ISO 10993-1 is recognized as the gold standard when it comes to the selection of applicable biological testing of medical devices and the associated risk assessment, while also providing valuable information pertaining to the potential need for additional testing based on available data.
In 2020, the FDA updated the guidance document ‘Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process’. Subsequently, in September 2023, the FDA announced it had again updated this same guidance. This document is arguably the most widely used guidance by medical device manufacturers, as reference to it is made in a variety of areas within quality management systems, including aspects of design, production, and in relation to compliance with various regulatory requirements. With much of the text in ISO 10993-1 already embedded into the lexicon of the industry, changes to this document raise the collective ears of the medical community.
The first, and likely the most important, change is that of how to address contact with intact skin. Devices manufactured using very-well known and widely used materials that have shown to pose little or low risk to biocompatibility in such applications are now being reconsidered. In an aim to lessen the use of unnecessary testing, material information is proposed to be included in a premarket submission instead which is now outlined in Attachment G (Biocompatibility of Certain Devices in Contact with Intact Skin). While this is a giant leap forward, it does not absolve manufacturers of the need to continue to apply risk management in these areas and it should be noted that this is not completely inclusive of all materials in all cases.
Manufacturers will also find that there has been a change to Table A.1. The table has been updated with new indicators as to where the testing endpoints are either considered in both the guidance and standard, and where additional testing should be considered when submissions are provided to the FDA. Having said that, there is a difference when it comes to how subacute and subchronic toxicity testing is viewed. ISO 10993-1 has them separated and the guidance does not. To ensure that there is no misunderstanding as to whether these tests should or should not be performed together, the guidance was written to include a clarification that the testing should be based on the device’s duration of use.
The wording in the guidance has been changed with respect to the use of a comparison article. A comparison article is one that directly compares alternative products, services, or solutions to help customers understand the differences and similarities. FDA’s position was that submissions required U.S. legally marketed devices and non-U.S. devices were not to be considered, but in this revision, while this has been removed from the general text body, it remains footnoted, so it does not seem to have a monumental effect.
A topic of great discussion surrounding this revision of the guidance was the conditions around the application of genotoxicity testing. The technical committee working group for ISO 10993-1 has offered that this requirement be applicable for all devices that contact blood, regardless of the duration, while the guidance document only notes this for those devices (with limited contact to blood) in the extracorporeal circuit. Beyond that, there is no change to the requirement for genotoxicity for either prolonged or long-term used devices having contact with blood.
Where not included previously, there is now a reference to the ASCA, the FDA’s Accreditation Scheme for Conformity Assessment. This program was initiated to determine if it would allow for a smoother submission process by raising the reviewer’s confidence in the testing validity and the use of labs certified under the program. During the 3-year evaluation period, indicators such as fewer questions arising from reviews and the inclusion of additional information from lab-related testing were considered as potential success factors for continuation of the ASCA. This is not to say the use of non-ASCA certified labs will not be accepted, it only means that the confidence will be lower, which in turn will likely require more detailed documentation.
Overall, the latest changes to the guidance document were warranted to provide further clarity on the expectations of the FDA in relation to regulatory submissions. Offering such information to the industry allows for a more robust assessment of risk through appropriate test methods and streamlining with overall quality planning. Ensuring that submissions are managed effectively on both ends will keep the overall goal of a less burdensome approach moving forward.
