments (TRA) for all extractables, evaluating:
- Patient exposure
- Safety margins
- Regulatory thresholds
- Acceptable daily intake
Support for Manufacturers
If unsafe compounds are detected, ResolveMass assists with:
- Material changes
- Supplier comparisons
- Reformulation
- Design modifications
This strengthens global E&L compliance.
9: Global E&L Compliance Strategy
To satisfy both U.S. and European regulators, ResolveMass creates harmonized E&L protocols.
Global Study Strategy
- Begin with USP <1663>/<1664> foundation
- Add Ph. Eur. and MDR toxicological requirements
- Use comprehensive analytical screening
- Document all justification thoroughly
This unified approach eliminates repeat studies and reduces time-to-approval.
Conclusion
Extractables and Leachables (E&L) Testing in the USA vs. Europe: Regulatory Differences directly impact regulatory submissions, risk assessment, and global market approval. While the USA uses a flexible, science-driven approach, Europe demands significantly more prescriptive and detailed evidence. ResolveMass Laboratories Inc. ensures full compliance across regions with advanced analytical capabilities, harmonized study designs, and strong toxicology support.
For expert E&L consultation, manufacturers are encouraged to reach out to ResolveMass.
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FAQs on Extractables and Leachables (E&L) Testing in the USA vs. Europe
E&L testing is mandatory because it ensures that harmful chemicals do not migrate from packaging, materials, or medical devices into drug products or patient-contact systems.
A complete E&L program protects patient safety, verifies material compatibility, prevents product contamination, and meets regulatory expectations for chemical safety. It also identifies extractables early, predicts potential leachables, and provides the toxicological evidence required for FDA, EMA, and MDR submissions.
Europe is generally stricter due to MDR, ISO 10993 expectations, and deeper toxicology requirements.
While the FDA and USP allow strong science-based justification, European reviewers expect more detailed unknown identification, lower reporting thresholds, and complete toxicological documentation. For medical devices in particular, the MDR framework demands extensive chemical characterization.
Yes, a single harmonized study can satisfy both USA and Europe if the study is designed properly from the beginning.
This requires using the strictest extraction conditions, solvent selections, AET levels, and toxicology requirements expected across both regions. Harmonized E&L studies reduce project timelines and avoid repeat testing for global submissions.
Yes, Europe accepts USP principles, but typically requires additional justification.
EMA and MDR reviewers often request more exhaustive toxicology, stronger identification of unknowns, and tighter analytical controls. USP is accepted as a baseline, but not always sufficient alone.
A full E&L program requires multiple complementary analytical techniques to detect all chemical classes.
Standard platforms include LC-MS/MS, GC-MS, ICP-MS, FTIR, Raman, and High-Resolution MS for organic and inorganic profiling. These cover volatiles, semi-volatiles, non-volatiles, metals, and unknown species.
Yes, medical devices and pharmaceuticals follow different regulatory pathways.
Drugs follow USP <1663>/<1664>, FDA, and ICH guidance, focusing on container-closure interactions. Devices follow ISO 10993-18, ISO 10993-17, and MDR, requiring deeper chemical characterization and toxicological justification. Combination products require both frameworks.
The Analytical Evaluation Threshold (AET) is the concentration above which any detected compound must be identified, quantified, and assessed toxicologically.
It acts as the reporting threshold for leachables and ensures that no clinically relevant chemical is ignored during analysis.
E&L testing should begin early in development—ideally during material and packaging selection.
Starting early allows identification of risky materials, prevents late-stage delays, reduces redesigns, and ensures the final formulation is compatible with the container or device system. Leachables testing continues through stability studies.
Toxicology assessments are performed by qualified toxicologists with expertise in exposure assessment and safety limit calculations.
Their role is to evaluate extractables/leachables profiles, derive PDE or TTC values, assess genotoxic risks, and produce a defensible toxicological risk assessment for regulatory review.
If a harmful leachable is detected, the risk is assessed, and mitigation steps are immediately taken.
This can include material replacement, supplier changes, adding barrier layers, reformulating the drug, or redesigning the device. After mitigation, confirmatory E&L testing is performed to ensure patient safety and regulatory compliance.
Reference
- Dr Balamurugan K VP:Extractables Leachables Testing in Pharma- Adapting to Latest Regulatory Changes,https://www.researchgate.net/publication/386228789_Extractables_Leachables_Testing_in_Pharma-_Adapting_to_Latest_Regulatory_Changes
- USP Chapters <1663>, <1664>, <661>, <663>. https://www.uspnf.com/pharmacopeial-forum.
- ISO 10993-18:2020(E), Biological evaluation of medical devices —Part 18: Chemical characterization of medical device materials within a risk management process. https://www.iso.org/standard/64750.html
- P. Booij and J. Creasey, Biopharma Asia (January, 2020). https://protect-us.mimecast.com/s/5ByTCL9R2RhnljLiq1kLN?domain=biopharma-asia.com/
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