MPMN_Medical Product Manufacturing News

Medical Product Manufacturing News, September/October 2015

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M E D I C A L P R O D U C T M A N U F A C T U R I N G N E W S Q M E D . C O M / M P M N 1 8 S E P T E M B E R / O C T O B E R 2 0 1 5 W hile there are many obstacles on the path to U.S. regulatory acceptance and validation of in vitro irritation and sensitization models, much progress has been made in developing a medical device specific irritation model. Every medical device manufacturer must conduct the "Big Three" biocompatibility tests for cytotoxicity, irritation, and sensitization, or provide justification for why the tests were not performed. Cytotoxicity testing is performed in vitro, while irritation and sensitization tests are currently conducted in vivo on guinea pigs and rabbits — something industry is working to change. Moving to in vitro testing for sensitization is important because the most common test is the guinea pig maximization test. This test is expensive, has a high animal burden, and can take up to nine weeks to complete. In an effort to minimize the time and cost of these tests, and to reduce animal testing, alternatives like in vitro irritation and sensitization testing are being developed. Even with irritation testing, cost and turnaround time could be dramatically reduced with widespread adoption. The Road to In Vitro Irritation Method Approval In vitro irritation is already widely accepted in Europe for chemicals and cosmetics. Currently, the medical device industry experts are collaborating to develop an extractable positive control for in vitro irritation testing which may correlate to U.S. regulatory acceptance. European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) has done much of the legwork in creating and validating a plan for in vitro irritation testing of cosmetics. The medical device industry endeavors to now incorporate ECVAM's validation into a medical device specific validation. U.S. FDA has indicated that they want a validation to show that a response can be derived via extraction in the form of a positive control before it will approve in vitro sensitization and irritation testing. In other words, FDA would like proof that extraction methods can pull off enough irritants to cause an irritation response. Validating for in vitro can be difficult because, by design, few medical devices contain irritants or sensitizers. While in vitro skin irritation test methods have historically produced results consistent within vivo data, they have involved the use of chemical solutions, or spiked extracts, as positive controls. To provide a method that more accurately mimics validated in vivo medical device test methods, in which devices are extracted in polar and non-polar solvents, in vitro research has focused on finding an extractable material that will induce a positive skin irritation response in both solutions. Nelson Laboratories' recent discovery that heat- pressed polyvinyl chloride (PVC) sheets infused with Genapol X-080 act as an irritant in both polar and non-polar fluid is a major step toward regulatory acceptance. Nelson Laboratories presented its findings and validation data at the 2015 Society of Toxicology (SOT) annual meeting. Regulatory response to the data, which indicates in vitro results are in line with in vivo results, was positive. How Is In Vitro Testing for Irritation Performed? In vitro irritation testing is performed by using human-derived epidermal keratinocytes (NHEK), also known as reconstructed human epidermis (RhE). The RhE is cultured in such a way as to form a multilayered, highly differentiated model of the human epidermis. Medical device extracts or chemicals are then applied to the epidermis to predict irritation by conducting an MTT cytotoxicity test. The RhE closely mimics the biochemical and physiological properties of the human epidermis. To acquire the extract to be applied to the epidermis, medical devices are put into polar and non-polar media, allowing elements to be extracted for epidermal testing where irritation can be tested. Current in vivo irritation testing is performed by extracting leachables from the device in a polar and non-polar medium. That resulting extraction is then injected intracutaneously into rabbit test subjects. Redness and/or swelling would indicate an irritation response, which is ranked according to the level of irritation to determine whether or not the device met the standard. In more than 30 years of testing, what we have observed at Nelson Labs is that most medical device materials are safe and have a low probability of causing an irritation. However, device residuals, like detergents and chemicals from the manufacturing process, may cause an irritation response. Should the in vitro irritation method gain regulatory approval in the U.S., we believe it would essentially function as an irritation screening process. If irritation is observed in vitro, an animal test would be a secondary verification of that failure. Currently, the cost and turnaround time for in vitro irritation testing is comparable to the cost and time involved with in vivo testing. However, cost and turnaround time could be dramatically reduced with widespread adoption. What About In Vitro Testing for Sensitization? The in vitro sensitization test is not as well defined in the industry as the in vitro irritation model. EURL ECVAM is in the process of validating this in vitro method. Nonetheless, the issue is that the in vitro sensitization test requires observation of multiple biomarkers to assess sensitization. A scientist performs in vitro skin irritation testing of medical device extracts. Better Animal Testing A L T E R N A T I V E S Are Coming to U.S. Progress is being made when it comes to moving away from guinea pigs and rabbits, and developing lab-based tests acceptable to FDA. Thor Rollins, Nelson Laboratories SPECIAL FEATURE: TESTING Reconstructed human epidermis (RHE) provides an accurate and reliable test system for in vitro skin irritation and sensitization testing.

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