[Federal Register Volume 86, Number 171 (Wednesday, September 8, 2021)]
[Notices]
[Pages 50363-50365]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-19335]


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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.

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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-Excipient-Program@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.

[[Page 50364]]

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/development-approval-process-drugs/novel-excipient-review-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)):
    [cir] Two-year carcinogenicity bioassays in two appropriate species 
by the relevant route;
    [cir] A 2-year carcinogenicity study in rat plus a transgenic mouse 
model; or
    [cir] 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.

[[Page 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]
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