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Medical Product Manufacturing News, March/April 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 2 2 M a r c h / a P r i l 2 0 1 5 sPecial feature: oRTHopedIcS Welcome to the orthopedic device Jungle orthopedic device makers might need a machete to cut through the thicket of uncertainty in the industry. Brian Buntz m aking orthopedic devices is anything but straightforward these days. while most orthopedic devices are made of common metals, plastics, or ceramics, it can be difficult to establish their long-term biocompatibility because it is not feasible to do long-term trials to gauge how they react in the human body over time. "there is no such thing as a 20-year animal study before an orthopedic device is approved for human use," John s. Bolinder, vice president of marketing and communications at nelson Laboratories (salt lake city; www.nelsonlabs.com), said at Md&M west. "we are learning as we go with orthopedics in clinical use." one of the most prominent examples of this learn-as-we-go dynamic is the metal-on-metal hip implant, which, when it debuted, was vaunted as having improved wear resistance over prior designs. initially cleared by fda via the 510(k) pathway and the ce Mark system in europe, metal-on- metal hip implants were thought to be substantially equivalent to hip implants already on the market. But several recalls and billions of dollars worth of lawsuit settlements later, metal-on-metal implants have emerged as a kind of case study about what can go wrong when orthopedic companies test new product ideas. in this case, as many as half of such hip implants had to be replaced after six years due to metallosis and other complications, according to the guardian newspaper in the uK. similar issues with osteolysis have occurred with ultra- high-molecular-weight polyethylene for total knee arthroplasty. as a result of the metal-on-metal hip implant fiasco, the regulatory bodies have become more risk-averse with regards to orthopedic implants in general and are continuing to rethink their approach to deeming products to be safe. another challenge for the sector is the precision required to produce orthopedic components. Many parts are machined from hard metals such as titanium or stainless steel—operations that require a very specialized skillset to do well. as a result, many orthopedic companies rely heavily on third-party manufacturers to perform such operations and have little to do with the actual manufacture of their own products. often, the oeM ends up being something like a contract packager, putting together the various pieces during the final manufacturing step for surgical kits and implants used in orthopedic procedures. in cases like this, it can be difficult for oeMs to maintain solid process controls over the production process when a considerable amount of it is performed outside their own facilities. the result is that regulatory agencies such as fda and the British standards institution (Bsi) have been coming down on orthopedic device makers for poorly managing their contract manufacturing operations and are frequently deciding to audit them. it all means that orthopedic device companies face plenty of challenges in the new regulatory environment. and although a device may be described as 'substantially equivalent,' the manufacture of the device may vary. the following sections highlight examples that are especially worth noting. messy machining the machining and milling that are widely employed to produce orthopedic implants are messy operations. in the process, shavings from the metal can fly off, and after the procedure is over, the product is still coated with an aqueous or oil-based residue from the cutting fluids that are used in the machining process. other contaminants include microbiological and particulate debris. failure to remove these manufacturing residues and contaminants can cause big problems for patients. also worrisome is the particulate debris itself caused by the machining process. in some machining facilities, metallic particle debris is visible in the air from machining, polishing, and finish processing. in some cases manufacturers fail to use an air or water wash to clean these products after deburring and put them directly into the final packaging. "sometimes, you can actually see metallic flakes in the packaging," Bolinder says. for patients receiving implants with metallic particle debris on them, major problems can arise. "for instance, i read an article about eight years ago about a patient with a metal knee implant who died from a stroke two weeks later," Bolinder says. "why? several complications, including infection and particulates coming off the device, entering the cardiovascular system, and ultimately causing his heart to stop." it is imperative to know the cleanliness of the devices in their finished state. anything on the device, but not intended to be part of the device, is a problem. Patients receiving an implant with metallic debris face a similar fate as those who received metal-on-metal implants. Both create contamination once they go into the body. "any time you get particulates in the bloodstream, you have a problem," Bolinder says. Metal shavings are problematic because metal doesn't metabolize. "once it gets into the body, it doesn't get out. so a patient starts building up a toxicity level, developing systemic toxicity issues, or experiencing device failure and discomfort when the metal contributes to wearing within a joint and adhesion issues with tissue at the implant site." Water System Risks while using a water system to clean machined orthopedic products can help protect patients, there has also been a recent uptick in fda citations related to orthopedic firm's use of such systems, since water can be a source of endotoxin. in addition, it is difficult to maintain strict change control over a firm that is machining orthopedic parts. "a machine shop working on orthopedic parts is kind of like a machine shop making auto parts—they are working on engines, rods, and various other things. their volumes are ebbing and flowing and their product range is constantly changing," Bolinder says. "But they are using the same water bath, the same processes, and the contamination is changing." in either case, machine shops likely don't have dedicated pieces of equipment for certain types of parts, which would help them keep better track of potential contamination, whether it be a cutting fluid or a detergent used in the process. "You really have to assess all of the process changes that occur as their manufacturing changes day to day," Bolinder says. "can you really do a one-time end-point validation test to make sure the product is safe when the manufacturing process is constantly changing? Manufacturers need to understand and control their processes, or those of their third-party partners, to ensure additional contaminants are not introduced due to process variability." moving Regulatory Goalposts another challenge is that orthopedic firms must have a solid understanding of fda's changing expectations, some of which are now ambiguous. even seemingly basic criteria such as the cleanliness of medical device components are undergoing fda review. "one thing we are facing right now has to do with the uncertainty around a guidance document the fda released nearly two years ago in april 2013," says thor rollins, biocompatibility specialist at nelson laboratories. titled "use of international standard iso- 10993, 'Biological evaluation of Medical devices Part 1: evaluation and testing,'" the document was the first guidance on the subject since 1995. "this new draft guidance had a lot of things that fda was enforcing but hadn't released guidance around," rollins remarks. "there were a couple of things that scared us though. two of them specifically had the potential to impact orthopedic companies." A technician performs a limulus amebocyte lysate (LAL) test, which may soon be required for orthopedic implants. iMage: nelson laBoratories

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