Inadequate Media Fill Studies
Severity: majorInformation regarding media fill studies is inadequate. Please update Section 3.2.P.3.5 of the BLA with summarized results from initial and latest requalification runs, description of hold periods simulated, and description of confirmatory growth promotion test including microorganisms used.
Recommended response: Provide comprehensive data for media fill validation runs, including detailed results, hold period descriptions, and growth promotion test specifics.
Inadequate Bacterial Retention Study
Severity: majorThe bacterial retention study for the sterilizing-grade filter was performed using the drug substance, which is not adequate. Please update BLA section 3.2.P.3.5 with protocol and data from validation studies using three different lots of the sterilizing filter intended for commercial production using the final drug product solution.
Recommended response: Conduct and submit a bacterial retention study using the final drug product solution with appropriate protocols and data.
Reserved Comment on Prescribing Information
Severity: infoComments on the proposed labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling resources and guidance documents.
Recommended response: Review FDA labeling resources and guidance, and update the content of labeling in SPL format upon resubmission, ensuring compliance with format items.
Cited: 21 CFR 601.14(b)
Reserved Comment on Carton and Container Labeling
Severity: infoComments on the proposed carton and container labeling are reserved until the application is otherwise adequate.
Recommended response: Ensure carton and container labeling is consistent with the approved prescribing information once other deficiencies are resolved.
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name was found acceptable pending approval, but needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name along with the complete response to the application deficiencies.
Unresolved Manufacturing Facility Inspection Findings
Severity: criticalAn inspection at Kashiv BioSciences' manufacturing facility revealed objectionable conditions. Satisfactory resolution of these conditions and verification by FDA is required before approval.
Recommended response: Address and resolve all objectionable conditions identified during the manufacturing facility inspection and ensure FDA verification of resolution.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required, including data from all nonclinical and clinical studies, significant changes in the safety profile, updated exposure information, a summary of worldwide experience, and English translations of current approved foreign labeling.
Recommended response: Provide a complete and updated safety summary incorporating all requested data from nonclinical and clinical studies, worldwide experience, and foreign labeling translations.
Missing Case Report Forms and SAE Narratives
Severity: majorProvide case report forms and narrative summaries for each patient who died during a clinical study or who did not complete a study because of an adverse event. In addition, provide narrative summaries for serious adverse events.
Recommended response: Submit all requested case report forms and narrative summaries for patient deaths and serious adverse events.
Updated Clinical Exposure Information Needed
Severity: majorProvide updated exposure information for the clinical studies (e.g., number of subjects, person time).
Recommended response: Provide updated and complete clinical exposure data for all relevant studies.
Worldwide Safety Experience Summary Required
Severity: majorProvide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with the use of the product and immunogenicity. Include an updated estimate of use for this product marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of worldwide safety experience, including adverse events, immunogenicity, and updated usage estimates.
English Translations of Foreign Labeling Required
Severity: minorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations of all current approved foreign labeling that has not yet been provided.
Insufficient Stability Data for Volume of Injection
Severity: majorStability data was not provided for volume of injection testing to support the proposed shelf-life of 24 months for the drug product. Submit stability data under long-term storage conditions for volume of injection.
Recommended response: Submit comprehensive long-term stability data for volume of injection to fully support the proposed 24-month shelf-life.
