Notice2023-07598
Center for Devices and Radiological Health Radiation Sterilization Master File Pilot Program
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Published
April 12, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 88 Issue 70 (Wednesday, April 12, 2023)</title>
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[Federal Register Volume 88, Number 70 (Wednesday, April 12, 2023)]
[Notices]
[Pages 22040-22043]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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, <a href="/cdn-cgi/l/email-protection#4f0c232e3d2a212c2a61023a3d3d2e360f292b2e6127273c61282039"><span class="__cf_email__" data-cfemail="22614e4350474c41470c6f575050435b624446430c4a4a510c454d54">[email protected]</span></a>.
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
[[Page 22041]]
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, <a href="https://www.fda.gov/news-events/fda-voices/fdas-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</a>.
\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: <a href="https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/sterilization-medical-devices">https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/sterilization-medical-devices</a>.
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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: <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device</a>.
\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<SUP>-</SUP>\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: <a href="https://www.fda.gov/medical-devices/premarket-approval-pma/master-files">https://www.fda.gov/medical-devices/premarket-approval-pma/master-files</a>.
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-7-2019-general-hospital-and-personal-use-devices-panel-medical-devices-advisory-committee">https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-7-2019-general-hospital-and-personal-use-devices-panel-medical-devices-advisory-committee</a>.
2. FDA, Sterilization for Medical Devices, available at: <a href="https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/ethylene-oxide-sterilization-medical-devices">https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/ethylene-oxide-sterilization-medical-devices</a>.
3. FDA, PMA Supplements and Amendments, available at: <a href="https://www.fda.gov/medical-devices/premarket-approval-pma/pma-supplements-and-amendments">https://www.fda.gov/medical-devices/premarket-approval-pma/pma-supplements-and-amendments</a>.
4. National Academies of Sciences, Engineering, and Medicine.
2021. Radioactive Sources: Applications and Alternative
Technologies. Washington, DC: The National Academies Press. <a href="https://doi.org/10.17226/26121">https://doi.org/10.17226/26121</a>.
5. FDA, ``Statement on Concerns With Medical Device Availability
Due to Certain Sterilization Facility Closures,'' available at:
<a href="https://www.fda.gov/news-events/press-announcements/statement-concerns-medical-device-availability-due-certain-sterilization-facility-closures">https://www.fda.gov/news-events/press-announcements/statement-concerns-medical-device-availability-due-certain-sterilization-facility-closures</a>.
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
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