BRIEFING

 Metyrosine. 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. Revise the Definition for the content specification from NLT 98.6% to NMT 101.0% to NLT 98.0% to NMT 102.0% on the dried basis, to be in line with the newly proposed Assay procedure.

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

3. Replace the use of 197U in Identification B with the chromatographic retention time agreement using the proposed Assay procedure.

4. Replace the current potentiometric Assay with a validated HPLC procedure sharing the same chromatographic system as the proposed Organic Impurities test. The HPLC procedure was validated using the Acclaim 120 C18 brand of column with L1 packing. The typical retention time for metyrosine is about 7 min.

5. Adjust the Acceptance criteria in the Assay from NLT 98.6% to NMT 101.0% to NLT 98.0% to NMT 102.0% on the dried basis in order to match applicable HPLC system limits.

6. Replace the TLC procedure for the Organic Impurities test with a validated HPLC procedure using similar chromatographic conditions as in the proposed Assay. The liquid chromatographic procedures in the Assay and in the Organic Impurities test are based on analyses using the Acclaim 120 C18 brand of column with L1 packing. The typical retention time for metyrosine is about 7 min.

7. Add a table and Note in the System suitability section of the Organic Impurities test to present relative retention times as an aid in peak assignment. The table in the Acceptance criteria section lists only the limits for Specified impurities, Any unspecified impurities (where applicable), and Total impurities. For more information, please see the USP Compendial Notice "Organic Impurities Procedures: Format Change for Presenting Relative Retention Times".

8. Add the Limit of Metyrosine R-Enantiomer test to replace the current Specific Rotation test. The HPLC procedure was validated using the Kromasil C4 column with L26 packing. The typical retention time for the metyrosine R-enantiomer is about 28 min.

9. Add USP Metyrosine R-Enantiomer RS, USP Metyrosine Related Compound A RS, and USP Phenol RS to the USP Reference Standards section to support the proposed tests for Organic Impurities and Limit of Metyrosine R-Enantiomer.

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

 (SM2: M. Tiedje)

 Correspondence Number—C238855