Federal Register / Vol. 86, No. 171 / Wednesday, September 8, 2021 / Notices 50363 

I. General Description of the Committee 

Duties 

The Tobacco Products Scientific 

Advisory Committee (the Committee) 

advises the Commissioner of FDA (the 

Commissioner) or designee in 

discharging responsibilities related to 

the regulation of tobacco products. The 

Committee reviews and evaluates 

behavior, dependence, and health 

issues, among others, relating to tobacco 

products and provides appropriate 

advice, information, and 

recommendations to the Commissioner. 

II. Criteria for Voting Members 

The Committee shall consist of 12 

members, including the Chair. Members 

and the Chair are selected by the 

Commissioner or designee from among 

individuals knowledgeable in the fields 

of science, medicine, medical ethics, or 

technology involving the manufacture, 

evaluation, or use of tobacco products. 

Almost all non-Federal members of this 

committee serve as Special Government 

Employees. The Committee shall 

include nine technically qualified 

voting members, selected by the 

Commissioner or designee. The nine 

voting members shall be scientists, 

physicians, dentists, or healthcare 

professionals practicing in the areas of 

oncology, pulmonology, cardiology, 

toxicology, pharmacology, addiction, 

epidemiology, behavioral health, or any 

other relevant specialty. One member 

shall be an officer or employee of a state 

or local government or of the Federal 

Government. The final voting member 

shall be a representative of the general 

public. Members will be invited to serve 

for terms of up to 4 years. 

III. Nomination Procedures 

Any interested person may nominate 

one or more qualified individuals for 

membership on the advisory committee. 

Self-nominations are also accepted. 

Nominations must include a current, 

complete re ́sume ́ or curriculum vitae for 

each nominee, including current 

business address and/or home address, 

telephone number, and email address if 

available and a signed copy of the 

Acknowledgement and Consent form 

available at the FDA Advisory 

Nomination Portal (see ADDRESSES). 

Nominations must also specify the 

advisory committee for which the 

nominee is recommended. Nominations 

must also acknowledge that the 

nominee is aware of the nomination 

unless self-nominated. FDA will ask 

potential candidates to provide detailed 

information concerning such matters 

related to financial holdings, 

employment, and research grants and/or 

contracts to permit evaluation of 

possible sources of conflicts of interest. 

This notice is issued under the 

Federal Advisory Committee Act (5 

U.S.C. app. 2) and 21 CFR part 14, 

relating to advisory committees. 

Dated: September 2, 2021. 

Lauren K. Roth, 

Acting Principal Associate Commissioner for 

Policy. 

[FR Doc. 2021–19444 Filed 9–7–21; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2019–N–5464] 

Center for Drug Evaluation and 

Research Office of New Drugs Novel 

Excipient Review Pilot Program 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration’s (FDA) Center for Drug 

Evaluation and Research (CDER) is 

announcing a Novel Excipient Review 

Pilot Program (Pilot Program). The Pilot 

Program is voluntary and intended to 

allow excipient manufacturers to obtain 

FDA review of certain novel excipients 

prior to their use in drug formulations. 

The Pilot Program seeks to foster 

development of excipients that may be 

useful in scenarios in which excipient 

manufacturers and drug developers 

have cited difficulty in using existing 

excipients. 

DATES: FDA is seeking initial proposals 

for the voluntary Novel Excipient 

Review Pilot Program through December 

7, 2021. 

FOR FURTHER INFORMATION CONTACT: 

Felecia Wilson, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, Novel-ExcipientProgram@fda.hhs.gov, 301–796–9590. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Excipient manufacturers and drug 

developers have cited product 

development challenges related to the 

use of certain excipients (also known as 

inactive ingredients), including issues 

related to formulation and stability. 

Novel excipients might be able to 

address some of these issues and 

provide additional public health 

benefits, such as enhanced drug 

bioavailability, more comfortable drug 

administration, new abuse-deterrent 

opioid formulations, new routes of drug 

delivery, and facilitation of new 

technologies. However, drug developers 

report that they have been hesitant to 

use novel excipients in drug 

development programs due to the 

uncertainty surrounding their 

acceptability. 

To address these issues, FDA issued 

a request for information in the Federal 

Register on December 5, 2019 (84 FR 

66669), seeking comment on a potential 

pilot program for FDA review of novel 

excipients. FDA received several 

comments to the public docket on these 

issues. After considering these 

comments, CDER has decided to 

establish this Pilot Program. 

A. Scope 

For purposes of the Pilot Program, an 

excipient is any ingredient intentionally 

added to a drug product (including a 

biological drug product) that is not 

intended to exert therapeutic effects at 

the intended dosage, although it may 

improve product delivery (see FDA 

guidance for industry entitled 

‘‘Nonclinical Studies for the Safety 

Evaluation of Pharmaceutical 

Excipients’’ (Ref.1)). Examples of 

excipients may include fillers, 

extenders, diluents, surfactants, 

solvents, emulsifiers, preservatives, 

flavors, absorption enhancers, modified 

release matrices, and coloring agents. 

Also, for purposes of this Pilot Program, 

a novel excipient is any excipient that 

is not fully supported by existing safety 

data with respect to the currently 

proposed level of exposure, duration of 

exposure, or route of administration 

(Ref. 1). This parallels the definition of 

‘‘new excipients’’ defined in Ref. 1. 

CDER proposes a more limited scope 

for this Pilot Program. The Pilot 

Program will initially be available for 

novel excipients that (1) have not been 

previously used in FDA-approved drug 

products, and (2) do not have an 

established use in food. CDER 

recognizes that there may be novel 

excipients not meeting this scope that 

may also address product development 

challenges or provide public health 

benefits. However, because of the 

limited scope of the initial phase of the 

Pilot Program (described further below), 

CDER will not be able to consider 

submissions for all kinds of novel 

excipients. CDER may expand the scope 

of the Pilot Program in the future 

depending on its success and as 

resources allow. 

The Pilot Program is voluntary. 

Existing processes for developing 

excipients for use in drug and biological 

products continue to be available. 


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50364 Federal Register / Vol. 86, No. 171 / Wednesday, September 8, 2021 / Notices 

B. Participation 

The Pilot Program will consist of two 

stages. The first stage is an initial 

proposal stage for excipient 

manufacturers to provide a high-level 

overview of their novel excipient. CDER 

intends to accept approximately four 

initial proposals (two for the first year 

of the Pilot Program, and two for the 

second year) but will consider accepting 

more proposals as resources allow. 

Excipient manufacturers whose initial 

proposals are accepted would then enter 

the second stage, during which they 

would provide a full data package 

consisting of toxicology and quality 

data. Both stages are described in 

further detail below. 

As mentioned above, CDER intends to 

consider for the Pilot Program novel 

excipients that (1) have not been 

previously used in FDA-approved drug 

products, and (2) do not have an 

established use in food. 

C. Procedures 

1. Initial Proposal Stage 

At the initial proposal stage, excipient 

manufacturers will submit brief 

summaries describing the novel 

excipient, its proposed use, and the 

public health or drug development need 

addressed by the excipient. The initial 

proposal is anticipated to include a 

summary of the supportive data 

generated or collected so far and some 

indication of the timing of any 

subsequent data needed for submission 

of the Full Package. FDA has posted an 

initial proposal model content outline 

on the Pilot Program web page (https:// 

www.fda.gov/drugs/developmentapproval-process-drugs/novel-excipientreview-pilot-program). 

Interested excipient manufacturers 

should submit initial proposals to FDA 

via email at Novel-Excipient-Program@

fda.hhs.gov. FDA will accept proposals 

for the pilot through December 7, 2021. 

FDA will notify all submitters whether 

their proposal is accepted into the Pilot 

Program. 

FDA will review the initial proposals 

and select approximately four proposals 

(two for the first year and two for the 

second year) to proceed to stage two of 

the program. FDA will consider the 

following factors, among other 

considerations, in determining which 

proposals to select: 

• Potential public health benefit of 

the novel excipient (for example, 

excipients that may facilitate opioid 

abuse-deterrent formulations or 

excipients that may promote 

development of new therapies for 

serious and life-threatening diseases). 

• Likelihood of the novel excipient 

manufacturer’s ability to submit a 

complete package within the timeframe 

established in this Notice. 

• Overall potential of the novel 

excipient to meaningfully improve 

pharmacokinetic characteristics that 

may lead to novel drug development. 

2. Procedures for Full Packages 

For novel excipients selected into the 

program, the developer should submit a 

full package consisting of toxicology 

and quality data as described below. See 

CDER Guidance for industry entitled 

‘‘Nonclinical Studies for the Safety 

Evaluation of Pharmaceutical 

Excipients’’ (Ref. 1). 

a. Toxicology data package. The 

toxicology data package should include 

adequate, supportive safety information 

for the novel excipient to verify that the 

proposed excipient is safe in the 

amounts and type of product(s) in 

which it may be administered as well as 

the proposed use (e.g., level, route, 

duration, patient population). 

Depending on the proposed use, the 

toxicology data package may include the 

information described below. 

Additional safety data may be requested 

if the proposed use is not fully 

supported by the available data. 

Reference is made to the relevant 

guidance for the proposed toxicology 

data package below. 

• Safety pharmacology: Novel 

excipients should be evaluated for 

pharmacological activity using a battery 

of standard tests (see FDA guidance for 

industry entitled ‘‘S7A Safety 

Pharmacology Studies for Human 

Pharmaceuticals’’ (Ref. 2)). 

• Pharmacokinetic testing 

(absorption, distribution, metabolism, 

and excretion): To determine the extent 

of exposure. A pharmacokinetic profile 

for an excipient that is extensively 

absorbed, undergoes extensive 

biotransformation, or both will be 

useful. 

• General toxicology: Chronic, 6- 

month repeat dose toxicology studies in 

a relevant species by appropriate route 

with complete clinical pathology, 

histopathology, and toxicokinetic 

analysis are recommended. Because 

excipients generally have low toxicity, 

the limit dose is recommended as the 

highest dose for testing (see FDA 

guidance for industry entitled ‘‘M3(R2) 

Nonclinical Safety Studies for the 

Conduct of Human Clinical Trials and 

Marketing Authorization for 

Pharmaceuticals’’ (Ref. 3)). 

• Genetic toxicology (see FDA 

guidance for industry entitled ‘‘S2B 

Genotoxicity: A Standard Battery for 

Genotoxicity Testing of 

Pharmaceuticals’’ (Ref. 4)). 

• Reproductive toxicology: Fertility, 

embryo-fetal, and pre- and post-natal 

development (see International Council 

for Harmonization harmonized guidance 

for industry entitled ‘‘Detection of 

Reproductive and Developmental 

Toxicity for Human Pharmaceuticals 

S5(R3)’’ (Ref. 5)). 

• Carcinogenicity: One of the 

following approaches may be used to 

evaluate carcinogenic potential (see 

FDA guidance for industry entitled 

‘‘The Need for Long-term Rodent 

Carcinogenicity Studies of 

Pharmaceuticals’’ (Ref. 6)): 

Æ Two-year carcinogenicity bioassays 

in two appropriate species by the 

relevant route; 

Æ A 2-year carcinogenicity study in 

rat plus a transgenic mouse model; or 

Æ Submission of documentation 

providing scientific justification that 

carcinogenicity data are not necessary 

based on the weight of evidence 

approach in an assessment to address 

the carcinogenic potential. 

• Special studies (e.g., local tolerance, 

Juvenile Animal Studies). 

b. Quality data package. The novel 

excipient chemistry, manufacturing, and 

controls data submitted to CDER should 

be similar to that provided in an 

investigational new drug application 

(IND). 

For evaluation of all novel excipients 

with a proposed use in formulations for 

small molecule and biological drug 

products reviewed by CDER/Office of 

New Drugs (OND), submitters should 

provide: 

• Excipient specifications. 

• A description of the source, 

synthetic pathway/fermentation or 

extraction for non-synthetic excipients, 

raw materials, in-process controls, 

manufacturing process description, 

characterization and analytical methods, 

or a letter of authorization (right of 

reference) for the excipient Type IV 

drug master file (DMF) or other master 

file if a master file has been submitted 

for the excipient. 

• If the excipient contains a novel 

moiety with immunogenic potential, an 

immunogenicity risk assessment that 

may include in vitro data. Additional 

information on immunogenicity risk 

assessment may be found in FDA 

guidance for industry entitled ‘‘S8 

Immunotoxicity Studies for Human 

Pharmaceuticals’’ for types of 

supporting in vitro studies (Ref. 7). 

• If the excipient is sourced from 

cells, clearance of host cell protein 

(absence in final excipient) and 

evidence of absence of adventitious 

agents such as viruses. 


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Federal Register / Vol. 86, No. 171 / Wednesday, September 8, 2021 / Notices 50365 

In addition, for evaluation of novel 

excipients with a proposed use in 

formulations for biological drug 

products reviewed by CDER/OND, 

submitters should provide: 

• Stability studies of the excipient 

under storage and potential in-use 

conditions (e.g., over infusion time). 

Novel excipients should be evaluated 

for their potential to prevent 

denaturation and degradation of 

proteins during storage. 

• For some excipients, studies should 

address their potential protein-excipient 

interaction and impact on drug product 

immunogenicity as well as their 

potential for masking process related 

impurities. 

Full packages should be submitted 

through a Type V DMF or other master 

file no later than 3 months after 

notification that FDA has selected the 

proposal. For more information on 

submitting Type V DMFs, see the FDA 

draft guidance for industry entitled 

‘‘Drug Master Files’’ (Ref. 8). 

FDA will evaluate the full package 

and determine whether the excipient is 

appropriate for the proposed use for use 

in clinical trials. FDA will issue a letter 

to the novel excipient submitter 

announcing its decision. 

For each novel excipient evaluated 

under the second stage of the program, 

FDA will publish on the Pilot Program 

web page the initial proposal and the 

determination letter. Information that 

cannot be publicly disclosed will be 

redacted. This web page will also 

include a content outline identifying 

information that should be included in 

an Initial Proposal and other relevant 

information regarding the pilot. 

3. Effect of Determination 

A determination that the excipient is 

appropriate for use in clinical trials 

means that FDA has determined it is 

appropriate to use the novel excipient in 

an IND within the defined use without 

additional justification. However, the 

drug sponsor would still need to 

demonstrate that the excipient is safe in 

the proposed formulation. The 

information submitted under the full 

package would remain in the Type V 

DMF or other master file, and the master 

file holder may grant authorization to 

reference the information in the master 

file at the holder’s discretion. Moreover, 

we do not anticipate that a novel 

excipient may be used in an abbreviated 

new drug application because data and 

information currently required to 

support use of a novel excipient may 

not be submitted in an abbreviated new 

drug application. After it has been used 

in approved drug products, the novel 

excipient would be added to the 

Inactive Ingredient Database in 

accordance with Agency practice. 

If FDA determines that the excipient 

is not appropriate for the proposed use, 

an IND sponsor would be expected to 

provide additional information to 

demonstrate that the use of the novel 

excipient is appropriate within the 

context of the IND. 

II. Paperwork Reduction Act of 1995 

The information collection activities 

associated with the Pilot Program refer 

to previously approved FDA collections 

of information. Therefore, clearance by 

the Office of Management and Budget 

(OMB) under the Paperwork Reduction 

Act of 1995 (PRA) (44 U.S.C. 3501– 

3521) is not required for this Pilot 

Program. The previously approved 

collections of information are subject to 

review by OMB under the PRA. The 

collections of information in 21 CFR 

part 314 pertaining to the submission of 

abbreviated new drug applications, new 

drug applications, and DMFs have been 

approved under OMB control number 

0910–0001. The collections of 

information in 21 CFR part 312 

pertaining to the submission of IND 

content and format; chemistry, control, 

and manufacturing data; pharmacology 

and toxicology data; and 

pharmacokinetics and biological data 

have been approved under OMB control 

number 0910–0014. The collections of 

information in 21 CFR part 58 

pertaining to good laboratory practice 

regulations for nonclinical laboratory 

studies have been approved under OMB 

control number 0910–0119. The 

collections of information in 21 CFR 

part 601 pertaining to biologics license 

applications have been approved under 

OMB control number 0910–0338. 

III. References 

The following references are on 

display at the Dockets Management Staff 

(HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852, 240–402– 

7500, and are available for viewing by 

interested persons between 9 a.m. and 4 

p.m., Monday through Friday; they are 

also available electronically at https://

www.regulations.gov. FDA has verified 

the website addresses, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

1. FDA, Guidance for Industry, ‘‘Nonclinical 

Studies for the Safety Evaluation of 

Pharmaceutical Excipients,’’ May 2005 

(available at https://www.fda.gov/media/ 

72260/download). For the most recent 

version of a guidance, check the FDA 

guidance web page at https://

www.fda.gov/regulatory-information/ 

search-fda-guidance-documents. 

2. FDA Guidance for Industry, ‘‘S7A Safety 

Pharmacology Studies for Human 

Pharmaceuticals,’’ July 2001 (available at 

https://www.fda.gov/media/72033/ 

download). 

3. FDA, Guidance for Industry, ‘‘M3(R2) 

Nonclinical Safety Studies for the 

Conduct of Human Clinical Trials and 

Marketing Authorization for 

Pharmaceuticals,’’ January 2010 

(available at https://www.fda.gov/media/ 

71542/download). 

4. FDA, Guidance for Industry, ‘‘S2B 

Genotoxicity: A Standard Battery for 

Genotoxicity Testing of 

Pharmaceuticals,’’ July 1997 (available at 

https://www.fda.gov/media/71971/ 

download). 

5. International Council for Harmonization 

(ICH), Guidance for Industry, ‘‘Detection 

of Reproductive and Developmental 

Toxicity for Human Pharmaceuticals 

S5(R3),’’ February 2020 (available at 

https://database.ich.org/sites/default/ 

files/S5-R3_Step4_Guideline_2020_

0218_1.pdf). 

6. FDA, Guidance for Industry, ‘‘The Need for 

Long-term Rodent Carcinogenicity 

Studies of Pharmaceuticals,’’ March 1996 

(available at https://www.fda.gov/media/ 

71921/download). 

7. FDA, Guidance for Industry, ‘‘S8 

Immunotoxicity Studies for Human 

Pharmaceuticals,’’ April 2006 (available 

at https://www.fda.gov/media/72047/ 

download). 

8. FDA, Draft Guidance for Industry ‘‘Drug 

Master Files,’’ October 2019 (available at 

https://www.fda.gov/media/131861/ 

download). 

Dated: September 1, 2021. 

Lauren K. Roth, 

Acting Principal Associate Commissioner for 

Policy. 

[FR Doc. 2021–19335 Filed 9–7–21; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Health Resources and Services 

Administration 

Agency Information Collection 

Activities: Proposed Collection: Public 

Comment Request; Information 

Collection Request Title: MCH 

Jurisdictional Survey Instrument for 

the Title V MCH Block Grant Program, 

OMB No. 0906–0042, Extension 

AGENCY: Health Resources and Services 

Administration (HRSA), Department of 

Health and Human Services. 

ACTION: Notice. 

SUMMARY: In compliance with the 

requirement of the Paperwork 

Reduction Act of 1995 for opportunity 

for public comment on proposed data 

collection projects, HRSA announces 


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