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Biocompatibility Guidance Webinar: 7/21/2016
ODE Final Biocompatibility Guidance

Use of ISO 10993-1 “Biological evaluation of 

medical devices – Part 1: Evaluation and testing 

within a risk management process”

Published: June 16, 2016

Jennifer Goode, B.S.

Office of Device Evaluation 

Center for Devices and Radiological Health
Outline 

• Goals for this guidance

• Guidance development history

• Guidance framework

• Key definitions

• When should biocompatibility be considered

• Risk-based focus for biocompatibility evaluation

• Focus on endpoint assessment instead of testing

• Endpoint assessment considerations

• Chemical assessment recommendations

• Considerations for labeling devices “-Free”

Slide 3 (Biocomp Guidance 2016-07-21)
Goals for this Guidance

1. To clarify how US FDA is currently using ISO 

10993-1 

2. To address common biocompatibility testing 

issues in submissions to the US FDA

3. To address changes in ISO 10993-1:2009

From: What biocompatibility testing is needed?

To: How to use risk management to:

1) Address biocompatibility, and

2) Leverage existing testing, if possible

Slide 4 (Biocomp Guidance 2016-07-21)

Final: 

New 

focus

Draft

Draft
Guidance Development History

Draft Guidance Published: April 23, 2013 

(Comments closed: July 22, 2013)

• 700+ comments received

• Document revised to be responsive to 

comments received

Final Guidance Published: June 16, 2016

Slide 5 (Biocomp Guidance 2016-07-21)

Website: 

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/

guidancedocuments/ucm348890.pdf
36 Groups/Individuals provided comments, 

including:

• 11 device companies 

• 7 trade associations

• 4 drug companies

• 3 biocompatibility test labs

• 2 standards development organizations

• 2 consulting groups

• 1 academic institution

Slide 6 (Biocomp Guidance 2016-07-21)

Guidance Development History (cont.)
Highlight of comments received on 

FDA’s draft Biocompatibility Guidance: 

• More emphasis on risk assessment 

• Additional considerations in lieu of biocompatibility 

testing 

• Inclusion of definitions for terminology 

• Testing considerations 

• Chemicals of concern 

• Tables and flow chart in attachments 

Slide 7 (Biocomp Guidance 2016-07-21)

Guidance Development History (cont.)
I. Introduction

II. Scope

III. Risk Management for Biocompatibility Evaluations *

IV. ISO 10993 – Part 1 and the FDA Modified Matrix

V. General Biocompatibility Testing Considerations

VI. Test-Specific Considerations

VII. Chemical Assessments

VIII. Labeling Devices as “-Free”

Slide 8 (Biocomp Guidance 2016-07-21)

Guidance Framework

* New
Att A: Evaluation Endpoints for Consideration

Att B: Device Master Files for Biocompatibility Evaluations * 

Att C: Summary Biocompatibility Documentation *

Att D: Biocompatibility Evaluation Flow Chart

Att E: Contents of a Test Report

Att F: Component and Device Documentation Examples

Att G: Glossary *

Slide 9 (Biocomp Guidance 2016-07-21)

Guidance Framework: Key Attachments

* New
Guidance Framework: Changes from Draft

• Removed issues more appropriate for separate 

guidances due to level of detail needed:

o Color additives

o Biocompatibility of gas pathway devices

Slide 10 (Biocomp Guidance 2016-07-21)
Key Definitions

• Biocompatibility: ability of a device material to 

perform with an appropriate host response in a 

specific situation

• Direct contact: term used for a device or device 

component that comes into physical contact with 

body tissue

• Indirect contact: ... device or device component 

through which a fluid or gas passes, prior to the 

fluid or gas coming into physical contact with body 

tissue (in this case the device or device component 

itself does not physically contact body tissue)

Slide 11 (Biocomp Guidance 2016-07-21)
Key Definitions (cont.)

• Final finished form (FFF): term used for a 

device or device component that includes all 

manufacturing processes for the “to be marketed” 

device including packaging and sterilization, if 

applicable

• Novel material: material that has not previously 

been used in any legally US-marketed medical 

device

• Sponsor: manufacturer, submitter or applicant

+ 15 more definitions

Slide 12 (Biocomp Guidance 2016-07-21)
When Biocompatibility is Considered

• As a critical part of FDA’s determination of safety 

and effectiveness for:

o New devices: if medical device materials come into direct 

or indirect contact with the human body; or

o Modified devices: if changes are to any direct or indirect 

contacting components, or could affect another 

component that has tissue contact.

Slide 13 (Biocomp Guidance 2016-07-21)

EXAMPLE – Modified Device: 

New internal component added (no body contact).

Heat applied to join to another component w/ body contact.

Heat could change chemistry, so biocompatibility should be 

evaluated.
When Biocompatibility is Considered (cont.)

• For all submission types: PMA, HDE, IDE, 510(k), 

and de novo requests.

• To determine the potential for an unacceptable 

adverse biological response.

• Biocompatibility standards can be used to 

facilitate information submission to FDA:

o ISO 10993-1 and related 10993 series of standards

o ASTM, ICH, OECD and USP biocompatibility 

standards

Slide 14 (Biocomp Guidance 2016-07-21)
Risk Based Approach (for Biocompatibility)

• Per ISO 10993-1, includes consideration of:

o device design, material components and manufacturing 

processes;

o clinical use of the device including the intended 

anatomical location; 

o frequency and duration of exposure;

o potential risks from a biocompatibility perspective;

o information available to address the identified risks; and

o information needed to address any remaining knowledge 

gaps, such as new biocompatibility testing or other 

evaluations that appropriately address the risks.

Slide 15 (Biocomp Guidance 2016-07-21)
Risk Based Approach (cont.)

• New biocompatibility testing may not be needed if:

o The device is made of materials that:

• Have been well characterized chemically and 

physically in the published literature; and 

• Have a long history of safe use; 

o Materials and manufacturing information is provided to 

demonstrate that no new biocompatibility concerns exist.

Slide 16 (Biocomp Guidance 2016-07-21)
Risk Based Approach (cont.)

• It may be possible to leverage previously 

conducted biocompatibility information if:

o The previously tested device has similar indications, 

type, and duration of contact; 

o An explicit statement is provided regarding any 

differences in materials or manufacturing between the 

new and leveraged devices under consideration; and

o Information is provided to explain why differences 

aren’t expected to impact biocompatibility.

Slide 17 (Biocomp Guidance 2016-07-21)
Endpoint Assessment vs. Testing

• Attachment A: 

o Provides a framework for the development of a 

biocompatibility evaluation.

o Is modified from ISO 10993-1, Annex A.

o Is not a checklist for testing.

X = ISO 10993-1:2009 recommended endpoints for 

consideration.

O = Additional FDA recommended endpoints for consideration

Slide 18 (Biocomp Guidance 2016-07-21)

Address all X’s and O’s in the biological safety evaluation.

Can use existing data, additional endpoint-specific testing, or 

a rationale for why the endpoint does not require additional 

assessment.
Endpoint Assessment vs. Testing (cont.)

• Biocompatibility evaluation: 

o All endpoints identified by an “X” or “O” in Attachment 

A may not be relevant for all devices in a particular 

category.

o For novel materials or manufacturing processes, 

additional evaluations beyond those recommended in 

Attachment A may be needed.

o Devices with multiple types of exposure should include 

information to address each exposure category.

Slide 19 (Biocomp Guidance 2016-07-21)
 

 

 

Endpoint Assessment vs. Testing (cont.)

Slide 20 (Biocomp Guidance 2016-07-21) *portion of table

* 
Endpoint Considerations

• If it is determined that some testing is needed, the 

guidance identifies:

o General testing considerations for sample preparation;

o Specific testing considerations for various 

biocompatibility endpoints (e.g., cytotoxicity); and

o Why literature is often used to assess specific endpoints 

(e.g., carcinogenicity, reproductive and developmental 

toxicity)

• Test-specific issues included where deficiencies 

are frequently identified in premarket submissions.

Slide 21 (Biocomp Guidance 2016-07-21)
Endpoint Considerations: Sample Preparation

• Use device in its final, finished form (FFF), e.g., 

sterile, if applicable.

• If not FFF, document any differences:

o Attachment F (example documentation language) may be 

helpful

Slide 22 (Biocomp Guidance 2016-07-21)

... 
Endpoint Considerations: Sample Prep (cont.)

• ISO 10993-12: for sample amount selection (e.g., 

surface area/extract volume).

• Extraction studies using polar and non-polar 

solvents.

• Simulation of extractables and leachables 

representative of clinical use conditions.

• Extract separately:

o Limited vs. prolonged vs. permanent components.

o New materials: assess separately from other material 

components.

Slide 23 (Biocomp Guidance 2016-07-21)
Endpoint Considerations: Test Specific

• Cytotoxicity (Section VI, A)

• Sensitization (Section VI, B)

• Hemocompatibility (Section VI, C)

• Pyrogenicity (Section VI, D)

• Implantation (Section VI, E)

• Genotoxicity (Section VI, F)

• Carcinogenicity (Section VI, G)

• Reproductive & development toxicity (Section VI, H)

• Degradation assessments (Section VI, I)

Slide 24 (Biocomp Guidance 2016-07-21)
Chemical Assessment

• Additional chemistry information may be needed for:

o Support of long history of safe use rationales;

o Devices with unexpected biocompatibility test findings;

o Devices manufactured from materials that intentionally 

change over time (e.g., in situ polymerizing or absorbable 

materials);

o Some devices including chemicals with known toxicities 

(e.g., carcinogenicity), where new biologic testing is rarely 

conducted;

o New chemicals used to modify material formulations or 

device manufacturing processes; and

o Devices made from novel materials.

Slide 25 (Biocomp Guidance 2016-07-21)
Chemical Assessment (cont.)

• Descriptive info can include:

o Chemical identity;

o Composition, formula/formula weight, structural 

information, and manufacturing and purity information;

o Amount by weight percent and total amount (e.g., ug);

o Identity of other devices marketed in the US where the 

chemical entity has been used previously.

• Possible chemistry information sources:

o Material/component supplier (MAF, Attachment B);

o Extractables/Leachables testing

Slide 26 (Biocomp Guidance 2016-07-21)
Chemical Assessment (cont.)

• Exposure assessment to include:

o Chemicals and related impurities that may be available 

over time;

o Consideration of repeat device use; and

o Extractables/leachables modeling or studies to optimize 

estimation of exposure during clinical use;

• Safety assessment for each chemical to consider:

o Known data from toxicology literature or material supplier;

o Derive Tolerable Intake (TI) or use Threshold of 

Toxicological Concern (TTC) for unknowns, if TI cannot 

be derived.

Slide 27 (Biocomp Guidance 2016-07-21)
Considerations for “-Free” Labeling

• Current methods may not be able to detect an 

allergen or toxic compound at very low levels that 

could still produce an adverse effect in a highly 

sensitive individual.

• Labeling statements that wouldn’t require testing:

o “Not made with [MATERIAL NAME]” (device + package)

o “[COMPONENT] not made with [MATERIAL NAME]”

Slide 28 (Biocomp Guidance 2016-07-21)
Questions? 

General questions about this webinar? 

Contact - Division of Industry and Consumer Education: 

DICE@fda.hhs.gov (800) 638-2041

Questions about this biocompatibility guidance? 

Contact - Jennifer Goode: jennifer.goode@fda.hhs.gov 

(301) 796-6374

Slide Presentation, Transcript and Webinar Recording will 

be available at: http://www.fda.gov/training/cdrhlearn

Under Heading: Specialty Technical Topics in the 

"Biocompatibility“ section

Slide 29 (Biocomp Guidance 2016-07-21)
FDA Guidance Team Members

• Absorbables & Implantation: Molly Ghosh, Joseph Nielsen, 

Charles Durfor, Judith Davis, Tory Hampshire (retired) 

• Chemistry: Brendan Casey, Irada Isayeva, Ji Guo, Jiwen Zheng

• Genotoxicity/Carcinogenicity/Risk Assessment: Rosalie 

Elespuru, Molly Ghosh, Joseph Nielsen, Ron Brown, Xin Fu

• Hemocompatibility: Qijin Lu, Molly Ghosh, Rich Malinauskas, 

Judith Davis, Tory Hampshire (retired), Eleni Whatley

• Sample Prep/Cytotox/Sensitization/Pyrogenicity: Molly Ghosh, 

Joseph Nielsen, Vicki Hitchins

• Reproductive/Developmental Tox: Michael Bailey

Slide 30 (Biocomp Guidance 2016-07-21)