Development of cGMP manufacturing processes for the large-scale production of cell-based therapies for commercial applications

The landmark discovery of induced pluripotent stem cells (iPSCs) ushered in a new era of cell and gene-based therapies and their potentially curative nature for a number of devastating diseases and disorders. This has resulted in a large number of clinical trials being initiated for the use of cell-based therapies for the treatment of various diseases, such as Parkinson’s disease, Type I diabetes, and large B-cell lymphoma. Additionally, the recent approval of therapies using immune cells and their success in the clinic are positive indicators of the commercial applicability of cell-based therapies. However, in order to reach the market it is necessary to develop industrialized cGMP manufacturing processes that are scalable, robust and reliable and can meet commercial demands. In addition, for a commercial process it is important to have a good understanding of the critical process parameters (CPPs) and their impact on the critical quality attributes (CQAs) of the final therapeutic product. Lonza has approached the development of industrialized bioprocesses with focus on (1) the development of cGMP manufactured, quality-assured cell bank processes (e.g. iPSC manufacturing process utilizing a robust cell culture system), (2) implementation of computational fluid dynamics (CFD) modeling to aid in scaling culture systems, (3) implementation of process analytical technologies (PAT) to monitor/control the culture conditions and automation to decrease labor and improve reproducibility of the process, (4) utilizing a standard approach to performing process characterization studies based on a failure mode and affects analysis (FMEA) to identify modes of failure, risks and mitigations and aid in commercial readiness, and (5) the development, optimization and qualification of analytical methods to characterize the state of the cultures and support release of cell-based products. Importantly, the development of analytical methods that can demonstrate the characteristics and potency of the final drug product as it relates to its in vivo mechanism of action are critical. In this respect, Lonza has developed a library of robust / qualified analytical methods that can be assessed and utilized for different clinical programs in order to support commercial activities. Here, we will discuss how we have applied our unique approach to support the industrialization of cell-based therapies for applications utilizing iPSCs and T-cells.

Bioreactor expansion of human neural precursor cells for the treatment of neurodegenerative disorders

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Human-Induced Pluripotent Stem Cells Manufactured Using a Current Good Manufacturing Practice-Compliant Process Differentiate Into Clinically Relevant Cells From Three Germ Layers

The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications

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<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p

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<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p

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<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p

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<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p

video_2.mp4

<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p

image_3.tif

<p>The discovery of reprogramming and generation of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine and opened new opportunities in cell replacement therapies. While generation of iPSCs represents a significant breakthrough, the clinical relevance of iPSCs for cell-based therapies requires generation of high-quality specialized cells through robust and reproducible directed differentiation protocols. We have recently reported manufacturing of human iPSC master cell banks (MCB) under current good manufacturing practices (cGMPs). Here, we describe the clinical potential of human iPSCs generated using this cGMP-compliant process by differentiating them into the cells from all three embryonic germ layers including ectoderm, endoderm, and mesoderm. Most importantly, we have shown that our iPSC manufacturing process and cell culture system is not biased toward a specific lineage. Following controlled induction into a specific differentiation lineage, specialized cells with morphological and cellular characteristics of neural stem cells, definitive endoderm, and cardiomyocytes were developed. We believe that these cGMP-compliant iPSCs have the potential to make various clinically relevant products suitable for cell therapy applications.</p