Submission and Review of Sterility
Information in Premarket
Notification (510(k)) Submissions
for Devices Labeled as Sterile
Guidance for Industry and Food
and Drug Administration Staff
Document issued on January 8, 2024.
This document has been revised on January 8, 2024 to update the lists of the
established sterilization methods.
This document supersedes Submission and Review of Sterility Information in
Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile
issued January 21, 2016, and subsequently updated March 16, 2016 to correct
an inadvertent editorial change regarding reporting of endotoxin limits.
For questions about this document regarding CDRH-regulated devices, contact the Sterility
Devices Team at OHT4_SterilityDeviceTeam@fda.hhs.gov.
For questions about this document regarding CBER-regulated devices, contact CBER’s Office of
Communication, Outreach, and Development (OCOD) at 1-800-835-4709 or 240-402-8010.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Center for Biologics Evaluation and Research
Contains Nonbinding Recommendations
Preface
Public Comment
You may submit electronic comments and suggestions at any time for Agency consideration to
http://www.regulations.gov. Submit written comments to the Division of Dockets Management,
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD
20852. Identify all comments with the docket number FDA–2008–D–0611. Comments may not be
acted upon by the Agency until the document is next revised or updated.
Additional Copies
CDRH
Additional copies are available from the Internet. You may also send an e-mail request to
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document
number GUI00001615 and complete title of the guidance in the request.
CBER
Additional copies of this guidance document are also available from the Center for Biologics
Evaluation and Research (CBER) by written request, Office of Communication, Outreach, and
Development (OCOD), 10903 New Hampshire Ave., WO71, Room 3128, Silver Spring, MD
20993-0002, or by calling, 1-800-835-4709 or 240-402-8010, by email, ocod@fda.hhs.gov, or
from the Internet at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics
Contains Nonbinding Recommendations
Table of Contents
I. Introduction ..............................................................................................................................1
II. Background ..............................................................................................................................1
III. Scope..........................................................................................................................................2
IV. Methods of Sterilization ..........................................................................................................3
V. Sterilization Information for Devices Labeled as Sterile .....................................................5
Contains Nonbinding Recommendations
Submission and Review of Sterility
Information in Premarket Notification
(510(k)) Submissions for Devices Labeled as
Sterile
Guidance for Industry and Food and Drug
Administration Staff
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on
FDA or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
or Office responsible for this guidance as listed on the title page.
I. Introduction
This guidance document updates and clarifies the information regarding sterilization processes
that we recommend sponsors include in 510(k)s for devices labeled as sterile. This guidance
document also provides details about the pyrogenicity information that we recommend sponsors
include in a 510(k) submission. For the current edition of the FDA-recognized standards
referenced in this document, see the FDA Recognized Consensus Standards Database. 1 For more
information regarding use of consensus standards in regulatory submissions, please refer to the
FDA guidance titled “Appropriate Use of Voluntary Consensus Standards in Premarket
Submissions for Medical Devices.” 2.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. Background
In recent years, FDA has received an increasing number of 510(k)s for devices labeled as sterile
that use sterilization methods other than the traditionally used methods of steam, dry heat,
1
Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm
2
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-
voluntary-consensus-standards-premarket-submissions-medical-devices
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ethylene oxide (EO), and radiation. FDA has experience with other methods, such as vaporized
hydrogen peroxide, ozone and flexible bag systems, and now considers them to be established
methods. However, we recognize that there may be alterations to the more recently developed
methods, as well as original, innovative sterilization technologies, which are being developed
and proposed for use in the manufacture of class I and class II devices. FDA considers these to
be novel methods. (The terms “established” and “novel” are defined in Section IV below.)
Under section 513(f)(5) of the Federal Food, Drug, and Cosmetic Act (the act), FDA may not
withhold 510(k) clearance for failure to comply with any provision of the act unrelated to a
substantial equivalence decision, including failure to comply with Good Manufacturing Practice
(GMP), 3 unless FDA finds that there is a substantial likelihood that failure to comply with the
provision “will potentially present a serious risk to human health.” We believe that novel
sterilization technologies carry a substantial risk of inadequate sterility assurance if not
conducted properly. Consequently, compliance with GMP for devices sterilized using these
technologies should be closely evaluated. Failure to assure sterility presents a serious risk to
human health because of the risk of infection. Therefore, we intend to inspect the manufacturing
facility before clearing a 510(k) for a device that is sterilized by a novel sterilization process.
Inspecting the manufacturing facility for devices sterilized using these sterilization technologies
will help ensure the safety and effectiveness of these devices and mitigate the risks to human
health.
III. Scope
The scope of this guidance is limited to the review of 510(k)s for devices labeled as sterile that
are subject to industrial terminal sterilization processes based on microbial inactivation.
Examples of these processes include radiation, steam, EO, and new technology sterilization
processes.
Exclusions
The following are excluded from this guidance:
1. Sterilizers that are themselves medical devices subject to 510(k). 4,5
2. Processes that rely on microbial exclusion, rather than microbial inactivation, are outside
the scope of this guidance. Examples of microbial exclusion processes include sterilizing
filtration methods and aseptic processing, commonly used in pharmaceutical
manufacturing.
3. Processes intended to sterilize medical devices that incorporate materials of animal origin
(i.e., human or animal tissues) are outside the scope of this guidance. We recommend
3
The implementing regulations for GMP requirements, section 520(f) of the Federal Food, Drug, and Cosmetic Act,
are referred to as Quality System (QS) requirements (see also 21 CFR Part 820).
4
Ethylene oxide gas sterilizer, 21 CFR 880.6860, dry-heat sterilizer, 880.6870, and steam sterilizer 880.6880.
5
See “Guidance on Premarket Notification (510(k)) Submissions for Sterilizers Intended for Use in Health Care
Facilities,” (available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-
premarket-notification-510k-sterilizers-intended-use-health-care-facilities )
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contacting the branch responsible for the review of your device to discuss questions about
devices that contain materials of human or animal origin. To assist sponsors in addressing
the concerns or issues related to viral contamination, we recommend review of United
States Pharmacopeia (USP) <1050>, Viral Safety Evaluation of Biotechnology products
derived from cell lines of human or animal origin, and related documents.
4. Processes that incorporate the use of liquid chemical sterilants. 6
5. Processes intended to be used by reprocessors of single-use devices. See “Medical
Device User Fee and Modernization Act of 2002, Validation Data in Premarket
Notification Submissions (510(k)s) for Reprocessed Single-Use Medical Devices”
(available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/medical-device-user-fee-and-modernization-act-2002-validation-data-
premarket-notification)
6. Information on the cleaning, disinfecting, and sterilizing of reusable devices that are
reprocessed at healthcare facilities (and for single-use devices that are provided non-
sterile for further sterilization at healthcare facilities). See “Reprocessing Medical
Devices in Health Care Settings: Validation Methods and Labeling” (available at
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/reprocessing-medical-devices-health-care-settings-validation-methods-and-
labeling)
Finally, FDA notes that the sterilization methods used in manufacturing settings are subject to
FDA’s Quality System (QS) regulation requirements, 21 CFR Part 820.
IV. Methods of Sterilization
FDA considers there to be two categories of sterilization methods currently used to sterilize
medical devices in manufacturing settings: established and novel. 7 These processes are defined
below, and examples are provided for each category.
A. Established Sterilization Methods:
1. Established Category A: These are methods that have a long history of safe and
effective use as demonstrated through multiple sources of information such as
ample literature, clearances of 510(k)s or approvals of premarket approval (PMA)
applications, and satisfactory QS inspections. For established methods such as dry
heat, EO, steam, radiation, and vaporized hydrogen peroxide, there are voluntary
6
Liquid chemical sterilants/high level disinfectants, 21 CFR 880.6885, and Automated endoscope reprocessors
under Endoscope and accessories, 21 CFR 876.1500.
7
This characterization scheme applies to processing methods used in manufacturing rather than for specific
sterilization cycles on FDA-cleared sterilizers intended for use in health care settings. Please note that this
categorization can change over time and sponsors are encouraged to contact FDA for updated information.
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consensus standards for development, validation, and routine control that are
recognized by FDA. 8
Examples of these Established Category A Sterilization Methods:
• Dry heat
• EO with devices in a fixed, rigid chamber
• Moist heat or steam
• Radiation (e.g., gamma, electron beam)
• Vaporized Hydrogen Peroxide (H2O2) 9
2. Established Category B: There are other established methods for which there are
no FDA-recognized dedicated consensus standards, but for which published
information on development, validation, and routine control is available.
In cases where FDA has previously evaluated sterilization development and
validation data for specific sterilizers using discrete cycle parameters and
determined the validation methods to be adequate, 10 we consider these to be
Established Category B.
Examples of these Established Category B Sterilization Methods:
• Ozone (O3)
• Flexible bag systems (e.g., EO in a flexible bag system, diffusion method,
injection method)
However, for those cases where the specific process does not appear to have been
evaluated by FDA, either because the parameters of an FDA-cleared sterilizer
have been altered, or because process validation data have not been evaluated and
found to be adequate in previous cleared or approved submissions, we consider
these methods to be novel.
B. Novel Sterilization Methods:
These are newly developed methods for which there exists little or no published
information, no history of comprehensive FDA evaluation of sterilization development
and validation data through an FDA-cleared 510(k) or approved PMA for devices
sterilized with such methods, and no FDA-recognized dedicated consensus standards on
8
For more information, please see FDA’s database, Recognized Consensus Standards at
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm
9
We encourage you to contact the review division for your device regarding the appropriate parameters to monitor
for parametric release of product loads sterilized with vaporized hydrogen peroxide. For more information, see the
Supplementary Information Sheet (SIS) for FDA’s recognition of 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 available at:
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/detail.cfm?standard__identification_no=44295
10
This evaluation may take place as part of the review of a 510(k) submission for a sterilizer intended for use in a
health care facility or as part of a previous clearance of a 510(k), or approval of a premarket approval application
(PMA) or Humanitarian Device Exemption (HDE), for a device sterilized using this specific process.
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development, validation, and routine control. A Novel Sterilization Method is a method
that FDA has not reviewed and determined to be adequate to effectively sterilize the
device for its intended use.
A sterilization method that uses chemical(s) that have not been previously cleared or
approved by FDA as a chemical sterilant or has not been identified in the scientific
literature as a chemical sterilant would be considered novel. In addition, a sterilization
method that uses a combination of chemicals, and the combination has not been
previously cleared or approved by FDA as a sterilant, would be considered novel even if
the individual chemicals in the combination have been previously cleared or approved
independently as chemical sterilants. FDA also considers methods where the specific
process does not appear to have been evaluated by FDA, either because the parameters of
an FDA-cleared sterilizer have been altered, or because process validation data have not
been evaluated and found to be adequate in previous cleared or approved submissions, to
be novel.
Examples of Novel Sterilization Methods:
• Vaporized peracetic acid
• High intensity light or pulse light
• Microwave radiation
• Sound waves
• Ultraviolet light
V. Sterilization Information for Devices Labeled as Sterile
A. Established Sterilization Methods
Sponsors should ensure that a 510(k) submission includes all of the information outlined
below.
1. For the sterilization method, the sponsor should provide the following:
a. a description of the sterilization method;
b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible
bag);
c. for those methods described in Section IV.A.2. (Established Category B):
• if the sterilizer has received 510(k) clearance, 11 the 510(k) number,
and the make (i.e., manufacturer) and model of the sterilizer.
Additionally, the submission should state whether or not the cycles for
which the sterilizer was granted clearance have been altered;
• if the sterilizer has not received 510(k) clearance, this should be stated;
• if the sterilization method has been evaluated through clearance of a
510(k) or approval of a PMA or HDE for a device using that method,
the submission number where the method was previously evaluated or
11
Sterilizers intended for use in healthcare facilities require 510(k)s. Industrial sterilizers do not require 510(k)s.
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the identification of a Device Master File 12 containing this
information. Additionally, the submission should state whether or not
the cycles that were previously evaluated in the cleared or approved
submission have been altered;
d. the sterilization site; 13
e. in the case of radiation sterilization, the radiation dose;
f. for chemical sterilants (e.g., EO, H2O2), the maximum levels of sterilant
residuals that remain on the device, and an explanation of why those levels
are acceptable for the device type and the expected duration of patient
contact.
In the case of EO sterilization, CDRH has accepted EO residuals
information based on the currently recognized version of the standard,
“ISO 10993-7, Biological Evaluation of Medical Devices – Part 7:
Ethylene Oxide Sterilization Residuals.”
2. For the sterilization method, the sponsor should provide a description of the
method used to validate the sterilization cycle (e.g., the half-cycle method) but
not the validation data itself. The submission should also identify all relevant
consensus standards used and identify any aspects of the standards that were
not met. In the absence of a recognized standard, a comprehensive description
of the process and the complete validation protocol should be submitted and
reviewed.
3. The sponsor should state the sterility assurance level (SAL) of 10-6 for devices
labeled as sterile unless the device is intended only for contact with intact
skin. FDA recommends a SAL of 10-3 for devices intended only for contact
with intact skin. For questions related to alternative SALs, we recommend
direct consultation and pre-submission meetings with FDA. 14
4. Pyrogenicity testing is used to help protect patients from the risk of febrile
reaction due to either gram-negative bacterial endotoxins or other sources of
pyrogens (e.g., material-mediated pyrogens). To address the presence of
bacterial endotoxins, devices that fall under the following categories should
meet pyrogen limit specifications:
• implants;
• devices in contact directly or indirectly with the cardiovascular system, the
lymphatic system, or cerebrospinal fluid, including devices that are
12
For more information on Device Master Files, please see https://www.fda.gov/medical-devices/premarket-
approval-pma/master-files
13
The identification of the sterilization site may be provided in the sterilization section of the 510(k) submission or
in Section I of Form 3514, CDRH Premarket Review Submission Cover Sheet (available at
https://www.fda.gov/media/72421/download)
14
For more information on pre-submission interactions, please see the guidance “Requests for Feedback on Medical
Device Submissions: The Pre-Submission Program and Meetings with FDA Staff” ( available at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program )
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present for similar systemic exposure; or
• devices labeled non-pyrogenic.
Note: The Agency recommends use of the expressions “non-pyrogenic” or
“meets pyrogen limit specifications” instead of “pyrogen free,” unless the
complete removal of pyrogens can be established. In addition, for devices that
should meet pyrogen limit specifications, we recommend the labeling state
that the device is non-pyrogenic.
The sponsor should provide the information outlined below:
a. a description of the method used to make the determination that the device
meets pyrogen limit specifications (e.g., bacterial endotoxins test (BET),
also known as the Limulus amebocyte lysate (LAL) test);
b. a statement confirming that endotoxin testing will be conducted on every
batch or if not, information regarding the sampling plan used for in-
process testing and/or finished product release, as recommended in the
FDA guidance, “Pyrogen and Endotoxins Testing: Questions and
Answers” (https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/pyrogen-and-endotoxins-testing-questions-and-
answers);
c. identification of the chosen testing limit; and
d. an explanation supporting the selected endotoxin limit.
We recommend the following endotoxin limits for the BET: 20 endotoxin
units (EU)/Device for general medical devices (e.g., blood contacting and/or
implanted) and 2.15 EU/Device for devices that contact cerebrospinal fluid.
See:
• USP <161>, Medical Devices-Bacterial Endotoxin and Pyrogen Tests
• ANSI/AAMI ST72, Bacterial endotoxins – Test methods, routine
monitoring, and alternatives to batch testing
• FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and
Answers” (available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/pyrogen-and-endotoxins-
testing-questions-and-answers)
Sponsors should also be aware that there are additional sources of pyrogens
beyond gram-negative bacteria. Material-mediated pyrogens are chemicals
that can leach from a medical device and are traditionally addressed as part of
the biocompatibility assessment.
For devices that do not need to meet pyrogen limit specifications because of
the nature of body contact, but are intended to be labeled as “non-pyrogenic,”
we recommend that both bacterial endotoxin and material mediated
pyrogenicity testing be conducted. 15 For device-specific questions, please
15
We recommend that you assess material mediated pyrogenicity using a pyrogenicity test such as the one outlined
in USP <151>, Pyrogen Test (USP Rabbit Test), or an equivalent validated method.
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contact the relevant review branch as limits vary for specific device types.
5. The sponsor should provide a description of the packaging (sterile barrier
system) and how it will maintain the device’s sterility, and a description of the
package test methods, but not package test data. 16
B. Novel Sterilization Methods
In addition to the information identified in Section V.A above, the sponsor should
provide the following information in a 510(k) for all novel sterilization methods:
1. a comprehensive description of the sterilization process;
2. the method used to validate the sterilization cycle (e.g., the half-cycle method);
3. the validation protocol; and
4. the sterilization validation data. The submission should also identify any
applicable published scientific literature. For novel sterilization methods, FDA
may also request additional information based on the specific device submitted
for review.
16
FDA recommends that package test methods include simulated distribution and associated package integrity, as
well as simulated (and/or real-time) aging and associated seal strength testing, to validate package integrity and shelf
life claims. Please refer to the currently FDA recognized version of the AAMI/ANSI/ISO 11607, Packaging for
terminally sterilized medical devices, series of consensus standards.
