Approval Letter Other 213895 (Jan 1, 2022)

Summary

This is a Complete Response Letter from the FDA to Xellia Pharmaceuticals, ApS, for their New Drug Application (NDA) 213895 for Vancomycin Injection. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to product quality, nonclinical toxicology, and safety updates. The letter outlines specific issues and recommendations for addressing them.

Key points

• Qualify all applicable leachables for the proposed vancomycin drug product.
• Provide a comprehensive toxicological risk assessment for any leachable that exceeds 5 mcg/day, based on long-term stability samples.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, detailing significant changes in the safety profile and substantial changes in the incidence of common adverse events.
• Resubmit the application or take other available actions under 21 CFR 314.110 within one year.
• Ensure any resubmission fully addresses all listed deficiencies and is clearly marked as 'RESUBMISSION' in the cover letter.
• If revising labeling, use the SRPI checklist and include updated content of labeling in structured product labeling (SPL) format.
• The acceptability of the proposed stopper cannot be determined until the identity and the safety profile of the leachables are considered acceptable from a nonclinical perspective. The data from the leachables study have not been submitted to the NDA.
• Provide a comprehensive toxicological risk assessment (e.g., local toxicity, systemic toxicity, mutagenicity, carcinogenicity, reproductive toxicity) for any leachable that exceeds 5 mcg/day. The risk assessment should be based on the levels of leachables detected in long-term stability samples that include any intended secondary container closure system(s) unless otherwise justified.

Cited reasons

• Qualify all applicable leachables and submit data
• Provide comprehensive toxicological risk assessment for leachables
• Safety update review of vancomycin administered intravenously and orally
• The application cannot be approved in its present form due to critical product quality and nonclinical toxicology deficiencies related to the qualification and toxicological risk assessment of leachables from the container closure system. Specifically, leachables study data were not submitted, and a comprehensive toxicological risk assessment for identified leachables is required.

Recommended actions

• Qualify all applicable leachables for the proposed vancomycin drug product.
• Provide a comprehensive toxicological risk assessment for any leachable that exceeds 5 mcg/day, based on long-term stability samples.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, detailing significant changes in the safety profile and substantial changes in the incidence of common adverse events.
• Resubmit the application or take other available actions under 21 CFR 314.110 within one year.
• Ensure any resubmission fully addresses all listed deficiencies and is clearly marked as 'RESUBMISSION' in the cover letter.
• If revising labeling, use the SRPI checklist and include updated content of labeling in structured product labeling (SPL) format.

Deficiency summary

The application cannot be approved in its present form due to critical product quality and nonclinical toxicology deficiencies related to the qualification and toxicological risk assessment of leachables from the container closure system. Specifically, leachables study data were not submitted, and a comprehensive toxicological risk assessment for identified leachables is required.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2)

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary issues preventing approval are related to the qualification and toxicological assessment of leachables from the drug product's container closure system, requiring additional data and a comprehensive risk assessment.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%