Type of Posting: Notice of Intent to Revise
Posting Date: February 24, 2023
Target Official Date: TBD
Expert Committee: Small Molecules 2
In accordance with the 2020–2025 Rules and Procedures of the Council of Experts, this is to provide notice that USP and the Small Molecules 2 Expert Committee intends to revise Clonidine Transdermal System monograph to remove the test for Organic Impurities.
Rationale for removing Organic Impurity test from Clonidine Transdermal System monograph.
In May 2021, USP and FDA experts met to discuss FDA regulatory concerns regarding USP monographs for Transdermal systems (TDS) and their utility to support generic drug development. Part of the discussion was dedicated to urgent regulatory concerns regarding acceptance criteria for organic impurities in the currently official Clonidine TDS monograph.
In May 2022, FDA submitted a letter pertaining to the official monograph for Clonidine TDS, requesting that USP delete “...the IMPURITIES section because of unique challenges of establishing compendial impurity specifications for TDS.”
In its letter, FDA indicated that TDS products developed by different manufacturers may have significant formulation differences, including different total drug loads, and these permitted differences pose challenges with respect to establishing monograph standards for impurities. FDA noted that the acceptance criteria for TDS are calculated using the total drug load (not strength) of the product. Further, FDA explained that a TDS compendial standard with set impurity limits is potentially misleading, as that impurity limit may be qualified for a TDS product containing a low drug load, but unqualified for a TDS product containing a high drug load. As a result, FDA pointed out that the numerical limit for impurities may create regulatory challenges for approval of generic products. In addition, FDA noted that the current acceptance limit with unit of μg/cm2 is based on a particular product and may be particularly misleading to generic manufacturers.
USP recognizes FDA’s concerns, and, as a result, USP intends to revise Clonidine Transdermal System monograph to remove the test for Organic Impurities. USP also recognizes the benefits of the test and will engage with stakeholders to explore new ways of including information regarding specified impurities/degradation products within the public standard in a manner that will not impede generic development. Future action will be determined, in part, based on the outcome of that engagement.
In addition, USP intends to revise the monograph to provide additional flexibility for the sample preparation under Assay, because different formulations may need different extraction procedures to achieve complete drug extraction from transdermal systems.
Should you have any questions, please contact Elena Gonikberg, Sr. Principal Scientist (eg@usp.org)
CN-23-032-00