BRIEFING

 Duloxetine Hydrochloride. This proposal is based on the version of the monograph official as of May 1, 2020. It is proposed to revise the monograph with the following changes:

1. In the Chemical Information section, update the molecular weight of duloxetine hydrochloride to be consistent with the current IUPAC values. Update the chemical name to be consistent with the current USP naming convention.

2. Revise Identification A to include 197A to allow the flexibility of using either 197A or 197K.

3. Replace the name of the duloxetine S-isomer with duloxetine in Identification B to align with the peak name in the test for Limit of Duloxetine Related Compound A.

4. Revise the Assay as follows:

   • Remove the sentence "(contains duloxetine related compound F)" and add USP Duloxetine Related Compound F RS to the System suitability solution at 0.1% of the nominal sample concentration, as the USP Duloxetine Hydrochloride RS may not always contain duloxetine related compound F.

   • Add the Standard solution to the System suitability section and update the Tailing factor and Relative standard deviation in the Suitability requirements to the Standard solution based on the supporting data.

   • Update the Run time for user flexibility, based on current USP style.

   • Revise the Relative standard deviation from NMT 1.0% to NMT 0.73% in the Suitability requirements, to be consistent with current USP practices, based on supporting data and with the expectations for modern chromatographic systems.

5. In the test for Organic Impurities:

   • Remove the sentence "(contains duloxetine related compound F)" and add USP Duloxetine Related Compound F RS to the System suitability solution at 0.1% of the nominal sample concentration, as the USP Duloxetine Hydrochloride RS may not always contain duloxetine related compound F.

   • Add a Standard solution at a concentration equivalent to the unspecified impurity limit.

   • Update the Sensitivity solution concentration to align with the expected reporting threshold, and update the Signal-to-noise ratio accordingly in the Suitability requirements.

   • Update the Run time for user flexibility, based on current USP style.

   • Add the Standard solution under Samples in the System suitability section and revise the Relative standard deviation from NMT 1.0% to NMT 5.0% in the Suitability requirements to reflect the Standard solution, based on current USP style and supporting data.

   • Add Table 1 and a Note to the System suitability section to present relative retention times as an aid in peak assignment.

   • Update the chemical name of Duloxetine β-naphthol-1-yl isomer impurity based on the IUPAC nomenclature.

   • Remove the Tailing factor requirement because there are sufficient system suitability parameters for the procedure.

   • Add the Standard solution to the Analysis section and revise the analysis equation for the calculation of impurities.

   • In the Acceptance criteria:

     • Replace the numerical reporting threshold with a reference to User-Determined Reporting Thresholds 〈477〉 for user flexibility.

     • Update the table number and revise Table 2 to list only the limits for specified impurities, any unspecified impurity, and total impurities.

6. In the Limit of Duloxetine Related Compound A test:

   • Update the Sensitivity solution concentration to align with the expected reporting threshold, and update the Signal-to-noise ratio accordingly in the Suitability requirements.

   • Update the Run time for user flexibility, based on current USP style.

   • Remove the Tailing factor requirement because there are sufficient system suitability parameters for the procedure.

7. Update the Packaging and Storage requirements to "store at controlled room temperature" based on the supporting information.

8. In the USP Reference Standards section, update the molecular weight of duloxetine related compound A, to be consistent with the current IUPAC values and add USP Duloxetine Related Compound F RS to support the proposed changes in the Assay and the test for Organic Impurities.

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

 (SM4: S. Singireddy)

 Case ID—SUB-1249, SUB-2990, SUB-3224