Toxicological Risk Assessment (TRA):

• Using chemical data to assess risks associated with systemic toxicity (acute, subacute, chronic), genotoxicity, carcinogenicity, and reproductive toxicity.
• Substantiate biocompatibility through non-animal testing when combined with a robust TRA.

Chemical Equivalency Comparisons:

Comparing a modified device with a previously approved version to demonstrate that changes in materials, suppliers, or processes do not negatively impact safety or effectiveness.

Extraction Conditions:

• Use exaggerated conditions (e.g., high temperatures or prolonged durations) to ensure a worst-case scenario evaluation. For example, a cardiac stent intended for long-term use might be immersed in saline at 50°C for 72 hours. This exceeds typical body conditions (37°C) to simulate worst-case scenarios and identify potential chemical leachables.
• Tailor the choice of solvent to reflect a range of polarities (polar, non-polar, and semi-polar). For example, water, hexane, and alcohols may be used depending on the material composition of the device.

Test Article Preparation:

• Ensure that the test article mimics the final, finished device, including any sterilization or packaging processes.
• Avoid destructive preparation methods such as cutting or heating unless justified.

Replicates and Pooling:

• Conduct triplicate extractions for each solvent unless pooling multiple devices is required for analytical feasibility (e.g., for small devices).
• Use the highest measured extractable concentration across replicates for worst-case exposure calculations.

Detection Methods:

• Employ a combination of techniques, such as gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and inductively coupled plasma-mass spectrometry (ICP-MS), to capture a comprehensive range of chemical properties.
• Use non-targeted analysis to identify unexpected chemicals, followed by targeted analysis to quantify substances of known concern.

Sensitivity and Calibration:

• Ensure detection limits (LOD) and quantification limits (LOQ) are below the AET.
• Use authentic reference standards (i.e. highly purified, well-characterized chemical substance) to calibrate equipment and provide accurate quantification.

Exhaustive Extraction Endpoint:

• Demonstrate extraction completeness by tracking the reduction in non-volatile residue (NVR) across successive extraction cycles until less than 10% of the initial residue remains.

Methodological Details:

• Provide complete descriptions of the extraction and analysis methods used, including solvent choices, temperatures, and durations.
• Justify any deviations from recommended protocols.

Test Results:

• Include raw data such as chromatograms, calibration curves, and spectra to support reported findings.
• Summarize all identified extractables with their concentrations and associated confidence levels (e.g., tentative, confirmed).

Device-Specific Context:

• Clearly define how the test article represents the device in its final form, considering size, surface area, and manufacturing processes.