The science of extractables and leachables (E&L) testing for medical devices is evolving quickly, as are the associated regulatory standards. In fact, change sometimes happens so quickly that the approach that was defensible when you started your program may not be defensible by the time it reaches a reviewer’s desk.
We see this pattern across dozens of submissions and labs every year. Companies typically aren’t failing because they lack technical capability. Rather, they’re falling behind because expectations are moving, and most E&L programs are built to meet yesterday’s standards.
Here’s what we consistently see going wrong and what it takes for you to get ahead of it.
The Pace of Change Is the Real Challenge
When we ask teams what’s hardest about ISO 10993-18 chemical characterization, the answer is rarely a specific technical requirement.¹ It’s keeping up.
Smaller MedTech companies with fewer devices in the market see fewer regulatory questions, which limits their exposure to evolving practices. On the one hand, that seems like it might be a good thing. However, they’re not getting the real-time feedback that larger companies receive, so they don’t see the shift in expectations until it shows up as a delay or a deficiency letter.
The result is reactive compliance instead of proactive strategy. And reactive compliance is expensive.
Pattern 1: Meeting Minimums Without Scientific Defensibility
Most E&L programs we review fall short in that they meet minimal expectations but lack strong scientific backing. FDA reviewers are asking increasingly granular questions about extraction methods, storage conditions, and quantification approaches.² These aren’t trick questions. They’re testing whether your program is built on a defensible scientific foundation or if you’re just checking boxes.
The programs that hold up under scrutiny go beyond the minimum. They document method capabilities, justify method selection based on device chemistry, and demonstrate how their analytical approach covers the relevant chemical space. That extra rigor builds trust and reduces future pushback.
Pattern 2: Underestimating the Shift Toward Identification Confidence
The Analytical Evaluation Threshold (AET) is well understood at this point.³ But the next big challenge is building confidence in chemical identification itself. We expect upcoming revisions to ISO 10993-18 to place even greater emphasis on identification accuracy.4 The question regulators are asking is “How confident are you that you found the right thing?”
This is because of a shift toward more precise and reliable identification as a core regulatory expectation. And this is across the board — not just for high-risk devices.
Pattern 3: Quantification Gaps That Surface Too Late
The other side of the accuracy equation is quantification. Multiple programs run into trouble because a significant portion of chemicals observed in extractables studies cannot be matched with empirical standards.
Sometimes the reference standard simply doesn’t exist. Sometimes synthesis is impractical. Either way, you’re left with a gap that shows up in your risk assessment.
This is where a risk-based E&L strategy becomes essential. Predictive response factors for E&L can fill part of that gap, using chemical properties to model instrument responses for tentatively identified compounds. That improves quantification accuracy without waiting for empirical data that may never come.
But predictive modeling isn’t a magic fix. It works for tentatively known compounds, but complete unknowns still require chemist expertise to identify chemical class or structure before modeling can be applied. The keys are knowing when prediction is appropriate and documenting that rationale clearly.
Notably, Lumo™ needs a structure to work from, but the precision of that structural identification is less critical to quantification accuracy than it would be under traditional approaches.
Pattern 4: Treating ISO 10993-18 as the Only Moving Target
It’s vital to understand that the changes aren’t limited to ISO 10993-18.
USP chapters on extractables and leachables assessment are evolving.5,6 Industry working groups are publishing new recommendations, and FDA interpretations are shifting based on what reviewers see in real submissions.² Companies that focus narrowly on a single standard often miss the broader pattern and end up navigating conflicting expectations without a clear strategy.
The companies that stay ahead treat E&L as a system, not a checklist. They partner with labs that understand the full landscape and can adapt quickly as expectations shift.
What “Modernized” Actually Looks Like
We’re not suggesting that every program needs to be rebuilt from scratch. But we are suggesting that “good enough” conservative defaults aren’t good enough anymore.
A modernized E&L program:
- Applies more rigorous testing where toxicology indicates higher risk, not uniformly across all materials
- Documents method capabilities and true accuracy assessments for each study
- Uses predictive modeling where empirical standards are unavailable and documents the rationale
- Treats early design decisions as upstream factors that influence downstream E&L outcomes
- Partners with a lab that understands the rapid pace of change and can adapt with you
The science supports better outcomes than most programs currently achieve. The question is whether your program is built to capture them.
Frequently Asked Questions
Stay Ahead of the Curve
This blog covers the patterns we see most often. But the full picture — including how predictive modeling works, where it fits in a risk-based strategy, and how to document defensibility for regulators — requires more space than a blog allows.
We’ve put together a guide for you that goes deeper on all of this, including the specific changes in ISO 10993-18, the quantification and identification challenges that trip up submissions, and the practical steps to modernize your approach.
References
1. International Organization for Standardization. (2020). ISO 10993-18:2020 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
2. U.S. Food and Drug Administration. (2023). Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and
3. Norwood, D.L., Paskiet, D., Ruberto, M., et al. (2006). Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations. https://pubmed.ncbi.nlm.nih.gov/18183477/
4. International Organization for Standardization. (2026). ISO/CD TS 25364-1 Chemical characterization of medical devices — Part 1: Identification of organic extractables in Non-Targeted Analysis (NTA). https://www.iso.org/standard/90930.html
5. United States Pharmacopeia. (2023). USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems. https://doi.usp.org/USPNF/USPNF_M7126_03_01.html
6. United States Pharmacopeia. (2023). USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems. https://doi.usp.org/USPNF/USPNF_M7127_03_01.html
