02.15.08
Fast-Paced Device Development Outpaces Testing Standards
Orthopedic companies outsource to keep up with testing and biocompatibility requirements.
Cindy Dubin
Contributing Writer
By most estimates, the global orthopedic market is worth roughly $30 billion. And while more established sectors such as large joint have slowed growth recently, other areas such as orthobiologics, spinal and trauma are poised for impressive gains in the next five years. Growth is being fuelled by a number of well-known factors, including the aging population, the uptake of orthopedic surgery at an earlier age, problems due to the increasing incidence of obesity, the development of better and longer-lasting implants and materials, as well as new procedures—in particular, minimally invasive surgery. All these, coupled with evolving requirements from regulatory agencies, surely will impact the amount and kinds of testing and analysis performed by manufacturers looking to get their new products to market as quickly as possible.
Today, OEMs are relying more on the expertise of third parties to facilitate the testing process. Photo courtesy of Nelson Laboratories. |
With all the different standards out there, and very little consensus among them regarding the optimal procedures for ensuring products and components are safe and effective, it’s easy to see why testing can become a complex process for orthopedic manufacturers today. Therefore, one thing on which OEMs, testing companies and even regulatory bodies can agree is that something needs to be done to standardize the standards.
It’s the age-old chicken-and-the-egg question: Do standards need to be written to produce better products, or are new products needed before standards can be better written?
When initial testing methods were developed in the 1980s by ASTM, the more well-established testing laboratories all had internal standard operating protocols that were satisfactory and produced valid results but were different from each other, said Kenneth St. John, PhD, chairman of F04.16 on Biocompatibility Test Methods for ASTM and associate professor, Department of Biomedical Materials Science, Department of Orthopaedic Surgery and Rehabilitation, University of Mississippi Medical Center.
“None of the protocols [they were using] were wrong, and members agreed on the parameters that were important to control—and those that were important to include as a part of a report but not specify,” St. John said. Back then, he explained, it would have been inappropriate to develop standards that were “so narrow as to preclude scientifically valid methodologies with a history of valid usage.”
St. John did say, however, that an attempt was made to guide those who might consult the standards in the process of setting up new standard operating procedures, while not excluding historically valid protocols (that is, even though methods were established, many companies were using their own internal standards, and that was acceptable to ASTM). “This may sometimes mean that the standards do not provide sufficient guidance to those not experienced in performing the procedures. One recipe for all can be problematic, yet many of the newer labs say there is not enough of a recipe for them to follow,” he said.
“The only way to improve the standards is by reaching a consensus, which is a long and arduous process. ASTM needs a champion to make this happen,” said Kevin Knight, president, Knight Mechanical Testing (KMT) in Fort Wayne, IN. Why all the problems with achieving consensus on standards? Knight said he believes the problem is that orthopedic product innovation is outpacing the development of newer standards. “Medical device design evolves faster than the standards,” he explained. “Many parts of the tests [today] don’t even apply to a variety of the devices out there. Obviously, the standards need to be revised.”
One type of testing that could benefit from new standards, the experts said, is hip wear testing.
“We are going on 30 years of this type of testing in the market. The orbital bearing test, [for example,] has been used to generate supporting data for manufacturers and the FDA for approximately 70% of the hip products on the market, yet there is still no approved standard for this test. It is one of numerous de-facto ‘standards’ in the industry,” said Luther Johnson, senior product manager for Eden-Prairie, MN-based MTS, a company that manufactures products used to perform physical property tests. As patients receiving hip replacements increasingly are younger than previous populations, he said, it is essential that tests and standards be able to examine the technology and ensure it can sustain a longer wear life. Today’s testing processes can evaluate wear characteristics for implantation over 10 to 15 years—a reasonable duration for elderly implant recipients—today’s younger candidates for implantation will require a longer-lasting device to help them stay active, Johnson said.
Meeting Global Standards
As discussed earlier, companies that want to launch their products in various continents must meet myriad requirements set forth by each area’s regulatory bodies. Although ASTM and ISO 10993 testing standards generally are accepted by the United States, Europe and Japan, each country may have different requirements for how the tests are performed.
Therefore, many smaller companies will launch in their primary market first and then consider launching in other countries at a later date, explained Terry Langenderfer, director of marketing for NAMSA, a global contract research organization headquartered in Northwood, OH. “It comes down to an issue of time,” he said. “Start-up organizations have milestones that need to be met in order to attain funding. Therefore, time is critical and, often, they are not going to spend additional time and resources trying to simultaneously meet US, Japanese and European regulatory standards. Larger firms, however, tend to have global strategies and test programs designed to meet the regulatory submission requirements of several markets.”
Large or small, turnaround time is paramount to any customer, as all are under pressure to produce and get to market more rapidly. Unfortunately, there are times when studies simply cannot be modified to reduce the “in-life” time of an assay, for example. Keeping in mind the challenges OEMs face in getting products through the testing phase quickly, NAMSA has designed some efficacy studies in such a way that biocompatibility data can be obtained in support of safety claims—helping to shorten timelines.
“If we get involved with clients at the front end, in the R&D phase, we can usually create test strategies that speed up the design and validation process,” said Langenderfer. “Our ultimate goal is to minimize the amount of testing required to demonstrate the medical device functions as intended and [that the device] is biologically safe.”
Again, though, standards—and the lack of standardization across the board—can come into play, Langenderfer said.
“The regulatory submission process has its challenges,” he explained. “Reviewers might interpret standards differently. Because of the subjectivity inherent in the process, what is acceptable and cleared through one reviewer might raise significant questions by another.”
Making Testing and Analysis More Effective
When it comes to mechanical testing and analysis for orthopedic devices, contract service providers envision that new standards will focus on probabilistic statistical analysis of test data rather than the current rudimentary, deterministic approach.
“The methods of analyzing test data outlined in the current test standards rely on more of a pass/fail approach. But when you put statistics around the results, you get a better understanding of the data and more confidence in your product’s performance,” explained KMT’s Knight, whose company, an independent contract laboratory, performs static and dynamic mechanical testing on implants, instruments, raw materials and various components and assemblies.
“As the products get more refined, so, too, do the standards need to be refined,” agreed MTS Bionix’s Johnson, whose company’s testing solutions are used for knee, hip and spine products. “Our customers want to offer their clients as close a simulation of how the devices will work—from a strength, durability and kinematic perspective—when [they are] actually implanted.” To achieve proper results, the company’s test uses include wear simulation, biomaterial and fixation device testing, as well as joint and structure characterization—all meant to accurately reproduce the forces and motions of the device.
Johnson said that, ideally, testing would become closer to mirroring real life—a better representation of how the device will work in the body. “The orthopedic industry hasn’t achieved this like the automotive and aerospace industries have, but it is catching up,” he added.
Biocompatibility Testing Gains Ground
With the explosive growth in the orthopedic implantable device market, no testing would be complete without a measure of biocompatibility—particularly as implants increasingly last longer. But given the number of different processes used to manufacture today’s implants along with the bevy of new materials and coatings, biocompatibility testing comes with its own set of unique challenges.
An increase in wear-debris studies designed to measure the systemic effect of particles for devices used in articulating joints, and the growing demand for studies involving surface coatings applied to devices to improve bone integration, are some of the hot trends in biocompatibility testing right now, experts said. As the use of these tests grows, however, products with newer classes of metals, polymers, ceramics and tissue-engineered materials often intensifies the complexities related to biocompatibility testing.
Given these complexities, an increasing number of OEMs are turning to outside help to be sure the tests are performed correctly and effectively.
“Safety is a focus at Nelson. Our customers are looking to ensure that their product is safe from the moment of use to the end of use,” said Thor Rollins, biocompatibility subcontracting section leader at Salt Lake City, UT-based Nelson Laboratories. To this end, Nelson performs in house in vitro tests and subcontracts out its chronic, toxicity and in vivo testing. “We encourage our clients to take a more active role with biocompatibility at the beginning of their development process to save time in the long run and achieve their ultimate goal: FDA approval.”
When it comes to biocompatibility testing, OEMs look for partners who have a record of success and experience.
“When we elect to outsource biocompatibility testing, we select vendors that have a proven record of such testing,” said Shilesh Jani, group manager, Advanced Bearings and Technology for Smith & Nephew Orthopaedic Research and Innovation in Memphis, TN. “We ensure that the vendor is appropriately certified for such testing, eg, GLP and ISO certifications, [and] the biocompatibility of medical implant materials must be conducted according to ASTM and ISO standards.”
The amount of biocompatibility testing conducted by Wright Medical Technology, Inc. has increased significantly in the last two or three years, according to Jon Moseley, PhD, technical director, Implant Technology, for the Arlington, TN-based company.
“Wright works with several companies that specialize in biocompatibility testing for medical devices,” said Moseley. The contract laboratories that it employs have handled that increased work without a noticeable loss in service or turnaround time, he added. Certain types of biocompatibility testing may be used in the early stages of development, especially if new materials or processes are involved. The testing used for a regulatory submission, however, must be conducted on materials or devices that meet the specifications of the final product.
For each class device, obviously the types of biocompatibility testing that are required vary considerably depending on the product classification and whether novel materials are used. Wright Medical has developed new materials that require a full range of biocompatibility tests according to ISO 10993-1 guidelines. This includes tests for cytotoxicity (ISO MEM elution and colony forming assay), sensitization (Kligman), intracutaneous irritation, systemic toxicity, implantation, pyrogenicity (LAL and in vivo) and genotoxicity (reverse mutation, chromosomal aberration and mouse micronucleus assay). New devices that employ well-characterized biocompatible materials and existing processes generally require less comprehensive testing, Moseley said.
Partnerships Help Get the Job Done
Whether it is biocompatibility, functional or mechanical testing, clearly many OEMs are relying more on the expertise of third parties to facilitate these tests. Even OEMs that perform these tests in-house often find that they go the route of a contractor when the situation calls.
Smith & Nephew, for instance, performs routine testing and evaluation in-house for materials and processes used in the company’s orthopedic reconstruction and fixation products (among others) that employ well-characterized materials (ie, those that have extensive history of clinical use) but turns to outside help for more complex projects or when internal teams are overloaded. “If we are constrained [by] available resources, we will typically seek out contract test facilities,” said Jani. “Occasionally, our requirements may require tests in which we have limited expertise and experience, in which case we will search for a test facility that best meets our needs.
“On some projects, we know from the outset that we will require outside services, either because of constrained internal resources or because of lack of internal expertise. On some projects the need for outside resources may arise during advanced stages of development,” Jani added.
Overall, relationships with third-party testing facilities are key to Smith & Nephew’s overall testing process. “When we need to complete urgent evaluation on tight deadlines, without compromising the timeliness of testing already underway in-house, these relationships can make the difference between launching a product on time and delayed launch,” Jani continued. “The skills and expertise of third-party test facilities are sometimes unique and often augment our own abilities in the specific area. So the relationships can serve to expand our knowledge and expertise. On some occasions, it helps that the testing was outsourced to an independent facility—allaying fears of bias.”
The extent to which Wright Medical relies on outside providers depends entirely on the type of testing required, explained Moseley. For example, the majority of mechanical testing and analysis work is done in-house, with only occasional use of a third-party provider when capacity issues arise. (The company also sponsors biomechanical research through several academic laboratories that have specific expertise, Moselely said.) In contrast, the majority of biocompatibility testing and sterility evaluations are performed by contract research facilities that specialize in those areas.
“We do have internal facilities for conducting limited cell culture research and endotoxin assay (eg, LAL), but all testing conducted according to GLP guidelines is contracted,” he said.
Chemical and physical testing are somewhere in between. Analytical techniques—eg, scanning electron microscopy, FTIR spectroscopy, X-ray diffraction and differential scanning calorimetry—that are heavily relied upon are conducted internally. Analyses that are only needed occasionally, and which require specialized equipment or expertise, are contracted to laboratories with validated methods.
“For testing that is only required occasionally, there is a huge cost benefit to using outside providers,” explained Moseley. “Many tests require expensive equipment and support facilities, as well as technicians and researchers with specialized knowledge. Unless you are utilizing those facilities continuously, it is difficult to justify the expense of setting it up internally. The same logic applies to temporary capacity issues with mechanical testing.”
There also can be a benefit in terms of providing a level of independence to the testing. For example, Wright Medical conducts biocompatibility testing through contract laboratories that are recognized for their integrity and for the quality of their work, and which are certified to conduct GLP-compliant research. This can be important both from a regulatory standpoint and in cases where legal issues could be raised, such as in product complaints.
“Depending on the type of service, we may use outside providers at any stages of a product’s lifetime. Chemical and physical testing are often relied upon early in the development cycle, while compiling data for a regulatory submission, during process validation or in analysis of a complaint or device retrieval,” Moseley said.
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Regardless of who is performing testing on products today, as standards for biocompatibility, testing and analysis continue to evolve, the orthopedic industry must sit tight and await more straightforward approaches as to how to perform these tests. ASTM is doing its part to make that happen more rapidly, St. John said. In particular, the standards development organization is relying more on electronic communication to solicit comments on standards to reach agreement faster, rather than meeting once every six months.
However, St. John admitted that “while testing standards will continue to evolve to keep up with new devices, there will always be a time lag.”