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[Federal Register Volume 90, Number 11 (Friday, January 17, 2025)]
[Notices]
[Pages 5892-5893]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-01182]

[[Page 5892]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-5975]

Use of a Type V Drug Master File for Model Master File 
Submissions To Support Abbreviated New Drug Applications; Establishment 
of a Public Docket; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency), Center for 
Drug Evaluation and Research (CDER), Office of Generic Drugs is 
establishing a public docket entitled ``Use of a Type V Drug Master 
File (DMF) for Model Master File (MMF) Submissions to Support 
Abbreviated New Drug Applications (ANDAs).'' The purpose of this docket 
to solicit input from interested parties on this topic.

DATES: Submit either electronic or written comments on the notice by 
April 17, 2025 to ensure that the Agency considers your comment. The 
docket number is FDA-2024-N-5975.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time April 17, 2025. Comments received by mail/hand 
delivery/courier (for written/paper submissions) will be considered 
timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2024-N-5975 for ``Use of a Type V Drug Master File for Model Master 
File Submissions to Support Abbreviated New Drug Applications; 
Establishment of a Public Docket; Request for Comments.'' Received 
comments, those filed in a timely manner (see ADDRESSES), will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Lanyan (Lucy) Fang, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 75, Rm. 4686, Silver Spring, MD 20993-0002, 301-
796-5005, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Computational (in silico) modeling and simulation (M&S) is a 
regulatory science priority at FDA given the rapid growth in drug 
developers' use of data science and model-based technologies. An 
example is the increasing use of quantitative methods and modeling 
(QMM) and simulation approaches by the generic drug industry and 
regulatory agencies, including FDA, to support generic product 
development and ANDA regulatory assessments.\1\ These QMM approaches 
generally involve mechanistic modeling such as physiologically based 
pharmacokinetic (PBPK) modeling and computational fluid dynamics (CFD) 
modeling, quantitative clinical pharmacology tool sets such as 
population pharmacokinetics (PPK) approaches, and advanced data 
analytics methodologies. Generic drug developers are utilizing QMM and 
simulation approaches to generate MIE to, for example, support 
alternative BE approaches and to minimize the burden

[[Page 5893]]

of, or even eliminate the need for, in vivo studies to establish BE.
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    \1\ See, e.g., guidance for industry ``Physiologically Based 
Pharmacokinetic Analyses--Format and Content'' (August 2018); see 
also, draft guidance for industry ``The Use of Physiologically Based 
Pharmacokinetic Analyses--Biopharmaceutics Applications for Oral 
Drug Product Development, Manufacturing Changes, and Controls'' 
(October 2020). When final, this guidance will represent the FDA's 
current thinking on this topic. FDA updates guidances periodically; 
the most recent version of a guidance can be found at FDA's Drugs 
guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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    While QMM approaches that generate MIE provide significant value to 
the development, review, and approval of high-quality generic drugs, 
these frameworks are evolving amidst challenges and complications 
facing industry that are incidental to the growing use of new and 
complex modeling technologies. For example, the data and information 
needed to verify and validate a model may not be available to the 
general public (e.g., proprietary), or if publicly available, 
insufficient, and generating original data for model verification and 
validation (V&V) can be a time-consuming and costly investment. At the 
same time, certain M&S approaches may provide an opportunity for 
certain models, once they are supported by sufficient V&V, to be viewed 
as shareable across different products and formulations and utilized by 
multiple ANDA applicants for the same context of use. For purposes of 
this notice, an ``MMF'' or ``MMF submission'' refers to a set of 
information and data on an in silico quantitative model or modeling 
platform supported by sufficient V&V. MMFs can be established to 
support MIE in a broad range of quantitative models, including, but not 
limited to, PBPK, CFD, PPK, and mechanistic in vitro in vivo 
correlation models. There are different types of MMFs, including, but 
not limited to, drug product-specific models, a verified and validated 
in silico framework for products following the same route of 
administration, and a recognized modeling methodology or framework for 
a particular context of use (Ref. 1).
    FDA recognizes the evolving role MIE plays in generic drug 
development and other regulatory applications, as well as industry's 
corollary desire for an improved framework for in silico model-sharing, 
model acceptance, and related communication with and submission to FDA. 
Use of the Type V DMF to efficiently leverage MMFs within the scope of 
successful MIE approaches may help advance generic drug development and 
facilitate the ANDA review and approval processes.
    A DMF is a voluntary submission that may be used to provide 
confidential detailed information to the Agency (Ref. 2). A DMF is 
submitted solely at the discretion of the DMF holder. There are several 
types of DMFs; a Type V is used for ``FDA-accepted reference 
information.'' (Sec.  314.420(a)(5) (21 CFR 314.420(a)(5))). The use of 
a DMF is not a requirement for the submission of MMFs to the Agency; 
however, the holder of a Type V DMF can authorize one or more ANDA 
applicants to incorporate by reference information and data contained 
in the DMF without having to disclose that information and data to the 
applicant(s). When authorized by the DMF holder, ANDA applicants can 
use information and data contained in the DMF to support, but not 
substitute for, their ANDA submissions. A DMF is neither approved nor 
disapproved. Its technical content (in this case, the MMF) is typically 
reviewed by FDA only in connection with the review of a premarket 
application (Ref. 2 at 6). A Type V DMF, including a Type V DMF for MMF 
submissions to support an ANDA, may be submitted on an ongoing basis.
    Prospective DMF holders who are interested in using a Type V DMF, 
including a Type V DMF for MMF submissions to support ANDAs, must first 
email a letter of intent to the DMF staff (see Ref. 2 at 16 (citing 
Sec.  314.420(a)(5))). The draft guidance for industry ``Drug Master 
Files'' provides detailed information about preparing and submitting 
DMFs and FDA's DMF review process, including that an emailed letter of 
intent should be sent to ([email protected]) and include a 
clearly stated subject field and other necessary information (Ref. 2 at 
16). For example, applicants that have submitted a Type V DMF for MMF 
submissions to support ANDAs have submitted the letter of intent with a 
subject field, such as ``Letter of Intent to Submit Type V DMF for MMF 
Submission to Support ANDAs''. For more information on submitting Type 
V DMFs, see FDA's DMF web page and the FDA Guidance for Industry 
``Providing Regulatory Submissions in Electronic Format--Certain Human 
Pharmaceutical Product Applications and Related Submissions using the 
eCTD Specifications'' (Ref. 3).\2\
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    \2\ See also, FDA's DMF web page, available at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.
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II. Request for Comments

    FDA is opening a docket to solicit feedback from the public on the 
use of a Type V DMF for MMF submissions to support ANDAs. FDA welcomes 
any relevant information that interested parties and other members of 
the public wish to share. At the close of the comment period, the 
Agency will collect this feedback for consideration.

III. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
Although 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. Fang, L., Y. Gong, A.C. Hooker, et al., 2024, ``The Role of 
Model Master Files for Sharing, Acceptance, and Communication with 
FDA,'' The AAPS Journal, 26(2):28-35 available at 10.1208/s12248-
024-00897-8.
    * 2. FDA Draft Guidance for Industry ``Drug Master Files,'' 
October 2019: https://www.fda.gov/media/131861/download.
    * 3. FDA Guidance for Industry ``Providing Regulatory 
Submissions in Electronic Format--Certain Human Pharmaceutical 
Product Applications and Related Submissions using the eCTD 
Specifications,'' September 2024, Rev. 8: https://www.fda.gov/media/135373/download.

    Dated: January 14, 2025.
P. Ritu Nalubola,
Associate Commissioner for Policy.
[FR Doc. 2025-01182 Filed 1-16-25; 8:45 am]
BILLING CODE 4164-01-P
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