From Single Batch to Mass Production–Automated Platform Design Concept for a Phase II Clinical Trial Tissue Engineered Cartilage Product

Abstract

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.

Scalable Biofabrication: A Perspective on the Current State and Future Potentials of Process Automation in 3D-Bioprinting Applications

“…Combined with AI applications, this allows real-time data to be analyzed, predictions to be made, and even parameter adjustments to be made automatically. This not only leads to higher process accuracy and productivity, but in the future can become the foundation for standardization and therefore also the driving force on the path to certification to meet regulatory guidelines for medical therapies or food products ( Li and Faulkner, 2017 ; Haeusner et al, 2021 ; Schmidt et al, 2021 ). Current studies predict, for instance, that clean meat could become part of the everyday diet in a few years ( Chriki and Hocquette, 2020 ; Lee et al, 2020 ).…”

Advances in hPSC expansion towards therapeutic entities: A review

“…As of 2021, only a few preparations of this subclass have been translated from academia to the clinic and beyond. 54 Automating manual processes during translation to GMP manufacturing can significantly enhance production scale‐up, and cut production times while lowering costs. In one example, manually processed autologous nasal septum‐derived cartilage cells cultured on a 3D carrier matrix for treatment of focal cartilage defects could theoretically be significantly improved by processing with an automated robotic system: This would potentially eliminate human interaction and decrease the risk of contamination, implement standardization and batch homogeneity, apply process controls and real‐time monitoring, and allow multiple TEPs to be manufactured in parallel.…”

“…In one example, manually processed autologous nasal septum‐derived cartilage cells cultured on a 3D carrier matrix for treatment of focal cartilage defects could theoretically be significantly improved by processing with an automated robotic system: This would potentially eliminate human interaction and decrease the risk of contamination, implement standardization and batch homogeneity, apply process controls and real‐time monitoring, and allow multiple TEPs to be manufactured in parallel. 54 …”

“…Their manufacture is both costly and labor intensive. As of 2021, only a few preparations of this subclass have been translated from academia to the clinic and beyond 54 . Automating manual processes during translation to GMP manufacturing can significantly enhance production scale‐up, and cut production times while lowering costs.…”

Retrospective Analysis of Autologous Chondrocyte-Based Cytotherapy Production for Clinical Use: GMP Process-Based Manufacturing Optimization in a Swiss University Hospital

“…Due to burdening temporal and logistical constraints, several initiatives for point-of-care manufacturing of cell-based therapeutic products have emerged, which imply small-batch processing and multi-professional specific expertise [17]. Alternatively, several cost rationalization drivers have led to the emerging technological transition toward mobile infrastructures and automated bioreactor systems, for the insurance of both flexibility and efficiency of the GMP-compliant cell production [18][19][20][21]. All of these historical and current elements, taken together, have shown that modern cell-based therapeutic technologies require more proportionate ratios for risk and that there is a tangible need for pioneering regulatory developments, which should always be guided by the consolidated scientific and clinical experience accumulated to date [8,10].…”