Around the world, various regulatory factors are driving the evolution of medical device risk evaluation. The industry is beginning to recognize the limitations of biocompatibility testing. While the data it can provide still have a pivotal role in the assessment process, it may not be able to measure other factors that are becoming increasingly important to consider, such as carcinogenicity or reproductive and developmental toxicological concerns. When it comes to patient and practitioner safety, you must address these risks.
Chemistry, toxicological risk assessment (TRA) and biocompatibility are necessary components of a biological evaluation. A biological evaluation provides evidence-based data focused on device nature and duration of patient contact which ultimately supports the safety of a device. With the additional expectations regarding chemistry were provided in 10993-18:2020, it is natural that the expectations of toxicological risk assessments also need to be further harmonized. ISO 10993-17 is under revision to provide guidance on toxicological risk assessments.
The toxicological risk assessment and biological testing are conducted to address the biological endpoints appropriate for the device duration and nature of body contact, to support the biological safety of the device. Regulations are the main driver behind the growing role of TRAs, including the EU Medical Device Regulation (MDR) and 2020 guidance from the U.S. FDA. These documents not only help to set expectations, such as the analytical evaluation threshold (AET) but also support the methodologies and approaches to performing this analysis.
ISO 10993 Biological Evaluation of Medical Devices
The ISO 10993 series of standards highlight the importance of biological evaluations as a part of the overall medical device risk management program. Part 1 demonstrates a need for detailed physical and chemical information, and if manufacturers do not provide sufficient data, additional testing, such as E/L studies, will be necessary before designing a biocompatibility testing plan.
In addition, Part 18, updated in 2020, faced an overhaul in its latest revision. This update increased the requirements for characterization of medical device chemical constituents in a final finished form of a medical device. This section has made it challenging for some to achieve characterization to the levels required by regulators. However, as the industry adjusts, the role of this data will become more evident as appropriate TRAs will rely on this information.
FDA Guidance on use of ISO 10993-1
For manufacturers seeking approval in the United States, it is important to consider that the U.S. FDA does not recognize all clauses of all parts of ISO 10993. The FDA Guidance on the Use of ISO 10993-1 most recently published in 2020, which is almost identical to the 2016 version, provides FDA recommendations that may differ from the ISO 10993 requirements.
ISO 14971 Application of Risk Management to Medical Devices
This document requires risk management, including biological evaluation, to continue throughout a product’s lifecycle.
ISO/TS 21726 Biological Evaluation of Medical Devices
When conducting chemical characterization and TRAs, applying the threshold of toxicological concern (TTC) will often reference this technical specification.
Medical Device Regulation
The EU MDR currently recognizes the most current versions of ISO 10993 standards as “state of the art,” meaning notified bodies expect applications to meet current ISO 10993 requirements.
Collating this information and staying updated is a complicated task. Fortunately, lab testing partners not only have an extensive background on regulatory standards but often play a part in shaping what the future of these standards will be.
Upcoming: ISO 10993-17
While not expected to publish until at least 2021, ISO 10993-17 is currently in the revision process and will provide additional guidance on conducting a TRA. The majority of the standard is expected to change, from defining terminology to summarizing recommended steps in the process. Performing these assessments will likely become more standardized, but this does not indicate process simplicity.
Because TRAs consider device risk as a combination of hazard and the level of exposure, detailed background on the device and its use are critical. Manufacturers need to provide as much contextual understanding of a device’s materials, production process and potential exposure parameters (e.g. maximum clinical use, and patient populations). These considerations are important in the design of chemical characterization and the conduct of a valid toxicological risk assessment. Without this information, the result may be under or over-predicting patient risk; both may lead to undesirable outcomes for different reasons.
Partnering with an informed, reliable testing partner can help prevent potential issues with changing guidance. Qualified, expert judgment will be necessary for many parts of this process, such as when scientists evaluate the results for the margin of safety for medical device chemical constituents. It can be an added benefit if the lab performing your device’s TRA has an inside look at what standards are coming.
An Evolving Outlook
As medical devices continue to evolve, so will the standards. Our industry continues to drive innovation, which is something to celebrate. While there are still opportunities for improvement, chemical characterization plays a critical role in modernizing the biological evaluation of medical devices.
For a more in-depth review of the TRA process, watch our webinar “Toxicological risk assessment of medical devices and proposed updates to 10993-17, including the application of TTC values.”
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