Approval Letter Other 211039 (Jan 1, 2020)

Summary

The FDA issued a Complete Response letter for NDA 211039 for fluorescein sodium and benoxinate hydrochloride ophthalmic solution, indicating that the application cannot be approved in its present form due to manufacturing facility non-compliance with current good manufacturing practice (cGMP) regulations.

Key points

• Resolve objectionable conditions observed at the manufacturing facility to comply with current good manufacturing practice regulations (21 CFR parts 210 and 211).
• Ensure all facilities used for the manufacture, processing, packing, or holding of the drug substance and drug product are in compliance with cGMP regulations.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to the deficiency, covering data from all nonclinical and clinical studies/trials of the drug.
• Provide the data requested for the two process deficiencies sent on May 22, 2019, related to manufacturing process validation.
• The methods, facilities, and controls used for the manufacture, processing, packing, or holding of the drug substance do not comply with current good manufacturing practice regulations (21 CFR Parts 210 and 211). A recent inspection observed objectionable conditions at the facility, requiring satisfactory resolution before approval.
• The applicant failed to provide the data requested for two process deficiencies previously communicated on May 22, 2019. The agency reminds the applicant that process validation is necessary to confirm the process design.
• Upon responding to the deficiencies, a safety update is required as described in 21 CFR 314.50(d)(5)(vi)(b). This update should include data from all nonclinical and clinical studies/trials of the drug under consideration, regardless of indication, dosage form, or dose level.

Cited reasons

• Manufacturing Facility cGMP Non-Compliance
• Outstanding Manufacturing Process Data
• Safety Update Required upon Resubmission
• The application cannot be approved in its present form primarily due to non-compliance with current good manufacturing practice (cGMP) regulations at the manufacturing facility, where objectionable conditions were observed during an inspection. Additionally, the applicant failed to provide requested data for previously identified manufacturing process deficiencies. A safety update will be required upon resubmission.

Recommended actions

• Resolve objectionable conditions observed at the manufacturing facility to comply with current good manufacturing practice regulations (21 CFR parts 210 and 211).
• Ensure all facilities used for the manufacture, processing, packing, or holding of the drug substance and drug product are in compliance with cGMP regulations.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to the deficiency, covering data from all nonclinical and clinical studies/trials of the drug.
• Provide the data requested for the two process deficiencies sent on May 22, 2019, related to manufacturing process validation.

Deficiency summary

The application cannot be approved in its present form primarily due to non-compliance with current good manufacturing practice (cGMP) regulations at the manufacturing facility, where objectionable conditions were observed during an inspection. Additionally, the applicant failed to provide requested data for previously identified manufacturing process deficiencies. A safety update will be required upon resubmission.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

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

Impact

Impact score

0.95

Estimated delay

180 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary reason for non-approval is significant manufacturing quality issues, including cGMP non-compliance at the facility and unresolved process validation data. A comprehensive safety update will also be required upon resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%