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Cytotherapy. 2019 Apr;21(4):468-482. doi: 10.1016/j.jcyt.2019.03.001. Epub 2019 Mar 27.

Translation of a standardized manufacturing protocol for mesenchymal stromal cells: A systematic comparison of validation and manufacturing data.

Author information

1
Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg - Hessia, Ulm, Germany. Electronic address: markus.rojewski@uni-ulm.de.
2
Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg - Hessia, Ulm, Germany.
3
Institute of Clinical Dentistry, University of Bergen, Bergen, Norway.
4
Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy.
5
Section for Haematology, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
6
Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg - Hessia, Ulm, Germany.
7
UMR5273 Centre national de la recherche scientifique (CNRS), UPS, Établissement francais du sang (EFS)-INSERM U1031, STROMAlab, Toulouse, France; Établissement francais du sang (EFS) Pyrénées-Méditeranée, Toulouse, France.
8
Inserm U957, Laboratory for Pathophysiology of Bone Resorption, Faculty of Medicine, University of Nantes, Nantes, France.

Abstract

BACKGROUND:

Many data are available on expansion protocols for mesenchymal stromal cells (MSCs) for both experimental settings and manufacturing for clinical trials. However, there is a lack of information on translation of established protocols for Good Manufacturing Practice (GMP) from validation to manufacturing for clinical application. We present the validation and translation of a standardized pre-clinical protocol for isolation and expansion of MSCs for a clinical trial for reconstitution of alveolar bone.

METHODS:

Key parameters of 22 large-scale expansions of MSCs from bone marrow (BM) for validation were compared with 11 expansions manufactured for the clinical trial "Jaw bone reconstruction using a combination of autologous mesenchymal stromal cells and biomaterial prior to dental implant placement (MAXILLO1)" aimed at reconstruction of alveolar bone.

RESULTS:

Despite variations of the starting material, the robust protocol led to stable performance characteristics of expanded MSCs. Manufacturing of the autologous advanced therapy medicinal product MAXILLO-1-MSC was possible, requiring 21 days for each product. Transport of BM aspirates and MSCs within 24 h was guaranteed. MSCs fulfilled quality criteria requested by the national competent authority. In one case, the delivered MSCs developed a mosaic in chromosomal finding, showing no abnormality in differentiation capacity, growth behavior or surface marker expression during long-term culture. The proportion of cells with the mosaic decreased in long-term culture and cells stopped growth after 38.4 population doublings.

CONCLUSIONS:

Clinical use of freshly prepared MSCs, manufactured according to a standardized and validated protocol, is feasible for bone regeneration, even if there was a long local distance between manufacturing center and clinical site. Several parameters, such as colony forming units fibroblasts (CFU-F), percentage of CD34+ cells, cell count of mononuclear cells (MNCs) and white blood cells (WBCs), of the BM may serve as a predictive tool for the yield of MSCs and may help to avoid unnecessary costs for MSC manufacturing due to insufficient cell expansion rates.

KEYWORDS:

Good Manufacturing Practice; advanced therapy medicinal products; cell production; karyotyping; mesenchymal stromal cells; quality control; translational medicine

PMID:
30926359
DOI:
10.1016/j.jcyt.2019.03.001
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