Chemical Analysis in Medical Device Biocompatibility Assessment (DRAFT)
This guidance provides recommendations for conducting chemical analysis as part of biocompatibility assessment of medical devices. It focuses on extractables studies methodology to: 1. Screen for unspecified extractables or test for specified extractables to evaluate certain biocompatibility endpoints in conjunction with toxicological risk assessment 2. Support chemical equivalency comparison to devices with previously demonstrated biocompatibility The guidance applies generally to medical devices but acknowledges that some device types may require different methods based on materials or established approaches.
This is a draft guidance. Not for implementation.
What You Need to Know? 👇
What are the key extraction conditions recommended for medical device biocompatibility testing?
Extraction conditions should provide worst-case exposure estimates using polar and non-polar solvents. For limited contact (<24h), use exaggerated extractions. For prolonged (1-30 days) and long-term (>30 days) contact, use exhaustive extractions with multiple solvent polarities and NVR analysis to demonstrate completion.
How many extraction replicates should be performed for chemical characterization studies?
Triplicate extractions are recommended for each solvent unless otherwise justified. This is particularly important for chemical equivalence studies, devices with potential variability, or when other data suggests product variability. Use the highest amount from any replicate as worst-case exposure estimate.
What analytical techniques are recommended for extractables profiling?
Primary techniques include GC-MS for VOCs/SVOCs, LC-MS for SVOCs/NVOCs, and ICP-MS for elemental constituents. High-resolution MS is recommended. Use ESI in positive/negative modes for LC-MS, with complementary techniques like UV, CAD, or ELSD to improve compound detection.
What identification confidence levels are required for toxicological risk assessment?
Confident or confirmed identifications are recommended for TRA. Tentative identification requires library match plus expert review. Confident identification needs library match plus orthogonal supporting data. Confirmed identification requires authentic reference standard verification with supporting analytical data.
How should the Analytical Evaluation Threshold (AET) be calculated?
Use the equation: AET = D×DBT×A/(B×C×UF), where D is dilution/concentration factor, DBT is dose-based threshold, A is number of test articles, B is extract volume, C is clinical exposure, and UF is uncertainty factor. Default UF of 4 for GC-MS is acceptable.
What information must be reported for identified extractables above the reporting threshold?
Report retention time, chemical name, CASRN, structural descriptor, major ions (m/z), identification data types, confidence level, amount in µg/device, quantification method, and reference standard used. For tentative identifications, report all plausible candidates. Include supporting identification information for unknown extractables.
What You Need to Do 👇
Recommended Actions
- Gather comprehensive information about device materials, components and manufacturing process
- Design appropriate extraction study based on:
- Device contact duration category
- Selection of extraction solvents
- Number of replicates
- Extraction conditions (temperature, time, volume)
- Implement analytical testing strategy including:
- Multiple complementary analytical techniques
- Appropriate calibration and controls
- Adequate sensitivity relative to reporting thresholds
- Chemical identification with justified confidence levels
- Document and report:
- Complete method details and justifications
- All extraction conditions and observations
- Chemical identities and quantities above reporting threshold
- Supporting data for identifications and quantification
- Consider need for:
- Additional targeted analysis for specific compounds of concern
- Device-specific testing approaches
- Supplemental studies to refine exposure estimates
- Evaluate results in context of overall biocompatibility assessment strategy
Key Considerations
Non-clinical testing
- Conduct extractables studies using appropriate extraction conditions based on device contact duration
- Use multiple extraction solvents of different polarities
- Perform triplicate extractions unless otherwise justified
- Demonstrate exhaustive extraction has been achieved when required
- Characterize any particulates observed in extracts
Biocompatibility
- Chemical analysis can be used to evaluate certain biocompatibility endpoints in conjunction with toxicological risk assessment
- Consider device characteristics and intended use when determining testing needs
- Chemical characterization is one approach within overall biocompatibility assessment strategy
Safety
- Identify and quantify extractables above the analytical evaluation threshold
- Investigate presence of cohort of concern compounds even below reporting thresholds
- Achieve confident or confirmed identification levels for toxicological risk assessment
- Justify sensitivity of analytical methods is adequate
Other considerations
- Provide complete test reports with method details and results
- Include information on device materials, components and manufacturing
- Document and justify all extraction conditions and analytical methods
- Report chemical identities and amounts with appropriate confidence levels
- Consider additional device-specific guidance when applicable
Relevant Guidances 🔗
- Use of ISO 10993-1 for Biological Evaluation and Testing of Medical Devices
- Biological Evaluation of Medical Devices Standards in the Accreditation Scheme for Conformity Assessment (ASCA) Pilot Program
Related references and norms 📂
- ISO 10993-1: Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
- ISO 10993-17: Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents
- ISO 10993-18: Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process
- ISO 10993-12: Biological evaluation of medical devices - Part 12: Sample preparation and reference materials
- ISO/TS 21726: Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents