BRIEFING

 Adapalene. This proposal is based on the version of the monograph official as of May 1, 2020. On the basis of comments received, it is proposed to revise the preparation of the Standard stock solution to address a possible solubility issue in the test for Organic Impurities, Procedure 1. Additionally, it is proposed to update the monograph with the following changes:

1. Under the Assay:

   • Add a Run time in the Chromatographic system section based on original validation data.

   • Add an assessment for Tailing factor in the Suitability requirements based on supporting data.

2. Under the tests for Organic Impurities, Procedure 1 and Organic Impurities, Procedure 2:

   • Add separate tables and Notes in the System suitability section to present relative retention times as an aid in peak assignment. Under Organic Impurities, Procedure 2, update the values of relative retention times to two significant figures.

   • Revise the existing tables under the Acceptance criteria to list only the relative response factors (if applicable) and acceptance criteria for specified impurities, any unspecified impurity, and total impurities.

   • In the Acceptance criteria, replace the numerical reporting threshold with a reference to User-Determined Reporting Thresholds 〈477〉 for user flexibility.

   • Revise the concentration for USP Adapalene Related Compound A RS in the Standard stock solution and Standard solution to reflect the concentration for the limit of adapalene related compound A in the test for Organic Impurities, Procedure 1.

   • Revise the Suitability requirements for Relative standard deviation from NMT 3.0% to NMT 5.0% and to include the assessment of adapalene related compound A and adapalene related compound B in the test for Organic Impurities, Procedure 1 to be consistent with the expectations for modern chromatographic systems.

   • Add Sensitivity solution, assessment for Signal-to-noise ratio, and the reporting threshold in the Suitability requirements of the test for Organic Impurities, Procedure 1. The proposed reporting threshold corresponds to that of the ICH guideline for products with maximum daily doses of 2 g. Manufacturers are encouraged to submit FDA's approved level, if different.

3. Include the following additional changes under the test for Organic Impurities, Procedure 2:

   • Update the chemical name of hydroxyadapalene in Table 4.

   • Add an assessment for Relative standard deviation in the Suitability requirements section based on supporting data.

4. Delete the Residual Solvent: Limit of Triethylamine test because this solvent is currently covered in Residual Solvents 〈467〉, as required by the USP General Notices.

5. Update the packaging requirements under the Packaging and Storage section.

6. Update the molecular weights of Adapalene in the Chemical Information section, and of USP Adapalene Related Compound A RS, USP Adapalene Related Compound B RS, USP Adapalene Related Compound D RS, and USP Adapalene Related Compound E RS in the USP Reference Standards section. In addition, delete USP Triethylamine RS from the USP Reference Standards section as it is no longer needed.

 Additionally, minor editorial changes have been made to update the monograph to current USP style.

 The comment period for this revision ends on July 31, 2026. In the absence of any significant adverse comments, it is proposed to implement this revision via an Interim Revision Announcement with an official date of January 1, 2027.

 (SM3: A. Leeks, Jr)

 Case ID—SUB-2519