[Federal Register Volume 88, Number 70 (Wednesday, April 12, 2023)]
[Notices]
[Pages 22040-22043]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-07598]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-0721]


Center for Devices and Radiological Health Radiation 
Sterilization Master File Pilot Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration's (FDA, Agency, or we) Center 
for Devices and Radiological Health (CDRH or Center) is announcing its 
Radiation Sterilization Master File Pilot Program (``Radiation Pilot 
Program''). The Radiation Pilot Program is voluntary and intends to 
allow companies that terminally sterilize single-use medical devices 
(``sterilization providers'') using gamma radiation or ethylene oxide 
(EO) to submit Master File(s) when making certain changes to 
sterilization sites, methods, or processes under the specific 
conditions outlined in this notice. Under this voluntary pilot program, 
manufacturers of class III devices subject to premarket approval (``PMA 
holders'') who have been granted a right of reference by a 
sterilization provider may, upon notification from FDA that a 
manufacturer may do so, include references to Master File(s) accepted 
into the Radiation Pilot Program in postapproval reports describing the 
particular changes noted above affecting the sterilization sites, 
methods, or processes of their class III devices, in lieu of submitting 
premarket approval application (PMA) supplements for such changes. By 
helping industry advance alternatives for gamma radiation and EO 
sterilization of medical devices, the Radiation Pilot Program seeks to 
help ensure patient access to safe medical devices and, through 
evaluation of data from pilot participants, provide insights into 
future regulatory approaches that may help address potential device 
shortages related to sterilization site, method, or process shifts and 
facilitate supply chain resiliency.

DATES: FDA is seeking participation in the voluntary Radiation Pilot 
Program beginning April 12, 2023. See the ``Participation'' section for 
eligibility criteria for participation in the Radiation Pilot Program 
and the ``Procedures'' section for instructions on how to submit a 
Master File for consideration for inclusion into the Radiation Pilot 
Program. Up to nine eligible participants may be selected for the 
Radiation Pilot Program.

FOR FURTHER INFORMATION CONTACT: Clarence W. Murray, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 4536, Silver Spring MD 20993, 301-796-
0270, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Radiation-based sterilization is widely used to sterilize medical 
devices and thereby keep them safe for patient use. Established sources 
of radiation that may be used to generate radiation for medical device 
sterilization in accordance with FDA-recognized international consensus 
standards include gamma radiation, x-rays, and electron beams. Of these 
three types of radiation-based sterilization, gamma radiation is the 
most frequently used radiation source for medical device sterilization 
and, more broadly, is the second most frequently used sterilization 
method by sterilization providers,\1\ accounting for approximately 40 
to 45 percent of sterile medical devices (Ref. 1). The most frequently 
used sterilization method is ethylene oxide (EO), which is used to 
sterilize approximately 50 percent of sterile medical devices (Ref. 2).
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    \1\ In this notice, ``method'' or ``modality'' generally refers 
to the type of sterilization and ``processes'' generally refers to 
steps within that method to achieve a sterile device.
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    Before sterile medical devices subject to PMA requirements are 
approved for marketing, FDA reviews the submitted PMA to determine if 
the sterility information is adequate (e.g., in accordance with 
internationally agreed upon voluntary consensus standards that FDA 
recognizes). If a medical device manufacturer changes the sterilization 
method (i.e., changes the type of sterilization modality used), 
process, or facility identified in its original PMA submission for 
sterilizing its devices, the manufacturer generally needs to submit a 
PMA supplement so the Agency can review these changes (Ref. 3).
    However, FDA recognizes the need to facilitate more timely changes 
to alternative sterilization methods, processes, or sites among 
sterilization providers who use gamma radiation or EO to support 
sterilization supply chain resiliency.\2\ In the case of gamma 
radiation, the radiation used for medical device sterilization is 
generated using radioactive cobalt (Co\60\) as a source material, and 
there may be potential supply chain constraints for Co\60\ relative to 
the level of demand for radiation sterilization (Ref. 4). FDA also is 
aware of ongoing supply chain considerations for EO sterilization of 
medical devices as well as concerns about the effects of EO exposure 
and environmental emissions. In 2019, FDA

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was made aware of closures of device sterilization facilities due to 
concerns about the level of EO emissions (Ref. 5). The Agency worked 
with device manufacturers affected by the closures to minimize impact 
to patients who needed device access and continues to work with 
manufacturers and collaborate with external stakeholders to mitigate 
the risk of device shortages related to reduction in EO sterilization 
capacity.\3\
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    \2\ Further, FDA more generally seeks to improve and strengthen 
the device supply chain through other broader initiatives, such as 
the planned Resilient Supply Chain and Shortages Prevention Program 
(RSCSPP). See FDA's Budget, Medical Device Supply Chain and 
Shortages Prevention Program, https://www.fda.gov/news-events/fda-voices/fdas-budget-medical-device-supply-chain-and-shortages-prevention-program.
    \3\ For more information regarding FDA's sterilization master 
file pilot programs and other ongoing efforts to facilitate 
innovation in medical device sterilization, see the Agency's 
website, Sterilization for Medical Devices, available at: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/sterilization-medical-devices.
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    For these reasons, FDA is announcing and soliciting voluntary 
participation in the Radiation Pilot Program. Under this pilot program, 
sterilization providers that sterilize single-use medical devices using 
gamma radiation may submit a Master File when making certain changes 
between sterilization sites, certain changes to sterilization methods 
to utilize non-gamma radiation sources (i.e., x-ray or electron beam), 
or certain changes to sterilization processes to utilize reduced gamma 
radiation doses. Also under this pilot program, sterilization providers 
that sterilize single-use medical devices using EO may submit a Master 
File when changing from an EO sterilization method to an x-ray or 
electron beam-based sterilization method. After a Master File has been 
submitted by a sterilization provider and accepted into the Radiation 
Pilot Program, a PMA holder may, upon FDA's permission, include a 
reference to a Master File in a postapproval report filed in accordance 
with Sec.  814.84 (21 CFR 814.84), as relevant to describe changes 
affecting the sterilization of the PMA holder's class III device(s) and 
provided that the PMA holder has a right of reference to the Master 
File. The PMA holder may include this reference in a postapproval 
report to satisfy the requirements of Sec.  814.39(a) and (e) (21 CFR 
814.39(a) and (e)) and in lieu of submitting a PMA supplement for such 
changes. This pilot program is intended to provide expeditious review 
and feedback to sterilization providers on Master File submissions used 
to support certain changes made to sterilization sites, methods, or 
processes, and to PMA holders on the ability to reference such Master 
Files in a postapproval report rather than a PMA supplement. A 
postapproval report filed under this pilot program does not remove or 
replace the requirement to submit periodic (annual) reports identifying 
changes made to the PMA under Sec.  814.39(b). FDA intends to evaluate 
pilot participation and the progress of the pilot in 6-month increments 
to inform possible longer term initiatives related to device 
sterilization methods and provide any updates to the pilot in a 
subsequent notice, if appropriate. At this time, PMAs reviewed by the 
Center for Biologics Evaluation and Research (CBER) and PMAs for 
combination products \4\ are not eligible for this pilot. FDA is not 
including 510(k) devices within the scope of the pilot at this time. 
Manufacturers of 510(k) devices that are sterilized using gamma 
radiation or EO, and that are affected by changes to sterilization 
sites, methods, and/or processes, should evaluate the changes according 
to FDA's Guidance, ``Deciding When to Submit a 510(k) for a Change to 
an Existing Device'' \5\ to determine whether a new 510(k) is 
required.\6\
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    \4\ See 21 CFR 3.2(e).
    \5\ FDA Guidance, ``Deciding When to Submit a 510(k) for a 
Change to an Existing Device'' is available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device.
    \6\ Generally, a new 510(k) would not be required for the types 
of changes described in this pilot if, following evaluation under 
the relevant regulations, a device manufacturer determines that the 
changes could not significantly affect the performance or 
biocompatibility of the device, or constitute a major change or 
modification in the intended use of the device.
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    For the purposes of this document, the term ``sterilization 
provider'' includes a device manufacturer's own in-house sterilization 
facility or a device manufacturer's contract sterilization provider and 
encompasses any subcontractor facilities utilizing the same quality 
system as the contract sterilization provider, as applicable.

A. Participation

    Up to nine sterilization providers may be included for 
participation in this voluntary Radiation Pilot Program. The pilot 
program is limited to selected sterilization providers that follow the 
procedures set forth in section I.B and that also meet the following 
eligibility criteria:
    1. Be a sterilization provider of a single-use device that is 
provided sterile;
    2. Be in good compliance standing with the Agency;
    3. Have an approved gamma radiation or fixed chamber EO 
sterilization process for the device in an existing PMA; and
    4. Be proposing one of the following changes:
    a. A change from a gamma radiation sterilization process at an 
existing PMA-approved sterilization site to the same gamma radiation 
sterilization process at a different site for the same sterilization 
provider;
    b. A change from a gamma radiation sterilization process at an 
existing PMA-approved sterilization site to an x-ray or electron beam 
radiation sterilization process at the same site or at a different site 
for the same sterilization provider;
    c. A change from a gamma radiation sterilization process at an 
existing PMA-approved sterilization site to a gamma radiation 
sterilization process with a lower radiation dose than the original 
process at the same site or at a different site for the same 
sterilization provider; or
    d. A change from a fixed chamber EO sterilization method at an 
existing PMA-approved sterilization site to an x-ray or electron beam 
radiation sterilization method at the same site or at a different site 
for the same sterilization provider.
    Sterilization processes that include changes to the sterilization 
dose, radiation source (e.g., gamma radiation changed to electron beam 
or x-ray radiation), or sterilization method that may impact the 
device's specifications, device performance, biocompatibility, 
toxicology, or safety and effectiveness profile, and for which 
appropriate risk mitigation measures that would prevent such impacts 
are not identified, are outside the scope of the Radiation Pilot 
Program. For the changes described in 4 above, the sterilization 
validation activities for the new radiation sterilization process 
should conform to the FDA-recognized consensus standards found in Parts 
1 through 3 of ISO 11137: Sterilization of health care products--
Radiation to be within the scope of this pilot program. Sterilization 
providers who do not meet criteria 1 to 4 listed above will be deemed 
ineligible for the Radiation Pilot Program.
    The following are outside the scope of the Radiation Pilot Program 
and are inappropriate for inclusion in this pilot:
    1. Reusable devices, reprocessed single-use devices, or devices 
that are provided non-sterile.
    2. Combination products.
    3. Devices regulated by CBER.
    4. Sterilization providers that do not have an approved gamma 
radiation or fixed chamber EO sterilization process for the device in 
an existing PMA.
    5. Changes in contract sterilization providers or addition of a new 
sterilization provider not approved in an existing PMA.
    6. Changes to device design, specifications, or materials.
    7. Sterilization processes used only for intermediate processing 
prior to final device assembly.

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    8. Devices with alternate sterility assurance levels other than 
10-\6\.

B. Procedures

    While the sterilization provider serves as the primary participant 
of the Radiation Pilot Program, FDA anticipates that close 
collaboration between sterilization providers and PMA holders will be 
necessary to ensure the success of the pilot program. Accordingly, the 
procedures for sterilization providers and PMA holders are set forth 
below.
1. Procedures for Sterilization Providers
    To be considered for the voluntary Radiation Pilot Program, a 
sterilization provider should submit the following information in a 
Master File for the Agency's review with a cover sheet clearly 
indicating ``Radiation Sterilization Master File Pilot Program'' in the 
subject heading:
    a. Name, address, and FDA Establishment Identification (FEI) number 
of the proposed sterilization facility.
    b. List of device(s) to be sterilized (identified by manufacturer, 
trade name, model number, and PMA number) if known at the time of 
submission, and a letter of authorization from each PMA holder for each 
identified device.\7\
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    \7\ List of device(s) should reflect known devices to be 
sterilized at the time of submission of the Master File. Subsequent 
revisions to the list of device(s) should be submitted as an 
amendment to the Master File.
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    c. Clear identification of all responsibilities of the 
sterilization facility and device manufacturers with respect to 
sterilization validation.
    d. For sterilization providers proposing to implement changes 
according to section (I)(A)(4)(a through c) above: a complete 
description of all qualification testing used to support validation of 
the device(s) under the proposed radiation sterilization process 
including:
    (1) A complete description of the proposed sterilization cycle(s) 
including radiation type, target dose, dose range, sterilization load 
geometry relative to the radiation source, etc.
    (2) A risk analysis with identified risk mitigation measures to 
address any risks that may impact the PMA approved device's product 
parameters or safety and effectiveness profile. This should also 
include an analysis of material compatibility considerations and how 
risks related to material compatibility are mitigated.
    (3) Installation Qualification, Operational Qualification, and 
Performance Qualification methodology.
    (4) Clear, detailed product definition, along with a documented 
procedure for determining whether a device meets the product 
definition, or confirmation that the product definition has not 
differed from the approved PMA.
    (5) All reports, protocols, and process summaries presented in an 
easily understandable template that supports incorporation of the PMA 
product to be sterilized in its defined package and load configuration.
    (6) Process capability for the radiation sterilization process.
    (7) Identification and explanation of common potential protocol 
deviations, along with proposed mitigation of potential deviations. The 
Master File should also include a strategy to address any deviations 
that could significantly affect the safety or effectiveness of a device 
and any deviations not addressed in the Master File.
    (8) Identification and explanation of management structure and 
involvement for process and facility review.
    (9) Acceptable installation and operational requalification 
schedule to support continuous process effectiveness.
    (10) A structured program and schedule for independent audits and 
monitors.
    (11) The sterilization facility's inspectional history and history 
of compliance with applicable regulations (including, but not limited 
to, requirements under parts 814 and 820 (21 CFR parts 814 and 820)).
    e. For sterilization providers proposing to implement changes 
according to section (I)(A)(4)(d) above: in addition to the description 
of all qualification testing used to support validation of the 
device(s) under the proposed radiation sterilization process requested 
in section (I)(B)(1)(d) above:
    (1) A description of how the change from EO sterilization to 
radiation sterilization is validated to not negatively impact device 
performance or specifications.
    (2) A description of how biocompatibility is assessed for devices 
that are switched from EO sterilization to radiation sterilization and 
the methods used to ensure that biocompatibility is not significantly 
affected.
    (3) A description of how material compatibility is assessed to 
support the change from EO sterilization to radiation sterilization.
    For more information on Master Files, see FDA's website: https://www.fda.gov/medical-devices/premarket-approval-pma/master-files.
    Upon receipt of a Master File containing the above information, FDA 
will determine a sterilization provider's eligibility in the pilot 
program by evaluating whether the criteria outlined in sections (I)(A) 
and (I)(B)(1) above have been met and provide written feedback that FDA 
either accepts the Master File into the Radiation Pilot Program, or 
rejects the Master File as not eligible for the pilot program. FDA 
intends to work interactively with the Master File holder to address 
any deficiencies with the information provided in the Master File. If a 
Master File is rejected from the pilot program, the written feedback 
will identify the reason(s) the Master File was rejected.
    If accepted into the pilot program, the Master File holder should 
submit amendments every 6 months with information on any process 
changes, new devices, or PMA submissions brought into the pilot 
program, and any other changes to the information contained in the 
Master File, to maintain participation in the pilot program. If there 
are no updates or changes, the Master File holder should notify FDA of 
the absence of any updates or changes in the amendment. If a 
sterilization provider is accepted into the pilot program and does not 
maintain participation (e.g., through non-submission of amendments, 
updates, or other information requested by FDA under the pilot program 
or through no longer meeting the eligibility criteria) or no longer 
wishes to participate in the pilot program, the sterilization provider 
should notify PMA holders to whom they granted a right of reference to 
the Master File. If the Master File holder does not maintain 
participation in the pilot program, FDA may determine that the Master 
File is outside the scope of the pilot program.
2. Procedures for PMA Holders
    FDA will consider permitting PMA holders affected by a 
sterilization provider's participation in the Radiation Pilot Program 
to reference the sterilization provider's existing Master File in a 
postapproval report to the Agency, as an alternative to the submission 
of a PMA supplement under Sec.  814.39(a) and (e). The postapproval 
report should be submitted with a cover sheet clearly indicating 
``Periodic Report for Radiation Sterilization Master File Pilot 
Program'' in the subject heading, in accordance with Sec.  814.84,\8\ 
and with the following information:
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    \8\ If the PMA holder chooses, they may provide a reference to 
the Master File in a postapproval report in lieu of the information 
required under Sec.  814.84(b)(2)(I) as it pertains to the 
sterilization changes described in the Master File, if the 
information included in the postapproval report is determined to be 
acceptable as described in this pilot notice.

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    a. Name, address, and FEI number of the sterilization facility.
    b. Master File number in which the referenced sterilization 
procedures are described, with signed right of reference from the 
Master File holder.
    c. List of device(s) sterilized (identified by manufacturer, trade 
name, model number, and PMA number).
    Upon receipt of a postapproval report containing the above 
information, FDA will notify the PMA holder of whether the postapproval 
report is permitted as an alternate submission under Sec.  814.39(a) 
and (e). Additionally, FDA will notify the PMA holder of whether the 
PMA identified device(s) and referenced Master File are eligible for 
the sterilization provider's participation in the pilot. If the PMA is 
not eligible for the sterilization provider's participation in the 
pilot program, FDA will notify the PMA holder of the reasons for 
rejection.
    This Pilot Program does not otherwise remove or replace any 
requirements, such as, but not limited to, recordkeeping and reporting 
requirements under part 814 or part 820. It is the manufacturer's 
responsibility to ensure compliance with applicable laws and 
regulations administered by FDA.
    During this voluntary Radiation Pilot Program, CDRH staff intends 
to be available to answer questions or concerns that may arise. The 
Radiation Pilot Program participants may comment on and discuss their 
experiences with the Center.

II. Paperwork Reduction Act of 1995

    This notice refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The 
collections of information in part 814, subparts A through E, regarding 
premarket approval, have been approved under OMB control number 0910-
0231. The collections of information in part 820, regarding the Quality 
System Regulation, have been approved under OMB control number 0910-
0073.

III. References

    The following references are on display at the Dockets Management 
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 
1061, Rockville, MD 20852, 240-402-7500, and are available for viewing 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they are also available electronically at https://www.regulations.gov. 
FDA has verified the website addresses, as of the date this document 
publishes in the Federal Register, but websites are subject to change 
over time.

    1. FDA, ``FDA Executive Summary Prepared for the November 6-7, 
2019 meeting of the General Hospital and Personal Use Devices Panel 
of the Medical Devices Advisory Committee,'' available at: https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-7-2019-general-hospital-and-personal-use-devices-panel-medical-devices-advisory-committee.
    2. FDA, Sterilization for Medical Devices, available at: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/ethylene-oxide-sterilization-medical-devices.
    3. FDA, PMA Supplements and Amendments, available at: https://www.fda.gov/medical-devices/premarket-approval-pma/pma-supplements-and-amendments.
    4. National Academies of Sciences, Engineering, and Medicine. 
2021. Radioactive Sources: Applications and Alternative 
Technologies. Washington, DC: The National Academies Press. https://doi.org/10.17226/26121.
    5. FDA, ``Statement on Concerns With Medical Device Availability 
Due to Certain Sterilization Facility Closures,'' available at: 
https://www.fda.gov/news-events/press-announcements/statement-concerns-medical-device-availability-due-certain-sterilization-facility-closures.

    Dated: April 6, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-07598 Filed 4-11-23; 8:45 am]
BILLING CODE 4164-01-P