Notice2025-19990
Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use; Guidance for Industry; Availability
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Published
November 17, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled "Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use." This guidance is intended to assist abbreviated new drug application (ANDA) applicants that reference a drug product intended for parenteral, ophthalmic, or otic use in seeking approval of a drug that is qualitatively (Q1) different or quantitatively (Q2) different from the reference listed drug (RLD) with respect to the pH adjuster(s). This guidance describes how FDA intends to evaluate a request for a waiver of Agency requirements for a Q1 or Q2 difference in pH adjuster, including recommendations on the type of information to provide in support of such a waiver request. This guidance finalizes the draft guidance of the same title issued on April 14, 2022.
Full Text
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<title>Federal Register, Volume 90 Issue 219 (Monday, November 17, 2025)</title>
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[Federal Register Volume 90, Number 219 (Monday, November 17, 2025)]
[Notices]
[Pages 51373-51374]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-19990]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-D-0108]
Considerations for Waiver Requests for pH Adjusters in Generic
Drug Products Intended for Parenteral, Ophthalmic, or Otic Use;
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 final guidance for industry entitled
``Considerations for Waiver Requests for pH Adjusters in Generic Drug
Products Intended for Parenteral, Ophthalmic, or Otic Use.'' This
guidance is intended to assist abbreviated new drug application (ANDA)
applicants that reference a drug product intended for parenteral,
ophthalmic, or otic use in seeking approval of a drug that is
qualitatively (Q1) different or quantitatively (Q2) different from the
reference listed drug (RLD) with respect to the pH adjuster(s). This
guidance describes how FDA intends to evaluate a request for a waiver
of Agency requirements for a Q1 or Q2 difference in pH adjuster,
including recommendations on the type of information to provide in
support of such a waiver request. This guidance finalizes the draft
guidance of the same title issued on April 14, 2022.
DATES: The announcement of the guidance is published in the Federal
Register on November 17, 2025.
ADDRESSES: You may submit either electronic or written comments on
Agency guidances at any time as follows:
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2022-D-0108 for ``Considerations for Waiver Requests for pH
Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic,
or Otic Use.'' Received comments will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 this 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 guidance document.
FOR FURTHER INFORMATION CONTACT: Susan Levine, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 75, Rm. 1674, Silver Spring, MD 20993-0002, 240-
402-7936, <a href="/cdn-cgi/l/email-protection#91e2e4e2f0ffbffdf4e7f8fff4d1f7f5f0bff9f9e2bff6fee7"><span class="__cf_email__" data-cfemail="31424442505f1f5d5447585f54715755501f5959421f565e47">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Considerations for Waiver Requests for pH Adjusters in
Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic
Use.'' The Federal Food, Drug, and Cosmetic Act (FD&C Act) does not
require an ANDA to have the same inactive ingredients as the RLD.\1\
Section 505(j)(4)(H) of the FD&C Act does, however, state that an ANDA
shall not be approved if information submitted in the application (or
other information available) shows (1) the inactive ingredients of the
drug are
[[Page 51374]]
unsafe for use under the conditions prescribed, recommended, or
suggested in the labeling proposed for the drug, or (2) the type or
quantity of inactive ingredients included or the manner in which the
inactive ingredients are included is unsafe under such conditions.\2\
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\1\ See section 505(j)(2)(A) of the FD&C Act (setting forth the
required contents of an ANDA).
\2\ Section 505(j)(4)(H) of the FD&C Act.
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The regulations at 21 CFR 314.94(a)(9)(iii) and (iv), with parallel
provisions in the approval regulations at Sec. 314.127(a)(8)(ii)(B)
and (C), specify that FDA will consider an inactive ingredient in, or
the composition of, a generic drug product intended for parenteral,
ophthalmic, or otic use to be unsafe and will refuse to approve the
ANDA unless the generic drug product contains the same inactive
ingredients (with certain listed exceptions) in the same concentration
as the RLD. Specifically, the inactive ingredient requirements in Sec.
314.94(a)(9)(iii) and (iv) apply to pH adjusters, which are not
expressly identified as one of the listed exceptions. Under Sec.
314.99(b), however, an applicant may ask FDA to waive any requirement
that applies to the applicant under Sec. Sec. 314.92 through 314.99.
Thus, an ANDA applicant for a drug product intended for parenteral,
ophthalmic, or otic use who seeks to use a pH adjuster(s) that is Q1 or
Q2 different from the RLD may ask the Agency to waive the inactive
ingredient requirements at Sec. 314.94(a)(9)(iii) or (iv) for the pH
adjuster(s). This guidance document provides recommendations on (1) the
type of information that applicants should consider submitting with a
Sec. 314.99(b) waiver request when an ANDA applicant asks the Agency
to waive the inactive ingredient requirements for pH adjusters and (2)
the format and process for submitting such waiver requests.
This guidance finalizes the draft guidance entitled
``Considerations for Waiver Requests for pH Adjusters in Generic Drug
Products Intended for Parenteral, Ophthalmic, or Otic Use'' issued on
April 14, 2022 (87 FR 22217). FDA considered comments received on the
draft guidance as the guidance was finalized. Changes from the draft to
the final guidance include recommendations for ANDA applicants to seek
FDA feedback on a proposed approach for justifying a Sec. 314.99(b)
waiver request for a difference in pH adjuster, as well as in instances
where the applicant also seeks to utilize a certain bioequivalence
approach with a formulation that contains a Q1 or Q2 difference in pH
adjuster.
In addition, this guidance includes information clarifying FDA's
obligations to maintain the confidentiality of trade secret and
confidential commercial information when responding to questions
regarding drug product formulations, and to distinguish the regulatory
provisions for requesting waiver of a Q1 or Q2 difference in a pH
adjuster from the provisions that support a request to waive submission
of evidence of in vivo bioequivalence.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``Considerations for Waiver Requests for pH
Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic,
or Otic Use.'' 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
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information
in 21 CFR part 314 relating to the submission of ANDAs, including
requests for waiver for a pH adjuster difference under Sec. 314.99(b)
and waivers under Sec. 314.90, have been approved under OMB control
number 0910-0001. The collections of information in 21 CFR part 320
relating to the requirements for demonstrating bioavailability and
bioequivalence, including waiver of evidence of in vivo bioavailability
or bioequivalence under Sec. 320.22(b), have been approved under OMB
control numbers 0910-0014 and 0910-0291. The collections of information
relating to the submission of controlled correspondence related to
generic drug development and FDA approval have been approved under OMB
control number 0910-0727.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
<a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-19990 Filed 11-14-25; 8:45 am]
BILLING CODE 4164-01-P
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