Biocompatibility is practically a universal hurdle for medical device companies seeking market access. U.S. Food and Drug Administration (FDA) guidance—specifically, “Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”—provides organizations with clear direction on testing/evaluation requirements. Thus, once organizations complete their cytotoxicity, sensitization, irritation testing, etc., it should be smooth sailing. But that doesn’t always happen. 

Postmarket device recalls still occur. But why, after the seemingly endless testing, do issues still arise?

In many well-known cases, seemingly one-off individual reports of fever, increased pain, etc., culminate to reveal trends that point to quality issues with the product on the market. Accordingly, these reports are crucial in continued medical device monitoring after approval.

A well-known instance of adverse tissue reactions resulted from metal-on-metal (MoM) hip implants. Growing reports of device failure and systemic bodily responses raised concerns at FDA. These concerns triggered more thorough investigations to identify a cause of the growing adverse event reports. Investigations revealed the metal-on-metal design caused metal ions to be released in the body, damaging surrounding structures and the device itself. Since the discovery, MoM implants have been removed from the market.

Beyond long-term material incompatibilities, postmarket data also can reveal a loss of control in manufacturing processes.

In 2021 and 2022, for instance, Exactech recalled numerous joint replacement devices including knees, hips, and ankles. A large number of patients experienced worsening pain and joint weakness, among other symptoms. An investigation concluded the approved packaging materials/process had changed since the implants were introduced to market; accordingly, devices were being sold/packaged in defective bags. Since these bags did not offer an adequate oxygen barrier, the implants were subject to increased oxidation, which impacted material integrity (eventually leading to accelerated device wear). The implants’ increased wear rates prompted the accumulation of wear particles in the body, leading to tissue reactions, inflammation, and bone loss.¹

While there are more examples of postmarket biocompatibility issues in the orthopedic industry, the impact of both product recalls was massive in scale. So, how can manufacturers avoid these issues? 

The latest revision of FDA’s Guidance for Industry on the Use of ISO 10993-1 was released in 2023. It provided clarifications on when and how to conduct established endpoints, like subacute, and subchronic toxicity and genotoxicity. The guidance, though cumbersome at times, has effectively harmonized the industry’s approach to premarket biocompatibility and alleviated significant downstream health consequences to consumers with its protective measures. Postmarket device assessment, however, is understandably less standardized.

The collection of postmarket data is driven by clinician and end user participation via Medical Device Reporting (MDR). MDR is especially important in the changing environment of implantable products. New hips and knees are being implanted earlier in younger populations, resulting in a longer implant life-span.² These shifts in treatment mean the long term function and durability of orthopedic and many other devices is critical to continued consumer safety, and increases the importance for post-implant consumer and clinician monitoring.

So, what is FDA’s standpoint on postmarket data collection and usage with respect to biocompatibility?

The biocompatibility guidance makes relatively few references to postmarket surveillance (PMS) and its utility. The guidance offers that “postmarket surveillance information can be informative” as an information source on potential biocompatibility risks and that generally, postmarket experience (from non-U.S. markets) should be used to shape the biocompatibility assessment in support of U.S. clearance or approval. The Device Manufacturing Record should document how biocompatibility risks were determined and how those risks have been addressed. 

The guidance points to implications of the design and manufacturing processes on overall device biocompatibility. Small changes in device geometry and manufacturing can have a big impact on a product’s downstream biocompatibility. For example, if the design is changed even slightly to introduce more angular surfaces, a new worst-case for sterilization could be introduced. Or, should the validated passivation methodology be changed, there may be consequences with respect to device pyrogenicity. A change in supplier may introduce different processing agents to the device materials, raising new toxicological concerns. Unfortunately, the consumer pays the consequences, realized in infections, fevers, and other physical ailments. Continued management of those risks is established through quality system requirements and postmarket controls, including purchasing controls, production and process control, acceptance activities, corrective and preventative action, complaint files, and medical device reporting.³ 

The biocompatibility guidance makes it clear that preexisting postmarket data should be leveraged to develop a comprehensive biocompatibility evaluation plan; but newly acquired postmarket data must also be used to iteratively monitor and shape product safety once a device reaches market, acting as a final but ongoing checkpoint to the design and manufacturing processes. 

The MDR regulation offers a mechanism for FDA and manufacturers to monitor adverse events and device malfunctions. “MDR reportable events” are events that reasonably suggest a manufacturer’s marketed device(s) may have caused or contributed to a death or serious injury, or has malfunctioned, and the malfunction of that device or a similar product would likely cause or contribute to a death or serious injury if the malfunction were to recur. The definitions of serious injury and malfunction follow.

• Serious Injury—An injury or illness that is life threatening, results in permanent impairment of a body function or permanent damage to a body structure or necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.
• Malfunction—The failure of a device to meet its performance specifications or otherwise perform as intended

A device-related complaint is defined as any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution [21 CFR 820.3(b)].⁴ 

Beginning at premarket, manufacturers should make every effort to select well-studied materials with a high degree of durability and design the device with biological safety in mind because if a device achieves its intended use but is not biologically safe, it cannot be effective. Manufacturers should seek to employ high-quality test labs for premarket device evaluation. Following market authorization, maintaining detailed control over suppliers and manufacturing processes is vital to ensuring continued product safety. Additionally, using postmarket surveillance to monitor device issues, specifically complaints with biocompatibility implications (irritation, fever, implantation site redness/swelling) is vital in identifying potential product risks. Swift identification and action will reduce the impact to consumers should issues with biocompatibility arise. Thus, postmarket data offer a continuing defense mechanism against biocompatibility challenges and MDR data should be leveraged accordingly. Given implant utilization trends shifting to a longer device lifespan, beyond the timepoints typically assessed in biocompatibility evaluations, MDR data offer a unique vantage point to better understand device performance. Manufacturers should consider ways to utilize MDR data in the initial development stages of new device design as industry moves toward longer implantation times.

References

1. bit.ly/4p6NoH2
2. https://www.novanthealth.org/healthy-headlines/why-are-knee-and-hip-replacement-patients-getting-younger
3. Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” Guidance for Industry and Food and Drug Administration Staff
4. Medical Device Reporting for Manufacturers Guidance for Industry and Food and Drug Administration Staff

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Sarah Welsh has over five years of experience and expertise in regulatory affairs consulting and industry. She supports the development of regulatory submissions such as Q-submissions, 510(k)s, De Novo, Breakthroughs, and PMAs for organizations seeking FDA clearance/approval. Additionally, Welsh helps manufacturers develop regulatory strategies, product landscape analyses, recommendations for pre-clinical testing, and clinical data collection. She is an accomplished regulatory technical writer and has experience in development and implementation of regulatory strategy and regulatory submissions in therapeutic areas including spine, orthopedics, wound care, sleep and anesthesia, and general surgery. Welsh earned bachelor’s and master’s degrees in biomedical engineering from Clemson University.