The U.S. Food and Drug Administration (FDA) has been actively engaged in the development of standards that medical device manufacturers use as their reference for conformance to FDA guidance. This is especially true for standards that address requirement for biomaterials used in medical devices that come in contact with the body.
Last year, AAMI hosted its first Biological Evaluation Standards Week, which brought together over 150 AAMI members, regulators and industry representatives to review the biological evaluation standards working program under the AAMI Biological Evaluation Committee and its 18 affiliated working groups. The week’s events fostered dialogue on further harmonizing biocompatibility testing in the U.S., which fits with the FDA program on biocompatibility presented on the last day of the week-long event.
FDA representatives offered an update on the agency’s actions and guidelines for manufacturers, including a discussion on conformity assessment of biocompatibility testing. Past FDA action related to biocompatibility includes a draft guidance published in October of 2020, Select updates for biocompatibility of certain devices in contact with intact skin. According to Jennifer Goode, biocompatibility program advisor for the FDA and co-chair of the AAMI Biological Evaluation Committee, this guidance will likely be published within the FDA’s target of a three-year interval between the first draft and final version. In short, the situation continues to develop, and further information and explanation from the FDA is expected soon.
The discussion also turned to the use of the 1.25 cm2/ml extraction ratio for elastomers as part of the U.S. recognition of the international standard, ISO 10993-12:2021, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials. Current guidance from ISO 10993-12:2021 includes a revision in Table A1 and Clause 10.3.4. Table A1 no longer includes the 1.25 cm2/ml extraction ratio for elastomers with a thickness of less than 1.0 mm, and clause 10.3.4 has been revised to indicate that use of this ratio for any thickness component is only appropriate, if justified. Goode stated that when this revision to ISO 10993-12 was published, test labs participating in the ASCA program were asked to update their procedures to address how they were going to conform to this standard.
“We decided at the time if they wanted to use it for thickness greater than 1 mm according to the prior revision of the standard that would be fine and we would accept that,” she said. “However, we knew there might be some cases where it would be appropriate to also use it for elastomer devices or components that were less than .5 mm thick or components between .5 and 1 mm thick.”
Providing an example of such an appropriate use, Goode said that using the 1.25 cm2/ml extraction ratio could be justified for elastomeric devices less than 0.5 mm thick, or of thicknesses between 0.5 to 1 mm when extraction is conducted at a higher surface area to extraction volume ratio, such as 6 cm2/ml or 3 cm2/ml, and results in the absorption of the entire extract volume or there is too little residual volume to conduct testing. That said, if a manufacturer uses the 1.25 cm2/ml extraction ratio for thicknesses of greater than 1 mm, they do not have to provide justification for that use.
Cumulative use determinations also featured prominently in the discussion. Drafted revisions of ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process, are currently under consideration by the member bodies of ISO/TC 194, (the International Organization for Standardization (ISO) technical committee on biological evaluation of medical devices). Goode requested input on language included in the revised standard regarding “cumulative use” and “total exposure period” and asked how these definitions would impact manufacturers and test labs.
Proposed changes to ISO 10993-1 are expected to define various levels of exposure based on the number of days elapsed between first and last use of a medical device. Considerations for cumulative use determinations will include how any changes in terminology and duration of contact impact biocompatibility evaluation, and how definitions are derived. Goode particularly focused on the importance of clarifying “cumulative use.” Invoking a hypothetical case where medical device use is catalogued as 30 minutes of use twice a day, and then added up to avoid breaking the 24-hour threshold, Goode indicated that adding up minutes may miss an important longer-term assessment. It would be a missed opportunity for data, she explained, that could be important for biological risk analysis.
However, even with cumulative use as a baseline principle, there are still several issues that the experts from AAMI’s Biological Evaluation Committee, which serve as the U.S. Technical Advisory Group to ISO/TC 194, will likely want to explore. These include:
Greater clarity of definitions and requirements surrounding cumulative use requirements.
The particulars of bioaccumulation, and how dosage may be a more pertinent concern than exposure over time.
The extent to which relying on cumulative use thresholds exists in tension with offering clear definitions of categories like infrequent use.
Whether caution is merited, and if treatment intervals are not the right metric for select medical devices. How different government agencies characterize frequent vs. infrequent use, and any need for consensus and coordination.
Whether future guidance documents that clarify ISO’s standards might be useful and appropriate.
Ultimately, the Biological Standards Week provided a great opportunity for AAMI members and industry players to interact with regulators and gain some clarity on FDA’s priorities on biocompatibility and some idea of what the future might hold.
