Induced pluripotent stem cells (iPSC) open up the unique perspective of manufacturing cell products for drug development and regenerative medicine in tissue-, disease- and patient-specific forms. iPSC can be multiplied almost without restriction and differentiated into cell types of all organs. The basis for clinical use of iPSC is a high number of cells (approximately 7 × 10⁷ cells per treatment), which must be produced cost-effectively while maintaining reproducible and high quality. Compared to manual cell production, the automation of cell production offers a unique chance of reliable reproducibility of cells in addition to cost reduction and increased throughput. StemCellFactory is a prototype for a fully automated production of iPSC. However, in addition to the already tested functionality of the system, it must be shown that this automation brings necessary economic advantages. This paper presents that fully automated stem cell production offers economic advantages in addition to increased throughput and better quality. First, biological and technological basics for a fully automated production of iPSC are presented. Second, the basics for profitability calculation are presented. Third, profitability of both manual and automated production are calculated. Finally, different scenarios effecting the profitability of manual and automated production are compared.

Laboratory automation is a key driver in biotechnology and an enabler for powerful new technologies and applications. In particular, in the field of personalized therapies, automation in research and production is a prerequisite for achieving cost efficiency and broad availability of tailored treatments. For this reason, we present the StemCellDiscovery, a fully automated robotic laboratory for the cultivation of human mesenchymal stem cells (hMSCs) in small scale and in parallel. While the system can handle different kinds of adherent cells, here, we focus on the cultivation of adipose-derived hMSCs. The StemCellDiscovery provides an in-line visual quality control for automated confluence estimation, which is realized by combining high-speed microscopy with deep learning-based image processing. We demonstrate the feasibility of the algorithm to detect hMSCs in culture at different densities and calculate confluences based on the resulting image. Furthermore, we show that the StemCellDiscovery is capable of expanding adipose-derived hMSCs in a fully automated manner using the confluence estimation algorithm. In order to estimate the system capacity under high-throughput conditions, we modeled the production environment in a simulation software. The simulations of the production process indicate that the robotic laboratory is capable of handling more than 95 cell culture plates per day.

Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) are amenable for use in a clinical setting for treatment of osteoarthritis (OA), which remains one of the major illnesses worldwide. Aside from iPSC-derived iMSCs, chondrocytes (iCHO) and extracellular vesicles (EV) are also promising candidates for treatment of OA. Manufacturing and quality control of iPSC-derived therapies is mainly manual and thus highly time consuming and susceptible to human error. A major challenge in translating iPSC-based treatments more widely is the lack of sufficiently scaled production technologies from seeding to fill-and-finish. Formerly, the Autostem platform was developed for the expansion of tissue-derived MSCs at scale in stirred tank bioreactors and subsequent fill-and-finish. Additionally, the StemCellDiscovery platform was developed to handle plate-based cultivation of adherent cells including their microscopic analysis. By combining the existing automation technology of both platforms, all required procedures can be integrated in the AutoCRAT system, designed to handle iPSC expansion, differentiation to iMSCs and iCHOs, pilot scale expansion, and formulation of iMSCs as well as extracellular vesicles and their purification. Furthermore, the platform is equipped with several in-line and at-line assays to determine product quality, purity, and safety. This paper highlights the need for adaptable and modular automation concepts. It also stresses the importance of ensuring safety of generated therapies by incorporating automated release testing and cleaning solutions in automated systems. The adapted platform concepts presented here will help translate these technologies for clinical production at the necessary scale.

Advanced Therapy Medicinal Products (ATMP) provide promising treatment options particularly for unmet clinical needs, such as progressive and chronic diseases where currently no satisfying treatment exists. Especially from the ATMP subclass of Tissue Engineered Products (TEPs), only a few have yet been translated from an academic setting to clinic and beyond. A reason for low numbers of TEPs in current clinical trials and one main key hurdle for TEPs is the cost and labor-intensive manufacturing process. Manual production steps require experienced personnel, are challenging to standardize and to scale up. Automated manufacturing has the potential to overcome these challenges, toward an increasing cost-effectiveness. One major obstacle for automation is the control and risk prevention of cross contaminations, especially when handling parallel production lines of different patient material. These critical steps necessitate validated effective and efficient cleaning procedures in an automated system. In this perspective, possible technologies, concepts and solutions to existing ATMP manufacturing hurdles are discussed on the example of a late clinical phase II trial TEP. In compliance to Good Manufacturing Practice (GMP) guidelines, we propose a dual arm robot based isolator approach. Our novel concept enables complete process automation for adherent cell culture, and the translation of all manual process steps with standard laboratory equipment. Moreover, we discuss novel solutions for automated cleaning, without the need for human intervention. Consequently, our automation concept offers the unique chance to scale up production while becoming more cost-effective, which will ultimately increase TEP availability to a broader number of patients.

Mesenchymal stem/stromal cells (MSCs) have been identified as a promising therapeutic option for osteoarthritis, graft vs. host disease and cardiovascular diseases, among others. For widespread application of these therapies, robust and scaled manufacturing processes are required that reliably yield high amounts of high quality MSCs. One of the primary challenges in MSC manufacturing is achieving robustness, due to the high donor-to-donor and batch-to-batch variability seen in MSC manufacturing. To achieve more consistent manufacturing, standardization of the manufacturing process and analytical methods to determine cell quality and control process parameters will be needed. Traditionally, MSCs are cultivated in two dimensional (2D) systems, such as flasks or plates. However, these systems are limited in their scalability. To enhance volumetric productivity, upscaling may be achieved using agitated bioreactors where the MSCs are grown on microcarriers or other types of scaffolds. In this article, we have reviewed existing publications on the manufacturing of MSCs in agitated bioreactor systems regarding the process conditions used and the quality parameters measured to define more clearly the most relevant cell quality and process parameters. Key cell quality parameters measured are cell number and viability, immunophenotype and differentiation potential, while key process parameters include the cultivation system (cell source, bioreactor type, media composition), physiochemical properties of the media such as pH and dissolved oxygen (DO), as well as nutrient supply. Defining these parameters more clearly will support the development of robust MSC manufacturing processes at scale using improved process control and facilitate the widespread clinical application of MSC-based cell therapies.

In biopharmaceutical production involving cells, cell-derived products, or tissues, the cleaning of surfaces that come into direct or indirect contact with the product is currently performed mostly by hand as the initial step in decontamination. This manual approach leads to production inefficiencies, reduced reproducibility of decontamination processes, and product losses. In food production, automated processes are preferred for the decontamination of interior product contact surfaces. This article studies the feasibility of adapting the automated cleaning-in-place concepts used in the food industry to biopharmaceutical production. The focus is on spray cleaning processes and validation by cleaning simulation. An existing automated cell production platform is used as a case study for validation. The results indicate that modifying an existing platform to support cleaning-in-place presents significant challenges. However, the article outlines general design guidelines for developing new biopharmaceutical production platforms that can accommodate automated cleaning.