BRIEFING

 Duloxetine Delayed-Release Capsules. 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. Update the molecular weight of duloxetine hydrochloride in the calculations of all the tests to be consistent with the current IUPAC values.

2. Replace the use of the spectroscopic identification test in Identification A with the UV spectrum agreement from the Assay. This revision avoids the use of a toxic solvent.

3. In the Assay:

   • Rename the Sample solution as Sample solution 1 and add a sentence to filter the solution based on the supporting data.

   • Add the Sample stock solution and Sample solution 2 to accommodate the sample preparation for formulations with different types of enteric-coated pellets.

   • Revise the Chromatographic system to include the information for diode array detection needed to support the proposed Identification A and update the Run time for user flexibility, based on the current USP style.

   • Remove the Resolution requirement between 1-naphthol and duloxetine related compound H in the Suitability requirements, as the other System suitability requirements are sufficient.

   • Add the Tailing factor requirement in the Suitability requirements, based on the supporting data.

   • Revise the Relative standard deviation from NMT 1.5% to NMT 1.0% in the Suitability requirements to be consistent with current USP practices.

4. Add a filter pore size for Dissolution, Test 1, Test 3, and Test 4, based on the supporting data.

5. In Dissolution, Test 3:

   • Update the pH value of the Buffer stage medium to one decimal place, based on the current USP style and the supporting data.

   • Remove the Acid stage standard stock solution, which is not needed in this test.

6. In Dissolution, Test 4:

   • Update the pH value of the Buffer stage medium to one decimal place, based on the current USP style and the supporting data.

   • Correct the analysis equation for the calculation of the concentration of duloxetine from duloxetine 4-naphthyl isomer (4-[3-(Methylamino)-1-(thiophen-2-yl)propyl]naphthalen-1-ol) in the Acid stage medium (C₃).

7. In the test for Organic Impurities:

   • Update the concentration of USP Duloxetine Hydrochloride RS in the Standard solution to align with the unspecified degradation product limit.

   • Rename the Sample solution as Sample solution 1 and add a sentence to filter the solution based on the supporting data.

   • Add the Sample stock solution and Sample solution 2 to accommodate the sample preparation for formulations with different types of enteric-coated pellets.

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

   • Add Table 2 and a note in the System suitability section to present relative retention times as an aid in peak assignment.

   • Remove the Resolution requirement between 1-naphthol and duloxetine related compound H in the Suitability requirements, as duloxetine related compound H may not be present in all the formulations and the other System suitability requirements are sufficient.

   • Revise the Relative standard deviation from NMT 1.5% to NMT 5.0% in the Suitability requirements, based on the supporting data and to align with the change in the Standard solution concentration.

   • Add a Sensitivity solution aligned with the expected reporting threshold and include an appropriate Suitability requirement for the Signal-to-noise ratio.

   • Add the Standard solution to the Analysis section and replace "each impurity" with "any degradation product" to be consistent with ICH Q3B terminology.

   • In the Analysis section revise the equation for the calculation of degradation products from area normalization to quantification using the external standard solution.

   • In the Acceptance criteria:

     • Add a reference to User-Determined Reporting Thresholds 〈477〉 for user flexibility.

     • Update the table number and revise Table 3 to list only the limits for specified degradation products, any unspecified degradation product, and total degradation products.

     • In Table 3, replace "Total impurities" with "Total degradation products" to be consistent with ICH Q3B terminology.

     • Add a column to the table to specify the relative response factor values for the specified degradation products and any unspecified degradation product to be consistent with the analysis equation.

     • Revise the acceptance criteria for total degradation products to be consistent with the limits of FDA-approved specifications.

8. Update the molecular weight of USP Duloxetine Related Compound F RS in the USP Reference Standards section to be consistent with the current IUPAC values.

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

 (SM4: S. Singireddy)

 Case ID—SUB-1250, SUB-1392, SUB-1406, SUB-2988