Yu Hao, Zhang Fan, He Yi-Chen, Zhang Lei-Sheng
School of Medicine, Nankai University, Tianjin 300071, China.
Faculty of Life Sciences and Medicine, Kunming University of Science and Technology, Kunming 650500, Yunnan Province, China.
World J Stem Cells. 2025 May 26;17(5):106547. doi: 10.4252/wjsc.v17.i5.106547.
Knee osteoarthritis (KOA), characterized by heterogeneous arthritic manifestations and complex peripheral joint disorder, is one of the leading causes of disability worldwide, which has become a high burden due to the multifactorial nature and the deficiency of available disease-modifying treatments. The application of mesenchymal stem/stromal cells (MSCs) as therapeutic drugs has provided novel treatment options for diverse degenerative and chronic diseases including KOA. However, the complexity and specificity of the "live" cells have posed challenges for MSC-based drug development and the concomitant scale-up preparation from laboratory to industrialization. For instance, despite the considerable progress in cell culture technology for fulfilling the robust development of drug conversion and clinical trials, yet significant challenges remain in obtaining regulatory approvals. Thus, there's an urgent need for the research and development of MSC drugs for KOA. In this review, we provide alternative solution strategies for the preparation of MSC drugs on the basis of the principle of quality by design, including designing the cell production processes, quality control, and clinical applications. In detail, we mainly focus on the quality by design method for MSC manufacturing in standard cell-culturing factories for the treatment of KOA by using the Quality Target Product Profile as a starting point to determine potential critical quality attributes and to establish relationships between critical material attributes and critical process parameters. Collectively, this review aims to meet product performance and robust process design, and should help to reduce the gap between compliant products and the production of compliant good manufacturing practice.
膝骨关节炎（KOA）以异质性关节炎表现和复杂的外周关节紊乱为特征，是全球致残的主要原因之一，由于其多因素性质以及缺乏有效的疾病改善治疗方法，已成为一个沉重负担。间充质干/基质细胞（MSCs）作为治疗药物的应用为包括KOA在内的多种退行性和慢性疾病提供了新的治疗选择。然而，“活”细胞的复杂性和特异性给基于MSCs的药物开发以及从实验室到工业化的同步扩大制备带来了挑战。例如，尽管在满足药物转化和临床试验的强劲发展所需的细胞培养技术方面取得了相当大的进展，但在获得监管批准方面仍存在重大挑战。因此，迫切需要研发用于KOA的MSCs药物。在本综述中，我们基于质量源于设计的原则，为MSCs药物的制备提供替代解决方案策略，包括设计细胞生产工艺、质量控制和临床应用。具体而言，我们主要关注在标准细胞培养工厂中用于治疗KOA的MSCs制造的质量源于设计方法，以质量目标产品概况为起点来确定潜在的关键质量属性，并建立关键物料属性与关键工艺参数之间的关系。总体而言，本综述旨在满足产品性能和稳健的工艺设计，并应有助于缩小合规产品与合规良好生产规范生产之间的差距。
