2023 FDA Science Forum
Alternative Solvents for Non-Targeted Extractables Analysis of Blood Contacting Medical Devices
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Contributing OfficeCenter for Devices and Radiological Health
Abstract
When medical device materials are subjected to extraction, extractables, including impurities, processing additives and material breakdown products may be released. These extractables have potential consequence on the biological response to the device during its use. Chemical characterization analyses of extractables are followed up with toxicological risk assessments, which evaluate potential harm from exposure to the extractables.
The standard ISO 10993-18:2020, which describes chemical characterization approaches, includes the statement “Based on published research, 40 % (by volume) mixture of ethanol/water is considered an appropriate surrogate for blood and blood related substances…”; however, the published research on this approach relies on very few material-extractable systems. This can be of concern since unreliable extraction systems can underestimate concentrations of extractables, leading to incorrect conclusions or greater uncertainties in toxicological risk assessment.
The goal of this study was to evaluate considerations for creating and justifying alternative solvents for non-targeted extractables analysis of blood contacting medical devices. We explore two approaches: 1. Create simpler simulators of blood with complex protein content that can be used in extractables studies; 2. Create simple solvents that may act like blood in certain extractables studies. A panel of extraction solvents from simple solvents, such as iso-propanol or 40% ethanol/water, to aqueous albumin solution, and blood is being pursued. A panel of medical device and material extracts (e.g. polycarbonates, polyurethanes, hemodialyzers) are being analyzed with an UHPLC/UV/CAD/MS system (Dionex Ultimate 3000, Dionex Corona Ultra RS, Agilent 6540B UHD QTOF-MS, UHPLC/MS with Agilent 1290- Agilent 6495C QQQ-MS) and data generated for UV, CAD, MS and MS/MS signals. Methods were customized for certain extractables in complex extraction solvents however, screening is also performed. The initial data indicated that, binding of medical device extractables to protein containing solutions such as albumin solution can be measured. The preliminary observation is that the total DEHP bound to Albumin was on the order of 0.4 µg/mg Albumin. This ongoing work continues to expand comparison of specified extraction solvents, conditions and verifying with all LC based analytical methods. This work will be a significant step toward reducing overestimation of the toxicological risk due to exhaustive/exaggerated extraction methods.
