[Federal Register Volume 84, Number 228 (Tuesday, November 26, 2019)]
[Notices]
[Pages 65162-65164]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-25631]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-5465]


Center for Devices and Radiological Health Ethylene Oxide 
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 or Agency or we) 
Center for Devices and Radiological Health (CDRH or Center) is 
announcing its Ethylene Oxide Sterilization Master File Pilot Program 
(``EtO Pilot Program''). The EtO Pilot Program is voluntary and intends 
to allow companies (``sterilization providers'') that sterilize single-
use medical devices using fixed chamber ethylene oxide (EtO) to submit 
a Master File when making certain changes between sterilization sites 
or when making certain changes to sterilization processes that utilize 
reduced EtO concentrations. Under this voluntary program, manufacturers 
(``PreMarket Application (PMA) holders'') of Class III devices subject 
to premarket approval that are affected by such changes may, upon FDA's 
permission, reference the Master File submitted by their sterilization 
provider in a postapproval report in lieu of submission of a premarket 
approval application (PMA) supplement. The EtO Pilot Program seeks to 
help ensure patient access to safe medical devices while encouraging 
new, innovative ways to sterilize medical devices that reduce the 
potential impact of EtO on the environment and on the public health 
while providing a regulatory approach that would address potential 
device shortages.

DATES: FDA is seeking participation in the voluntary EtO Pilot Program 
beginning November 26, 2019. See the ``Participation'' section for 
selection criteria for participation in the EtO Pilot Program and the 
``Procedures'' section for instructions on how to submit a Master File 
for consideration for inclusion into the EtO Pilot Program. Up to nine 
eligible participants may be selected for the EtO Pilot Program.

FOR FURTHER INFORMATION CONTACT: Steven Elliott, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 4630, Silver Spring, MD 20993, 301-796-5285, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    EtO sterilization is an important sterilization method that is 
widely used to keep medical devices safe. Medical devices made from 
certain polymers (such as plastic or resin), metals, or glass--or 
devices that have multiple layers of packaging or hard-to-reach 
crevices (such as catheters)--are often sterilized with EtO to avoid 
product damage during the sterilization process. It is estimated that 
approximately 50 percent of all sterile medical devices in the United 
States are sterilized using EtO (Ref. 1).
    For many medical devices, sterilization with EtO may be the only 
method \1\ currently evaluated that effectively sterilizes and does not 
damage the device during the sterilization process. However, there have 
been recent concerns about the effects of EtO exposure and 
environmental emissions. Earlier this year, the FDA was made aware of 
the closures of two device sterilization facilities due to concerns 
about the level of EtO emissions (Ref. 2). Since then, the Agency has 
been closely monitoring the situation and working with device 
manufacturers affected by the closures to minimize impact to patients 
who need device access. FDA continues to work with manufacturers on 
site changes and engage with manufacturers about potential solutions to 
shortage concerns. FDA has also taken several actions to advance 
medical device sterilization, including sponsoring two innovation 
challenges to identify alternatives to EtO sterilization methods (Ref. 
3) and approaches to reduce EtO emissions (Ref. 4), and convening the 
General Hospital and Personal Use Devices Panel on November 6 to 7, 
2019 (November 2019 Panel Meeting), to discuss the role of EtO 
sterilization in maintaining public health (84 FR 46546; see also Ref. 
5).
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    \1\ In this notice, ``method'' generally refers to the type of 
sterilization and ``processes'' generally refers to steps within 
that method to achieve a sterile device. Changes from a conventional 
EtO cycle to reduced/optimized EtO cycles would be considered a 
process change.
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    Before most sterile medical devices are on the market, FDA reviews 
premarket submissions to determine if the sterility information is 
adequate (e.g., in accordance with internationally agreed upon 
voluntary consensus standards that the FDA recognizes). If a medical 
device manufacturer changes the method, process, or the 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. 6). However, considering recent 
events and concerns regarding EtO emissions, FDA recognizes the need to 
facilitate timely site changes to keep supply interruptions at a 
minimum and to facilitate changes to sterilization processes that 
utilize reduced EtO concentrations. At the November 2019 Panel Meeting, 
FDA received feedback from Panel members and stakeholders that the 
Agency could help prevent medical device shortages and advance medical 
device sterilization by expediting approvals of certain changes to EtO 
sterilization methods, processes, and facilities (Ref. 5).
    For these reasons, FDA is announcing and soliciting participation 
in the EtO Pilot Program. Under this pilot program, sterilization 
providers that sterilize single-use medical devices using fixed chamber 
EtO would submit a Master File when making certain changes between 
sterilization sites or when making certain changes to sterilization 
processes that utilize reduced EtO concentrations. Under this voluntary 
program, PMA holders of Class III devices affected by such changes may, 
upon FDA's permission, reference the Master File submitted by their 
sterilization provider in a postapproval report, in accordance with 
Sec.  814.84 (21 CFR 814.84), in lieu of submission of a PMA 
supplement, to satisfy the requirements of Sec.  814.39(a) and (e) (21 
CFR 814.39(a) and (e)). The pilot program is intended to provide 
expeditious review and feedback to sterilization providers and PMA 
holders on Master File submissions used to support changes made to 
sterilization site and/or processes in a postapproval report rather 
than a PMA supplement. FDA intends to evaluate pilot participation and 
the progress of the pilot in 6 months and provide any updates to the 
pilot in a subsequent notice, if appropriate. This postapproval report 
does not remove or replace the

[[Page 65163]]

requirement to submit periodic (annual) reports identifying changes 
made to the PMA under Sec.  814.39(b). At this time, PMAs reviewed by 
the Center for Biologics Evaluation and Research and PMAs for 
combination products \2\ are not eligible for this pilot.\3\
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    \2\ See 21 CFR 3.2(e).
    \3\ FDA is not including 510(k) devices within the scope of the 
pilot at this time. Manufacturers of 510(k) devices affected by such 
changes should evaluate the changes according to FDA's Guidance, 
``Deciding When to Submit a 510(k) for a Change to an Existing 
Device'' in determining whether a new 510(k) is required (available 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device). 
Generally, a new 510(k) would not be required for the types of 
changes subject to this pilot.
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    For the purposes of this document, the term ``sterilization 
provider'' is used to refer to 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. For the purposes of this document, the term 
``Conventional EtO cycle'' is used to refer to an EtO cycle that 
utilizes concentrations of sterilant greater than 600 mg/L to sterilize 
medical devices, and the term ``Reduced/Optimized EtO Concentration 
cycle'' is used to refer to an EtO cycle that utilizes concentrations 
of sterilant significantly below 600 mg/L to sterilize medical devices.

A. Participation

    Up to nine sterilization providers are eligible to participate in 
this voluntary EtO 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 selection qualities:
    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 fixed chamber EtO sterilization process for the 
device in an existing PMA; and
    4. Be proposing one of the following changes:
    a. A change from a Conventional EtO cycle at an existing PMA-
approved sterilization site to a Conventional EtO cycle at a different 
site for the same sterilization provider (including EtO chamber changes 
within the same sterilization site);
    b. A change from a Conventional EtO cycle at an existing PMA-
approved sterilization site to a Reduced/Optimized EtO Concentration 
cycle at the same site for the same sterilization provider; or
    c. A change from a Conventional EtO cycle at an existing PMA-
approved sterilization site to a Reduced/Optimized EtO Concentration 
cycle at a different site for the same sterilization provider.
    Sterilization processes that include cycle parameters (e.g., 
increased temperature, pressure, humidity) outside validated tolerances 
that may impact device specifications, device performance, EtO 
residuals, biocompatibility or toxicology from the approved PMA device 
are outside the scope of the EtO Pilot Program. For site changes from a 
Conventional EtO cycle at an existing site to a Conventional EtO cycle 
at a different site (including EtO chamber changes within the same 
sterilization site) described in 4a above, the sterilization validation 
activities for the new cycle should be conducted in accordance with the 
validation activities in the manufacturer's approved PMA to be eligible 
for this pilot program. For changes from a Conventional EtO cycle to a 
Reduced/Optimized EtO Concentration cycle described in 4b and 4c above, 
the sterilization validation activities for the new cycle should 
conform to the FDA recognized consensus standard ISO 11135: 2014 
``Sterilization of health care products--Ethylene oxide--Requirements 
for development, validation and routine control of a sterilization 
process for medical devices'' to be eligible for this pilot program. 
Participants who do not meet these criteria will be deemed ineligible 
for the EtO Pilot Program.
    The following are outside the scope of the EtO Pilot Program and 
are inappropriate for inclusion in this program:
    1. Reusable devices, reprocessed single-use devices, or devices 
that are provided non-sterile.
    2. Sterilization providers that do not have an approved fixed 
chamber EtO sterilization process for the device in an existing PMA.
    3. Changes in contract sterilization providers or addition of a new 
sterilization provider using a sterilization process not approved in an 
existing PMA.
    4. Changes to device design, specifications, or materials.
    5. Packaging changes.
    6. Load configuration/composition changes.
    7. Sterilization processes used only for intermediate processing 
prior to final device assembly.
    8. Devices with alternate sterility assurance levels other than 
10-6.
    9. Devices with specialized requirements for biocompatibility or 
sterilant residual compatibility that differ from ISO 10993-7 
``Biological evaluation of medical devices--Part 7: Ethylene oxide 
sterilization residuals.''

B. Procedures

    While the sterilization provider serves as the primary participant 
of the EtO Pilot Program, FDA anticipates that close collaboration 
between sterilization providers and PMA holders will be necessary to 
ensure the success of the 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 EtO 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 ``Ethylene Oxide 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 PMA device(s) to be sterilized (identified by 
manufacturer, trade name, model number, and PMA number) and letter of 
authorization from each PMA holder for each identified device.\4\
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    \4\ 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 the device manufacturer.
    d. Complete description of all sterilization validation information 
\5\ used to support validation of the PMA device(s) under the proposed 
EtO sterilization process including:
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    \5\ Sterilization providers may wish to refer to ISO 11135:2014 
for information regarding sterilization validation.
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    i. A risk analysis with identified risk mitigation measures to 
address any risks that may impact the PMA approved device with respect 
to its product parameters or safety and effectiveness profile.
    ii. Installation Qualification, Operational Qualification, and 
Performance Qualification methodology.
    iii. 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.
    iv. All reports, protocols and process summaries presented in an 
easily understandable template that supports incorporation of the PMA 
device to be

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sterilized in its defined package and load configuration.
    v. The process capability for the EtO sterilization process.
    vi. 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 may be subject to differences of opinion regarding safety and 
effectiveness between FDA and the sterilization facility and any 
deviations not addressed in the Master File.
    vii. Identification and explanation of management structure and 
involvement for process and facility review.
    viii. Installation and operational requalification schedule to 
support continuous process effectiveness.
    ix. A structured program and schedule for independent audits and 
monitors.
    e. The sterilization facility's inspectional history and history of 
compliance with applicable regulations (including, but not limited to, 
requirements under 21 CFR parts 820 and part 814).
    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 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 either accepts the Master File into 
the EtO Pilot Program, or which rejects the Master File as not eligible 
for the pilot program. FDA intends to review the information 
expeditiously and make a decision within 60 days when possible. If a 
Master File is rejected from the program, the written feedback will 
identify the reasons the Master File was determined to be ineligible 
for the program. FDA intends to work interactively with the sponsor to 
address any deficiencies with the information provided in the Master 
File.
    Sterilization providers (i.e., Master File holders) that are 
accepted into the pilot program should submit amendments to their 
Master File every 6 months with information on any process changes or 
new devices or PMA submissions brought into the program to maintain 
participation in the pilot program. If there are no modifications or 
changes, this should be stated in the amendment. If a sterilization 
provider is accepted into the pilot program or does not maintain 
participation, they should notify PMA holders for which they granted a 
right of reference to the Master File.
2. Procedures for PMA Holders
    For sterilization providers to be considered for the voluntary EtO 
Pilot Program, PMA holders affected by a sterilization provider's 
participation in this program should use the following procedures. As 
an alternative to the submission of a PMA supplement under Sec.  
814.39(a) and (e), FDA will consider permitting PMA holders to 
reference the existing Master File in a postapproval report to the 
Agency with a cover sheet clearly indicating ``Periodic Report for 
Ethylene Oxide Sterilization Master File Pilot Program'' in the subject 
heading. The postapproval report should contain the following 
information in lieu of the information in 21 CFR 814.84(b)(2)-(4):
    a. Name, address, and FDA FEI number of the proposed 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) to be sterilized (identified by manufacturer, 
trade name, model number, and PMA number).
    Upon receipt of a postapproval report containing the above 
information, FDA will advise PMA holders 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 devices, and referenced Master File are eligible for 
the sterilization provider's participation in the program. 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 parts 820 or 814. It is the manufacturer's 
responsibility to ensure compliance with applicable laws and 
regulations administered by FDA.
    During this voluntary EtO Pilot Program, CDRH staff intends to be 
available to answer questions or concerns that may arise. The EtO 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 820, regarding the Quality System 
regulations, have been approved under OMB control number 0910-0073. The 
collections of information in part 814, subparts A through E, regarding 
Premarket approval, have been approved under OMB control number 0910-
0231.

III. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES), 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, ``Ethylene Oxide Sterilization for Medical Devices,'' 
available at: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/ethylene-oxide-sterilization-medical-devices.
    2. 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.
    3. FDA, ``FDA Innovation Challenge 1: Identify New Sterilization 
Methods and Technologies,'' available at: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/fda-innovation-challenge-1-identify-new-sterilization-methods-and-technologies.
    4. FDA, ``FDA Innovation Challenge 2: Reduce Ethylene Oxide 
Emissions,'' available at: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/fda-innovation-challenge-2-reduce-ethylene-oxide-emissions.
    5. FDA, ``November 6 to 7, 2019: General Hospital and Personal 
Use Devices Panel of the Medical Devices Advisory Committee Meeting 
Announcement,'' 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.
    6. FDA, ``PMA Supplements and Amendments,'' available at: 
https://www.fda.gov/medical-devices/premarket-approval-pma/pma-supplements-and-amendments.

    Dated: November 21, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-25631 Filed 11-25-19; 8:45 am]
 BILLING CODE 4164-01-P