Approval Letter Other 209529 (Jan 1, 2020)

Summary

The FDA issued a Complete Response letter for NDA 209529 for solifenacin succinate oral suspension, indicating that the application cannot be approved in its current form due to manufacturing facility deficiencies, inadequate control of raw material quality, and insufficient drug product specifications and stability programs regarding objectionable microorganisms. The letter outlines specific actions required for resubmission.

Key points

• Satisfactorily resolve objectionable conditions observed during the manufacturing facility inspection.
• Submit results from ongoing characterization studies, including a summary of investigations and corrective/preventive actions taken to address the root cause of raw material quality issues.
• Establish and validate additional tests and acceptance criteria for the raw material.
• Submit batch analyses from three verification/validation batches demonstrating that drug product manufactured with the raw material meeting NF and additional quality requirements has the requisite quality (e.g., viscosity), including executed batch records, validation protocol, and final summary report.
• If suitable additional controls for the raw material cannot be identified and validated, or if the supplier cannot provide raw material meeting enhanced specifications, propose a revision of acceptance criteria for drug product viscosity, with justification and release/stability data confirming no adverse impact on quality and performance.
• Revise the drug product specification to include test method(s) and acceptance criteria to assure the product is free of objectionable microorganisms.
• Update relevant sections of the application to reflect revised drug product specifications.
• Revise the post-approval stability program to include testing to confirm the absence of objectionable microorganisms.

Cited reasons

• Unresolved Manufacturing Facility Inspection Observations
• Inadequate Control of Raw Material Quality
• Insufficient Microbial Control in Drug Product Specification and Stability Program
• Prescribing Information and Carton/Container Labeling Deficiencies
• Required Safety Update for Resubmission
• The application cannot be approved due to unresolved objectionable conditions at the manufacturing facility, inadequate control over raw material quality leading to out-of-specification drug product, and insufficient drug product specifications and stability program to ensure freedom from objectionable microorganisms. Additionally, the proposed prescribing information and carton/container labeling require revisions to comply with regulatory requirements, and a comprehensive safety update is needed for resubmission.

Recommended actions

• Satisfactorily resolve objectionable conditions observed during the manufacturing facility inspection.
• Submit results from ongoing characterization studies, including a summary of investigations and corrective/preventive actions taken to address the root cause of raw material quality issues.
• Establish and validate additional tests and acceptance criteria for the raw material.
• Submit batch analyses from three verification/validation batches demonstrating that drug product manufactured with the raw material meeting NF and additional quality requirements has the requisite quality (e.g., viscosity), including executed batch records, validation protocol, and final summary report.
• If suitable additional controls for the raw material cannot be identified and validated, or if the supplier cannot provide raw material meeting enhanced specifications, propose a revision of acceptance criteria for drug product viscosity, with justification and release/stability data confirming no adverse impact on quality and performance.
• Revise the drug product specification to include test method(s) and acceptance criteria to assure the product is free of objectionable microorganisms.
• Update relevant sections of the application to reflect revised drug product specifications.
• Revise the post-approval stability program to include testing to confirm the absence of objectionable microorganisms.

Deficiency summary

The application cannot be approved due to unresolved objectionable conditions at the manufacturing facility, inadequate control over raw material quality leading to out-of-specification drug product, and insufficient drug product specifications and stability program to ensure freedom from objectionable microorganisms. Additionally, the proposed prescribing information and carton/container labeling require revisions to comply with regulatory requirements, and a comprehensive safety update is needed for resubmission.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA 505(b)

Impact

Impact score

0.95

Estimated delay

600 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary concerns revolve around fundamental manufacturing quality control, raw material specifications, and microbial contamination risk, indicating significant product quality and safety issues. Additionally, the application requires substantial updates to labeling for regulatory compliance and a comprehensive safety update for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%