BRIEFING

 Norgestimate. This proposal is based on the version of the monograph official as of May 1, 2020. A revision to the test for Organic Impurities, Procedure 1 to replace USP Deacetylnorgestimate RS with USP Norelgestromin RS in the preparation of the System suitability solution is necessary to address a reference material issue and ensure continuity of supply. These reference standards are the same chemical compounds and possess similar contents of both of (E)- to (Z)-isomers. The revision eliminates a redundant reference material from the USP Reference Standards catalog. The following changes to the monograph are also proposed:

1. Update the molecular weight for norgestimate in the Chemical Information section to be consistent with the current IUPAC name.

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

3. Update Identification B to provide clarification.

4. Revise the Assay as follows:

   • Update the Relative standard deviation requirement from NMT 2.0% for the peak area ratio of (E)-norgestimate and (Z)-norgestimate to NMT 0.73% for the sum of the peak responses of (E)-norgestimate and (Z)-norgestimate to be consistent with the expectations for modern chromatographic systems of quantitation method.

   • Delete the Sensitivity solution and Signal-to-noise ratio from the Assay because the remaining Suitability requirements are sufficient to establish the system suitability.

   • Add a Run time to the Chromatographic system based on validation data.

   • Add an equation supporting the calculation of the ratio of (E)- and (Z)-isomer.

5. Revise the test for Organic Impurities, Procedure 1 as follows:

   • Replace USP Deacetylnorgestimate RS with USP Norelgestromin RS in the System suitability solution. Revise the Standard solution concentration to better align the peak response of (E)-norgestimate with the acceptance criterion for any unspecified impurity and update the Relative standard deviation requirement from "NMT 2.0% for the peak area ratio of (E)-norgestimate and (Z)-norgestimate, System suitability solution" to "NMT 5.0% for (E)-norgestimate, Standard solution".

   • Revise the Sensitivity solution, the assessment for Signal-to-noise ratio, and add the reporting threshold based on the current procedure. The proposed reporting threshold corresponds to that of the International Council for Harmonisation (ICH) Q3A guideline for a drug substance with a maximum daily dose of ≤2 g per day.

   • Add a Note and table in the System suitability section to present relative retention times as an aid in peak assignment. Revise the table in the Acceptance criteria section to list only the limits for specified impurities and any unspecified impurity.

   • Add a Run time to the Chromatographic system based on validation data.

   • Replace deactylnorgestimate with Norelgestromin in Table 1, the Suitability requirements, and Table 2.

   • Revise the Signal-to-noise ratio from NLT 3.0 for (Z)-norgestimate to NLT 10 for (E)-norgestimate based on the revised sensitivity solution concentration.

6. Revise the test for Organic Impurities, Procedure 2 as follows:

   • Add a Note and table in the System suitability section to present relative retention times as an aid to peak assignment. Revise the Acceptance criteria section to list only the limits for specified impurities and total impurities.

   • Add the chemical names of the unidentified impurities for clarity based on the available validation data.

7. Revise the test for Limit of Residual Solvents to delete the procedure for all the solvents and to include only the Limit of Diisopropyl Ether as the relevant control of residual solvents must be followed based on General Notices, 5.60.20 Residual Solvents in USP and NF Articles.

8. Revise the test for Optical Rotation based on the Norgestimate monograph in European Pharmacopoeia 11.0 to eliminate the use of chloroform, a hazardous reagent.

9. Revise the USP Reference Standards section as follows:

   • Remove the reference to USP Deacetylnorgestimate RS and add a reference to USP Norelgestromin RS.

   • Update USP Norgestimate Related Compound A RS to reflect current chemical information.

   The monograph lacks recommended temperature storage conditions for Norgestimate. Manufacturers with approved storage conditions are encouraged to submit this information to USP for consideration in a future revision.

 The comment period for this revision ends January 31, 2024. 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 May 1, 2024.

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

 (SM5: P. Jagu)

 Correspondence Number—C318836