Development of a robotic cluster for automated and scalable cell therapy manufacturing.

BACKGROUND AIMS: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products. METHODS: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells. RESULTS: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility. CONCLUSIONS: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies.

Quality considerations on the pharmaceutical applications of fused deposition modeling 3D printing.

3D printing, and particularly fused deposition modeling (FDM), has rapidly brought the possibility of personalizing drug therapies to the forefront of pharmaceutical research and media attention. Applications for this technology, described in published articles, are expected to grow significantly in 2020. Where are we on this path, and what needs to be done to develop a FDM 2.0 process and make personalized medicines available to patients? Based on literature analysis, this manuscript aims to answer these questions and highlight the critical technical aspects of FDM as an emerging technology for manufacturing safe, high-quality personalized oral drug products. In this collaborative paper, experts from different fields contribute strategies for ensuring the quality of starting materials and discuss the design phase, printer hardware and software, the process, the environment and the resulting products, from the perspectives of both patients and operators.

Lego-Inspired Capsular Devices for the Development of Personalized Dietary Supplements: Proof of Concept With Multimodal Release of Caffeine.

Dietary supplement companies have recently started to focus on the personalization of products and the improvement of the relevant performance. In this respect, a versatile, easy-to-handle capsular delivery platform with customizable content and release kinetics was here proposed and evaluated after filling with caffeine as a model dietary ingredient. In particular, capsular devices comprising 1 to 3 independent inner compartments were attained by Lego-inspired assembly of matching modular units with different wall compositions, manufactured by injection molding and fused deposition modeling 3D printing. Accordingly, one-, two- and three-pulse release profiles of the dietary ingredient were obtained from differently assembled devices following the breakup of the compartments occurring promptly (immediate-release), on pH change (delayed-release) or after tunable lag times (pulsatile-release). The latter release mode would enable the onset of the stimulating effect of caffeine at different times of the day after a single administration when convenient. The performance of each individual compartment only depended on the composition (i.e., promptly soluble, swellable/soluble or enteric soluble polymers) and thickness of its own wall, while it was not affected by the composition and number of joined modular units. Moreover, the delivery platform was extended to include an external gastroresistant shell enclosing previously assembled devices.

Industrial Development of a 3D-Printed Nutraceutical Delivery Platform in the Form of a Multicompartment HPC Capsule.

Following recent advances in nutrigenomics and nutrigenetics, as well as in view of the increasing use of nutraceuticals in combination with drug treatments, considerable attention is being directed to the composition, bioefficacy, and release performance of dietary supplements. Moreover, the interest in the possibility of having such products tailored to meet specific needs is fast growing among costumers. To fulfill these emerging market trends, 3D-printed capsular devices originally intended for conveyance and administration of drugs were proposed for delivery of dietary supplements. Being composed of separate inner compartments, such a device could yield customized combinations of substances, relevant doses, and release kinetics. In particular, the aim of this work was to face early-stage industrial development of the processes involved in fabrication of nutraceutical capsules for oral pulsatile delivery. A pilot plant for extrusion of filaments based on pharmaceutical-grade polymers and intended for 3D printing was set up, and studies aimed at demonstrating feasibility of fused deposition modeling in 3D printing of capsule shells according to Current Good Manufacturing Practices for dietary supplements were undertaken. In this respect, the stability of the starting material after hot processing and of the resulting items was investigated, and compliance of elemental and microbiological contaminants, as well as of by-products, with internal specifications was assessed. Finally, operating charts highlighting critical process variables and parameters that would serve as indices of both intermediate and final product quality were developed.

Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling.

Fused deposition modeling (FDM) is a 3D printing technique based on the deposition of successive layers of thermoplastic materials following their softening/melting. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment. Accordingly, a number of polymers of common use in pharmaceutical formulation were evaluated as starting materials for fabrication via hot melt extrusion of filaments suitable for FDM processes. By using a twin-screw extruder, filaments based on insoluble (ethylcellulose, Eudragit(®) RL), promptly soluble (polyethylene oxide, Kollicoat(®) IR), enteric soluble (Eudragit(®) L, hydroxypropyl methylcellulose acetate succinate) and swellable/erodible (hydrophilic cellulose derivatives, polyvinyl alcohol, Soluplus(®)) polymers were successfully produced, and the possibility of employing them for printing 600µm thick disks was demonstrated. The behavior of disks as barriers when in contact with aqueous fluids was shown consistent with the functional application of the relevant polymeric components. The produced filaments were thus considered potentially suitable for printing capsules and coating layers for immediate or modified release, and, when loaded with active ingredients, any type of dosage forms.