What we’ve heard at CDRH’s recent medical device sterilization town halls

Life Sciences | By LAURA DIANGELO, MPH

Feb. 13, 2024

With industry’s continued concerns about an impending rule change from the Environmental Protection Agency (EPA) on ethylene oxide emissions, the FDA’s device center has been hosting a series of town halls on medical device sterilization issues. AgencyIQ recaps top-line issues from the last two town halls and previews the agency’s next meeting.

Quick background: Medical device sterilization, ethylene oxide (EtO) and impending policy shifts

  • Medical devices labeled as sterile: Many medical devices are intended for use (and are labeled accordingly) as sterile products. A variety of methods, including heat and radiation, can be used to sterilize medical devices that are labeled as sterile; however, the most widely used method is ethylene oxide (EtO) sterilization. The sterilization methods need to be validated as part of the medical device’s development process, to ensure both that the sterilization works as intended for microbial inactivation and that the device itself maintains its integrity and performance following sterilization.
  • The EPA, the FDA and EtO: While EtO is still the primary method for medical device sterilization, it is also a known carcinogen. The U.S. Environmental Protection Agency (EPA) has raised concerns for several years about exposure to EtO in manufacturing sites, and proximity of communities to facilities that use EtO. In 2023, EPA issued a new proposed regulation that would severely curtail EtO emissions in the U.S., which have already raised concerns for the medical device industry given a lack of other available, acceptable options for device sterilization. The final version of those regulations is currently pending administrative review at the White House Office of Management and Budget (OMB), the last step before a regulation can be released, with a targeted publication date of March 2024 (which is legally required under a consent decree).
  • For its part, FDA has acknowledged those federal efforts and has tried to advance alternatives, but options are still limited. The FDA does acknowledge that “sterilization with ethylene oxide may be the only method that effectively sterilizes and does not damage the device during the sterilization process” – but the agency has still been looking for alternatives. So far, results of that work have been limited. The agency has looked into alternative sterilization methods and options that could reduce the amount of EtO being used, as well as working to ease the regulatory pathways for changing or updating sterilization processes. These include the agency’s Sterilization Master File Pilot programs, which allow for manufacturers of certain products (with different pilots based on their marketing authorizations) to streamline some processes for changing or updating their manufacturing processes.
  • The concerns about EPA limiting EtO emissions are largely based around ensuring sufficient device supply. The EPA’s concerns about emissions have led to uncertainty for sterilization facilities, which in some cases have even closed. In 2019, the FDA put out a statement indicating that the agency was aware of these issues and outlining steps to mitigate supply concerns if sterilization processes were disrupted. The agency held an advisory committee meeting on the subject in 2019, and launched two associated innovation challenges – one to identify new methods for sterilization. That said, there are still significant concerns in this area, and the FDA’s Center for Devices and Radiological Health (CDRH) has recently been touting its new 506J medical device shortage or disruption voluntary reporting system as a way to keep the agency in the loop about disruptions, but without additional information about what next steps look like there.

For 2024, CDRH launched a series of town halls about device sterilization issues

  • The first town hall was held in January 2024, providing, as AgencyIQ noted at the time, an overview of the FDA’s perspectives on sterilization and the work it had undertaken in recent years. That session did not offer concrete recommendations or next steps for device industry representatives concerned about the impending rule change. The next two town halls – on January 26 and February 7 – followed in the same vein, with the agency largely recapping its own work since 2019 and taking some questions from the audience, but without broader discussions of any impending challenges. That said, it did provide a general opportunity to go over recent developments in sterilization policy.
  • The January 26 meeting: Identification of the challenges with switching modalities. The January 26 town hall focused on the outcomes of the 2019 advisory committee meeting (see the committee’s recommendations here), and what FDA had done to act on those recommendations. This included an FDA overview of the challenges that manufacturers face when seeking to update their approaches. As LISA SIMONE, EtO incident lead for CDRH’s Office of Strategic Partnerships and Technology Innovation (OST), acknowledged, “FDA understands that many portfolios are still heavily reliant on EtO use.” She also observed that “challenges shifting away from EtO use fall into several categories, including materials of construction, device and manufacture complexity and scale-up, and regulatory constraints, just to name a few.” In particular, Simone cited “material compatibility.” She went on to highlight “logistical challenges in switching modalities, for example, device and manufacturing complexity, sterilant penetration, and scalability.” Finally, she said, “we also understand that some devices might not be candidates to transition from EtO at this time.”
  • So, what can FDA do about that? For its part, the agency can focus on reducing the overall regulatory burden of switching modalities and invest in research in alternatives. Per Simone, “FDA can provide assistance by providing clarity to industry on understanding the current regulatory review practices and when a new submission may be necessary,” but also acknowledged that “validating a new sterilization modality is time and resource intensive” for manufacturers. During the town hall, representatives from CDRH noted that a medical device pre-submission could be a good option for seeking help with granular questions about regulatory expectations related to sterility.
  • The February 7 meeting: Pre-market submissions and an overview of the new 510(k) sterility guidance. In June 2023, FDA recognized a new consensus standard on the use of hydrogen peroxide as a sterilization method. As AgencyIQ discussed at the time, the FDA announced recognition of standards and technical information reports that focused both on hydrogen peroxide as a method and processes for changing methods. The newly recognized standards are ISO 22441:2022 and two Technical Information Reports (AAMI TIR104:2022 and AAMI TIR17:2019/(R)2020). ISO 22441 outlines processes for the sterilization of medical devices with low temperature hydrogen peroxide, while the technical reports focus on methods for manufacturers to make changes to radiation sterilization processes related to compatibility of materials, and also offer guidance on transferring products between methods.
  • In January 2024, the FDA issued a new version of its guidance for 510(k) pre-market notification submissions to bump vaporized hydrogen peroxide (VHP) up to an “Established Category A” (from a Category B) sterilization method. With this new version of the guidance, based on the standard recommendation, the agency effectively streamlined the regulatory requirements for switching to VHP as a sterilization method. The February town hall saw CDRH staff recapping what the different designations mean – Established Categories A and B, as well as Novel Sterilization methods – for the purposes of the 510(k) guidance (see an explainer here) and reviewing the Center’s existing recommendations for submitting sterility information in device Pre-Market Approval (PMA) applications.
  • A key option discussed at both town halls: Reduce paper labeling. Initially brought up by AdvaMed Senior Vice President of Technology and Regulatory Affairs KHATEREH CALLEJA at the January town hall, with reinforcement at the February town hall, the simple but effective solution of reducing sterilized paper labeling could reduce EtO loads. Notably, the 2019 advisory committee also recommended reducing or removing paper labeling wherever possible, given paper’s ability to absorb EtO. At the January town hall, Simone agreed that “the paper and e-labeling discussion is something… that’s been raised for several years,” conversations that recently saw some accelerating during the Covid-19 pandemic and “flexibilities” granted during the pandemic. However, the discussions appear to be ongoing: “we do have some internal discussions trying to explore how that might be possible. At this point in time, there are some advances in some areas with devices from the public health emergency that may or may not be the best starting avenue for e-labeling at this time. We are looking to find a device area or a particular situation that could make an impactful change in the amount of ethylene oxide that’s used, so something that could be a disposable high-volume device. And we’re focusing some of those efforts in that area,” Simone explained.
  • So, what’s next? FDA wants to hear from industry. Per the agency, they received several queries about this topic before the February 7 town hall. Notably, statutory requirements do allow for certain device labels to be made available solely by electronic means. CDRH’s AFTIN ROSS, deputy office director of OST’s Office of Readiness and Response, discussed next steps in looking at e-labeling as a way to reduce EtO emissions, noting that the agency is currently looking to hear directly from industry about the options for paper versus e-labeling, and the way it fits into the current regulatory framework. “We’re interested in the following,” said Ross: “First, if you’re using paper labeling for EtO sterilized devices where the statute permits electronic only, have you ever considered shifting from paper labeling to e-labeling as a risk mitigation measure for EtO reduction? If so, what are the strategies or best practices you considered? And are there any challenges or showstopper issues to be aware of?” She went on: “For those who might have already shifted to e-labeling, for EtO sterilized devices where permitted, we are looking for insights on whether you saw reduction in EtO use and if so what types of devices.” Finally, Ross asked “if there were any strategies or best practices that you considered as you made that transition, and what if any challenges you face as part of that transition?”
  • That said, it looks like these discussions at FDA are preliminary, with the agency still in fact-finding mode.

The next town hall will be February 29

  • The town hall will be at 1 pm ET. Per the webpage for the February 7 town hall, “tentative topics” include “FDA Modifications (Mods) Guidances and the use of Master Files in Review.” This will likely include a deep-dive overview into the master file pilot programs.
  • After that will come a March 21, 2024, town hall. “Tentative topics: Using Standards in Premarket Submissions and the FDA Standards Program.”
  • So far, the town halls appear to be more of a fact-finding mission for the FDA, and a way for the agency to publicize its last five years of work on sterilization policy. The agency continues to emphasize that it wants to hear directly from impacted industry about the logistical and operational challenges they are facing, which could potentially be rolled into new regulatory flexibility. However, the way that regulatory flexibility can mitigate the cross-cutting scientific, financial and practical barriers that industry faces transitioning away from EtO remains to be seen.

To contact the author of this item, please email Laura DiAngelo ( ldiangelo@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

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