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1 
Submission and Review of Sterility 

Information in Premarket Notification (510(k)) 

Submissions for Devices Labeled as Sterile

FDA Final Guidance

Issued January 21, 2016

Steven Turtil, M.S.

Biologist 

Posterior Spine Devices Branch

Division of Orthopedic Devices

Office of Device Evaluation

Center for Devices and Radiological Health

2 
Submission and Review of Sterility Information in 

Premarket Notification (510(k)) Submissions for 

Devices Labeled as Sterile 

FDA Final Guidance

There is a 60-day delayed implementation period, to allow:

• Industry to prepare prospective submissions 

• Completion of 510(k) submissions currently under review 

• Training of FDA review staff on new guidance & review procedures 

To be fully implemented March 21, 2016

3 
WEBINAR OUTLINE

BACKGROUND

• 1990 — K90-1 510(k) Sterility Review Guidance

• 2002 — Updated 510(k) Sterility Review Guidance K90-1 

• 2008 — Draft – Sterility Information in 510(k) Submissions 

• 2016 — Final – Sterility Information in 510(k) Submissions 

SCOPE 

• What is included; what is excluded

STERILIZATION METHOD CATEGORIES

• Definitions (terminology change)

• Examples

INFORMATION TO BE INCLUDED IN SUBMISSIONS

• Established A

• Established B

• Novel

4 
BACKGROUND

1990 — K90-1 — 510(k) Sterility Review Guidance

2002 — Updated 510(k) Sterility Review Guidance K90-1 

2008 — Draft – Sterility Information in 510(k) Submissions 

for Devices Labeled as Sterile

 

2016 — Final – Sterility Information in 510(k) Submissions 

for Devices Labeled as Sterile

 

Published to bring greater consistency to the review process of 510(k) devices 

across divisions and product classes. All divisions to collect and analyze the 

same 510 (k) data for sterile devices.

Issued to address several significant changes that had occurred in the regulatory 

environment, including enactment of the Food and Drug Administration (FDA) 

Modernization Act of 1997 (FDAMA).

Proposed to address advances in sterilization technology, provide clearer 

definition for “Novel” sterilization methods, as well as update guidance related to 

pyrogenicity claims. 

5 

Revised to provide public comment resolution from the 2008 Draft, providing 

clarification of the scope, definition of “novel” sterilization methods, and additional 

guidance related to pyrogenicity; assuring 510(k) review consistency. 
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. 

6 
EXCLUSIONS — 2008 DRAFT

1. 

Outside the scope of this guidance:

2. 

3. 

4. 

Processes that rely on microbial exclusion, rather than microbial 

inactivation.

Processes intended to sterilize medical devices that incorporate materials 

of animal origin. 

Processes intended to be used by reprocessors of single-use devices.

Information on the cleaning, disinfecting, and sterilizing of reusable 

devices that are reprocessed at healthcare facilities. 

7 
EXCLUSIONS — 2008 DRAFT

Outside the scope of this guidance:

Processes that rely on microbial exclusion, rather than microbial 

inactivation.

Processes intended to sterilize medical devices that incorporate materials 

of animal origin. 

Processes intended to be used by reprocessors of single-use devices.

Information on the cleaning, disinfecting, and sterilizing of reusable 

devices that are reprocessed at healthcare facilities. 

8 
EXCLUSIONS — 2016 FINAL

Outside the scope of this guidance:

Processes that rely on microbial exclusion, rather than microbial 

inactivation.

Processes intended to sterilize medical devices that incorporate materials 

of animal origin. 

Processes intended to be used by reprocessors of single-use devices.

Information on the cleaning, disinfecting, and sterilizing of reusable 

devices that are reprocessed at healthcare facilities. 

4. 

1. 

Processes that incorporate the use of liquid chemical sterilants.

Sterilizers that are themselves medical devices subject to 510(k).

5. 

2. 

6. 

3. 

9 
IV. Methods of Sterilization

10
II. METHODS OF STERILIZATION – 2008 DRAFT

A. Definitions

1. Traditional Sterilization Methods: 

2. Non-traditional Sterilization Methods: 

3. Novel Non-traditional Sterilization Methods: 

B. Examples of Sterilization Methods 

1. Traditional

2. Non-traditional

3. Novel non-traditional

11
IV. METHODS OF STERILIZATION – 2016 FINAL

A.Established Sterilization Methods: 

1. Established Category A: 

 Examples of Established Category A: 

2. Established Category B: 

 Examples of Established Category B:

B. Novel Sterilization Methods: 

Examples of Novel Sterilization Methods: 

12
IV. METHODS OF STERILIZATION - 2016

1. Established Category A: a long history of safe and effective use demonstrated by: 

a. ample literature, 

b. clearances of 510(k)s or approvals of PMAs 

c. satisfactory Quality Systems inspections

d. FDA-recognized standards for development, validation, and routine control

Examples of these Established Category A Sterilization Methods:

• Dry heat

• Ethylene oxide (EO) in a fixed, rigid chamber

• Moist heat or steam

• Radiation (e.g., gamma, electron beam)

A. Established Sterilization Methods:

13
IV. METHODS OF STERILIZATION - 2016

2. Established Category B: methods for which 

a. there are no FDA-recognized dedicated consensus standards 

b. there is published information on development, validation, and routine 

control 

c. FDA has previously evaluated sterilization development and validation 

data for specific sterilizers using discrete cycle parameters and 

determined the validation methods to be adequate

 Examples of these Established Category B Sterilization Methods:

• Hydrogen peroxide (H2O2) 

• Ozone (O3) 

• Flexible bag systems (e.g., EO)

A. Established Sterilization Methods:

14
IV. METHODS OF STERILIZATION - 2016

a. little or no published information, 

b. 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

c. no FDA-recognized dedicated consensus standards on development, validation, 

and routine control. 

FDA has not reviewed and determined to be adequate to effectively sterilize the device.

Examples of Novel Sterilization Methods: 

• Vaporized peracetic acid 

• High intensity light or pulse light 

• Microwave radiation 

• Sound waves 

• Ultraviolet light 

B. Novel Sterilization Methods — newly developed methods for which there is: 

15
KEY MESSAGE — Evaluation by FDA

Where the specific process has not been evaluated by FDA 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.

16
V. Sterilization Information 

for 

Devices Labeled as Sterile

17
ORIGINAL K90-1 — 1990

18
UPDATED K90-1 — 2002

Regardless of the method of sterilization, ODE scientific reviewers should gather and review the 

following sterilization information for all 510(k)s for devices labeled as sterile: 

• The sterilization method that will be used (e.g., dry heat, moist heat, EO, radiation);

• A description of the method that will be used to validate the sterilization cycle, but not the 

validation data itself;

• A description of the packaging to maintain the device’s sterility, not including package 

integrity testing data;

• If sterilization involves EO, the maximum levels of residuals of EO and ethylene chlorhydrin

that remain on the device (note: the ethylene glycol residual level was dropped from this 

updated guidance because the recognized standard, “ANSI/AAMI/ISO 10993-7:1995 

Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide sterilization residuals,” 

does not include measurement of ethylene glycol residuals);

• If the product is labeled “pyrogen free,” a description of the method used to make the 

determination, e.g., limulus amebocyte lysate (LAL);

• The SAL (e.g., 10-6 for all devices, except 10-3 for devices only contacting intact skin); and

• In the case of radiation sterilization, the radiation dose.

19
III. Sterilization Information for Devices Labeled as Sterile - 2008

A. ODE and CBER scientific reviewers should evaluate traditional sterilization 

methods submitted in 510(k)s for the following information. ODE and CBER 

scientific reviewers should also document that this information was provided.

1. For the sterilant, the reviewer should document the following:

a. a description of the sterilization method;

b. in the case of radiation sterilization, the radiation dose; and

c. 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 EtO sterilization, CDRH has accepted EtO residuals 

information based on the recognized standard, “ANSI/AAMI/ISO 10993-

7:1995 Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide 

Sterilization Residuals.”

20
V. Sterilization Information for Devices Labeled as Sterile - 2016

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 Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

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, 

“AAMI/ANSI/ISO 10993-7, Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide 

Sterilization Residuals.” 21

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

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 Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

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, 

“AAMI/ANSI/ISO 10993-7, Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide 

Sterilization Residuals.” 22

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

23

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 

Where the specific process has not been evaluated by FDA 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

24

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

25

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

26

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

27

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

28

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide the following: 

b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);

c. for Established Category B methods:

• if the sterilizer has received 510(k) clearance, 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 the identification of a Device Master File 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; 

29

Sponsors should ensure that a 510(k) submission includes all of the information outlined below. 
III. Sterilization Information for Devices Labeled as Sterile - 2008

2. For the sterilization method, the reviewer should document 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 aspects of the standards that were not met.

3. The reviewer should document the sterility assurance level (SAL) of 

10-6 for devices labeled 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.

30
V. Sterilization Information for Devices Labeled as Sterile - 2016

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 presubmission meetings with FDA.

31
UPDATED K90-1 — 2002

Regardless of the method of sterilization, ODE scientific reviewers should gather and review the 

following sterilization information for all 510(k)s for devices labeled as sterile: 

• The sterilization method that will be used (e.g., dry heat, moist heat, EO, radiation);

• A description of the method that will be used to validate the sterilization cycle, but not the 

validation data itself;

• A description of the packaging to maintain the device’s sterility, not including package 

integrity testing data;

• If sterilization involves EO, the maximum levels of residuals of EO and ethylene chlorhydrin

that remain on the device (note: the ethylene glycol residual level was dropped from this 

updated guidance because the recognized standard, “ANSI/AAMI/ISO 10993-7:1995 

Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide sterilization residuals,” 

does not include measurement of ethylene glycol residuals);

• If the product is labeled “pyrogen free,” a description of the method used to make the 

determination, e.g., limulus amebocyte lysate (LAL);

• The SAL (e.g., 10-6 for all devices, except 10-3 for devices only contacting intact skin); and

• In the case of radiation sterilization, the radiation dose.

32
III. Sterilization Information for Devices Labeled as Sterile - 2008

4. The reviewer should document the testing performed to demonstrate that all blood 

contacting devices, permanent implants, devices that contact cerebrospinal fluid, and 

devices labeled pyrogen free or non-pyrogenic are, in fact, non-pyrogenic. The 

documentation should include the following:

a. a description of the method used to make the determination, e.g., bacterial 

endotoxins test (BET), also known as the limulus amebocyte lysate (LAL) test;

b. identification of the testing endpoint that was reached; and 

c. an explanation supporting the selected endpoint. We recommend the following 

endotoxin endpoint: 0.5 EU/ml for general medical devices (e.g., blood contacting) 

and 0.06 EU/ml for devices that contact cerebrospinal fluid. These endpoints assume 

an extraction methodology described in the guidance or standards listed below (i.e., 

based on a 40 ml extraction volume per device). See: 

• FDA “Guideline on Validation of the Limulus Amebocyte Lysate Test as an End 

Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological 

Products, and Medical Devices” (1987) 

• United States Pharmacopeia (USP) <85> Bacterial Endotoxins Test

• ANSI/AAMI ST72:2002 Bacterial endotoxins—Test methodologies, routine 

monitoring, and alternatives to batch testing

33
III. Sterilization Information for Devices Labeled as Sterile - 2008

4. The reviewer should document the testing performed to demonstrate that all blood 

contacting devices, permanent implants, devices that contact cerebrospinal fluid, and 

devices labeled pyrogen free or non-pyrogenic are, in fact, non-pyrogenic. The 

documentation should include the following:

a. a description of the method used to make the determination, e.g., bacterial 

endotoxins test (BET), also known as the limulus amebocyte lysate (LAL) test;

b. identification of the testing endpoint that was reached; and 

c. an explanation supporting the selected endpoint. We recommend the following 

endotoxin endpoint: 0.5 EU/ml for general medical devices (e.g., blood contacting) 

and 0.06 EU/ml for devices that contact cerebrospinal fluid. These endpoints assume 

an extraction methodology described in the guidance or standards listed below (i.e., 

based on a 40 ml extraction volume per device). See: 

• FDA “Guideline on Validation of the Limulus Amebocyte Lysate Test as an End 

Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological 

Products, and Medical Devices” (1987) 

• United States Pharmacopeia (USP) <85> Bacterial Endotoxins Test

• ANSI/AAMI ST72:2002 Bacterial endotoxins—Test methodologies, routine 

monitoring, and alternatives to batch testing

34
III. Sterilization Information for Devices Labeled as Sterile - 2008

4. The reviewer should document the testing performed to demonstrate that all blood 

contacting devices, permanent implants, devices that contact cerebrospinal fluid, and 

devices labeled pyrogen free or non-pyrogenic are, in fact, non-pyrogenic. The 

documentation should include the following:

a. a description of the method used to make the determination, e.g., bacterial 

endotoxins test (BET), also known as the limulus amebocyte lysate (LAL) test;

b. identification of the testing endpoint that was reached; and 

c. an explanation supporting the selected endpoint. We recommend the following 

endotoxin endpoint: 0.5 EU/ml for general medical devices (e.g., blood contacting) 

and 0.06 EU/ml for devices that contact cerebrospinal fluid. These endpoints assume 

an extraction methodology described in the guidance or standards listed below (i.e., 

based on a 40 ml extraction volume per device). See: 

• FDA “Guideline on Validation of the Limulus Amebocyte Lysate Test as an End 

Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological 

Products, and Medical Devices” (1987) 

• United States Pharmacopeia (USP) <85> Bacterial Endotoxins Test

• ANSI/AAMI ST72:2002 Bacterial endotoxins—Test methodologies, routine 

monitoring, and alternatives to batch testing

35
V. Sterilization Information for Devices Labeled as Sterile - 2016

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:

a. implants; 

b. devices in contact directly or indirectly with the cardiovascular system, the lymphatic system, or cerebrospinal 

fluid, including devices that are present for similar systemic exposure; or

c. 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” 

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf);

c. identification of the chosen testing limit;

d. an explanation supporting the selected endotoxin limit; and

e. the endotoxin unit/device.

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>, Transfusion and Infusion Assemblies and Similar Medical Devices

• ANSI/AAMI ST72:2011, Bacterial endotoxins – Test methods, routine monitoring, and alternatives to batch testing

• FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and Answers” (available at 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf) 36
V. Sterilization Information for Devices Labeled as Sterile - 2016

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:

a. implants; 

b. devices in contact directly or indirectly with the cardiovascular system, the lymphatic system, or cerebrospinal 

fluid, including devices that are present for similar systemic exposure; or

c. 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” 

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf);

c. identification of the chosen testing limit;

d. an explanation supporting the selected endotoxin limit; and

e. the endotoxin unit/device.

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 38-NF 33: 2015, <161> Medical Devices — Bacterial Endotoxin and Pyrogen Tests

• ANSI/AAMI ST72:2011, Bacterial endotoxins – Test methods, routine monitoring, and alternatives to batch testing

• FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and Answers” 2012 (available at 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf) 37
III. Sterilization Information for Devices Labeled as Sterile - 2008

5. The reviewer should document a description of the packaging and 

how it will maintain the device’s sterility, and a description of the 

package test methods, but not package test data. 

38
V. Sterilization Information for Devices Labeled as Sterile - 2016

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.

39
V. Sterilization Information for Devices Labeled as Sterile - 2016

1. For the sterilization method, the sponsor should provide:

a. a description of the sterilization method; 

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. 

40

A. Established Sterilization Methods
V. Sterilization Information for Devices Labeled as Sterile - 2016

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.

41

B. Novel Sterilization Methods
Content Changes — 2008 Draft to 2016 Final

1. Clarifying Nomenclature Change, from: 

Traditional, Non-traditional, and Novel Non-traditional, 

to Established A, Established B, and Novel. 

42

2. Added clarification of FDA’s review policy for new 

sterilization technologies: validation data accountability. 

3. Pyrogenicity recommendations and information requested 

have been updated. 

4. Updated guidance and expanded references. 
Questions? 

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

 

Slide Presentation, Transcript and Webinar 

Recording will be available at:

http://www.fda.gov/training/cdrhlearn

Under ‘Specialty Technical Topics’ Heading

43