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.

Keywords: ATMP; GMP; autologous; automation; automation & robotics; cartilage regeneration; manufacturing; tissue engineering.

Figure 1

BIO-CHIP manual manufacturing process and surgical procedure. The whole process is graphically depicted in (A). An autologous cartilage biopsy is taken via outpatient surgery in a clinical site from the patients' nasal septum according to SOP. The biopsy is shipped to the manufacturing site, where the tissue is digested and the cartilage cells are isolated and expanded in-vitro. In the next step, cells are manually seeded on a collagen membrane in a certified cleanroom facility. Various parameters are monitored continuously throughout tissue cultivation. After 2 weeks of static tissue culture, final quality testing is conducted. The amount of extracellular matrix proteins is evaluated using histological grading by modified Bern score, also cell viability and transplant stability are assessed. When all defined release criteria are met, the N-TEC is packed and sent back to the clinic to be implanted into defect site in a surgical procedure (B). The patch is secured by surrounding absorbable sutures during the surgical procedure. The initial focal cartilage defect in the knee is depicted in (C), asterisks indicate the defect site where the N-TEC is inserted.

Figure 2

Automation scheme and visual representation. In this figure, a 2D (A) and 3D [(B): frontal view, (C): sliced view] representation of this concept is shown. The platform is equipped with devices for each handling step: 01 Ventilation system, 02 Freezer (−20°C), 03 Fridge (4°C), 04 Disposables storage, 05 Packaging material, 06 Incubator (37°C), 07 Storage for plates and membranes, 08 Gate, 09 Barcode reader, 10 Washing station, 11 Sampling station, 12 Shaker, 13 Air-lock, 14 Cell counting device, 15 Storage for Cell culture tubes (temperature controlled), 16 Six axis dual arm robot, 17 Centrifuge, 18 Plate handling positions, 19 Decapper (centrifuge flask), 20 Decapper (Cell culture tubes), 21 Tissue grinder, 22 Pipettes, 23 Liquid waste, 24 Sealing machine, 25 Solid waste, 26 Microscope. The central six axis dual arm robot (16) can reach the circumference shown in (A). Necessary equipment, disposables and liquids are safely channeled in through an air lock linked glove box (orange), without the need of personnel entering the isolator directly from an unclassified maintenance back side. Pre-packed, sanitized disposables, materials or biologicals can be unpacked easily and set in place for robot-driven procession. Devices for cell culture (green) and quality control (blue) are included in the design. The platform is scaled to the parallel production of five N-TECs at a time, with the possibility of increasing manufacturing capacity further e.g., by implementation of larger storage devices.