Issued January 1, 2021
Issued
January 1, 2021
Application
Other • 212045
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response letter from the FDA to Hikma Pharmaceuticals USA Inc. regarding their New Drug Application (NDA) for naloxone nasal spray, 8 mg. The FDA has determined that the application cannot be approved in its present form due to various deficiencies identified in product quality, manufacturing, and device-related aspects.
The application received a Complete Response due to significant deficiencies in product quality (extractables/leachables, impurity control, method validation, structural assignment), manufacturing process controls, and device-related reliability testing and quality system procedures. A critical manufacturing facility inspection could not be completed.
Different maximum daily doses (MDD) were used to calculate AETs for extractables studies, leading to inconsistencies.
Recommended response: Clarify discrepancies and provide revised AETs with the correct MDD.
The design for leachables testing (ICH Q1D concept) was not agreed upon, potential secondary leachables were not fully addressed, and stability studies were not conducted in the worst-case (inverted) position for stopper/drug product contact. Also, AETs for leachables were inconsistent and reporting limits were too high.
Recommended response: Follow full stability protocol for leachable trend, re-run leachables studies in inverted position or justify, clarify AET discrepancies and provide revised AET.
Cited: ICH Q1D
The acceptance criterion for 'Total Impurities' in release and stability specifications is too wide.
Recommended response: Tighten the acceptance criterion based on data trend.
The potential degradation impurity is not included in both release and stability specifications as per ICH Q3B.
Recommended response: Include acceptance criterion for the impurity in specifications or provide batch data showing its absence with validated methods.
Cited: ICH Q3B
While an impurity is controlled in the vendor's COA, the analytical method's ability to detect it and its absence in the drug product has not been demonstrated.
Recommended response: Demonstrate analytical method can detect the impurity and that it is absent in the drug product.
Forced degradation studies for assay/identification are missing, system suitability requirements are missing for several methods, and a complete method validation report for a specific impurity is missing. Details for a referenced report are also needed.
Recommended response: Provide forced degradation studies, system suitability requirements, complete method validation reports, and details for referenced reports.
The structural assignment for an impurity is based on an unclear signal, and direct spectroscopic evidence is lacking, especially since a reference standard is unavailable.
Recommended response: Clarify signal source, provide direct spectroscopic evidence, or list as a specified unknown impurity with RRT.
The design and materials of construction for the labels used on the primary container are not provided.
Recommended response: Provide the design and materials of construction for the labels.
The vendor COA for the vial is not provided.
Recommended response: Provide the vendor COA for the vial.
A wider pH range was adopted for release and stability specifications despite stability study results showing optimum impurity profile at a narrower range.
Recommended response: Justify the wider pH ranges with data or revise the pH specification.
The proposed commercial batch record in 3.2.P.3.3 needs revision.
Recommended response: Revise the proposed commercial batch record.
Leachable and extractable studies results are missing for all product-contact materials used in the manufacturing process, and compliance with ASTM standards and pertinent CFR sections for indirect food additives is not demonstrated.
Recommended response: Provide leachable and extractable data for all formulation contacting components, confirm ASTM compliance, and provide a statement of compliance to pertinent CFR sections.
Cited: ASTM standards, pertinent CFR sections for indirect food additives
The primary themes are extensive CMC and manufacturing quality control issues, including extractables/leachables, impurity specifications, analytical method validation, and process controls. Additionally, deficiencies in device reliability testing and CAPA procedures, coupled with an uncompleted facility inspection, contributed to the non-approval.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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