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Orthopedic manufacturers realize biocompatibility is non-negotiable to getting devices cleared by regulators, but that doesn’t mean it’s not a frustratingly complex process. The evolving, unharmonized global standards and guidance have created significant gray areas for companies — and even regulators — when it comes to deciding which tests and documentation are required for product submissions.
For instance, ISO 10993-1:2025 was published in November. The standard defines the principles and requirements for assessing a device’s biological safety within the risk management framework established by ISO 14971 and is intended to guide manufacturers through the process of identifying, assessing and managing risks associated with materials, design choices and tissue contact during a device’s intended use.
The update also adds expectations for misuse risk assessments and end-of-life testing, which some believe are overly stringent requirements.
While OUS agencies expect manufacturers to comply with the new standard, FDA continues to use the 2018 version of 10993-1, along with its own guidance to clear devices for the U.S. market.
“Different regulatory agencies are using different standards and criteria to evaluate methods, which leads to a lack of harmonization internationally,” said Ron Brown, Principal Toxicologist at Risk Science Consortium. “As a practical matter, manufacturers need to develop different biological evaluation plans for different parts of the world. That can certainly be a challenge.”
Brown spent 25 years working at FDA, most recently serving as the senior toxicologist responsible for developing and reviewing toxicological risk assessments of extractable and leachable compounds for medical devices. He spoke at the Orthopaedic Surgical Manufacturers Association (OSMA) Spring Meeting and provided guidance for manufacturers on ways to think more strategically about their biocompatibility testing, especially when working with FDA.
What Tests are Really Needed?
FDA created a framework for biological evaluation endpoints by device category in an effort to bring clarity to the types of testing medical device manufacturers should complete for their submissions. Brown argued that the approach doesn’t always correlate with FDA’s “least burdensome” principles and history has shown that some of the tests required are irrelevant to demonstrate safety for certain devices.
“It’s important to question whether we need to conduct all of these tests to reach a conclusion about the safety of the device, and whether the test methods that we’re using are appropriate for the safety assessment of the device,” Brown said, adding that certain tests are probably not needed for low-risk devices and well-known materials.
He advised that as companies establish their plans to meet biocompatibility requirements, one of the first questions they should ask is: Can a different set of tests return the same answers in a shorter timeframe? Contract research organizations often work with numerous clients and could be leveraged for perspective on how other manufacturers have successfully met requirements with compressed testing and timelines, as well as whether a justification letter could be submmited instead of testing data with a regulatory submission.
“Manufacturers want the smoothest pathway to get their device on the market and avoid regulatory problems,” Brown said. “When you provide justification instead of performing testing, it opens you up to a challenge. Today’s environment is such that manufacturers will take the path of least resistance and do testing so as not to raise red flags with FDA.”
Justifications can be successful, though. Orthopedic companies mentioned that they’re using them during FDA submissions. Even if the agency comes back with a nonconformity, companies are often submitting a new justification instead of completing additional testing.
A successful justification requires robust information and data, Brown said. “If you’re leveraging data from a legacy device for a new device, you need to establish toxicological equivalence,” he said. “Justifications do a lot better when you marry your reasoning to test data. That doesn’t mean that you need to perform a full battery of tests, but you do need data.”
Companies that don’t thoroughly outline their justification are guaranteed to fail, Brown said.
Another recommendation is to utilize FDA’s Q-Submission Program to gain a greater understanding of which testing the agency requires for your device. Brown advised companies to consider the pre-submission program, noting that there are benefits to fully mapping out a plan and getting FDA buy-in prior to execution of testing.
“Some of the biocompatibility tests take a long time to conduct, and after extensive evaluation, we still have devices failing at the end of the pipeline,” Brown said. “What information would be useful to you at the beginning of that process to make more informed decisions?”
How Soon Should You Test?
FDA guidance and ISO standards require biological evaluation to be conducted on the final medical device, but missteps along the way can lead to additional testing and extended product development timelines.
“If the first biocompatibility test you’re conducting is on the final finished device and it fails, you’ve invested a lot of time and money to ask what you could have done differently to get to that outcome earlier in the process,” Brown said.
Manufacturers should take a tiered approach to biocompatibility assessments by conducting a limited battery of testing in early development stages. Often, companies conduct cytotoxicity testing to screen materials, but front-loading toxicity earlier in the R&D process will ultimately help manufacturers make more informed decisions downstream.
“FDA is still going to want data on the final finished device, but from a business perspective, early data will help you make decisions about the direction of your device and the sequence of testing to perform,” Brown said. “I’m a strong advocate for this. Cytotoxicity testing can provide biocompatibility data and be a strategic business tool to help make decisions earlier in the product development process.”
Better communication between toxicologists and chemists can also help manufacturers better select which tests to execute and data to collect during the initial R&D phase. Early conversations can eliminate big surprises in the chemical characterization report, Brown said.
“There can be tension between what the biocompatibility person and chemist want,” Brown said. “Instead of front-loading toxicology, consider front-loading the chemistry. Start the dialogue early on so that there aren’t many surprises on the back end.”
How to Shape the Future?
Unfortunately, biocompatibility requirements have not gotten easier for orthopedic manufacturers. Brown would like regulators to take a more streamlined approach that accounts for a device’s risk profile and evolving scientific perspectives. He also recommends that orthopedic manufacturers continue to be direct about their challenges and engage with regulatory agencies and standards working groups to help shape the future of biocompatibility requirements.
“If you have the opportunity to participate in the standards development process, I encourage you to do so,” Brown said. “Also engage within your companies. Look at what evidence-based, science-based approaches make sense for your devices.”
