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FDA outlines criteria for granting waivers for pH adjusters in generic drugs

Posted on April 13, 2022 | By Joanne S. Eglovitch

The United States Food and Drug Administration (FDA) has released draft guidelines on its criteria for authorizing the use of pH adjusters in parenteral, ophthalmic, or abbreviated otic new drug applications (ANDAs). The FDA said that under certain circumstances, certain differences in pH adjusters “may be scientifically appropriate and acceptable.”

These guidelines outline the process for requesting exemption from complying with generic drug regulations under §314.94(a)(9)(iii) and (iv). These regulations specify that a drug product intended for parenteral, ophthalmic or otic use in general “must contain the same inactive ingredients and at the same concentration as the reference drug indicated by the applicant”.

Since the publication of these regulations, the agency has changed its thinking on pH adjusters, considered as excipients.

“Over time, there has been increased interest and questions about waivers of applicable inactive ingredient requirements for pH adjusters in ANDAs,” the guidance states. “The FDA’s current thinking is that pH adjusters operate in such a way that, under certain circumstances, a waiver of the inactive ingredient requirements of §314.94(a)(9)(iii)-(iv) for a pH adjuster in a generic drug produced for parenteral, ophthalmic or otic use may be appropriate.

The FDA concluded that “there may be circumstances in which an ANDA applicant can establish that a difference greater than 5% in the amount of pH adjuster in an ANDA product compared to the [reference listed drug] RLD would not change the final characteristics of the proposed drug product in an unacceptable way.

The agency said pH adjusters are typically used “as needed to achieve a specified pH range in the drug product.” The primary function of a pH adjuster “is to alter the equilibrium concentration of hydronium ions in solution (i.e. pH)”.

The following items must be submitted to support a waiver request:

  • pH, buffering capacity, or both if applicable with respect to the RLD;
  • The osmolality relative to the RLD;
  • Viscosity with RLD; or
  • Electrophoretic mobility with the RLD.

In addition to this documentation, the FDA recommends that waiver requests include the following:

  • An explanation of why the applicant cannot comply with the requirements of 21 CFR 314.94(a)(9)(iii) and (iv);
  • A description of an alternative submission that satisfies this requirement; or
  • Other information justifying a derogation.

The agency will grant a waiver request if the applicant’s compliance with the requirement is deemed unnecessary, or if the applicant’s alternative submission supports the waiver.

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

The deadline for submitting comments is June 14.

FDA Guidelines

© 2022 Society of Regulatory Affairs Professionals.


Joan J. Dean

The author Joan J. Dean