Approval Letter Other 211321 (Jan 1, 2019)

Summary

This document is a Complete Response letter from the FDA to Proximagen, LLC regarding their New Drug Application (NDA) 211321 for Nayzilam (midazolam) nasal spray. The FDA has determined that the application cannot be approved in its present form due to several deficiencies, primarily related to Quality System requirements, prescribing information, labeling, and facility inspections.

Key points

• Update responses to FDA's November 8, 2019, Quality System deficiencies to identify how UCB BioPharma SPRL (UCB) integrates into the Quality System.
• Describe specific management control responsibilities at each facility (Proximagen, UCB) associated with the medical device constituent of the combination product, including a summary of how management ensures compliance with CGMP requirements (21 CFR Part 4) and a description of each facility's functions and responsibilities.
• Explain the extent of UCB's involvement in the design control process and provide UCB's procedures for implementing design controls, including planning, input, output, review, verification, validation, transfer, changes, and design history file (21 CFR 820.30).
• Provide a summary of UCB's procedure(s) for purchasing controls, delineating responsibilities at Proximagen, and UCB, including supplier evaluation, maintenance of acceptable supplier records, purchasing data approval, and balancing purchasing assessment with receiving acceptance (21 CFR 820.50).
• Explain how purchasing procedures ensure changes by contractors/suppliers do not affect the final combination product and how purchasing controls are applied to suppliers/contractors.
• Summarize the firm's Corrective and Preventive Action (CAPA) System, specifically delineating each facility's responsibility, ensuring it covers identification of nonconforming practices/products, investigation of nonconformities, identification/implementation of corrective/preventive actions, and verification/validation of actions (21 CFR 820.100).
• Provide a production flow diagram identifying steps in manufacturing the finished combination product and specifying which facility is responsible for each step.
• Explain how UCB integrates into processes for controlling manufacturing through receiving/incoming, in-process, and final acceptance activities, specifying which firm performs acceptance activities and providing acceptance/rejection criteria.

Cited reasons

• Inadequate Management Responsibility for Combination Product CGMP
• Insufficient Design Control Procedures for UCB
• Inadequate Purchasing Controls Procedures
• Deficient CAPA System Integration
• Missing Production Flow Diagram with Facility Responsibilities
• Unclear Integration of UCB into Manufacturing Controls
• Non-compliant Prescribing Information
• Draft Carton and Container Labeling Required

Recommended actions

• Update responses to FDA's November 8, 2019, Quality System deficiencies to identify how UCB BioPharma SPRL (UCB) integrates into the Quality System.
• Describe specific management control responsibilities at each facility (Proximagen, UCB) associated with the medical device constituent of the combination product, including a summary of how management ensures compliance with CGMP requirements (21 CFR Part 4) and a description of each facility's functions and responsibilities.
• Explain the extent of UCB's involvement in the design control process and provide UCB's procedures for implementing design controls, including planning, input, output, review, verification, validation, transfer, changes, and design history file (21 CFR 820.30).
• Provide a summary of UCB's procedure(s) for purchasing controls, delineating responsibilities at Proximagen, and UCB, including supplier evaluation, maintenance of acceptable supplier records, purchasing data approval, and balancing purchasing assessment with receiving acceptance (21 CFR 820.50).
• Explain how purchasing procedures ensure changes by contractors/suppliers do not affect the final combination product and how purchasing controls are applied to suppliers/contractors.
• Summarize the firm's Corrective and Preventive Action (CAPA) System, specifically delineating each facility's responsibility, ensuring it covers identification of nonconforming practices/products, investigation of nonconformities, identification/implementation of corrective/preventive actions, and verification/validation of actions (21 CFR 820.100).
• Provide a production flow diagram identifying steps in manufacturing the finished combination product and specifying which facility is responsible for each step.
• Explain how UCB integrates into processes for controlling manufacturing through receiving/incoming, in-process, and final acceptance activities, specifying which firm performs acceptance activities and providing acceptance/rejection criteria.

Deficiency summary

The FDA issued a Complete Response Letter for Nayzilam (midazolam) nasal spray, citing significant deficiencies primarily related to the Quality System for the combination product, particularly concerning the integration and responsibilities of the new manufacturer, UCB. Specific issues include inadequate management responsibility, design controls, purchasing controls, and CAPA systems, as well as unresolved facility inspection findings at UCB. Additionally, the application requires updates to prescribing information and carton/container labeling.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2) of the Federal Food, Drug, and Cosmetic Act

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary themes are critical gaps in the Quality Management System (QMS) for a combination product, specifically regarding the clear delineation of responsibilities and implementation of controls (management, design, purchasing, CAPA) across multiple manufacturing sites, including a newly integrated manufacturer (UCB). Unresolved inspection findings and non-compliant labeling also contribute to the unapprovable status.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%