US FDA recognition of Vaporized Hydrogen Peroxide sterilization as Established Category A method

Over the past years, the US FDA has announced a number of initiatives, including Ethylene Oxide (EO) Innovation Challenges and Master File Pilot programs, to advance innovation and streamline the regulatory pre-market approval process. On 8 January 2024, the US FDA announced the re-issue of the guidance titled “Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile”, superseding its 2016 version. [1] In this blog, we will explore what are the significant changes in the guidance; what prompted these changes; and what are the implications for medical device manufacturing.

What has changed in the guidance?

A key update in the guidance is the inclusion of Vaporized Hydrogen Peroxide (VHP) as an Established Category A sterilization method. [2] VHP is now added to the list of examples of established methods, which previously included dry and Moist Heat, EO and radiation.

What is a Cat A sterilization method?

Established methods are those that “have a long history of safe and effective use” and, most importantly, where there are “consensus standards for development, validation, and routine control that are recognized by FDA”.

How does VHP meet the criteria of Cat A?

VHP has a long history of use in device sterilization. [3] In more recent times, VHP sterilization has been used for larger scale terminal sterilization applications. [4] Currently, terminal sterilization of medical devices is provided by EO and radiation in equal proportions. [5] Albeit limited in application for large scale device sterilization, the use of VHP is being explored for many niche sterilization applications. Due to incompatibility with cellulosic materials, such applications are typically in-line/end-of-line operations. Devices that may potentially avail of VHP terminal sterilization include pre-filled syringes, orthopaedic implants, heat and radiation sensitive devices, and implants with electronics and sensors. As part of industry’s efforts to develop VHP for such applications, fundamental research has been performed to confirm the appropriateness of validation methods (e.g. half-cycle and cycle calculation overkill methods), which, in parallel, has helped inform the generation of a dedicated ISO consensus standard. [6]

In August 2022, ISO issued ISO 22441 “Sterilization of health care products - Low temperature vaporized hydrogen peroxide - Requirements for the development, validation and routine control of a sterilization process for medical devices” and, significantly, the US FDA recognized this standard in July 2023. [7]

Note: Recognition of ISO 22441 resulted in the standard being included in the US FDA database of Recognized Consensus Standards applicable to medical devices. [8] It is this recognition which was the final element for VHP in achieving Cat A status.

What does this all mean?

As described in the FDA guidance, [9] manufacturers of devices submitting a 510(k) should follow the same process as other traditional and established methods, such as EO and radiation. In the submission, the validation method used in compliance with ISO 22441 should be stated. However, there is no requirement for the validation data itself in the submission. [10] Such submissions for non-established methods will demonstrate compliance to ISO 14937 and usually require evidence of sterilant microbicidal efficacy in accordance with section 5.3. [11] Also, in accordance with other FDA guidance, [12] when changing sterilization methods for a Class II medical device from an established category B or Novel method to an established category A method, a new 510(k) submission is generally recommended. However, changes from one established category A method to another established category A method may not require a new submission as long as the change could not significantly impact the performance or biocompatibility of the medical device. Therefore, the regulatory burden of requiring a new 510(k) submission and clearance is reduced when switching sterilization methods from EO or radiation to VHP as long as there is no impact on device performance or biocompatibility.

In summary, this revision to the guidance by the US FDA demonstrates the acceptance of VHP as an Established Method and allows for streamlined regulatory pathways, consistent with those long established for steam, dry and moist heat, EO and radiation. As stated by the US FDA, “Moving VHP from Established Category B to Established Category A reduces the regulatory burden on manufacturers using this sterilization process for devices that need a 510(k)”. [13] 

[1] Sterilization for Medical Devices | FDA (www.fda.gov/medical-devices/general-hospital-devices-and-supplies/sterilization-medical-devices#FDAStandards).

[2] Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile (www.fda.gov/media/74445/download).

[3] McEvoy, B. and Rowan, N.J., 2019. Terminal sterilization of medical devices using vaporized hydrogen peroxide: a review of current methods and emerging opportunities. Journal of applied microbiology, 127(5), pp.1403-1420.

[4] McEvoy, B. and Eveland, R., 2020. Vaporized Hydrogen Peroxide: A Well-Known Technology with a New Application. Biomedical Instrumentation & Technology, 54(s1), pp.74-79.

[5] http://gipalliance.net/wp-content/uploads/2013/01/GIPA-WP-GIPA-iia-Sterilization-Modalities-FINAL-Version-2017-October-308772.pdf.

[6] McEvoy, B., Maksimovic, A. and Rowan, N.J., 2023. Geobacillus stearothermophilus and Bacillus atrophaeus spores exhibit linear inactivation kinetic performance when treated with an industrial scale vaporized hydrogen peroxide (VH2O2) sterilization process. Journal of Applied Microbiology, 134(1), p.lxac028.

[7] ISO 22441:2022 - Sterilization of health care products — Low temperature vaporized hydrogen peroxide — Requirements for the development, validation and routine control of a sterilization process for medical devices (https://www.iso.org/standard/73214.html).

[8] Recognized Consensus Standards: Medical Devices (www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm).

[9] Ibid 2.

[10] Note: For other non-established methods where a recognized dedicated standard does not exist, ‘a comprehensive description of the process and the complete validation protocol should be submitted’ for review.

[11] ISO 14937:2009 - Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices (www.iso.org/standard/44954.html).

[12] Deciding When to Submit a 510(k) for a Change to an Existing Device | FDA (www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device).

[13] Ibid 1.