Slower Reconstitution Time and Stability Bridging Issues
Severity: criticalBatch EH15031 shows slower reconstitution time compared to previous registration batches, likely due to changes in batch formula and manufacturing process. Only one month of accelerated stability data is available for EH15031, showing an increase in reconstitution time approaching the specification limit. This raises concerns about bridging stability data from previous batches (EH12023, EH12024, EH13001). The agency requests additional stability data for EH15031, additional batch data for drug product batches manufactured with the revised process, and justification for the observed changes in reconstitution time relative to Velcade®.
Recommended response: Conduct additional stability studies for batch EH15031 and new batches, provide comprehensive batch data for the revised manufacturing process, and submit a detailed justification for the observed changes in reconstitution time, addressing potential impact on product quality and medication errors.
Incomplete Manufacturing Flow Diagram
Severity: minorThe submitted manufacturing flow diagram does not include lyophilization, capping, and packaging steps. The agency requests a revised flow diagram including all steps.
Recommended response: Submit a revised and complete manufacturing flow diagram that clearly depicts all steps, including lyophilization, capping, and packaging.
Biowaiver Request and Comparability to Reference Product
Severity: majorConcerns exist that physico-chemical characteristics (e.g., reconstitution time) of the proposed commercial lyophilized drug product at the end of its shelf-life may not be comparable to the reference drug product (Velcade®). To facilitate review of the biowaiver request for intravenous administration, the agency requests a side-by-side comparison table of physico-chemical properties of exhibit batches (using the final proposed commercial manufacturing process) at release and during long-term stability testing versus the Listed Drug. Justification is needed if differences exist, explaining why they would not impact usability, bioavailability, or efficacy.
Recommended response: Provide a detailed side-by-side comparison of physico-chemical properties between the proposed product and the reference drug (Velcade®) at release and throughout stability. Justify any observed differences regarding their impact on usability, bioavailability, and efficacy to support the biowaiver request.
Clinical Study Report for Biowaiver Support
Severity: majorExhibit Batch EH15031 is being used in an ongoing BE study (14-VIN-648) in multiple myeloma patients. The agency requests the clinical study report when available, so that PK, PD, and safety findings can be considered as supportive evidence for the biowaiver request for the intravenous route.
Recommended response: Submit the clinical study report for the ongoing BE study (14-VIN-648) once available, to provide supportive PK, PD, and safety data for the intravenous biowaiver request.
Labeling Revisions for Vial Type and Sterility
Severity: minorThe labels refer to the product as a 'single-use vial' and need to be changed to 'single-dose vial'. Additionally, the labels must include a statement indicating the product is sterile. The agency requires updated content of labeling in SPL format, with a marked-up copy and a clean Microsoft Word version.
Recommended response: Revise draft labeling and carton/container labeling to change 'single-use vial' to 'single-dose vial' and add a statement indicating the product is sterile. Provide updated content of labeling in SPL format, with a marked-up copy and a clean Microsoft Word version.
Cited: 21 CFR 201.100
Unresolved Facility Inspection Deficiencies
Severity: criticalDuring a recent inspection of Dr. Reddy’s Laboratories Limited manufacturing facility (FEI 3006549835), deficiencies were conveyed to the facility representative. Satisfactory resolution of these deficiencies is required before this application may be approved.
Recommended response: Address and resolve all deficiencies identified during the recent manufacturing facility inspection. Provide documentation of satisfactory resolution to the agency.
Cited: 21 CFR 211.22
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required, including data from all nonclinical and clinical studies/trials regardless of indication, dosage form, or dose level. This includes describing significant changes in the safety profile, presenting new safety data combined with original NDA data, comparing frequencies of adverse events, providing retabulation of premature trial discontinuations, case report forms/narrative summaries for deaths/serious adverse events, information on changes in common adverse events, updated exposure information, worldwide safety experience, and English translations of current approved foreign labeling.
Recommended response: Submit a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), incorporating all new nonclinical and clinical safety data, including detailed analyses, comparisons, case reports, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Inadequate Drug Master File (DMF) and Biowaiver Denial
Severity: criticalThe referenced Drug Master File (DMF 23996) was found inadequate, and a deficiency letter was sent to the DMF holder. These deficiencies must be adequately addressed. The biowaiver request for an in vivo bioequivalence study for the intravenous route cannot be granted at this time due to outstanding issues with the identity of the drug substance (referencing DMF) and the identity of the structures in the drug product and reconstituted solution. The applicant may resubmit the biowaiver request or conduct a bioequivalence study.
Recommended response: Ensure the DMF holder addresses all deficiencies in DMF 23996. Resolve outstanding issues regarding drug substance and drug product identity. Resubmit the biowaiver request with adequate supporting data or conduct a bioequivalence study for the intravenous route.
Cited: 21 CFR 314.50(d)(1)
