Technical and regulatory challenges in cell therapy products: lessons from unsuccessful IND and BLA/NDA approvals

Cell therapy products have advanced rapidly owing to their unique biological advantages and transformative therapeutic potential. However, the inherent complexity of living cell-based products, coupled with disease-specific uncertainties, poses significant technical and regulatory challenges throughout the stringent review and approval process as biologics. This commentary offers an in-depth analysis of current regulatory practices and relevant literature, systematically examining unsuccessful approval scenarios for cell therapy products at both the Investigational New Drug (IND) application stage and the Biologics License Application/New Drug Application (BLA/NDA) stage. Particular attention is given to recurring issues such as manufacturing and quality deficiencies, comparability challenges, and gaps in supporting evidence that frequently lead to clinical holds, delays, or Complete Response Letters. By highlighting these critical failure modes, the article aims to provide actionable regulatory compliance guidance and practical technical risk-mitigation strategies to assist research and development organizations in improving product quality, strengthening regulatory submissions, and enhancing the likelihood of successful development and market authorization.