To keep pace, testing services must evolve with their own new technologies. “Although medical device testing will still require traditional standardized methods, non-standardized customized protocols for testing are increasing the necessity to address specific clinical questions or potential risks of a new technology,” said Lisa Ferrara, CEO and owner of OrthoKinetic Testing Technologies, a Shallotte, N.C.-based provider of medical device and tissue testing.
Other services medical device manufacturers (MDMs) expect from their testing partners are assistance with protocols and study designs, guided by a well-defined forensic approach toward engineering and failure analyses—from design through production and packaging.
“Testing equipment helps measure the quality of medical devices at many different stages of the manufacturing process, ranging from the raw material stage to the finished products and assemblies,” said James M. Clinton, product manager for Force and Material Test Products, an L.S. Starrett Company in Athol, Mass., that manufactures force and material testing and metrology equipment.
Most companies are keenly focused on being ready for MDR (re)certifications in May 2020—many are not as far along in their preparations as they had hoped. Their “last minute” needs regarding compliance to the MDR are stressing the testing market, with labs scrambling to keep up with demands for certain tests, such as extractables chemistry for toxicological risk assessment. Also, with new submissions, ISO 10993-1 and ISO 14971 are placing emphasis on applying a risk-based approach when evaluating biocompatibility of a medical device.
With increased medical device and regulatory complexity, “more testing services are trying to differentiate themselves by offering a full-service, turn-key approach for medical devices, which can be a challenging task,” said Ferrara. “It requires having experienced personnel with significant expertise in multiple areas of medical devices including regulatory, manufacturing, engineering, basic science, tissue mechanics, and clinical translational medicine.”
The advent of new biomaterials, surface technologies, smart materials, and smart systems, with structures that range in size from macro to nano, can significantly impact the requirements for what needs to be tested, and by what method (perhaps requiring advanced equipment and expertise). More rigorous testing is not necessarily a bad thing—for example, newer technologies that require more testing also allow more control with increased measurement precision during each test, which can actually reduce costs and lead times.
“It is essential to assess the entire system—the device plus the delivery system plus the software—and implement test strategies and protocols that validate the entire system as a whole,” said Ferrara.
Designing parts and components for the medical device industry requires extremely high levels of accuracy. Production errors are costly. Stringent regulatory requirements—and the expensive costs of failing to meet standards—ensure components are safe, fully functional, and reliable. Advanced testing software and the Internet of Things can help MDMs achieve these standards. For example, to simplify quality management and improve accuracy, manufacturers are choosing sophisticated force measurement and metrology systems to test the components they make. “Force measurement software for example, can provide a comprehensive analysis of a measurement test—providing exact force measurement results from simple peak load measurement to more complex break determination,” said Clinton.
By exporting measurement data through USB or wirelessly across Bluetooth, manufacturers can access data far beyond the basic figures provided by other force measurement approaches. “Inputting the requirements of a part, material, or component allows the software to generate high-resolution graphs based on load, distance, height, and time of measurement,” said Clinton. “Historical test data is archived and available for analysis at a later date, helping speed up future tests and navigating potential problems or errors.”
Testing methods and approaches continue to be shaped by regulatory changes. At the end of 2019, the Association for the Advancement of Medical Instrumentation (AAMI) completed a new Technical Information Report (TIR 76), Entitled “Sterilization of Health Care Products—Radiation—Substantiation of a Selected Sterilization Dose at a Specified Sterility Assurance Level: Method VDmaxSD-S.” “This document allows a company to optimize the sterilization dose so it corresponds exactly to its bioburden count, or the company can select a sterilization dose slightly or significantly higher, depending on the specific need of company and product,” said Martell Winters, director of scientific competency for Nelson Labs, a Salt Lake City, Utah-based provider of testing for medical devices.
Another new document from AAMI, TIR 104, provides additional guidance on transferring a product from one irradiator to another within the same modality, or from one modality of radiation to another—for example, from gamma to electron beam or vice versa. “The guidance will provide further guidance on carrying out this process, whether the transfer is to make a long-term change or to rationalize a backup for sterilization processing,” Martell added.
Another change that will impact testing is the publication of the newly updated ISO 10993-18 for chemical characterization of medical devices. “This revision will provide further detail on the extractables and leachables testing, which had previously been designated as a required step in the workflow of biocompatibility testing,” said Christopher Scott, vice president for Eurofins Medical Device Testing, a Lancaster, Pa.-based provider of testing services for medical devices.
What OEMs Want
OEMs want high quality, ease of use, low costs, and especially, speed to market—which means having well-thought-out testing protocols. For example, the adoption of ISO 80369 by the FDA as the recognized consensus standard for medical connector testing in place of ISO 594 “has many companies working to address the required changes before the FDA stops accepting ISO 594 testing,” said Matt Pasma, test engineer for DDL, an Eden, Minn.-based provider of package, product, and materials testing for the medical device and pharmaceutical industries. “Although the FDA has extended the deadline and not yet announced a new one, we continue to see demand for testing with both standards.”
There has been a significant increase over the past year in requests for extractables/leachables (E&L) testing. The use of a chemical characterization approach, in combination with a toxicological risk assessment, whenever applicable, has greatly reduced the number of animals used in the testing—for example, systemic toxicity endpoints. This has reduced the cost and turnaround time for the valuable data needed for regulatory submissions for medical devices that are in prolonged or permanent contact with the patient.
OEMs are also asking for a guaranteed path to regulatory acceptance. Even with the abundance of published documents by multiple agencies and governments, the path can be a bit different for every device and/or every agency. “We focus on building good working relationships with the regulatory agencies around the world to ensure we understand current expectations and can have open dialogue regarding important devices that require unique assessments prior to going to market,” said Audrey Turley, senior biocompatibility expert for Nelson Labs.
Ultimately, OEMs want to find testing partners who can provide the necessary expertise and services that will lead to a smooth, successful submission.
“They want honest expertise and feedback to test efficiently and correctly and that we will have their back at the end if there are questions,” said Matthew Jorgensen, senior E&L expert for Nelson Labs. “The current expectation is worlds away from just three years ago, when a customer would simply order a palette of tests. Today, OEMs want an expert that can truly partner with them throughout the planning, execution, and submission process for their medical devices.”
New Technology Advancements
In-vitro testing is a very hot topic in the realm of biocompatibility. The push toward identifying adverse patient responses via an in-vitro platform will make animal models obsolete. “We are discovering that in-vitro models are more predictive of an actual human response than animal models,” said Turley.
In-vitro irritation tests use reconstructed human epidermis cells to predict irritation from medical devices instead of the standard rabbit test. Extractable and leachable tests can also help determine risks for genotoxicity, systemic toxicity, and carcinogenicity.
“The biggest limits for these new tests revolve around regulatory acceptance,” said Thor Rollins, toxicology and E&L expert for Nelson Labs. “Regulatory bodies are asking for excessive validations on these new in-vitro test methods, even though the current animal tests were never held to the same validation requirements that are being asked for the current test replacements.”
Additive manufacturing (AM) materials and methods continue to advance at a rapid pace. Extra tests that may be required for AM-manufactured products include testing for residual sacrificial material contaminating the product, especially inside complicated structures, material strength, and unique cleaning validations to prove cleanliness. “If the device is made from polymers, the chemistry can be challenging due to the novelty of the materials, so preparation in terms of pre-validation of ingredients may be necessary,” advised Jorgensen.
“Additive manufacturing continues to be an area where a lot of development is occurring and there is still significant work to be done in terms of characterizing and standardizing the powders, materials, and final products,” said Maciej Jakucki, medical device manager for Fairfield, Ohio-based Element Materials Technology, which provides product and materials testing for the medical device industry.
Testing is important for 3D-printed parts because, in many cases, the printed part’s performance is evaluated against its traditionally manufactured (machined, molded) counterpart. This is especially true for determining the strength characteristics of a 3D-printed part or product. When testing materials, “test sample dimensions are a critical component of the result,” said Clinton. “Wireless tools such as electronic micrometers and calipers can send dimensional measurement data directly to material measurement equipment, which, in turn, allows for stress and strain calculations.”
“There are also concerns about build plate variation, and consistent performance and validation during both the R&D and production phases, which, in turn, results in additional testing,” said Jakucki. “Requirements include coupon testing, but companies take different approaches to characterizing their print batches. Our materials characterization business has definitely seen an increase in metallurgical, tensile, and chemistry testing. Final additive manufacturing products also have increased scrutiny on cleanliness and debris characterization.”
The regulatory landscape is dynamic and constantly changing. “Old rules and pathways no longer apply,” said Ferrara. “Identifying risks and mitigation strategies are an important part of the regulatory requirements to minimize potential problems when implemented into patients. Risk assessment and mitigation are key, as well as clinically relevant testing. Although it is difficult to predict unexpected potential device hazards when implanted per the manufacturer’s instructions for use, assessment of potential risks is needed throughout the entire process of device design, manufacturing, testing, and utilization to provide enough reassurance that the device will not impart potential risks or harm to patients.”
There has been an increasing focus on validation of test methods as regulatory agencies focus more on the quality of data, including repeatability and reproducibility, as well as a shift toward using more deterministic methods for testing, including unconventional and non-standardized tests. “This allows companies to receive more statically sound data to analyze to ensure their product is conforming to the standard,” said Pasma. “This shift has brought unique challenges in how tests are performed and how they are validated.”
For example, the Center for Devices and Radiological Health (CDRH) within the FDA has renewed its focus on the way chemistry studies are conducted on medical devices. This attention has resulted in some important shifts in terms of expectations for these studies and the way the results are interpreted. Greater detail is now required in reporting, as well as a more expansive set of complimentary analytical methods. Although these shifts are good in principle, they have created some uncertainty in the planning phase of studies because the regulatory target continues to evolve.
Nelson Labs is also seeing more requests for assistance with regulatory submission for nanoparticles. “As these are typically complicated projects with very custom recommendations or needs for testing due to incompatibility with many standard approaches, it is very important to factor in a pre-submission to discuss the testing plan and study setup to be taken with the regulatory bodies,” said Helin Raagel, biocompatibility expert for Nelson Labs.
More companies are taking advantage of the pre-submission process offered by the FDA.
“We highly recommend planning for a pre-submission or Qsub whenever possible,” said Turley. “This is especially if there are unique test designs or if justification out of testing is being proposed. The FDA has strongly encouraged up-front conversations with manufacturers, which can greatly reduce the questions on the back end of a submission.”
New advances in testing equipment and software make testing more accurate and efficient. Organizations such as ISO and ASTM continue to update and refine the standards to improve testing methodologies. In addition, as the methods for shipping and delivering products change, so must testing standards. For example, manufacturers of prefilled syringes have realized ambient air pressure changes during transport, such as in an unpressurized cargo plane, or land transit over mountainous regions, can result in motion of the syringe plunger—potentially compromising the sterile seal integrity. “In response, we have developed a highly accurate method for tracking plunger movement when a prefilled syringe is subjected to changes in air pressure,” said Scott. “This data can then be coupled with in-house container closure integrity testing (CCIT) or sterility testing.”
Testing labs are often asked by OEMs to do the impossible when it comes to completing testing in an unrealistic time period, or speeding up testing, such as accelerated testing, which is not feasible or recommended. With any testing project, the earlier it starts, the better—especially for more complicated devices, materials, and processes that increasingly require customized testing approaches to fully assess them. This often requires adjusting standard methods in order to demonstrate biocompatibility, and to ensure the tests to be conducted are actually feasible for the specific devices. “Therefore, a custom study set-up is often needed,” said Raagel. “It is imperative to have conversations with the regulatory bodies on these special projects to get their buy-in up front on the approaches.”
OEMs new to testing sometimes consider doing testing in-house as a cost-saving measure. They need to keep in mind, however, the cost to purchase, maintain, and calibrate the equipment and hire expert technical staff to run the equipment and perform the testing. “Time is also a critical aspect to consider, especially if a test needs to be done quickly in order to meet a deadline,” said Pasma. “For many MDMs, it is more cost-efficient to outsource their testing. Also, having a third-party lab do the testing provides a more independent and less-biased view of the data.”
Turley also points out that, just because a manufacturer can do the testing (has the time, samples, and budget), it does not mean it is capable of doing the testing. “The data needs to be relevant to the device, its intended clinical use, and its intended duration of contact,” she emphasized. “We see manufacturers perform extensive testing on devices that does not necessarily correlate to the use of the device and has even caused some manufacturers to discontinue a project because the data was not applied correctly. Ensure that the testing plan is laid out with a justification not only for what is not tested, but for why the testing is appropriate for the device and its intended use.”
Regulations for medical devices will continue to evolve, especially in Europe with the new MDR. Multiple ISO standards that apply to many medical devices are also changing. “In 2018, the entire philosophy of the biocompatibility standard ISO 10993-1 changed to favor chemical risk assessment as the first resource,” said Mark Turner, managing director and president for Medical Engineering Technologies, a Dover, U.K.-based provider of device testing for the medical, biotech, and pharmaceutical industries. “The emphasis on chemical testing was reinforced by the publication of a new standard ISO 21726, which examines the threshold of toxicological concern of materials and devices. Now in 2020, ISO 10993-18 has been updated, again emphasizing the importance of chemical analysis.”
On the political stage, Turner believes the Brexit decision will have little negative impact on medical device validation. “Test houses are usually accredited to ISO 17025, which is, of course, an international standard,” said Turner. “The standards applied in testing are either international or specific to the country of use of the device. In reality, the FDA actually ‘rules the roost’ and in the end, people around the world will test their devices to the FDA requirements.”
With medical devices becoming much more complex and challenging, there is pressing need for a broader spectrum of high-precision testing than ever before. As a result, MDMs seek testing partners that have the skills and equipment to handle this extra load, thereby shortening the supply chain and still getting to market quickly. For Element Materials Technology, the solution is bringing in other trusted partners within the industry to help them complete complex, urgent projects.
“This way, we can support projects where we can combine multiple external services and manage them with the customer,” said Jakucki. “I’ve heard the term ‘one-stop-shop’ come up repeatedly. It is quite a challenge to implement, especially since most issues don’t usually neatly fit together. We have been able to offer regulatory, inspection, environmental, and functional testing, and facilitating relationships between different partners that would have had difficulty aligning on their own, all while maintaining focus on our core testing business.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books.