BRIEFING

 Gadoteridol. This proposal is based on the version of the monograph official as of August 1, 2024. It is proposed to revise the monograph with the following changes:

1. Revise the chemical structure of gadoteridol to be consistent with the label reflecting the chelate structure of gadoteridol.

2. Delete the stereochemical designation before the chemical name to be consistent with the description section in the approved label.

3. Replace Identification B with the retention time agreement of the major peak in the Sample solution and Standard solution obtained in the Assay.

4. Update the references to the following impurities for consistency with current USP nomenclature.

   1. Replace "regioisomer" with "gadoteridol isomer".

   2. Replace gadoteridol related compound D with gadoterate.

   3. Replace gadoteridol related compound E with tetraxetan urea analog.

   4. Replace gadoteridol related compound F with tetraxetan lactam.

5. Update the Assay, based on supporting data, as follows:

   1. Include pH adjustment in the Buffer preparation step.

   2. Change the Injection volume from 50 μL to 20 μL.

   3. Add a Run time in the Chromatographic system for consistency with current practice.

   4. Delete the Resolution requirement in the Suitability requirements because of the potential absence of detectable levels of the gadoteridol isomer in the Standard solution.

   5. Add a Tailing factor requirement in the Suitability requirements to be consistent with the validated method.

   6. Revise the Relative standard deviation requirement from NMT 2.0% to NMT 0.73%.

   7. Revise the calculation equation to be consistent with the current format.

6. Revise the Limit of Gadoteridol Isomer test as follows:

   1. Add a reference for the solutions and Chromatographic system used in the Assay, a Sensitivity solution, and Suitability requirements to strengthen the quality standard.

   2. Add a relative retention time and relative response factor for the gadoteridol isomer.

   3. Replace the sum of the gadoteridol isomer peak response and gadoteridol peak response with the sum of all peak responses.

7. Update the Limit of Gadoteridol Related Compound A test based on comments received and associated supporting data, as follows:

   1. Revise the solution titles and preparations.

   2. Replace the instructions to "immediately inject into the Chromatographic system" with the solution storage temperature requirements of "Store between 2° and 8°" as appropriate.

   3. Add a Sensitivity solution and Blank preparation.

   4. Update the inner diameter and add the particle size of the column.

   5. Add an autosampler temperature requirement. The low temperature may enhance the stability of the copper–gadoteridol related compound A complex.

   6. Add a Run time requirement.

   7. Revise the System suitability requirements by adding requirements for the Tailing factor and Signal-to-noise ratio and by widening the Relative standard deviation requirement from NMT 2.0% to NMT 5.0%.

   8. Revise the calculation equation to include Blank corrections for peak responses.

8. Combine the tests for Limit of Free Gadolinium (III) and Gadolinium-Containing Impurities into a single test: Limit of Free Gadolinium and Gadoteridol Impurities with Gadolinium. Revise this test based on comments received and associated supporting data as follows:

   1. Revise the solution titles and preparations as appropriate.

   2. Add a statement to clarify that the analytical solution concentrations are described on the anhydrous basis.

   3. Add a Sensitivity solution and Signal-to-noise ratio requirement.

   4. Add an autosampler temperature requirement.

   5. Change the Injection volume and Run time.

   6. Add a Tailing factor requirement.

   7. Revise the calculation equations.

   8. Add a footnote to clarify that the acceptance criteria are provided on the anhydrous basis, and revise the acceptance criterion for total gadoteridol impurities with gadolinium.

9. Rename the Nongadolinium-Containing Impurities test to the Limit of Gadoteridol Impurities without Gadolinium and revise the procedure, based on comments received and associated supporting data, as follows:

   1. Revise the solution titles and preparations as appropriate.

   2. Add a statement to clarify that the analytical solution concentrations are described on the anhydrous basis.

   3. Add a Sensitivity solution and Signal-to-noise ratio requirement.

   4. Replace the System suitability solution and Resolution requirement with a Sensitivity solution and requirements for Tailing factor and Signal-to-noise ratio.

   5. Add the particle size of the column.

   6. Revise the Run time requirement.

   7. Revise the relative retention times listed in Table 3.

   8. Widen the acceptance criterion for the Relative standard deviation requirement.

   9. Revise the calculation equations.

   10. Add a footnote to clarify that the acceptance criteria are provided on the anhydrous basis, and revise the acceptance criterion for total gadoteridol impurities without gadolinium.

10. Replace the Other Requirements section with the separate Bacterial Endotoxins Test and Sterility Test.

11. Add a Labeling section and requirements.

12. Update the chemical information presented in USP Reference Standards.

 Additional changes have been made to update the monograph to current USP style.

 (SM4: R. Nguyen)

 Case ID—SUB-823