Isoquinolinium, 2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-, dibenzenesulfonate;
2-(2-Carboxyethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium benzenesulfonate, pentamethylene ester [64228-81-5]
BRIEFING
Atracurium Besylate. This proposal is based on the version of the monograph official as of June 1, 2022. It is proposed to revise the monograph with the following changes:
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Revise Identification A to allow the flexibility of using either 197A or 197K.
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Revise the Assay as follows:
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Add Tailing factor to the Suitability requirements.
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Update the Relative standard deviation requirement from NMT 2.0% to NMT 0.73% to be consistent with the expectations for modern chromatographic systems and supporting data.
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Add the calculation for calculating percentage of each isomer in the portion of Atracurium Besylate.
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Revise the test for Organic Impurities as follows:
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Add the Sensitivity solution and revise the Suitability requirements to align with the reporting threshold.
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Add Relative standard deviation for cis-cis isomer in the Suitability requirements.
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Add Table 2 and a Note to the System suitability section to present relative retention times as an aid in peak assignment.
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Revise Table 3 in the Acceptance criteria to list only the limits for specified impurities, any unspecified impurity, and total impurities.
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Include the relative retention time of the counter ion benzenesulfonic acid in the new Table 2.
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Rename all the compounds in the new Table 2 based on the updated nomenclature.
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In the Acceptance criteria, the disregard limit (numerical reporting threshold) has been replaced with 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”.
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Tighten the limits of the 3-methylpentanediol analog, hexanediol analog, and 1-methylpentanediol analog impurities based on the FDA-approved specification.
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Revise the test for Limit of Methyl Besylate as follows:
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Rename impurity J based on the updated nomenclature.
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Revise Table 4 to reflect the equilibration time and run time.
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Introduce the Reference Standard, USP Methyl Besylate RS, for the test.
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Revise the concentration of the Standard solution in line with the revised acceptance criteria.
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Add an Autosampler temperature in the Chromatographic system.
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Add a Signal-to-noise ratio and Relative standard deviation assessment to the Suitability requirements.
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Add a calculation to calculate the content of methyl besylate in the Analysis.
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Tighten the limit from NMT 0.01% to NMT 0.001% based on the FDA-approved specification.
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Add the Bacterial Endotoxins Test, Sterility Tests, Microbial Enumeration Tests, and a Labeling section to support preparation of sterile drug products.
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Add USP Methyl Besylate RS to the USP Reference Standards section to support the Limit of Methyl Besylate test.
Additionally, minor editorial changes have been made to update the monograph to current USP style.
(SM4: D. Singh)
Correspondence Number—C151192; C157589