Quality by Design to Mitigate Aggregation: Mechanistic Insights and Analytical Strategies for Biopharmaceutical Manufacturing.

This review highlights the problem of protein molecule aggregation, which represents a significant challenge in the field of biopharmaceuticals. Protein aggregation is critical because it can affect the efficacy and safety of biopharmaceuticals, including those used to treat autoimmune diseases and various cancers. From a regulatory perspective, protein aggregation is recognized as a critical quality attribute (CQA) by health authorities such as the FDA and EMA, due to its potential impact on immunogenicity, product consistency, and patient safety. This article reviews various aggregation mechanisms, pathways, and strategies to minimize aggregation at various stages of drug development and manufacturing. Attention is paid to the latest analytical control techniques, addressing their applicability and limitations, as well as the possibility of integrating them into the QC flow, in alignment with current regulatory expectations for robust, science- and risk-based control strategies. The QbD principles emphasize their role in improving the understanding of manufacturing processes and enhancing the quality of finished pharmaceutical products, consistent with ICH Q8-Q11 guidelines and the regulatory push toward lifecycle-based pharmaceutical quality systems. The article offers valuable recommendations for the scientific community and manufacturers to effectively address protein aggregation and improve the safety and efficacy of biopharmaceuticals, while supporting regulatory compliance and facilitating more predictable interactions with health authorities.