FDA CRL - Hikma Pharmaceuticals USA Inc.

Hikma Pharmaceuticals USA Inc. received a Complete Response Letter (CRL) from the FDA regarding its New Drug Application (NDA) for naloxone nasal spray, 8 mg, submitted on April 30, 2019. The FDA determined the application could not be approved in its current form due to significant product quality and manufacturing control deficiencies, reviewed under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act.

Key product quality issues included inconsistencies in extractables studies, particularly regarding the maximum daily dose used for analytical evaluation thresholds, and missing supporting information. For leachables studies, the FDA disagreed with the stability testing design and required re-evaluation with different storage orientations or strong justification, along with clarification of evaluation threshold discrepancies. The agency also cited overly broad acceptance criteria for total impurities, a missing specification for a potential degradation impurity, and the need for more robust method validation data, including forced degradation studies and system suitability requirements. Furthermore, the structural assignment of an impurity required direct spectroscopic evidence.

Manufacturing deficiencies highlighted the need for revised commercial batch records and comprehensive leachable and extractable studies for all product-contact materials to ensure compliance with relevant standards and regulations. The FDA also mandated the establishment and justification of in-process controls for pH, viscosity, and density, along with revisions to yield reconciliation limits which were deemed inadequate for reflecting process performance, citing 21 CFR 211.103 and 211.186(b)(7).

To achieve approval, Hikma must address all identified issues by providing updated studies, revised specifications, complete method validation reports, and improved manufacturing controls in accordance with regulatory expectations.