Issued January 1, 2021
Issued
January 1, 2021
Application
Other • 212156
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response letter from the FDA to Par Sterile Products, LLC, informing them that their New Drug Application (NDA) for Micafungin for Injection cannot be approved in its current form. The letter outlines specific deficiencies across product quality, nonclinical studies, labeling, safety updates, and facility inspections that must be addressed before approval.
The application cannot be approved due to significant deficiencies in product quality (low assay values, impurity limits exceeding qualification thresholds), inadequate nonclinical assessments (leachables, impurity qualification), non-compliant prescribing information and carton/container labeling, and an outstanding manufacturing facility inspection. A comprehensive safety update is also required with the response.
Assay values for the 5% dextrose diluted admixture were significantly off target (more than % off from 0.5 mg/mL), which could affect drug efficacy.
Recommended response: Conduct a root cause analysis, correct the issue, and reconduct the assay test for the in-use-stability study to support labeling.
The proposed acceptance criterion for an impurity is NMT %, which needs to be tightened to NMT 0.2% per ICH Q3B or justified with toxicology data.
Recommended response: Tighten the limit to NMT 0.2% or provide toxicology data to justify the current limit.
Cited: ICH Q3B
The proposed acceptance criterion for a specified impurity at is NMT %, which is above the qualification threshold and requires toxicology data justification or tightening to NMT 0.2% per ICH Q3B.
Recommended response: Justify the limit with toxicology data or tighten it to NMT 0.2% per ICH Q3B.
Cited: ICH Q3B
The limit NMT % for any unspecified impurity is above the qualification threshold and needs to be tightened per ICH Q3B.
Recommended response: Tighten the limit per ICH Q3B.
Cited: ICH Q3B
The revised leachables assessment, including the toxicological assessment, was not provided as planned.
Recommended response: Provide the revised leachables assessment, including the toxicological assessment.
Proposed acceptance criteria for Impurity, impurity at, and any unspecified impurity are above ICH Q3B qualification thresholds (NMT 0.2%). Requires characterization and comprehensive toxicological assessment if limits cannot be tightened.
Recommended response: If limits cannot be tightened to NMT 0.2%, provide adequate characterization and comprehensive toxicological assessment for impurities > 0.2%. Additional nonclinical studies may be recommended.
Cited: ICH Q3B(R1), ICH M7(R1)
The proposed PI does not conform to content and format regulations (21 CFR 201.56(a) and (d), 201.57). Formatting errors need correction, and updated content of labeling in SPL format is required.
Recommended response: Submit draft labeling addressing proposed revisions, use the SRPI checklist for formatting, and submit updated content of labeling in SPL format. Provide marked-up and clean Word versions.
Cited: 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57, 21 CFR 314.50(l)(1)(i)
Revised draft carton and container labeling based on agency's proposed revisions is required.
Recommended response: Submit revised draft carton and container labeling based on agency's proposed revisions.
A comprehensive safety update is required with the response, including detailed changes in safety profile, new safety data, retabulation of adverse events, case reports for deaths/serious AEs, updated exposure info, worldwide experience, and English translations of foreign labeling.
Recommended response: Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b), covering all specified aspects.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
An inspection of the facility is required before approval to assess CGMP compliance. Due to U.S. Government and/or Agency-wide restrictions on travel, the inspection could not be conducted during the current review cycle.
Recommended response: Address other deficiencies; however, approval is contingent on a successful facility inspection once travel restrictions are lifted.
The application is not approvable due to a combination of significant product quality and nonclinical safety concerns related to impurities and stability, non-compliant labeling, and an outstanding manufacturing facility inspection. A comprehensive safety update is also required.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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