FDA Issues Final Guidance For pH Adjuster Waiver Requests For Generic Drugs

By Tim Sandle, Ph.D.

The U.S. FDA has issued a final guidance for industry titled Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use.¹ The document was previously issued as a draft in April 2022.

The general requirement when producing generics is that the substances “must contain the same active ingredients and in the same concentration as the reference listed drug identified by the applicant.” However, variations are occasionally permitted with respect to “inactive ingredients.” The 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 different or quantitatively different from the reference listed drug.²

The reason for the guidance is, officially, an increased interest in and questions about waivers from generic drug manufacturers concerning the applicable inactive ingredient requirements for pH adjusters in ANDAs. However, there was a Citizen Petition (Docket No. FDA-2013-P-0203) submitted to the FDA calling for greater clarity and flexibility about excipient use.

The guidance sets out how the FDA intends to evaluate a request for a waiver for the standard requirements for qualitative or quantitative differences in pH adjusters. This extends to describing the type of information needed by the applicant when making a request.

Abbreviated New Drug Applications

The standard ANDA application process requires a data package to be submitted to the FDA for review and potential approval of a generic drug product. This includes showing the proposed generic drug product has the same:³

• active ingredient
• dosage form
• route of administration
• strength
• conditions of use
• labeling

as the reference product. And the submission must show the bioequivalence of the generic drug in relation to the reference drug. However, inactive ingredients can differ between the two products, provided any inactive ingredients in the generic drug have been assessed as safe. Examples of “unsafe” include a change that results in the product no longer comping with an official compendium (like the USP) – that is interfering with the drug’s therapeutic properties – or with an inactive ingredient that has not been previously approved for use in the same product type as the reference product (that is, the ingredient might pose a risk of toxicity). Examples of different inactive ingredients include different preservatives, buffers, or antioxidants (parenteral drugs); preservatives, buffers, or substances to adjust tonicity; or thickening agents in ophthalmic or otic products. These are classified by the FDA as “exception excipients.”

Excluded from this list are pH adjusters; these are non-exception excipients and therefore permission from the FDA is required before use. This does not mean a pH adjuster cannot be changed; the FDA can consider a waiver to permit a qualitative or quantitative difference in a pH adjuster in a generic drug product.

Why The Focus On pH Adjusters?

The FDA has noted an increased number of applications seeking to amend pH adjusters as part of the inactive ingredient component of a submission. A pH adjuster is a chemical used to control the acidity or alkalinity of water (thereby altering the equilibrium concentration of hydronium ions in each solution).⁴ As examples, adding acidic agents like sulfuric acid can lower the pH, whereas alkaline agents like sodium hydroxide can raise it. Care needs to be taken during development, since products can undergo a changed state or become precipitated when the pH is altered.⁵ The scientific basis for seeking an alternative rests on how pH adjusters function or react in the drug formulation. If this can be demonstrated, there may be circumstances where certain differences in pH adjusters in an ANDA, as compared to a reference listed drug, are scientifically appropriate and acceptable.

pH adjusters are used on an as-needed basis to achieve a specified pH range in the drug product. Due to the variations in processing, the quantity of pH adjuster used is as much or as little as necessary to achieve a specified pH range for each batch of the drug product. In other words, the objective is the specified pH range of the drug product, whereas the amount of pH adjuster used can be varied.

The use of a pH adjuster can often be in conjunction with a buffer to alter the properties of a weak acid or a base. When this occurs, the pH adjuster is regarded as an indistinguishable part of the buffer system. For example, consider sodium hydroxide added to acetic acid; the reaction produces sodium acetate:

NaOH + HOAc ⇌ NaOAc + H₂O

Hence, adding NaOH to an acetic acid-sodium acetate buffer converts some acetic acid to sodium acetate, and with this example, the pH adjuster (sodium hydroxide) becomes part of the buffer.

Requirements For The Application Process, Per The Final Guidance

Generic drug manufacturers seeking to change a pH adjuster under the conditions outlined need to provide scientific evidence of:

• comparative pH to show similar hydronium concentrations between the reference product and the generic drug product
• the extent of any protonation and/or deprotonation of the ingredients in the formulation
• comparative buffer capacity to support similar capacities to resist changes in pH between the reference product and the generic drug product
• drug product stability for the proposed generic drug product, showing it is not affected, and comparative osmolality for similar total solute concentrations between the reference and generic drug products
• comparative viscosity
• comparative electrophoretic mobility
• comparable active ingredient release rates
• information regarding the safety of a proposed difference in pH adjuster.

Other relevant information can include pharmacokinetic data from in vivo bioequivalence studies for non-solution products or in vitro release testing data from in vitro bioequivalence studies.

Where a manufacturer wishes to use an alternative inactive ingredient, the FDA waiver provision set out in 21 CFR 314.99(b)⁶ applies. This regulation states, “an applicant may ask FDA to waive under this section any requirement that applies to the applicant under 314.92 through 314.99.”

In the case of pH adjusters, generic manufacturers seeking a waiver for a pH adjuster need to demonstrate assurance that there are no changes to the drug product’s physicochemical characteristics (such as the pH, osmolality, or viscosity). Assurance needs to be demonstrated through showing any differences that occur in the form of new counter-ion species⁷ (an anion or a cation) not present in the reference drug or the occurrence of different concentrations of the counter-ion species compared to the reference material.

As well as specifying a different pH adjuster, the generic drug manufacturer can also seek to alter the use and quantity of pH adjuster added between different batches by more than 5% (with the reference drug product, keeping this variation within 5% is a registration requirement). This requires scientific justification.

Further to the application and approval process, the waiver will only be considered in the ANDA after submission. 

References:

1. FDA. Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use Guidance for Industry, U.S. Department of Health and Human Services, November 2025: https://www.fda.gov/media/157655/download
2. Nguyen, B. D., and Vaughn-Cooke, M. (2015). Design and labeling differences between generic and reference listed drug inhalers: human factors considerations in U.S. FDA-approved devices. Expert Opinion on Drug Delivery. https://doi.org/10.1080/17425247.2025.2587187
3. Graham, S. and Higgins, M. (2009) Balancing Innovation and Access: Patent Challenges Tip the Scales. Science. 326 (5951): 370–371
4. Covington, A., Bates, R., and Durst, R. (1985). Definitions of pH scales, standard reference values, measurement of pH, and related terminology, Pure Appl. Chem. 57 (3): 531–542
5. Bianchini, R., Bruni, G., Gazzaniga, A. e Vecchio, C. (1992). Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters. Drug Development and Industrial Pharmacy, 18(14), 1485–1503. https://doi.org/10.3109/03639049209040854
6. § 314.99 Other responsibilities of an applicant of an ANDA https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-C/section-314.99
7. Krossing and I. Raabe (2004). Noncoordinating Anions - Fact or Fiction? A Survey of Likely Candidates. Angewandte Chemie International Edition. 43 (16): 2066–2090

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.