Abstract
BackgroundCell banks are widely used to preserve cell properties as well as to record and control the use of cell lines in biomedical research. The generation of cell banks for the manufacturing of Advanced Therapy Medicinal Products, such as cell and gene therapy products, must comply with current Good Manufacturing Practice regulations. The quality of the cell lines used as starting materials in viral-vector manufacturing processes must be also assessed.MethodsThree batches of a Master Cell Bank and a Working Cell Bank of the HEK293T cell line were manufactured under current Good Manufacturing Practices regulations. Quality control tests were performed according to product specifications. Process validation includes the training of manufacturing personnel by performing simulation tests, and the continuous measurement of environmental parameters such as air particles and microorganisms. Cell number and viability of cryopreserved cells were periodically measured in order to define the stability of these cellular products.ResultsAll batches of HEK293T Master and Working Cell Banks met the acceptance criteria of their specifications showing the robustness and homogeneity of the processes. In addition, both Master and Working Cell Banks maintained the defined cell viability and concentration over a 37 month-period after cryopreservation.ConclusionsManufacturing cell banks under Good Manufacturing Practice regulations for their use as raw materials or final cellular products is feasible. HEK293T cell banks were used to manufacture clinical-grade lentiviral particles for Chimeric Antigen Receptor T-cell based clinical trials.
Highlights
Cell banks are widely used to preserve cell properties as well as to record and control the use of cell lines in biomedical research
European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulatory bodies recently approved several gene-derived Advanced Therapy Medicinal Products (ATMPs). This is the case of Zolgensma®, a treatment for spinal muscular atrophy (SMA) based on the in vivo administration of adeno-associated viruses (AAVs), which deliver a functional version of the survival motor neuron 1 (SMN1) gene; [6, 7] and Zynteglo®, an autologous ex vivo gene therapy for beta thalassemia that uses lentiviruses to insert a functional hemoglobin subunit beta (HBB) gene in the hematopoietic stem cells of the patient [8]
The present work shows the approach established at Creatio to validate the production of Good Manufacturing Practices (GMP)-compliant Master Cell Bank (MCB) and Working Cell Bank (WCB) of the HEK293T cell line which are currently being used as packaging cells for GMP-grade lentivirus manufacturing in several Chimeric Antigen Receptor (CAR) T-cell clinical trials [11, 19]
Summary
Cell banks are widely used to preserve cell properties as well as to record and control the use of cell lines in biomedical research. Advanced Therapy Medicinal Products (ATMPs) such as cell therapy, gene therapy and tissue engineering [1, 2] have emerged as promising candidates for the treatment of currently incurable diseases. This is the case of Alofisel®, a cell therapy product based on adipose-derived mesenchymal stem cells, used to treat perianal fistulas in Crohn’s disease, [3] and Holoclar®, a tissue engineered product used to repair damaged corneal tissues, based on fibrin membranes coated with a population of corneal cells, including limbal stem cells [4]. Anti-CD30 CAR Tcells and Anti-BCMA CAR T-cells are promising therapies based on the CAR T-cell technology [12, 13]
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