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In 2017, Whitney Christian, Ph.D., was helping Medtronic build out its hazardous substances compliance program to meet the biocompatibility expectations of EU MDR. The regulation lists about 2,000 hazardous substances to test for and requires companies to possess an intimate knowledge of the chemical composition of the materials and manufacturing processes used to develop a device.
The work is a heavy lift, and Dr. Christian, Senior Director of Global Toxicology & Biocompatibility at Medtronic, wondered whether the medical device industry was being unfairly treated in terms of the knowledge they need to obtain and document about their products. Then, during an internet search, he found a list of the chemicals found in a Reebok shoe.
“Do they know more about the chemicals in the materials of tennis shoes than we do in our medical devices?” he asked himself. “It was a bit embarrassing to discover. I needed to remember, though, that’s how the industry was regulated at the time. Regulators used to provide a list of tests to perform, and if you passed them, you were fine. Now they ask more questions.”
Biocompatibility has been a frustratingly difficult topic for orthopedic device manufacturers in recent years. Updates to the EU regulation, ISO standard and FDA guidance require companies to execute their biocompatibility programs with greater expertise and strategy. It has created confusion about test protocols, led to regulatory deficiencies and postponed product launches. As the regulatory focus on biocompatibility evolves, the bar on expectations will likely continue to move.
“Aligning with the recently updated standards and the proposed changes to ISO 10993-1 is challenging,” said Janelle Lauer, Ph.D., Biocompatibility Expert at Nelson Laboratories. “It seems the goalposts are constantly moving, and we must adjust.”
How Did We Get Here?
The scrutiny of medical device biocompatibility may have come as a surprise to some in industry, but Dr. Christian said events over the last decade created a foundation for today’s regulatory environment. He pointed to four specific instances, some of which were prompted by the metal-on-metal hip catastrophe that shook orthopedics.
At a Society of Toxicology meeting in 2018, a talk was given on variations in chemical characterization results from different testing labs. Johnson & Johnson detailed how they sent four devices to four testing labs and obtained different results from each one. The labs had been used to obtain data to register products on the market, Dr. Christian said.
“This indicated that FDA had not standardized this aspect of the safety analysis, and some companies were registering devices with inadequate safety data sets,” he said. “Companies weren’t playing on a level field.”
Also in 2018, the documentary “The Bleeding Edge” was released. The movie cast a negative portrayal of the medical device industry and FDA in regard to conducting safety evaluations of devices. The Society of Toxicology presentation and the documentary resulted in FDA increasing requirements for biocompatibility and medical device companies receiving a wave of related deficiencies from the agency, according to Dr. Christian.
Meanwhile, in Europe, MDR raised the burden of proof for compliance with biocompatibility standards. The regulation treats medical devices on the market like new products, and requires companies to provide safety data in addition to safety rationales for their devices.
ISO 10993-1, the global standard for biological evaluation of medical devices, was revised in 2018 to emphasize a risk-based rather than a check-box approach. The revision required companies to conduct biocompatibility evaluations not just at the material level, but also after the manufacturing, packaging and sterilization processes. The standard placed emphasis on the final, finished device.
“The standard also required testing after the maximum number of reprocessing cycles for reusable devices and components to ensure biocompatibility throughout the life cycle of a device,” Dr. Christian said. “This required more testing and data gathering beyond a time zero data point, which was new to the industry.”
The outcomes of these events required big changes for orthopedic companies’ biocompatibility strategies. Those plans must continue to evolve as the standard is updated and regulatory bodies progress their thinking about biocompatibility. ISO 10993-1 updates are pending, and FDA is expected to release a guidance document on chemical characterization.
What Changes are Challenging for Companies?
Companies could face myriad challenges in meeting biocompatibility requirements based on their type of device, expertise in interpreting the standards and regulations, the size of their company and even the structure of their supply chain.
“Larger companies with a large portfolio of devices are on better footing because the steps for alignment are largely the same for different devices. There is efficiency in the cut-and-paste process of the analyses,” Dr. Lauer said. “A smaller company may not be able to take advantage of that efficiency.”
FDA, testing labs and regulatory consultants reviewed common biocompatibility and chemical characterization deficiencies at a 2023 Orthopaedic Surgical Manufacturers Association (OSMA) meeting.
The list of biocompatibility deficiencies included unclear language when indicating predicate rationale, test articles that do not represent the final finished devices, test methods that do not utilize worst-case extraction conditions, no justification for when cytotoxicity testing grades of >1 are expected, and no biocompatibility assessment performed on packaging that is close to the device.
The list of chemical characterization deficiencies included extraction testing conditions that do not represent worst-case clinical exposure, deviation of analytical evaluation threshold that does not reflect sources of instrument variability inherent to semi-qualitative techniques, and standard selection and concentration ranges that do not reflect sample analyses or produce a conservative estimate of quantities for method validation.
Dr. Christian, who led the OSMA discussion, noted that he was fortunate to know how to plan for most of the deficiencies discussed due to the large number of FDA submissions that Medtronic makes every year. Big companies, he said, still encounter surprises with respect to biocompatibility compliance because regulators aren’t always transparent with their thinking.
His situation also highlights how important it is to have the right experience on the team. Most companies rely on engineers and material scientists to handle biocompatibility, but those aren’t suitable backgrounds for today’s regulatory landscape, Dr. Christian said.
“The practice of biocompatibility has evolved beyond a checkbox approach, in which someone orders the tests needed for a device type from a third-party test lab, staples the results together and submits them to the regulator,” he added. “It has become much more granular and toxicology focused, and I think the skillset required is scarce among the medical device industry, making it difficult for companies to complete the required work correctly and efficiently.”
Orthopedic companies need to gather significant data before they perform tests. The data collected spans an understanding of the chemical composition of materials and manufacturing process aids used to manufacture implants to the precise details of the manufacturing process, which can alter the chemical composition of the device materials.
Leveraging a toxicologist, whether as an internal or external resource, can help companies collect, analyze and develop a strategy around the data. Dr. Christian said the expertise is not only needed for U.S. submission. EU MDR’s hazardous substances compliance has presented numerous hurdles for orthopedic companies that must ensure their products do not contain — or contain acceptable levels of — nearly 2,000 regulated chemicals.
Additionally, the more stringent biocompatibility requirements have led to greater interaction and information exchange between device manufacturers, their contract manufacturers and material providers, Dr. Christian said. The requests for information have not been welcomed by some players in the supply chain that have declared the information proprietary. This hurdle has impacted the timeliness of product introductions and created supply chain issues when companies have needed to qualify new suppliers.
“If a company doesn’t tell us the chemical characterization of a material, I need to conduct a test,” he said. “This increases the cost and turnaround time associated with biocompatibility and, in turn, device registration.”
The pending revision of ISO 10993-1, which proposes that device misuse may require evaluation, will cause new challenges for orthopedic companies. The change could create a Pandora’s Box for medical device companies, according to Dr. Lauer.
“In my mind, ‘misuse’ is open to interpretation by the reviewers, which may make laying out evaluation plans more difficult because it’s impossible to know the background or knowledge base of the reviewers when creating a testing plan,” she said. “There are other changes being proposed for the pending revision of ISO 10993-1, but I see this one as being very problematic.”
What Best Practices Should You Follow?
Drs. Christian and Lauer stress that the best practice is hiring people with strong biocompatibility backgrounds and connections.
“Either develop the necessary expertise in-house or develop a relationship with a consultant who can provide the necessary expertise,” Dr. Lauer said.
When hiring a consultant or testing lab, Dr. Lauer noted that it’s important to work with experts with experience in guiding recent, successful submissions. She also recommended that companies ask consultants about their support during post-submission feedback. Regulatory reviewers usually have questions that require an answer from someone with technical expertise. Companies should expect their biocompatibility experts to respond to technical questions within a tight window of time.
Testing labs can be helpful in not only performing tests but also strategizing around which tests to perform, because they have robust experience working with different companies. “I use my past successes to guide future projects,” Dr. Lauer said.
She also stressed the importance of getting help early in the process and referred to a recent client who came to Nelson Labs with a failed FDA submission. “There was room for a well-thought-out justification to avoid some or all in vivo tests,” she said. “However, that was not part of the initial submission, and FDA demanded a full testing plan. It cost the medical device company time and might increase the testing burden. Now they’re behind schedule and over budget.”
Dr. Christian recommended the use of testing labs that possess deep expertise in orthopedics and that invest in building their biocompatibility competencies and capabilities. Beyond that, he uses the value triangle of cost, turnaround time and quality when considering the best lab for a project.
He said it’s also important for anyone active in the biocompatibility process to stay engaged and informed by getting involved in conferences, societies and working groups.
“I recommend that stakeholders take this topic seriously,” he said. “It’s important to have resources around understanding the regulatory requirements, monitoring when and where regulatory changes are occurring, being involved in influencing change and holding planning meetings to devise strategies that achieve compliance in this dynamic regulatory environment without breaking the bank.”
AdvaMed and OSMA are two organizations that have brought together industry and regulators to discuss biocompatibility. AdvaMed is supporting industry in conversations with FDA in regard to the least burdensome approach to biocompatibility evaluation when qualifying a supplier or making a material change. Industry and its advocates believe that some supply chain challenges could have been avoided if there was a quicker path to qualifying new suppliers.
OSMA has started a biocompatibility working group and seeks to devise guidance on best practices for biocompatibility. The insight will be compiled based on member contributions.
Dr. Christian is also working on a framework that will provide regulators with methods to consistently and fairly evaluate the biocompatibility package for a device as a weight-of-evidence approach. The framework will also provide industry guidance on how to assess the adequacy of biocompatibility data packages for devices prior to submission. It is expected to be published in the Journal of Regulatory Toxicology and Pharmacology in the coming months under the title, “Taring the Scales: Weight-of-Evidence Framework for Biocompatibility Evaluations.”
Biocompatibility will be a consistent topic for industry to consider for the foreseeable future. Dr. Christian said orthopedic professionals with biocompatibility roles should stay educated on the changes and share their experiences with peers in the industry.
“It’s important that we get it right and build confidence and competency in this area within the orthopedic industry,” he said. “It should be an important part of product development and change management of devices.”
