A novel, flexible and automated manufacturing facility for cell-based health care products: Tissue Factory

Abstract

IntroductionCurrent production facilities for Cell-Based Health care Products (CBHPs), also referred as Advanced-Therapy Medicinal Products or Regenerative Medicine Products, are still dependent on manual work performed by skilled workers. A more robust, safer and efficient manufacturing system will be necessary to meet the expected expansion of this industrial field in the future. Thus, the ‘flexible Modular Platform (fMP)’ was newly designed to be a true “factory” utilizing the state-of-the-art technology to replace conventional “laboratory-like” manufacturing methods. Then, we built the Tissue Factory as the first actual entity of the fMP.MethodsThe Tissue Factory was designed based on the fMP in which several automated modules are combined to perform various culture processes. Each module has a biologically sealed chamber that can be decontaminated by hydrogen peroxide. The asepticity of the processing environment was tested according to a pharmaceutical sterility method. Then, three procedures, production of multi-layered skeletal myoblast sheets, expansion of human articular chondrocytes and passage culture of human induced pluripotent stem cells, were conducted by the system to confirm its ability to manufacture CHBPs.ResultsFalling or adhered microorganisms were not detected either just after decontamination or during the cell culture processes. In cell culture tests, multi-layered skeletal myoblast sheets were successfully manufactured using the method optimized for automatic processing. In addition, human articular chondrocytes and human induced-pluripotent stem cells could be propagated through three passages by the system at a yield comparable to manual operations.ConclusionsThe Tissue Factory, based on the fMP, successfully reproduced three tentative manufacturing processes of CBHPs without any microbial contamination. The platform will improve the manufacturability in terms of lower production cost, improved quality variance and reduced contamination risks. Moreover, its flexibility has the potential to adapt to the modern challenges in the business environment including employment issues, low operational rates, and relocation of facilities. The fMP is expected to become the standard design basis of future manufacturing facilities for CBHPs.

Cell sheet tissue engineering: Cell sheet preparation, harvesting/manipulation, and transplantation

“…An automatic apparatus for cell sheet stacking using the plunger cell sheet manipulator enables us to precisely align and stack five cell sheets into a myoblast tissue 70–80 μm thick . Based on this technology, an automated cell sheet production system called “Tissue‐Factory (T‐Factory)” was developed for producing clinical‐grade myoblast tissues …”

“…62 Based on this technology, an automated cell sheet production system called "Tissue-Factory (T-Factory)" was developed for producing clinical-grade myoblast tissues. 63…”

A bench‐top molding method for the production of cell‐laden fibrin micro‐fibers with longitudinal topography

“…The method consists of four main steps: (a) the injection of the fibrin components including the cells into the silicone tube, (b) the gelation process, (c) the ejection of the gel after polymerization and (d) the stretching of the resulting fiber. We expect that already existing solutions for automated pipetting, handling, collection, gripping of samples and controlled linear displacement could be assembled to create an ad‐hoc automated system for the production of the fibers in a sterile, closed environment (Bhuthalingam, Lim, Irvine, & Venkatraman, ; Bartolo, Domingos, Gloria, & Ciurana, ; P. F. Costa et al, ; Kikuchi et al, ; Mekhileri et al, ). A GMP conform production is facilitated by the limited number of parts in contact with the materials composing the fibers and the commercial availability of GMP‐conform cell‐work stations.…”

Physiological Microenvironmental Conditions in Different Scalable Culture Systems for Pluripotent Stem Cell Expansion and Differentiation

“…To overcome the difficulty of handling, an automated culture system has been developed by utilizing a machine, robotics, and programming to conduct cell propagation. Automation systems show many benefits, such as the ability to significantly reduce the working time for the technician, provide automated and scheduled screening, imaging, or cell maintenance based on cell growth, and minimize the risk of contamination [106,107]. Most of the commercially available automated culture systems, such as Cytogration™ systems, SelecT™ systems, and AcCelerator™ systems, are based on continuous cell maintenance, which automatically delivers media containing nutrients and removes cellular waste products [108].…”