FDA CRL - Aft Pharmaceuticals Ltd

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to AFT Pharmaceuticals, Ltd. regarding their New Drug Application (NDA) for COMBOGESIC (ibuprofen 97.5 mg/acetaminophen 325 mg) Film-Coated Tablets, submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act. The application was not approved due to multiple deficiencies across clinical, statistical, nonclinical, product quality, and manufacturing facility aspects. Key issues included insufficient description of product exposure in clinical studies and inadequate quality of statistical datasets for Study AFT-MX-6, hindering efficacy confirmation. Nonclinical concerns involved inadequate justification for a drug substance specification linked to chromosomal aberrations and a failure to address elemental impurities in accordance with ICH Q3D guidance. Product quality deficiencies cited illegible analytical chromatograms, unsupported total impurity acceptance limits, missing regulatory specifications for release and stability, and lack of BSE/TSE certification for an excipient. Additionally, the company referred to non-commercial scale batches as validation batches, requiring validation at full commercial scale per FDA guidance. A significant issue was an unsatisfactory inspection at a manufacturing facility (COG), where product/process controls, lab controls, and quality assurance functions were found unacceptable. To address these, AFT Pharmaceuticals must provide detailed exposure data, re-analyze efficacy datasets, revise drug substance specifications, conduct elemental impurity analysis, update analytical procedures and specifications, provide excipient certifications, confirm commercial-scale process validation, resolve all facility observations, and submit a comprehensive safety update.