BRIEFING

 Guaifenesin. This proposal is based on the version of the monograph official as of May 1, 2020. On the basis of comments received, the following revisions are proposed:

1. Replace Identification B based on a UV test with the retention time agreement of the major peak in the Assay.

2. Revise portions of the chromatographic procedure in the Assay to align with current expectations. The updated procedure was validated using the Symmetry C18 brand of column with L1 packing. The typical retention time for guaifenesin is about 7.3 min. Accordingly, the following revisions are proposed:

   • Update the solvent from acetonitrile to water in the analytical solutions to improve the guaifenesin peak shape and add a Tailing factor requirement for the Standard solution.

   • Revise the Mobile phase gradient to end with a 5-min equilibration step.

   • Revise the System suitability solution to include USP Isoguaifenesin RS and USP Guaifenesin RS because isoguaifenesin is a critical pair with guaifenesin, and add a Resolution requirement to ensure baseline separation of the two compounds.

   • Update the Relative standard deviation criterion to be consistent with Chromatography 〈621〉, System Suitability.

   • Remove the inclusion of the content of isoguaifenesin to the determined amount in the Assay based on specifications from multiple, active Drug Master Files (DMF).

3. Revise the impurity name for guaifenesin β-isomer with isoguaifenesin throughout the monograph which is deemed more informative of the chemical structure of the impurity.

4. Revise portions of the chromatographic procedure in the Organic Impurities test to align with current expectations. The procedure was validated using the updated chromatographic procedure in the Assay to incorporate an external Standard solution quantitation approach. Accordingly, the proposed procedure has the following changes:

   • Replace the Standard solution with a solution containing USP Guaifenesin RS, USP Isoguaifenesin RS, and USP Guaiacol RS at concentration levels aligned with the proposed unspecified and specified impurity limits, respectively. Accordingly, add a Relative standard deviation requirement for each component.

   • Add a Sensitivity solution containing guaifenesin and guaiacol and propose Signal-to-noise ratio requirements appropriate for both compounds.

   • Revise the Analysis to add the quantitation equation for the specified impurities using the corresponding USP Reference Standards and the equation for any unspecified impurities.

   • Revise the table in the Acceptance criteria to list limits for specified impurities, any unspecified impurity, and total impurities. The relative response factors are also listed in this table. For more information about this format change, please see the USP Compendial Notice “Organic Impurities Procedures: Format Change for Presenting Relative Retention Times″.

   • Revise the Acceptance criteria to add a reference to User-Determined Reporting Thresholds 〈477〉 for user flexibility. For more information about this change, please see the USP Compendial Notice “New Chapter 〈477〉 User-Determined Reporting Thresholds and its Implementation in USP–NF Monographs”.

   • Revise the Acceptance criteria for any unspecified impurity from NMT 0.5% to NMT 0.05% to align with International Council for Harmonisation guidelines based on the CFR §21 listed maximum daily dose of >2 g.

   • Add guaifenesin dimer and dianisylglycerol to the impurity profile of the chromatographic procedure with the corresponding relative response factor values and the limits at the unspecified impurity level.

5. Revise the USP Reference Standards section to add USP Isoguaifenesin RS to support the revised Assay and Organic Impurities test, and add the chemical information for USP Guaiacol RS.

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

 (SM2: T. Bililign)

 Case ID—SUB-757