FDA finalizes guidance on criteria for granting waiver requests for pH adjusters

The US Food and Drug Administration (FDA) recently finalized guidance detailing the criteria it will use to evaluate waiver requests for pH adjusters submitted by sponsors of abbreviated new drug applications (ANDAs). This guidance is applicable to parenteral, ophthalmic, and otic drugs that are Q1 (qualitatively) or Q2 (quantitatively) different from the reference listed drug.

The guidance contains some changes from a draft version issued in April 2022. (RELATED: FDA outlines criteria for granting waiver for pH adjusters in generic drugs, Regulatory Focus 13 April 2022)

A pH adjuster is commonly an acid or base which is used to alter the concentration of hydronium ions in a solution, thereby changing the pH level. Generally, a higher concentration of hydronium ions results in a lower pH value, which is measured on a logarithmic scale.

The guidance outlines the use of waivers under 21 CFR 314.99(b). This section states that an ANDA applicant for a drug product intended for parenteral, ophthalmic, or otic use may request a waiver for pH adjusters that differ from the reference listed drug (RLD) by Q1 or Q2. These pH adjusters are classified as inactive ingredients.

Under FDA regulations, Q1 and Q2 refers to a generic drug's formulation being "qualitatively" (Q1) and "quantitatively" (Q2) the same as the RLD.

In the guidance, FDA stated that its experience with pH adjusters, coupled with the specific role pH adjusters generally play in drug formulations, “support the conclusion that in certain circumstances it may be appropriate for FDA to consider a waiver to permit a Q1 or Q2 difference in a pH adjuster(s) in a generic drug product intended for parenteral, ophthalmic, or otic use.”

To support a waiver request, the FDA recommends that applicants submit the following:

The pH, buffer capacity, or both compared to the RLD;
The osmolality compared with the RLD;
The viscosity with the RLD;
Or the electrophoretic mobility with the RLD.

Sponsors should also submit at least one of the following:

An explanation of why the applicant's compliance with the requirement is unnecessary or cannot be achieved;
A description of an alternative submission that fulfills the purpose of the requirement;
And/or any additional information that justifies a waiver.

FDA recommends that waiver requests be submitted through a controlled correspondence.

Among the changes from the draft guidance is a recommendation that ANDA applicants seek FDA feedback on a proposed approach for justifying a waiver request. The finalized version adds a new footnote stating that “where an ANDA applicant is considering submitting a § 314.99(b) waiver request for a pH adjuster difference, FDA encourages applicants to seek FDA feedback on their proposed approach(es) for justifying the waiver request.”

The guidance also includes a footnote to clarify the regulatory provisions for requesting a waiver of a Q1 or Q2 difference in a pH adjuster, distinguishing this from the provisions that support a waiver for submitting in vivo bioequivalence studies. The footnote reads that “a waiver of evidence of in vivo BE is different than a waiver for a difference in pH adjuster under § 314.99(b).”

Final guidance

FDA finalizes guidance on criteria for granting waiver requests for pH adjusters

Related topics

Recommended content

Welcome to the new RAPS Digital Experience