[Federal Register Volume 85, Number 191 (Thursday, October 1, 2020)]
[Notices]
[Pages 61953-61955]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-21652]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-D-1517]


The Use of Physiologically Based Pharmacokinetic Analyses--
Biopharmaceutics Applications for Oral Drug Product Development, 
Manufacturing Changes, and Controls; Draft Guidance for Industry; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry entitled ``The Use of 
Physiologically Based Pharmacokinetic Analyses--Biopharmaceutics 
Applications for Oral Drug Product Development, Manufacturing Changes, 
and Controls.'' This guidance provides general recommendations 
regarding the development, evaluation, and use of physiologically based 
pharmacokinetic (PBPK) analyses for biopharmaceutics applications 
employed by sponsors of investigational new drug applications, new drug 
applications, or abbreviated new drug applications, and supplements to 
these applications, for oral drug product development, manufacturing 
changes, and controls. The guidance covers how to develop, evaluate, 
and apply PBPK models for biopharmaceutics-related uses, such as 
establishing clinically relevant dissolution specifications and quality 
risk assessment for postapproval manufacturing changes.

[[Page 61954]]


DATES: Submit either electronic or written comments on the draft 
guidance by November 30, 2020 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

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-2020-D-1517] for ``The Use of Physiologically Based Pharmacokinetic 
Analyses--Biopharmaceutics Applications for Oral Drug Product 
Development, Manufacturing Changes, and Controls.'' Received comments 
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.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one 
self-addressed adhesive label to assist that office in processing your 
requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Paul Seo, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 21, Rm. 1628, Silver Spring, MD 20993-0002, 301-796-4874.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``The Use of Physiologically Based Pharmacokinetic Analyses--
Biopharmaceutics Applications for Oral Drug Product Development, 
Manufacturing Changes, and Controls.'' This draft guidance provides 
general recommendations regarding the development, evaluation, and use 
of PBPK analyses for biopharmaceutics applications employed by sponsors 
of investigational new drug applications, new drug applications, or 
abbreviated new drug applications, and supplements to these 
applications, for oral drug product development, manufacturing changes, 
and controls. PBPK analyses use models and simulations that combine 
physiology, population, and drug characteristics to mechanistically 
describe the pharmacokinetic and/or pharmacodynamic behaviors of a drug 
product.
    Submission of these analyses to FDA is discussed in the guidance 
for industry entitled ``Physiologically Based Pharmacokinetic 
Analyses--Format and Content'' (available at https://www.fda.gov/media/101469/download). However, the application of PBPK modeling in support 
of drug product development is an evolving field. FDA recognizes this 
challenge and encourages the development and use of new tools and 
approaches for linking pharmaceutical quality to clinical performance.
    Advances in modeling and simulation have enabled the integration of 
factors such as the physicochemical properties of the active 
pharmaceutical ingredient, dissolution data, and the physiology of the 
gastrointestinal tract into the development of PBPK models. As such, 
PBPK modeling has become a promising tool in predicting systemic drug 
exposure of oral drug products.
    PBPK analyses for biopharmaceutics applications combine dissolution 
modeling, biopredictive dissolution profiles, or other in vitro testing 
inputs with PBPK modeling strategies to quantitatively describe the 
differential and potential interactions of formulation variants with 
the body and their effect on drug exposure.
    This guidance describes recommended PBPK model structure, which 
provides a mechanistic framework of drug oral absorption by 
representing the in vivo drug absorption process and accounting for the 
relevant

[[Page 61955]]

product quality attributes that affect drug dissolution and absorption, 
and discusses how to capture and present model assumptions and 
parameters. Model validation and refinement are also discussed.
    In addition, the guidance discusses the major regulatory uses of 
PBPK modeling for biopharmaceutics applications with respect to 
supporting product quality. Factors regarding the development of 
clinically relevant dissolution specifications to aid in biopredictive 
dissolution method development and to support clinically relevant 
dissolution acceptance criteria are presented, as well as 
considerations for conducting virtual bioequivalence studies.
    PBPK modeling for biopharmaceutics applications also can be used to 
establish clinically relevant drug product quality specifications other 
than dissolution, which can be used to ensure bioequivalence of batches 
within the specification limits, to the pivotal clinical/
bioavailability batches, or to the reference listed drug for generic 
drugs. Finally, the guidance discusses the use of PBPK analyses for 
biopharmaceutics applications as an advanced tool for quality risk 
assessment and management in both the pre- and postapproval stages.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on ``The Use of 
Physiologically Based Pharmacokinetic Analyses-- Biopharmaceutics 
Applications for Oral Drug Product Development, Manufacturing Changes, 
and Controls.'' It does not establish any rights for any person and is 
not binding on FDA or the public. You can use an alternative approach 
if it satisfies the requirements of the applicable statutes and 
regulations.

II. Paperwork Reduction Act of 1995

    This draft guidance refers to previously approved FDA collections 
of information. These collections of information are subject to review 
by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3521). The collections of 
information in 21 CFR part 314 have been approved under OMB control 
number 0910-0001.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at either https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs or https://www.regulations.gov.

    Dated: September 23, 2020.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2020-21652 Filed 9-30-20; 8:45 am]
BILLING CODE 4164-01-P


