Rigorous fatigue testing, wear testing, in-vitro testing and particle characterization are some of the procedures that medical device, orthopedic companies in particular, are asking for—especially regarding wear debris from metal-on-metal devices (knee, hip) and other modular implants.

A study director weighs a crucible for gravimetric analysis as part of a residual manufacturing materials test. Photo courtesy of Nelson Labs.

“Wear testing requires complex equipment capable of simulating anatomic conditions, which makes testing more expensive,” said John McCloy, president of Accutek Testing Laboratory, a Fairfield, Ohio-based firm that provides mechanical testing and engineering services for the medical device and other markets. “Few manufacturers sell wear test equipment and even fewer testing organizations have the capability to build it in-house. The actual testing process involves minute amounts of wear that can be difficult to accurately characterize. Other factors that may influence results are test fluid recipe and preparation, cleaning and weighing methodology and test fixture design.”

ADMET, a Norwood, Mass.-based provider of material testing machines, is seeing more demand for axial-torsion, dynamic and low-force testing equipment for biomedical research. “These tests cover a variety of medical testing applications and are needed to keep up with the constant development of technology in this sector,” indicated Vinny Milano, account director for the biomedical and testing lab sectors for ADMET.

When it comes to concept and design, more orthopedic manufacturers are taking human factors engineering and testing into account—both as a way to improve performance and meet or exceed FDA requirements.

“The application of usability engineering is quickly becoming a critical aspect of medical product development and is given equal importance with other development activities,” said R. Reade Harpham, manager of human centric design for Battelle, a Columbus, Ohio-based firm that conducts human factors studies for medical device companies. “The FDA expects to see clear evidence that an organization has planned and implemented robust human-factors activities that include involvement from the earliest stages of usability research through validation testing, and all tied directly to product risk.”

Other procedures requested by OEMs include extractable and leachables testing (for medical devices as well as packaging and process materials) and regulatory testing, including supporting 510(k) submissions for premarket approval.

“Requests involving sterilization and cleaning devices, as well as combination drug-medical devices, are also increasingly common,” indicated Daniel Prince, president of Gibraltar Laboratories Inc., a Fairfield, N.J.-based provider of extensive testing and consultation services to the medical device market. “One of the biggest challenges is determining what category these combination devices fall into per the FDA and then meeting the necessary regulatory requirements.”

Kyle Copeland agreed. Copeland is a senior technical consultant at Polymer Solutions, an independent testing laboratory in Blacksburg, Va., that works with medical device testing companies.

“Clients often need to look for changes in the polymer structure due to sterilization, which could include reduction in molecular weight and generation of unexpected compounds,” he said. “In some cases, sterilization can lead to cross-linking of the material, which makes analysis more difficult since the sample will no longer dissolve. However, just the fact that unsterilized is soluble while sterilized is not indicates the process is affecting the material.”

Polymer Solutions also helps clients with failure analysis—including prototypes, failed parts that didn’t make it to production and explants from live subjects. Safety is a huge concern for producers and all failures must be examined thoroughly.

“Failure analysis is always customized, as each client has unique challenges,” continued Copeland. “This type of analysis has the potential to utilize microscopy, wet chemistry, spectroscopy, thermal and physical testing.”

Copeland noted it’s critical to have a known good part for comparison that shows what the properties, such as molecular weight, should be. The other key to failure analysis is having the client provide as much information as possible. “This includes things like is the failure limited to a single lot of resin, were any changes to the process, or does the issue occur seasonally,” he said. “All this information helps direct us to the answer.”
 

New Materials, New Technologies
OEMs continue to look for, and experiment with, new materials and testing methods that will improve device function and reduce risk. This, however, may increase device complexity, as well as cost. For example, in addition to complex drug/device combinations, products made from biological materials also are being registered as devices. This can lead to a certain degree of regulatory uncertainty, which usually requires more complex testing.

“When you’re dealing with a device that may include biologically derived materials, there is always an extra concern about potential interaction with the patient,” indicated Aaron Burke, director of business development for Pacific BioLabs, a Hercules, Calif.-based firm that specializes in good laboratory practice (GLP) regulatory studies for medical devices related to patient safety. “Certain devices are more challenging in determining the testing needed, based on the composition and use of the device. For instance, a device that includes biologically derived materials may not withstand sterilization using traditional methods, and may require engineering runs and testing to determine what sterilization method is effective and does not negatively affect the function of the device.”

The wide range of materials that contract testers encounter on a daily basis makes sample preparation, instrument calibration and changeover efficiency critical for meeting production timelines. For example, some of the most difficult compounds to work with are those that are cross-linked or otherwise difficult to dissolve, such as ultra-high molecular weight polyethylene (UHMWPE).

“For UHMWPE and other challenging compounds, many of the techniques we utilize rely on getting the sample into solution; if that route is blocked, we lose many of the analytical approaches that provide the most information,” said Copeland. “Usually these materials are chosen for particular properties that make them much more attractive for the given application compared to other, more easily tested materials. In addition, the documentation required for high-consequence work is substantial. We must be extremely diligent in these areas to remain cost-effective and to provide quick turnaround times.”

New combination products continue to be designed with increasingly complexity. These designs often include bioabsorbable materials, drug coatings, drug-eluting devices, embedded polymers, antimicrobials and inclusion of tissue products and derivatives. Although these products and materials perform well, sterilization validation, sterility assurance and biocompatibility testing can be challenging. Test methods often require special product preparation, neutralization or modified sterilization validation techniques to ensure reproducible test results.

Assessment of residual manufacturing materials on devices and implants is becoming more relevant as manufacturers use a greater variety of manufacturing and cleaning processes for devices prior to patient use. Residual manufacturing materials are any materials on the final product that are not intended to be part of the product. This includes metallic remnants from machining processes, oil residues from processing, soap residue from cleaning or decontamination processes, mold-release agents and microorganisms from the manufacturing process or environment.

“Occasionally manufacturing processes add materials to the manufactured device which must be removed through cleaning, sonication or other means,” said John S. Bolinder, chief strategy officer for Nelson Laboratories, a Salt Lake City, Utah-based provider of microbiological and analytical test services for medical device companies. “For example, a patient who receives a knee implant that is not free of residual manufacturing material may have post-implantation issues. These may range from basic infections and soreness due to natural body reactions to foreign material (other than the implant itself) to more severe complications like particulate matter that enters the bloodstream forming clots, causing strokes or heart attacks. Manufacturers have a responsibility to ensure that implanted devices are free from residual manufacturing materials that may cause adverse events. Validation of these processes is necessary to ensure the device contains no residual manufacturing materials.”

ISO 10993-18 continues to be adopted in phases as many companies and service providers assess more materials for leachable and extractable content using analytical methods according to this guidance—especially polymers, colorants and metals used in the manufacture of medical devices.

“Many manufacturers are choosing to differentiate their product on the market with unique or novel color schemes with the use of colorants in polymers,” added Bolinder. “However, we are seeing an increased incidence of biocompatibility failures in cytotoxicity assays where a colorant has been used. In simulated use extraction assays the colorant is leaching from the polymer causing an adverse toxicological result. Cytotoxicity is a very sensitive assay and several studies on polymer materials with and without a colorant have demonstrated that certain colorants can leach out of the product, causing an adverse reaction.”

Some OEMs are seeking nanoparticle analysis, especially the identification and quantitation of particles generated from device components. This presents a unique challenge—in addition to measuring the size and quantity of particles, the chemistry also must be identified to ensure that contamination has not occurred.

“There are many possible types of nanoparticles and uses,” said Copeland. “I expect that custom methods are going to be required. Right now we are focusing on identification and quantitation, more than behavior. The function of nanoparticles is a vast and rapidly evolving field, so we will need to tackle these requests on a case-by-case basis.”

As more products incorporate delicate materials, such as small fibers (optical, silicon carbide, carbon, plant and nano fibers) and biomaterials (muscle fibers, hydrogels, tendons and tissues), OEMs are requesting low-force, high-resolution testing solutions for these products.

“Initially we were approached by several major players in the medical industry to build a custom low-force system,” said Milano. “Since then we have applied this technology to a number of other low-force biomedical research projects.”

ADMET provides voice-coil solutions for low-force, high-speed testing that are highly suited for high-frequency, low-displacement tests of tissues, such as native and bioprosthetic heart valve tissue. Other solutions include linear motor testing systems for high-speed, high-force testing of medical implants, especially hip and spine.

Product improvements, however, don’t always have to be the result of new technology or advanced materials—sometimes standard products and materials, when analyzed from the human factors viewpoint, can be redesigned to provide higher performance. More device companies are asking for human factors activities that are risk-based and conducted under a robust quality system, following all the relevant consensus standards and guidelines. This is a paradigm shift from the industry assumption that human factors (HF) testing is simply a marketing activity designed to gauge user preference.

“HF activities must focus on human performance rather than human preference,” said Harpham. “For example, asking a patient ‘which device do you like and why?’ provides great insight for marketing purposes, but should not be considered human factors testing. Because they must be tied to evaluating risk, HF activities seek to understand if the end-user can perform the task required, such delivering medication within a specific time, or setting the controls correctly ona system.”

Battelle recently worked on a system that required medication to be delivered within a specific amount of time, under stressful conditions. The operation of the device could not be changed because it was already a FDA-approved product.

“All we had to work with were the instructions for use,” said Harpham. “From our initial testing with the existing system, 50 percent of users were able to complete the medication delivery task within the allotted time. Leveraging some of our cognitive psychologists, we were better able to understand how people follow instructions while in stressful situations. This helped guide the design team to re-design the instructions to take these cognitive issues into consideration. After testing the improved instructions, 100 percent of users were able to complete the task.”

Reducing Cycle Time
The sense of urgency and pressure to launch new OEM products—and to start providing a return on R&D efforts—is ever-increasing. Many OEMs are challenged themselves by the timelines they have established. Coordinating all aspects of development and testing for device developers is, in many cases, akin to a juggling act. When OEM timelines become compressed or shifted, the burden of meeting testing deadlines is passed along to testing firms in the supply chain.

Pacific BioLabs recently purchased an analytical chemistry and bioanalytical laboratory, adding to its existing in-vivo and in-vitro capabilities. “Having an analytical department pairs well with our GLP toxicology and drug development services, as well as with our device development testing, as device material characterization and packaging leachables and extractables are increasingly requested by clients,” said Burke. “When projects require input from more than one department, there are definite benefits. When everyone understands the whole process of testing, and knows the timelines and how their work fits in, things run more smoothly and clients are happier.”

Another way to reduce cycle times is simply improve communication and collaboration in the earliest phases of product development, so everyone is on the same page.

“It is good practice for OEMs to solicit input from their testing lab during the product design phase,” McCloy noted. “We can often predict mechanical failure based on a design flaw. More often than not, we are proven correct during the testing phase. These failures are often remedied by a design change that, when made early in the process, saves time and money during the development process.”

“Accurate and reliable testing during the development phase is considered an added value because critical issues can be identified much further upstream and quickly corrected,” agreed Corey D. Hensel, general manager for DDL Inc., an Eden Prairie, Minn.-based provider of package validation and product and material testing services. “For example, a client needed to make material choices on a recent project. A prototype of the part was functionally tested and experienced failures. It was found that key dimensions were adversely affected by the sterilization process. This quick verification helped the manufacturer avoid a costly surprise further downstream and allowed the final product to get to market faster at a cheaper cost.”

Over the last year, DDL has explored other ways to decrease project turnaround time. It discovered that a big factor in decreasing turnaround times is putting extra effort into the sales process.

“We work closely with customers early on to ensure that both parties are clear on project needs, timing, deadlines and any issues related to test standards,” added Hensel. “It’s all about the mutual need for clarity. In some cases, we’ve helped customers cut off a few days from their project timeline and in others it has been more than a week after understanding test specimen availability and timing.”

NAMSA, a full-service medical research organization in Minneapolis, Minn., that provides contract medical research and testing services to the medical device industry, creates cross-functional teams that span the entire development process for its clients.

“This has allowed us and our clients to integrate as many of the activities as possible and create new opportunities to parallel-path activities,” said Chris Pulling, vice president of NAMSA. “The result is hitting the client’s major milestones sooner, which often releases more funding to the company as it reduces or eliminates risk. This is especially true for venture-backed start-ups. Some companies we work with have as many as four or five such milestones, just in the course of a human clinical trial. This places more emphasis than ever before on speed, efficiency and results.”

Pressure to Perform
Clients continue to push for lower and lower detection limits on compounds of interest. Both the FDA and the general public are more aware of the health risks of low levels of foreign materials in the body, such as BPA (bisphenol A) or metal particles from implants.

“Analysis techniques are getting more and more sensitive, which allows the regulatory bodies to require lower and lower detection limits,” indicated Copeland. “This is especially relevant in our chromatography laboratories. We must be very aware in the early stages of constructing a testing plan to account for the need for low detection limits. Planning for low detection limits must be a part of the entire testing procedure, starting with how the samples are stored and shipped, including the early testing steps of sample preparation and the choice of detector.”

Then there are regulatory demands.

“Clients are constantly in need of assistance or guidance due to the growth of regulations and technology involved in the development and expansion of new products and product lines,” said Prince. “This often involves reworking previous programs to take into account these technological leaps. However, equally important is the need to understand the new technology and the risks and benefits of the new innovation. This is critical to development of new testing strategies.”

For clinical trials, the FDA has clearly raised the scientific standards, especially for 510(k) products. “Our job moving forward,” Pulling told Medical Product Outsourcing, “is to figure out new ways of doing things that meet these higher standards, but not necessarily add cost and time to the testing.”

“While more stringent regulations help to ensure safer products, those same regulations act as a barrier to entry for medical device startups,” added Copeland. “As a result, testing needs to become faster and more reliable to keep that entry barrier as low as possible without sacrificing quality. It is up to us, as an independent testing lab, to provide testing that is cost efficient to the manufacturer with quick turnaround times. A cost-effective and time-efficient third-party testing lab can significantly aid medical device manufacturers as they seek approval.”

Interestingly, as demands for contract testing increase, the number of labs available to handle the increased workload actually has diminished.

“The past five years have seen consolidation in the testing industry with a number of acquisitions and labs closing up shop,” said McCloy. “Consolidation, coupled with increased operational overhead, has left the testing industry with less availability.”

Quite simply, there are fewer independent, ISO-17025 accredited laboratories than before to do the work that OEMs need—all the more reason for existing labs to maximize efficiencies and streamline their OEM relationships.

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Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. He also writes a variety of feature articles for regional and national publications and is the author of five books. Contact him at mark.crawford@charter.net.