Challenging the Database: Day-of-Analysis Calibration and UF Modeling for Reliable RRF Use in Medical Device Chemical Characterization

Accurate quantitation during chemical characterization─also referred to as extractables and leachables (E&L)─within a toxicological risk assessment for medical device biocompatibility hinges on the appropriate application of relative response factors (RRFs). This study investigates the variability of RRFs across a chemically diverse set of compounds and evaluates the implications of quantitation model selection on analytical outcomes. Using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), we demonstrate that RRFs are highly context-dependent and influenced by factors such as ionization mode, compound class, concentration, and instrument conditions. We propose an approach to RRF determination, emphasizing day-of-analysis calibration and uncertainty factor modeling to improve reproducibility. Our findings support a statistically grounded application of analytical evaluation thresholds, enhancing the reliability of semiquantitative assessments in medical device biocompatibility.