Manufacturing Facility Non-Compliance with GMP Regulations
Severity: criticalThe methods, facilities, and controls used for the manufacture, processing, packing, or holding of the drug substance or drug product do not comply with current good manufacturing practice regulations (21 CFR Parts 210 and 211). This deficiency was identified following a pre-license inspection of the manufacturing facility, and satisfactory resolution of all observations is required before the BLA can be approved.
Recommended response: Address all observations from the pre-license inspection, implement comprehensive corrective and preventive actions (CAPAs), and provide robust evidence of satisfactory resolution to the FDA. Consider conducting an internal re-inspection readiness assessment.
Cited: current good manufacturing practice regulations in parts 210, current good manufacturing practice regulations in parts 211
Proprietary Name Resubmission Requirement
Severity: minorThe proposed proprietary name, Eylea HD, was found acceptable pending approval of the application in the current review cycle. The sponsor is required to resubmit the proposed proprietary name when responding to the application deficiency.
Recommended response: Ensure the proprietary name resubmission is included with the complete response to the manufacturing deficiency to avoid further administrative delays.
Safety Update Requirement for Resubmission
Severity: majorA safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included when responding to the primary manufacturing deficiency. This update should encompass data from all nonclinical and clinical studies/trials of the product, regardless of indication, dosage form, or dose level.
Recommended response: Compile a comprehensive safety update, ensuring all relevant nonclinical and clinical data are included as per the cited regulation, and submit it with the complete response.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Recommendation for Real-World Shipping Studies
Severity: infoThe agency recommends performing real-world shipping studies, covering worst-case conditions (e.g., routes, modes of transportation, distance, duration, temperature, packing configuration, and shipping containers), on the final drug product in the proposed container closure system. This is to ensure no impact on product quality and sterility, with pre-shipment to post-shipment data compared against pre-defined acceptance criteria. This is an additional comment and not an approvability issue for the current BLA.
Recommended response: While not an approvability issue, conducting these studies proactively and including the data in a future submission or as a post-approval commitment would demonstrate robust product quality control and potentially prevent future issues.
