In March of this year, the U.S. Food and Drug Administration (FDA) released new draft guidance¹ that outlined the type of information that should be included in premarket submissions for orthopedic non-spinal bone plates, screws, and washers. The draft guidance aims to clarify information in 510(k) submissions for Class II orthopedic non-spinal, non-resorbable medical devices including bone plates, screw systems, standalone bone screws, and washers for bone fixation.

The draft’s recommendations cover indications for use, device description, predicate comparison, labeling, sterility, reprocessing, pyrogenicity, shelf life and packaging, biocompatibility, MRI compatibility for passive implants, and non-clinical testing. It also contains a section about device modifications that could warrant a new 510(k) submission.

Devices in the guidance’s scope are those made with titanium alloy, commercially pure titanium, stainless steel, cobalt-chrome alloy, polyetheretherketone (PEEK), and chopped carbon fiber reinforced. Devices not included in the scope are those made with nitinol, devices that are coated or resorbable, have surface modification, incorporate antimicrobial agents, have complex geometries, differing granularities, unique geometric features, involvement in unconventional surgical techniques, that are additively manufactured, or have “other unique technological characteristics,” according to the FDA.

FDA recommended avoiding vague language and clarifying appropriate use whenever possible. Submissions for devices intended for use in osteopenic bone should have a comparison to a similar device in the same anatomical area for a similar indication, while devices meant for osteoporotic bone may need further information on simulated implant use to be considered for an indication. FDA said devices should be identified using regulation numbers contained within the guidance, and the agency recommended including pictures for bone plates and screws in the submission and engineering pictures for all devices. Some devices are special cases and require further information, like those using PEEK.

All 510(k) submissions for these medical devices should also have a comparison to a similar predicate device, and whether any similarities and differences could possibly impact safety and effectiveness. Labeling should satisfy requirements from 21 CFR part 801 with information on device description and use, contraindications, warnings, magnetic resonance safety information, cleaning and sterilization instructions, and removal instructions.

“For devices provided sterile, you should provide a description of the packaging, including how it will maintain the device’s sterility, a description of the package integrity test methods, but not the package integrity test data,” FDA wrote. “We recommend that package integrity test methods include simulated distribution and associated package integrity testing, as well as simulated (and/or real time) aging and associated seal strength testing, to validate package integrity and shelf life claims.”

This FDA regulatory guidance is merely one of the medical/orthopedic device industry trends affecting testing and analysis service and equipment providers. In order to get more information on other medical device/industry trends affecting device testing and analysis, ODT spoke to the following experts over the past few weeks:

• Ed Arscott, RM (NRCM), principal strategy consultant-microbiology at NAMSA , a medical contract research organization (CRO).
• Richard Brown, vice president and principal engineer at Engineering & Quality Solutions, a Colorado Springs, Colo.-based consulting firm to support medical device projects.
• Eunhee Cho, scientific director—biocompatibility at NAMSA.
• Stephen Doherty, head, analytical chemistry of preclinical medical device development at Labcorp, a Burlington, N.C.-based global laboratory services company.
• Andrew Gottfried, director, North American sales at Eurofins Medical Device Testing.
• Chris Parker, head, in vivo biocompatibility of preclinical medical device development at Labcorp.
• Bryce Telford, bioburden, microbiology, and sterilization expert at Nelson Labs, a Sotera Health company based in Salt Lake City, Utah, that provides microbiological and analytical chemistry testing and advisory services for the medical device and pharmaceutical industries.
• Victoria Trafka, president and principal engineer of Engineering & Quality Solutions.
• Don Tumminelli, senior technical manager, client services at HIGHPOWER Validation Testing & Lab Services, a Rochester, N.Y.-based validation and testing laboratory serving the medical, dental, pharmaceutical, and industrial industries.
• Thaddeus Williams, head, efficacy and surgical research services of preclinical medical device development at Labcorp.

Sam Brusco: What types of testing and analysis do orthopedic device makers usually outsource, and why?

Ed Arscott: Manufacturing cleaning analysis for orthopedic implants per ISO 19227 – verification testing to support cleaning and residual toxicity for implants. Radiation sterilization validations for implants compliance with ISO 11137-2, and reprocessing validations (manual cleaning, automated cleaning, and steam sterilization) for reusable instruments and sterilization tray sets for compliance with AAMI ST98 and AAMI TIR12 and FDA guidance.

Richard Brown: We still see a lot of clients outsourcing what we consider to be the required basic mechanical testing for spine devices such as ASTM F1717, Spinal Implant Constructs in a Vertebrectomy Model for Pedicle Screw systems and F2077 and F2267 for intervertebral body fusion devices (IBFDs). The reasons for the outsourcing vary by client. Sometimes the client has no test facilities to perform the mechanical testing, sometimes the client has test facilities but not necessarily the experience with the type of testing that must be completed, or enough experience to handle more complex geometries of newer device designs.

Additionally, we are now seeing a need for outsourcing for ASTM F3574 for sacroiliac (SI) joint devices, which was released in June 2022. Because the standard is so new, not very many labs are familiar and confident enough to carry out the testing with valuable and limited test specimens.

Eunhee Cho: Ortho device makers do not have a testing lab capability or toxicologists to perform a toxicological risk assessment (TRA) of chemical characterization results. They may have biocompatibility SMEs like biocompatibility scientists/engineers, so developing an overall biocompatibility eval strategy and protocol/report can be done internally.

Stephen Doherty: Chemical characterization conducted in accordance with 10993: Part 18 is often outsourced. Device makers will look to work with companies with experience in this testing and the requirements, as well as the specialized instrumentation and methods needed. Outsourcing this testing has the advantage for manufacturers in that outsourced companies have significant experience in data interpretation necessary to get the most comprehensive information and compound identification to support a successful toxicological risk assessment in accordance with 10993: Part 17 to provide the needed context for the analytical data.

Andrew Gottfried: The range of testing required by the orthopedic device industry is very broad, including mechanical, chemical, biocompatibility, electrical safety, human factors, and microbiological testing. Each of these requires specialized equipment, skill sets, and sometimes environmental controls, which require significant resources to establish and maintain. As manufacturers weigh the costs and benefits of outsourcing any of this testing against making the investments to perform testing in-house, the primary driver often turns out to be demand. It is very difficult to justify the costs needed to build and maintain a competency in any one of these areas if the testing is only needed once per month, or even once per week. In these cases, it will almost always be more effective to partner with an outside laboratory.

Bryce Telford: It seems most laboratory testing is outsourced for ortho devices (bioburden, sterility, endotoxin, packaging, biocompatibility). The manufacturer focuses on design, engineering, and making the product but laboratory testing is usually specialized.

Victoria Trafka: Device makers commonly outsource finite element analysis (FEA) due to its unique nature, which requires specialized software, advanced computer capabilities, and a high level of experience and expertise. Additionally, over the past several years, the FDA and ASTM have created multiple guidance documents and standards applying to use of FEA for spinal and orthopedic devices. This effort added analysis and reporting requirements and raised the bar for proving FEA models and results are valid. These requirements may be difficult or cumbersome to navigate, so outsourcing to an expert makes sense in many situations.

We recently worked on a foot plating system where FEA and testing was outsourced by a company that had a well-equipped internal test lab. In the system being developed there were 25 different plate designs and the geometries were very complex. The complex geometry meant the plates didn’t fit well into the applicable test standard—ASTM F382 Standard Specification and Test Method for Metallic Bone Plates—which is written for a more generic straight plate. So, they outsourced determination of the worst-case device for testing, test fixture design, and mechanical testing. The worst-case plate was identified using FEA and the test fixtures were designed using alternate configurations. Extensive experience with the test standard, allowable deviations, and an understanding of physiologically relevant conditions were required to successfully develop a test strategy.

Don Tumminelli: When it comes to reusable device testing such as validating the sterilization process, biocompatibility, and disinfection, many ortho companies will use a contract lab with the experience. Due to the very specialized and complex nature of testing, most ortho companies don’t have the infrastructure and/or degreed personnel to perform these types of validations. For instance, a sterilization validation requires a degreed microbiologist trained in aseptic technique. Similarly, with biocompatibility, the many different analyses required involve both analytical chemists and microbiologists following FDA GLP requirements. Most ortho companies don’t have these resources or real estate to put these types of labs in place. Using a contract lab allows them to stay focused on what they do best.

Brusco: In what ways are innovative materials for orthopedic devices affecting testing and analysis strategies?

Arscott: New materials must be demonstrated as stable with a specific sterilization modality (radiation, ethylene oxide, or other novel sterilization process). New materials may need uniquely different cleaning techniques and processes specifically designed for their material compatibility.

Brown: With the increasing use of additive manufacturing (3D printing), material selections for use with additive manufacturing continue to expand. The design capabilities of additive manufacturing—along with new material selections—are pushing the boundaries of standard test methods for fixturing. The implants are becoming more porous with the intent of providing for better osseointegration, utilizing trabecular structures. These structures are being increasingly used for entire implants, and are rough when compared to a standard, machine-finished implant. Something as simple as a rough surface on the exterior portions of an implant creates the need for new fixturing strategies in order to properly contact and restrain the devices for mechanical testing.

Cho: Biodegradable implants have been a trend for many ortho companies. (I am personally unaware of biodegradable metal implants for ortho applications.) Degradable polymer-based or degradable biomaterial implants are either available or there are more coming. This type of product requires a degradation study to demonstrate the product degradation profile/kinetics through a defined degradation mechanism and potential hazards of degradation products over time. Implant studies with histopathology over the course of product degradation time must be performed and it’s common to perform long-term implant toxicity studies. Chemical characterization and TRA become more complex to explain E&L as well as degradation products’ toxicological risk acceptance over time.

Antibiotic incorporation into implants (e.g., bone cement) is another material innovation. The presence of antibiotics can cause false positive results in genotoxicity.

This is not truly material innovation, but there’s a regulatory challenge to injectable devices for pain management. Although injectable devices for pain management are commercially available already as medical devices, FDA challenges the same product intended for a new application site to be on IND and (A)NDA. Although there are a few overlapping biological evaluations (systemic toxicity, genotoxicity), the medical device manufacturer does not have expertise in such a submission pathway and should outsource the work to a CRO.

Doherty: Resorbable materials can present special challenges. This can include difficulties extracting the device as it dissolves in some solvents, which may be the intended mode of operation. This may prevent the typical device extraction and extract analysis process from being done. Analytical analysis of the solubilized material may be utilized, which would typically represent a worst-case scenario. However, this can also present analytical challenges with the respective methods. Most of these challenges can be overcome but for more novel materials and devices, additional timing may be needed. This can also be a good time to solicit comments from regulatory bodies if testing strategies may deviate from the norm.

Gottfried: As novel materials are introduced by the industry, the testing requirements become more comprehensive. The path to market for establishing equivalency to a similar titanium and polyethylene device will be much more straightforward than a device manufactured from a novel material. A risk analysis must consider every way a new material may behave differently in use and provide sufficient test data to ensure safety and effectiveness. Regulators will also scrutinize well-known materials if they are processed in a different manner than the predicate device, such as switching from a traditional machining or injection molding process to 3D printing.

Telford: Innovative could mean that you are the first to try something out. That means material compatibility, microbial compatibility, and biocompatibility are all unknown. That also tends to mean there is less experience and more trial and error. For testing and analysis strategies, that generally means more testing and associated time and cost for that testing.

Tumminelli: New materials and coatings are always a challenge. With the popularity of 3D printing also comes challenges to validating material compatibility, durability, and the device’s end of life. If the device is reusable, multiple cycles of reprocessing should be completed to assure these new materials and coatings hold up to the environments they’re subject to over repetitive uses.

Brusco: What recent regulatory/quality initiatives are affecting orthopedic device testing and analysis?

Brown: The ASTM specifications for testing are continually being updated and new ones added. One of the newer releases is ASTM F3574, Standard Test Methods for Sacroiliac Joint Fusion Devices, released in June 2022. Being a newer standard, it’s caused companies to utilize outsourced testing until they can get their internal labs caught up with ready to perform the testing internally.

Gottfried: Orthopedic companies find regulatory agencies place greater emphasis on lab-generated data integrity. The expectation of regulators is data records and systems are established in a way that prevents any opportunity for data to be compromised by human error. Many companies struggle to meet these expectations, particularly as more and more data is managed by electronic systems that require an additional layer of dedicated IT resources to maintain.

Tumminelli: The MDR in the EU has really challenged many companies to meet compliance deadlines with reclassification of some devices and the UDI (Unique Device Identifier) compliance. As many companies scramble to meet requirements, they may find out some types of UDI labeling are not holding up at end of life, throwing them back to the drawing board for another labeling process. The most interesting type of labeling that has surprised many is laser etching, which has been found to have many variables that need to be assessed to be compatible with the requested modality of cleaning and sterilization. Finding out after multiple cycles of reprocessing that UDI is not legible could cost a company months of lost time.

Trafka: FDA has been collecting device test performance data from regulatory submissions for years and has recently started releasing aggregated data via publications and guidance documents. Some examples are orthopedic fracture fixation plates, non-spinal metallic bone screws and washers, and spinal plating systems. These documents and data provide minimum performance values for specific device tests, which may eliminate the need to physically test a predicate device; instead, a new device can simply be tested and the results compared to FDA published data. However, since the data is aggregated, there are certainly devices previously cleared that fall below these values and were found substantially equivalent. So essentially, using published data instead of testing against a single predicate sets a higher standard for device performance. It may also cause difficulties when working on a design change for an existing device that was cleared and launched with lower test result values.

Brusco: What trends in the medical/orthopedic device industry as it pertains to testing and analysis do you anticipate having to address soon?

Arscott: 3D manufacturing provides custom devices (both implants and instruments) to be designed for specific patients and assist the surgeon in providing better outcomes. This may involve new or modified cleaning and sterilization methods for these processes and materials.

Cho: It is well known the medical device industry will continuously have high demands of chemical characterization and TRA. This can be truer to ortho companies because they have catch-up to do. Many ortho companies have not had sufficient biocompatibility data, especially a gap in chemical characterization and toxicological profile because they’ve had a history of safe use of materials (especially for metal products) as a rationale for a long time, or relying on cleaning validation results for risk assessment and justification of not performing biocompatibility testing. The recent regulatory requirements change (MDR) pushed ortho companies to evaluate the existing/already marketed products with chemical characterization and TRA, as well as new products in development.

Doherty: The use of chemical characterization as part of medical device testing continues to expand, from both the initial approval stage through product lifecycle, especially related to material or component changes as part of a change control or risk mitigation process.

Gottfried: More companies are critically assessing their business models and determining their core competencies lie in designing novel products that meet unserved clinical needs, as well as manufacturing and selling those products. They find the costs and resources needed to maintain true competency in testing is not feasible, and making strategic decisions to outsource that work.

Telford: There is a trend toward making devices more patient-specific and less generic. In other words, more tailored to individuals. That’s challenging what is considered a batch and classical sampling. A broad definition of a batch is uniform in character and quality during a defined cycle of manufacture. When a single device is tailored to the patient, that defined cycle of manufacture may be one single device. That is and will continue to be a challenge, as many of the standards and regulations are based on “classical” manufacturing of many identical units.

Trafka: ASTM committees are actively working on updating current testing standards and developing new test standards and, once released, device companies will need to understand and incorporate these tests into development projects. One example is a new test standard in the works for spinal cage impact testing. The development of this standard was initiated by FDA representatives as a result of FDA data indicating device issues caused by impact. Therefore, it’s very likely the FDA will place a high priority on testing and compliance once the formal standard is released.

Tumminelli: Many ortho companies have decided to validate their instrument sets in both a wrapped and rigid container configuration for sterilization. This allows them to market their device to a broader range of healthcare facilities. The same has been true for validating multiple methods of cleaning the devices. Many companies have been validating both a manual and an automated way to clean the devices, once again giving more choice to the healthcare facility when it comes to reprocessing.

Thaddeus Williams: The FDA is looking for more toxicology endpoints, which include incorporating other safety testing and assessments that includes toxicology. There are also more visuals of implant sites and photo micrographs, which we have been proactive in incorporating into study designs. 

Reference

1. bit.ly/odttesting09231