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CA Webinar: 2/12/2016 1 
Color Additives and the 

Medical Device Review

Jennifer Goode, BS

Biomedical Engineer

Office of Device Evaluation 

Center for Devices and Radiological Health

CA Webinar: 2/12/2016 2 
Webinar Goal

• Describe and clarify ODE’s current policy and approach 

for the evaluation of marketing applications for 

medical devices that contain color additives (CAs). 

• Ensure a consistent approach is being applied to 

reviews for medical devices that contain CAs 

CA Webinar: 2/12/2016 3 
Outline

• Background

• Definitions 

• ODE color additives (CA) approach

• When should this approach be used?

• Hierarchical risk-based approach

• Guiding principles for the CA approach

• Detailed CA approach including some examples

• Next steps

CA Webinar: 2/12/2016 4 
Background

• § 721 of the FD&C Act

– Outlines listing and certification requirements of color 

additives for foods, drugs, devices and cosmetics:

• 721(a): a color additive to be used in a device is exempt from 

listing unless “the color additive comes in direct contact with the 

body of man or other animals for a significant period of time.” 

• ODE does not consider use of a color additive in or on a 

device to be in contact with the body for a “significant 

period of time” if the contact duration is 30 days or less. 

– see 721 of the FD&C Act, 21 CFR 70, 21 CFR 71, 21 CFR 73, 21 

CFR 74(d), 21 CFR 80

CA Webinar: 2/12/2016 5 
Definitions

CA Webinar: 2/12/2016 6 
Definitions

• Color Additive (CA): “a dye, pigment, or other substance 

made by a process of synthesis or similar artifice, or 

extracted, isolated, or otherwise derived, with or without 

intermediate or final change of identity, from a vegetable, 

animal, mineral, or other source, and...when added or 

applied to a food, drug, or cosmetic, or to the human body 

or any part thereof, is capable (alone or through reaction 

with other substance) of imparting color thereto; except 

that such term does not include any material which the 

Secretary, by regulation, determines is used (or intended to 

be used) solely for a purpose or purposes other than 

coloring” (per 201(t) of the FD&C Act)

CA Webinar: 2/12/2016 7 
Definitions (cont.)

• Color Additive (CA) (cont.): 

A coloring substance intended for use in a medical device is 

a color additive under this definition if the substance is 

capable of imparting color when it is added or applied to 

the human body. Importantly, a coloring substance in a 

medical device need not actually impart color to the body 

from its use in a device to be a color additive. 

CA Webinar: 2/12/2016 8 
Definitions (cont.)

• US legally marketed device: refers to any US marketed 

device (i.e., for 510(k)’s this can refer to either a predicate 

device or a reference device) which has similar tissue 

contact (i.e., type and duration). 

EXAMPLE: 

Coronary balloon angioplasty devices & delivery systems for 

superficial femoral artery stents could be appropriate 

reference devices for a CA assessment.

Both contact cardiovascular tissue and blood for < 24 hours 

(per the G95-1 and ISO 10993-1 approaches).

CA Webinar: 2/12/2016 9 
Definitions (cont.)

• Direct contact: term used for a device or device component 

that comes into physical contact with body tissue 

• Indirect contact: term used for a 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.

• Transient contact: term used for a device or device 

component that comes into very brief/transient contact with 

body tissue (e.g., lancets, hypodermic needles, capillary 

tubes that are used for less than 1 minute) 

CA Webinar: 2/12/2016 10
Definitions (cont.)

• Tolerable Intake (TI): a dose (in mg/kg/day) below which 

adverse systemic effects are not likely to occur in exposed 

patients. 

– This dose is not intended to be protective for all adverse 

effects (e.g., hypersensitivity) 

– The TI is derived using the approach outlined in ISO 

10993-17 “Biological evaluation of medical devices – Part 

17: Methods for the establishment of allowable limits for 

leachable substances.”

CA Webinar: 2/12/2016 11
ODE color additives approach

• Based on G95-1, & ISO 10993-1 information (if 

available), and ODE current practice 

• Intended to be risk-based, least burdensome, and 

scientifically based 

• Leverages information already available (i.e., 

biocompatibility testing of the device in its final 

finished form) 

• Minimizes the need for additional color additive 

information or extraction studies to look specifically for 

CA release, where appropriate.

CA Webinar: 2/12/2016 12
When to use this approach?

• In marketing applications: 510(k)s, PMAs, de novo 

requests, HDEs

• What about IDEs?

– Not required to initiate IDEs, per §721 of the FD&C Act (21 USC 

§379e)

– Caveats: 

• If there is a toxicity risk identified for any chemicals used to 

manufacture the device (including any color additives), it may 

be necessary for us to ask for appropriate safety information 

prior to investigation in humans.

• Risk based approach to be used.

CA Webinar: 2/12/2016 13
Hierarchical risk-based approach

• Uses “type/duration of contact categories” outlined in 

ISO 10993-1 and G95-1 

• Different CA information needed for devices/components 

with:

– Section I slides: No patient contact (direct or indirect)

– Section II slides: Less than 24 hour contact

– Section III slides: 24 hour to 30 day contact

– Section IV slides: Greater than 30 day contact

CA Webinar: 2/12/2016 14
Guiding principles (GPs) for 

the CA approach: GP#1

To determine whether CA information is needed (per 

GP#7 and GP#8*):

• Use a least burdensome, risk-based approach

• Interpret GP#7 and GP#8 in the appropriate regulatory 

context (i.e., compared to other similar marketed 

products).

CA Webinar: 2/12/2016 15

*GP#7 = descriptive info

GP#8 = risk assessment info
Guiding principles for the CA 

approach: GP#2

If your marketing submission is for a:

• New device, or 

• Device where the identified US legally marketed 

comparison device is made by a different manufacturer 

Follow the concepts described in slides for Sections I – IV

CA Webinar: 2/12/2016 16
Guiding principles for the CA 

approach: GP#3

If you have made a device modification:

• Focus the CA evaluation on:

– only the device or component modifications 

– unless the change could affect other parts of the device that 

were not changed 

• Provide CA for the impacted portions of the device.

CA Webinar: 2/12/2016 17
Guiding principles for the CA 

approach: GP#4

When assessing device modifications:

• Explain why modification is not expected to affect CA release 

Types of changes that may affect CA release include: 

• material changes

• design changes

Prior testing that may help with assessment:

• Biocompatibility extracts: visual observation of color/turbidity 

change &/or particulates

• Performance: in vitro particulate or wear testing w/colored 

particles; or animal studies with colored fragments at explant

CA Webinar: 2/12/2016

18
Guiding principles for the CA 

approach: GP#4 (cont.)

Examples of material changes that may affect CA release 

include: 

Changes to: formulation of polymer matrix, CA amount or CA type

Examples of design changes that may affect CA release 

include: 

Changes to: how the CA is incorporated into the patient 

contacting portion of the device, such as mixed into the polymer 

vs. stamped on the surface

CA Webinar: 2/12/2016 19
Guiding principles for the CA 

approach: GP#5

If device change is not likely to affect release of CA (per 

available evidence):

• No CA information (per GP#7 or GP#8) is needed.

• Perform biological evaluation:

– Device in its final finished form (FFF) in accordance with G95-1 

– May include device testing and/or a rationale for why testing was not 

performed 

CA Webinar: 2/12/2016 20
Guiding principles for the CA 

approach: GP#6

Contact = intact skin for up to 30 days: 

• No CA information (per GP#7 or GP#8) is needed. 

For other types of contact up to 30 days: 

• CA information may be needed (see slides for Sections II & III). 

For contact greater than 30 days, regardless of type of 

contact:

• CA information (per GP#7, and possibly GP#8) is needed (see slides 

for Section IV). 

CA Webinar: 2/12/2016 21
Guiding principles for the CA 

approach: GP#7

If CA information is needed (per Sections II-IV), provide the 

following: 

1. Chemical Name/CAS #

2. Purity information:

– CFR color listing (e.g., in 21 CFR 73 or 21 CFR 74), or

– Raw material’s Certificates of Analysis (COA), or 

– Raw material or final device testing for impurities; 

3. Estimated/calculated maximum amount of each CA (in weight) per 

device 

ID: US legally marketed device with same CA, same matrix material, same 

processing

CA Webinar: 2/12/2016 22

OR
Guiding principles for the CA 

approach: GP#7 (cont.)

NOTE: Letters of Authorization from CA manufacturers 

allowing FDA access to relevant material supplier master 

files (e.g., MAFs) may be helpful to address the following 

GP#7 issues: 

1. Chemical Name/CAS #

2. Purity information:

– CFR color listing (e.g., in 21 CFR 73 or 21 CFR 74), or

– Raw material’s Certificates of Analysis (COA), or 

– Raw material or final device testing for impurities; 

3. Estimated/calculated maximum amount of each CA (in weight) per 

device 

CA Webinar: 2/12/2016 23
Guiding principles for the CA 

approach: GP#8

No additional CA info needed if:

• CA amount is less than or equal to: 

– Comparator device* w/ same CA, same type and duration of tissue 

contact, same matrix material, & similar intended use; or

• CA/impurity amounts are less than: 

– Tolerable intake (TI) for the CA/impurities

*Prior submissions can be used as comparators, even if prior submissions 

did not include CA info 

CA Webinar: 2/12/2016 24
Guiding principles for the CA 

approach: GP#8 (cont.)

Additional CA risk assessment needed if:

• CA amount is greater than: comparator device* 

(w/ same CA, same type and duration of tissue contact, same matrix 

material, & similar intended use)

• CA amount is same or less than comparator, but: 

Conditions of device use are not comparable 

(tissue/body fluid interface or duration)

CA Webinar: 2/12/2016 25

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Guiding principles for the CA 

approach: GP#8 (cont.)

Examples: Benefit/risk assessment 

• Life saving device is used in patients with <1 year life expectancy 

• Amount of CA in device is needed for proper placement 

• Color/impurity risks (e.g., cancer) don’t outweigh benefits

CA Webinar: 2/12/2016 26

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Guiding principles for the CA 

approach: GP#8 (cont.)

Examples: Reduce CA amt? 

• Reduce the amount of the CA in device to the same or below a US 

legally marketed device with the same duration and route of 

exposure (e.g., “appropriate comparator”)

• Reduce exposure to a level corresponding to an acceptable risk in 

accordance with the risk assessment

CA Webinar: 2/12/2016 27

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Guiding principles for the CA 

approach: GP#8 (cont.)

Examples: Other possible options?

• Under certain circumstances (e.g., for colored absorbable devices), 

conduct in vivo “fate” testing (e.g., absorption, distribution, 

metabolism, and excretion [ADME]); and/or

• Perhaps submit a color additive petition (CAP), depending on further 

risk assessment, fate test outcomes, and discussion with CDRH (e.g., 

Q-submission)

CA Webinar: 2/12/2016 28

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Guiding principles for the CA 

approach: GP#9

If other CA concerns identified during the review process: 

• Review staff to discuss with management whether or not 

additional testing is needed. 

• If you have questions about the CA information 

requested, contact the review staff and management to 

discuss.

CA Webinar: 2/12/2016 29
Detailed CA Approach

Section I: No patient contact*

• No biocompatibility information needed.

• No CA information needed (per GP#7 or GP#8)

*direct or indirect

CA Webinar: 2/12/2016 30
Detailed CA Approach

Section II: < 24 hour contact

a) Contact < 1 minute (transient) & device may release CA:

– Perform biological evaluation:

• Device in FFF in accordance with G95-1 

• May include device testing and/or a rationale for why testing was not 

performed 

– No CA information needed (per GP#7 or GP#8), unless 

performance testing suggests colored material release:

CA Webinar: 2/12/2016 31

In vitro particulate release testing 

(e.g., for coated catheters) showing 

colored particles.

Embolized/migrated 

colored material in an 

animal study.

Wear testing 

demonstrating colored 

particulate.
Detailed CA Approach

Section II: < 24 hour (cont.)

b) Contact > 1 minute & device may release CA:

i. Cytotoxicity, sensitization, and irritation (CSI) tests:

• Performed on device in FFF with acceptable results; AND 

• Extracts: no change in color/turbidity and no visible 

particulates 

Then:

• Perform biological evaluation of the device in FFF per G95-1 

(may include other tests and/or rationale for why testing was 

not performed). 

• No CA information needed (per GP#7 or GP#8)

CA Webinar: 2/12/2016 32
Detailed CA Approach

Section II: < 24 hour (cont.)

b) (cont.) Contact > 1 minute & device could release CA:

ii. If CSI tests of the device in FFF: 

• NOT performed with acceptable results; OR 

• Performed with acceptable results, but 

– Extracts: change in color/turbidity, and/or visible 

particulates: 

Then 

• Perform biological evaluation of the device in FFF per G95-1 

(may include other tests and/or rationale for why testing was 

not performed). 

• CA (per GP#7); AND Risk Assessment (per GP#8) needed

CA Webinar: 2/12/2016

33
Detailed CA Approach

Section II: < 24 hour (cont.)

b) (cont.) Contact > 1 minute & device could release CA:

– If CA amount less than or equal to appropriate* comparator, OR 

less than TI 

– No CA information (per GP#8) needed

CA Webinar: 2/12/2016 34

GP7: 

- Chemical name/CAS#;

- Purity info; and

- Max amount of each CA (in wt)/device

OR

- Identification of US marketed device 

w/same CA, matrix, processing

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Detailed CA Approach

Section III: 24 hour–30 day use*

If device may release CA:

i. Cytotoxicity, sensitization, and irritation (CSI) tests:

• Performed on device in FFF with acceptable results; AND 

• Other G95-1 biocomp tests: Performed on device in FFF

w/acceptable results

• Extracts: no change in color/turbidity and no visible 

particulates 

Then: No CA information needed (per GP#7 or GP#8)

CA Webinar: 2/12/2016 35

* Includes repeat use equivalent to 24 hours up to 30 days. For example, an inhaler used 

daily, may be intended for use with a medication that is prescribed for two weeks, so 

the assessment should be conducted using this 24 hr to 30 day category. 
Detailed CA Approach

Section III: 24 hour–30 day use*

If device may release CA:

i. Cytotoxicity, sensitization, and irritation (CSI) tests:

• Performed on device in FFF with acceptable results; AND 

• Other G95-1 biocomp tests: Performed on device in FFF

w/acceptable results

• Extracts: no change in color/turbidity and no visible 

particulates 

Then: No CA information needed (per GP#7 or GP#8)

CA Webinar: 2/12/2016 36

* Includes repeat use equivalent to 24 hours up to 30 days. For example, an inhaler used 

daily, may be intended for use with a medication that is prescribed for two weeks, so 

the assessment should be conducted using this 24 hr to 30 day category. 
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

ii. (cont.)For biocomp tests of the device in FFF, if:

• CSI Tests: NOT performed with acceptable results; OR 

• Other G95-1 biocomp tests: Not performed w/acceptable 

results; OR

• All tests performed with acceptable results, but 

– Extracts: change in color/turbidity, and/or visible 

particulates: 

Then 

• Perform biological evaluation of the device in FFF per G95-1 

(testing and/or rationale). 

• CA info (per GP#7); AND Risk Assessment (per GP#8) needed

CA Webinar: 2/12/2016 37
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

EXAMPLE 1: Multi-day infusion catheter

– CSI: performed on device in FFF w/ acceptable results 

– Other G95-1 tests: performed w/acceptable results 

– Extracts (all tests): no change in color/turbidity, and no 

visible particulates 

Then: No CA info needed (per GP#7 or GP#8)

CA Webinar: 2/12/2016 38
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

EXAMPLE 2: Multi-day infusion catheter

– Cytotoxicity & Sensitization: performed on device in FFF w/ 

acceptable results 

– Irritation testing showed slight toxicity 

– Other G95-1 tests: performed w/acceptable results 

– Extracts (all tests): no change in color/turbidity, and no 

visible particulates 

Then: CA info (per GP#7); AND Risk Assessment (per GP#8) needed

CA Webinar: 2/12/2016 39
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

EXAMPLE 3: Multi-day infusion catheter

– CSI: performed on device in FFF w/ acceptable results 

– No genotoxicity testing on device in FFF provided

– Other G95-1 tests: performed w/acceptable results 

– Extracts (all tests): no change in color/turbidity, and no 

visible particulates 

Then: CA info (per GP#7); AND Risk Assessment (per GP#8) needed

CA Webinar: 2/12/2016 40
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

EXAMPLE 4a: Multi-day infusion catheter

– CSI: performed on device in FFF w/ acceptable results 

– Other G95-1 tests: performed w/acceptable results 

– Extracts (one test): no change in color/turbidity, but visible 

particulates present 

Then: CA info (per GP#7); AND Risk Assessment (per GP#8) needed

CA Webinar: 2/12/2016 41
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

EXAMPLE 4b: Multi-day infusion catheter

– CSI: performed on device in FFF w/ acceptable results 

– Other G95-1 tests: performed w/acceptable results 

– Extracts (one test): no change in color/turbidity, but visible 

particulates present* 

Then: CA info (per GP#7); AND Risk Assessment (per GP#8) needed

*CAVEAT: If info is provided to confirm the source of particulates is not from leaching of 

CA during biocompatibility extraction studies (e.g., images to document particulates are 

cutting artifacts that occur prior to extraction, chemical identification of particulates), 

CA information (per GP#7 or GP#8) is not needed. 

CA Webinar: 2/12/2016 42
Detailed CA Approach

Section III: 24 hr–30 d (cont.)

ii. (cont.)

– If CA amount less than or equal to appropriate* comparator, OR 

less than TI 

– No CA information (per GP#8) needed

CA Webinar: 2/12/2016 43

GP7: 

- Chemical name/CAS#;

- Purity info; and

- Max amount of each CA (in wt)/device

OR

- Identification of US marketed device 

w/same CA, matrix, processing

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Detailed CA Approach

Section IV: > 30 day use*

If the device may release CA: 

• Perform biological evaluation of the device in its FFF per G95-1 

(testing and/or rationale); AND 

• CA information (per GP#7); AND Risk Assessment per (GP#8) needed

CA Webinar: 2/12/2016 44

*Includes repeat use beyond 30 days. For example, hemodialyzers are used for 

approximately 3 hours at a time, but can be used multiple times per week, and for 

more than 30 days; therefore, the assessment should be conducted using this >30 day 

category. 
Detailed CA Approach

Section IV: > 30 day use (cont.)

(cont.)

– If CA amount less than or equal to appropriate* comparator, OR 

less than TI 

– No CA information (per GP#8) needed

CA Webinar: 2/12/2016 45

GP7: 

- Chemical name/CAS#;

- Purity info; and

- Max amount of each CA (in wt)/device

OR

- Identification of US marketed device 

w/same CA, matrix, processing

GP8: 

- Amt is > TI or Amt in device unknown

- Model/determine expected release via elution

- Amt released > TI

- Benefit/risk assessment

- Reduce CA amt? 

- In vivo fate testing?

- Perhaps a CAP?
Other Considerations

• If devices with different types & amounts of colors 

(e.g., contact lenses) are being proposed:

– A device sample incorporating all colors could be used for 

biocompatibility testing.

• If a device is offered in a range of shades of a 

particular color (e.g., colored dental composite resins): 

– The device with the most CAs could be used for 

biocompatibility testing.

CA Webinar: 2/12/2016 46
Summary: ODE CA approach

• Based on G95-1, & ISO 10993-1 information (if 

available), and ODE current practice 

• Intended to be risk-based, least burdensome, and 

scientifically based 

• Leverages information already available (i.e., 

biocompatibility testing of the device in its final 

finished form) 

• Minimizes the need for additional color additive 

information or extraction studies to look specifically for 

CA release, where appropriate.

CA Webinar: 2/12/2016 47
Next Steps

• Future Draft Level 1 Guidance planned for color 

additives in medical devices

CA Webinar: 2/12/2016 48
Questions? 

General questions about the use of color additives in medical 

devices? Contact - Division of Industry and Consumer 

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

Questions about use of color additives in a specific device? 

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

CA Webinar: 2/12/2016 49