USFDA Guidance: Waiver Requests for pH Adjusters in Generic Parenteral, Ophthalmic, or Otic Drugs
- Sharan Murugan
- 45 minutes ago
- 3 min read
The U.S. Food and Drug Administration (FDA) has released a final Guidance for Industry yesterday (17 November, 2025) titled “Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use” that 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.
Why pH Adjusters Matter—and When Waivers Are Possible
pH adjusters (acids or bases) are critical for maintaining product stability, efficacy, and safety by controlling the solution’s hydronium ion concentration and overall pH. They are typically added “quantum satis” (q.s., or as needed) to reach the desired pH. However, regulatory rules for ANDAs require most inactive ingredients—including pH adjusters—to be qualitatively (Q1) and quantitatively (Q2) the same as in the RLD, meaning identical chemical ingredients and concentrations, unless exceptions are scientifically justified.
The FDA recognizes circumstances where a different type or quantity of pH adjuster may be scientifically appropriate and not adversely affect product performance. In these cases, an ANDA sponsor may seek a waiver of Q1/Q2 requirements for the pH adjuster, provided robust justification is submitted.
Scientific Considerations for Waiver Requests
Waivers may be appropriate where:
The RLD lists the pH adjuster as q.s. and batch-to-batch variations occur in approved product.
Equivalent physicochemical attributes are demonstrated (pH, osmolality, viscosity, buffer capacity).
The pH adjuster has previous FDA-approval for the same route of administration and concentration.
No formation of new, untested counter-ions or inactive ingredient species occurs.
The alternate pH adjuster is justified as safe in relevant databases (e.g., FDA’s Inactive Ingredient Database).
Differences that introduce new active ingredient forms, new inactive species not previously approved, or impact key product attributes (e.g., a different form of the active, critical changes in pH, or counter-ion profile) are unlikely to be approved.
What FDA Reviews When Evaluating a Waiver Request
Applicants should submit comparative physicochemical data, such as:
pH and buffer capacity
Osmolality
Viscosity
Electrophoretic mobility
Comparative concentration of any new salt species formed
Safety information from sources such as the Inactive Ingredient Database (IID)
Data showing the change does not affect bioequivalence
FDA emphasizes that these data help demonstrate that the final product remains safe, stable, and therapeutically equivalent.
How and When to Submit a Waiver Request
The guidance provides detailed process steps:
Before ANDA Submission
FDA recommends using the controlled correspondence pathway to confirm whether your formulation would trigger an inactive-ingredient deficiency.
At Time of ANDA Submission
The actual waiver request must be included in the ANDA (Module 1 cover letter + product quality module).
FDA will refuse to receive the ANDA if a pH adjuster difference exists but no waiver request is submitted.
A complete waiver request must include:
Description of the Q1/Q2 difference
Explanation with supportive data
Reference to relevant modules and sections
Justification meeting one of the three criteria under 21 CFR 314.90
Outcome
FDA will grant the waiver only if:
The requirement is unnecessary or cannot be met
An alternative approach satisfies the requirement
The scientific justification fully supports the change
Waiver approval does not guarantee ANDA approval—other statutory requirements must still be met.
FDA’s new Guidance on pH Adjuster Waiver Requests marks an important step in modernizing generic drug development. For more details, please refer to the full guidance document: