A risk-based approach that tailors test requirements to the specific risks of each device.
As the medical device industry continuously evolves and processes become more streamlined, others, like biocompatibility, becomes more complex. In the past, biocompatibility standards have been more black-and-white, but changing regulatory requirements are shifting the methodology and processes for manufacturers to adhere to. Historically, the typical checklist to address risks with biocompatibility tests was sufficient, but recent and upcoming regulatory changes require a more thoughtful approach to medical device testing.
The primary force behind changing methodology lies in the purpose of various testing methods and the answers they can provide. Ideally, addressing the biological safety of medical devices is facilitated by a program that is risk-based and has the appropriate data, whether through biological testing or chemistry, to address the recommended biological endpoints of concern. Biocompatibility testing on medical device extracts may provide evidence of a potential adverse effect, but chemical characterization provides specific information on the possible chemical hazards which can be further assessed for toxicological risk.
While biocompatibility testing is necessary to address some biological endpoints, like local tissue effects and hemocompatibility, it does not typically address all biological endpoints indicated in ISO 10993-1 specific to the nature and duration of exposure to medical devices. For example, though some biological endpoints, like genotoxicity, may be addressed by either methodology, biocompatibility testing or chemical characterization and risk assessment, the latter is a sharper tool for detection of potential mutagens in medical devices.
Chemical characterization tends to be more practical and potentially more specific in addressing other endpoints like carcinogenicity, reproductive and developmental toxicity with a toxicological risk assessment. It’s clear that chemistry and biocompatibility testing each resolve different questions pertaining to device risks.
Even though a risk-based approach to biological evaluations is a significant focus of ISO 10993-1:2018, an additional focus is a reduction in unnecessary in vivo testing. In vitro models and chemical characterization testing are preferred to in vivo in “situations where these methods yield equally relevant information to that obtained from in vivo models.”
Regulatory bodies have been increasingly accepting the use of alternative in vitro models. Yet, the approach and speed of implementation differ between the U.S. and the EU. Balancing varying expectations can be difficult and result in differing degrees of in vivo testing, so taking the time to familiarize yourself with each regulatory body’s approach is essential.
The EU’s Swift Approach
With the EU’s transition to the Medical Device Regulation (MDR), the overhaul in submission requirements accelerates the pace of changes in biocompatibility testing. Manufacturers should only pursue in vivo testing when alternative methods cannot mitigate the risk. For example, in vivo testing might be appropriate when local effects at the implant site are a concern due to significant device design changes or when complaints indicate there are patient safety concerns with a product.
To avoid overuse of in vivo testing, EU regulators recommend creating stopping points in the testing process to prevent replicate or unnecessary studies. Unnecessary in vivo testing can put submissions in a negative light to regulators, so whenever possible, taking a proactive approach to using alternative methods is essential. Thus, there may be a noticeable shift to in vitro testing to resolve unanswered questions from the limited use of in vivo testing.
The U.S. Approach
In the U.S., in vivo testing will not decrease as noticeably compared to the EU. The key focus for U.S. submissions is meeting the recommendations of the FDA Guidance on the Use of ISO 10993-1:2016, which is primarily based on ISO 10993 principals with some differences. This guidance has been implemented consistently now for several years, meaning currently, there is less of a learning curve for manufacturers.
To satisfy these recommendations, testing labs will no longer run through a predetermined list of tests. Scientists will need to have a deeper understanding of devices to determine relevant risks and choose appropriate tests.. Regulators hope this approach will minimize the amount of testing required for submissions and support the shift away from using in vivo testing, when possible.
Adjustments Across the Board
As labs change their approach to biocompatibility evaluations, the order in which many labs perform their testing will likely become more consistent with ISO 10993-1, enhancing the importance of chemical characterization. Because the exact certainty of device materials is unknown until the completion of chemical characterization, delaying this step or using unverified information could misdirect testing.
To accomplish addressing risks, scientists start by determining any gaps that need to be addressed by biocompatibility testing. ISO 10993-1:2018 requires a description of the medical device chemical constituents, and consideration of material characterization, including chemical characterization, before proceeding to any biological testing. Completing chemistry testing sooner in the testing process helps to minimize potential setbacks. Additionally, facilitating communication between engineers that select materials and toxicologists and biocompatibility experts can increase the lab’s understanding of your device and the likelihood of success with your submission.
Building relationships and having regular discussions with suppliers is also essential. Consistent communication about material selection and materials used in manufacturing processes is critical. If suppliers make any changes, you need to know in advance, as it could affect device safety and delay manufacturing while the change is evaluated. Therefore, developing proactive communication practices can help you get ahead of issues and risks.
Patient safety drives changes in medical device regulations, which may impact biocompatibility evaluations. As the approach to biological evaluations continues to evolve, it is critical to develop partnerships across the industry to collaborate and stay apprised of coming changes.
Discover more on the importance of chemical characterization and identifying unknowns in chemical makeup in Unknowns are Unacceptable.
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