Designing a set of reference standards for non-targeted analysis of polymer additives extracted from medical devices.

Background: The accurate analysis of extractables and leachables (E&L) from medical devices is crucial for the reliable safety risk assessment of substances to which patients and users may be exposed. The extractable profile of medical devices is often complex and unpredictable, thus improper selection of reference standards can lead to irreproducible chemical analyses between laboratories. ISO 10993-18, the international consensus standard for chemical characterization of medical devices, does not specify a process for selection of appropriate chemical reference standards for non-targeted analysis of E&L, leading to a variety of approaches being used.

Objective: This study seeks to set out requirements for building a comprehensive list of chemical reference standards for non-targeted analysis of E&L and propose suggestions for selecting appropriate standards to enhance the consistency of chemical analysis.

Methods: Criteria for selecting reference standards for non-targeted analysis of E&L in medical devices were developed using relevant polymer additives as a model system. The Relative Response Factor (RRF) values of the selected reference standards were determined using GC-MS and LC-MS analysis across three different concentrations. A system was developed to rank the toxicological hazards of the selected reference standards.

Results: A list of 106 reference standards of polymer additives was compiled, encompassing a wide range of physicochemical properties and broad toxicological coverage. Statistical analyses of these chemicals revealed there was no significant correlation between their six physicochemical properties and the corresponding relative response factors measured by GC-MS and LC-MS techniques.

Impact: Accurate chemical identification and quantification of extractable substances from medical devices is important for chemical characterization of medical devices. The accurate quantitation of extractable chemicals in medical devices through non-targeted analysis is dependent on the proper selection of reference standards. We have proposed a set of reference standards intended to enhance the confidence in quantitation of device extractables, covering a broad range of structural and physicochemical diversity. This set of reference standards may assist chemistry laboratories in developing robust screening methods for extractables in medical devices, supporting the accurate characterization of medical devices.