Document ID: FDA-2022-D-0108-0001
Agency: fda
Document Type: Notice
Title: Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use; Draft Guidance for Industry; Availability
Posted Date: 2022-04-14T04:00Z

[Federal Register Volume 87, Number 72 (Thursday, April 14, 2022)]
[Notices]
[Pages 22217-22218]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-08012]

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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Drug Products Intended for Parenteral, Ophthalmic, or Otic Use; Draft 
Guidance for Industry; Availability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the availability of a draft guidance for industry entitled 
``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 
draft guidance describes how FDA intends to evaluate a request for a 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 This draft guidance also includes 
recommendations on the timing and process for submitting such waiver 
requests.

DATES: Submit either electronic or written comments on the draft 
guidance by June 13, 2022 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 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-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 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: Melissa Mannion, Center for Drug

[[Page 22218]]

Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 75, Rm. 1611, Silver Spring, MD 20993-0002, 301-
796-2747.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Considerations for Waiver Requests for pH Adjusters in 
Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic 
Use.'' 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 
``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.
    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 (21 U.S.C. 355(j)(4)(H)) 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 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 Agency has interpreted section 505(j)(4)(H) of the FD&C Act as 
permitting the Agency to deny approval of an ANDA ``if there is a 
reasonable basis to conclude that its inactive ingredients or 
composition raise serious questions about the drug's safety.'' \3\
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    \3\ 21 CFR 314.127(a)(8)(ii); 54 FR 28871 at 28903 (July 10, 
1989).
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    The regulations at Sec.  314.94(a)(9)(iii) and (iv) (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) (21 CFR 
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. These regulations also identify permissible 
differences in certain inactive ingredients for drug products intended 
for parenteral, ophthalmic, or otic use, commonly referred to as 
``exception excipients,'' if the ANDA contains sufficient information 
to demonstrate that any such differences do not affect the safety or 
efficacy of the drug. The regulations do not, however, expressly 
identify pH adjusters as one of these ``exception excipients,'' and, as 
such, the inactive ingredient requirements in Sec.  314.94(a)(9)(iii) 
and (iv) apply to pH adjusters.
    Under Sec.  314.99(b) (21 CFR 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 (21 CFR 314.92 through 314.99). Such a 
request under Sec.  314.99(b) must comply with the requirements at 21 
CFR 314.90. FDA may grant a Sec.  314.99(b) waiver if the Agency finds 
one of the following: (1) The applicant's compliance with the 
requirement is unnecessary for the Agency to evaluate the ANDA or 
compliance cannot be achieved; (2) the applicant's alternative 
submission satisfies the requirement; or (3) the applicant's submission 
otherwise justifies a waiver. Even if FDA grants a waiver of a 
requirement in Sec. Sec.  314.92 through 314.99 in a particular 
application, the application still must meet all applicable statutory 
requirements for approval. If FDA grants the applicant's waiver request 
with respect to a requirement under Sec. Sec.  314.92 through 314.99, 
the waived requirement will not constitute a basis for refusal to 
approve an ANDA under Sec.  314.127. 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 draft 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.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
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 guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR part 314 have been approved under OMB control 
number 0910-0001; the collections of information in 21 CFR part 320 
been approved under OMB control numbers 0910-0014 and 0910-0291; and 
the collections of information for the submission of controlled 
correspondence related to generic drug development and FDA approval 
have been approved under OMB control number 0910-0797.

III. Electronic Access

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

    Dated: April 11, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08012 Filed 4-13-22; 8:45 am]
BILLING CODE 4164-01-P