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

Regulatory NewsRegulatory News | 13 April 2022 |  By 

The US Food and Drug Administration (FDA) has issued a draft guidance on its criteria for permitting the use of pH adjusters in parenteral, ophthalmic or otic abbreviated new drug applications (ANDAs). FDA said in certain circumstances, certain differences in pH adjusters “may be scientifically appropriate and acceptable.”
This guidance outlines the process for requesting a waiver from complying with the 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 generally “must contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant.”
Since these regulations have been issued, the agency has evolved its thinking on pH adjusters, which are considered excipients.
“Over time there has been increased interest in and questions about waivers of the applicable inactive ingredient requirements for pH adjusters in ANDAs,” states the guidance. “FDA’s current thinking is that pH adjusters function in such a way that, in some circumstances, a waiver of the inactive ingredient requirements in §314.94(a)(9)(iii)-(iv) for a pH adjuster in a generic drug product intended for parenteral, ophthalmic, or otic use may be appropriate.”
FDA has concluded that “there may be circumstances where an ANDA applicant can establish that a greater than 5% difference in the amount of pH adjuster in an ANDA product compared to the [reference listed drug] RLD would not change the proposed drug product’s final attributes in an unacceptable manner.”
The agency said pH adjusters are typically used on an “as-needed basis to achieve a specified pH range in the drug product.” The primary function of a pH adjuster “is to change the equilibrium concentration of hydronium ions in solution (i.e., the pH).”
The following should be submitted to support a waiver request:
  • The pH, buffer capacity, or both if applicable compared with the RLD;
  • The osmolality compared with the RLD;
  • The viscosity with the RLD; or
  • The electrophoretic mobility with the RLD.
Along with this documentation, FDA recommends that waiver requests include the following:
  • An explanation why the applicant cannot comply with the requirements under 21 CFR 314.94(a)(9)(iii) and (iv);
  • A description of an alternative submission that satisfies this requirement; or
  • Other information justifying a waiver.
The agency will grant a waiver request if the applicant’s compliance with the requirement is considered unnecessary, or the applicant’s alternate submission supports the waiver.
FDA recommends that waiver requests be submitted through a controlled correspondence.
The deadline for submitting comments is 14 June.
 FDA guidance


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Tags: adjusters, ANDAs, FDA, pH

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