Guidance: Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use

Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use; Guidance for Industry; Availability

DATES:

The announcement of the guidance is published in the Federal Register on November 17, 2025.

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 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.

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 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⁾

The regulations at 21 CFR 314.94(a)(9)(iii) and (iv), with parallel provisions in the approval regulations at § 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 § 314.94(a)(9)(iii) and (iv) apply to pH adjusters, which are not expressly identified as one of the listed exceptions. Under § 314.99(b), however, an applicant may ask FDA to waive any requirement that applies to the applicant under §§ 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 § 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 § 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 § 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 § 314.99(b) and waivers under § 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 § 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 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.

⁽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.