EMDT_European Medical Device Technology

European Medical Device Technology, Spring 2014

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50 | Spring 2014 European Medical Device Technology emdt.co.uk materials The Risky Role of Extractables and Leachables in Dialysis Treatment Medical device engineers must understand possible polymer degradation products that can be released into body tissue, blood or organs during dialysis and cause serious complications. D ialysis treatment has been optimized to the point that, in Japan, more than 80,000 patients have been undergoing dialysis therapy three times a week for more than ten years 1 . Yet despite the treatment's track record, dialysis systems pose a threat to patients through the leachables and extractables that can originate from the polymers in the tubing, syringes and filters that make up the extra- corporeal blood circuit. Extractables, of course, are chemicals that are generated under exaggerated temperature and time conditions in the presence of an appropriate solvent. Leacha- bles, on the other hand, are chemicals that migrate spontaneously from a container- closure system, from packaging compo- nents and/or from processing equipment under recommended or routine conditions of use and storage. Leachables are often a subset of extractables. The Threat The extracorporeal blood circuit used for dialysis therapy is engineered from polymers commonly employed in medical applications, such as polycarbonate, sili- cone, polypropylene, polysulfone and poly- urethane. During clinical application, these polymers are exposed to bodily fluids, such as plasma or whole blood. In addition to blood cells, both human and animal blood contains water, elec- trolytes, proteins, hormones and enzymes (Table 1). Because of these compounds, both blood plasma and whole blood are able to wet any biomaterial, independ- ent of its chemical composition—whether hydrophilic, hydrophobic or possessing an amphiphilic, domain-like surface. Blood components offer an ideal envi- ronment for extracting substances from bulk polymers, such as oligomers or bio- degradable compounds. Bodily fluids, thus, possess ideal solvent-like properties. Consequently, leachables generated through this process may accumulate in the body, particularly in the bodies of patients with long-term exposure to the polymers. For these reasons, the 2009 edition of ISO 10993-1 recommends that manufacturers consider extractables and degradation products during the biological evaluation process of their medical devices 2 . Problems always arise in regards to how to simulate the extractive capacity of blood at its best, however. An answer is provided by ISO 10993-12 3 . It reads: "The solvent selected as extractants shall: a) be suitable for use in the specific biological test system b) simulate the extraction which occurs during clinical use of the device and/or c) maximize the amount of the extract." The following media for extraction are suggested; one per type should be subsequently and not exclusively used in an extraction experiment: 0 Polar solutions (water, saline [0.9% NaCl in water], culture media without serum). 0 Nonpolar solutions (vegetable oil). 0 Additionally: Polyethyleneglycol (PEG 400), dimethylsulfoxide (DMSO), cul- ture media with serum. My own experiments have shown that an ethanol/water mixture of 17.5% has proven optimal for simulating the extraction capacity of whole blood towards polymers in medical devices. Furthermore, a practical guide and scheme for testing medical devices is provided in ISO 10993-17 4 . Real-Life Examples of Clinical Events A series of reports from recent literature have shown that extractables may provoke adverse clinical sequaelae. In the 1980s, for example, leachable ethylene oxide (EtO) after gas sterilization of medical devices, mostly dialyzers, induced severe allergic reactions in hypersensitive patients. Physi- cians defined these reactions as "first-use syndrome" as they disappeared after either a careful rinsing or after reuse of the filter. ISO 10993-7 refers to EtO residuals 5 . Jörg Vienken, Nephro-Solutions, Hamburg, Germany Leachables may accumulate in the body, particularly in the bodies of patients with long-term exposure to the polymers. ES433751_EMDT1405_050.pgs 05.01.2014 21:49 UBM black yellow cyan

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