Insufficient Control Strategy for Sodium Bicarbonate Strength and Stability
Severity: majorThe proposed control strategy is insufficient to assure the identity, strength, purity, quality, and bioavailability of the drug product. Specifically, the strength of sodium bicarbonate throughout the product shelf-life and during the in-use period is not adequately assured. The suitability of the proposed assay method for sodium bicarbonate has not been fully demonstrated, potentially leading to overestimation or underestimation. Furthermore, there are no data demonstrating that the diluent and constituted suspension will consistently meet the requisite sodium bicarbonate assay acceptance criterion at release and throughout shelf-life and in-use period.
Recommended response: Revise specifications for the diluent and constituted oral suspension to include tests, analytical procedures, and acceptance criteria for sodium bicarbonate identification and assay. Provide evidence that the analytical procedure is suitable for its intended use by demonstrating the range of recoveries does not significantly overestimate or underestimate bicarbonate measurement, or revise the method to minimize the wide range in percent recovery.
Cited: 21 CFR 314.50
Lack of Assurance for Omeprazole Strength and Uniformity
Severity: majorThe strength and uniformity of omeprazole in the constituted suspension at release and on stability are not assured. The analytical procedure MET-CDM-000025 for omeprazole identification, assay, and within-bottle uniformity differs from the assay procedure used in registration stability studies. The Analytical Method Validation Report does not cover the current method, and comparability between the methods has not been demonstrated.
Recommended response: Provide method validation reports for omeprazole assay procedures, including MET-CDM-000025, and provide evidence of the comparability of the results obtained using each test.
Cited: 21 CFR 314.50
Missing In-Process Control for Manufacturing
Severity: majorAn in-process control for a critical manufacturing step has not been established.
Recommended response: Provide the sampling plan (sampling number and locations) and acceptance criteria, supported by batch data and in line with product release acceptance criteria. Update relevant sections of the application accordingly and include in-process testing results.
Cited: 21 CFR 314.50
Insufficient Stability Data and Manufacturing Process Documentation
Severity: majorInsufficient batch release data and long-term/accelerated stability data for the diluent and constituted suspension. The manufacturing process for diluent batches and the revised control strategy are not adequately documented or demonstrated.
Recommended response: Submit batch release data and a minimum of 6 months of long-term and accelerated stability data from at least one batch of each filling configuration of the diluent and constituted suspension, tested per revised specifications. Submit in-use stability data. Ensure diluent batches are manufactured per the manufacturing process and revised control strategy, and submit representative batch records.
Cited: 21 CFR 314.50
Inadequate Clinical Data for Proposed Indication
Severity: majorThe clinical information provided is not adequate to support the proposed indication of 'reduction of risk of upper gastrointestinal bleeding in critically ill patients'. Specifically, data to support administration of the product via nasogastric and orogastric tube is necessary for this indication.
Recommended response: Provide additional clinical data to support administration of omeprazole and sodium bicarbonate for oral suspension via nasogastric and orogastric tube to adequately support the proposed indication.
Labeling Comments Reserved
Severity: infoComments on the proposed labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling review resources.
Recommended response: If labeling is revised, use the SRPI checklist to ensure conformity with format items in regulations and guidances. Include updated content of labeling in structured product labeling (SPL) format.
Cited: 21 CFR 314.50(l)(1)(i)
Carton and Container Labeling Submission Required
Severity: infoDraft carton and container labeling based on agency proposed revisions is required.
Recommended response: Submit draft carton and container labeling based on the agency's proposed revisions dated January 8, 2021.
Proprietary Name Resubmission Required
Severity: infoThe proposed proprietary name, Konvomep, was found acceptable pending approval of the application. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name when responding to the application deficiencies.
Safety Update Required for Resubmission
Severity: infoA comprehensive safety update is required as part of the resubmission, including data from all nonclinical and clinical studies/trials, detailed changes in safety profile, retabulations of adverse events, case reports for deaths/serious adverse events, updated exposure information, and worldwide safety experience.
Recommended response: Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b), encompassing all nonclinical and clinical study data, significant changes in safety profile, retabulated adverse events, case reports for serious events, updated exposure, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
