Abstract
Adipose tissue (AT) represents a commonly used source of mesenchymal stem/stromal cells (MSCs) whose proregenerative potential has been widely investigated in multiple clinical trials worldwide. However, the standardization of the manufacturing process of MSC-based cell therapy medicinal products in compliance with the requirements of the local authorities is obligatory and will allow us to obtain the necessary permits for product administration according to its intended use. Within the research phase (RD), we optimized the protocols used for the processing and ex vivo expansion of AT-derived MSCs (AT-MSCs) for the development of an Advanced Therapy Medicinal Product (ATMP) for use in humans. Critical process parameters (including, e.g., the concentration of enzyme used for AT digestion, cell culture conditions) were identified and examined to ensure the high quality of the final product containing AT-MSCs. We confirmed the identity of isolated AT-MSCs as MSCs and their trilineage differentiation potential according to the International Society for Cellular Therapy (ISCT) recommendations. Based on the conducted experiments, in-process quality control (QC) parameters and acceptance criteria were defined for the manufacturing of hospital exemption ATMP (HE-ATMP). Finally, we conducted a validation of the manufacturing process in a GMP facility. In the current study, we presented a process approach leading to the optimization of processing and the ex vivo expansion of AT-MSCs for the development of ATMP for use in humans.
Highlights
Introduction published maps and institutional affilMesenchymal stem/stromal cells (MSCs) represent one of the most investigated type of adult stem cells (SCs)
The designed experimental layout aimed at the optimization of the manufacturing process of HE-Advanced Therapy Medicinal Product (ATMP) containing adipose tissue (AT)-mesenchymal stem/stromal cells (MSCs) as an active substance, which was divided into the following stages: (1) isolation of stromal vascular fraction (SVF) cells, (2) culture of AT-derived MSCs (AT-MSCs), and (3) termination of AT-MSC culture, and formulation of the final cell-based product followed by quality control (QC) tests of the released final product (Figure 1)
According to the European Medicines Agency (EMA) regulatory framework, “advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells” providing “groundbreaking new opportunities for the treatment of disease and injury”
Summary
Mesenchymal stem/stromal cells (MSCs) represent one of the most investigated type of adult stem cells (SCs). In 2006, the International Society for Cellular Therapy (ISCT) proposed minimal criteria for defining MSCs of various origins, including (1) an ability to adhere to plastic surfaces under standard culture conditions in vitro; (2) a specific antigenic profile—the presence of CD73, CD90, and CD105 antigens (at least 95% of positive cells) and a parallel lack of the following antigens: CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR (less than 2% of positive cells); and (3) the capacity to differentiate into mesodermal lineages, including osteoblasts, chondroblasts, and adipocytes in vitro [3]. A number of different mechanisms of MSC action may be responsible for their proregenerative activity in injured tissues, including their (1) direct differentiation capacity, iations.
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