Current cell therapies' workflows are highly manual and generally consist of islands-of-automation. As the cell therapy industry continues to scale, novel manufacturing technologies are needed to automate, integrate, and streamline these complex workflows. This talk will discuss current technology limitations, opportunities for improvement, and product lifecycle stage-specific strategies to manage these changes in manufacturing.

Autologous cell therapies for solid tumors are on the horizon, however the high cost and complexity of manufacturing these therapies remain a challenge. We have developed a fully closed, autologous bioprocess for generating MAGE-B2-specific TCR-expressing T cells, with enriched memory T cell phenotype and enhanced metabolic fitness. This bioprocess supports scale-out feasibility by enabling the processing of multiple patients’ batches in parallel within a Grade C cleanroom.

Due to the need for robust manufacturing large numbers of specific T cells, conventional GMP-compliant cell selection methods such as centrifugation, directed cell culture and magnetic field-based technologies, are no longer suitable. Purification of specific T cells by multiparameter cell sorting is a well-established procedure in research but the technique is difficult to scale up and generally lacks robustness and safety. We present requirements and status quo of this technique, including performance reports of a number of recently developed devices that are suitable for use in clinical trials.

This presentation will summarize CGT-related FDA guidance released over the last year: 

• Potency assurance: Multifaceted strategies to reduce risks to product potency.
• CAR T cell products: Autologous and allogeneic, for hematologic malignancies and solid tumors. CMC, nonclinical, clinical aspects.
• Gene-edited products: CMC, nonclinical, and clinical considerations at IND-stage.
• Safety testing of ex vivo expanded allogeneic cells: IND- or BLA-stage. Covers expanded primary cells, MCB and WCB testing, and cell lines.
• Human- and animal-derived materials in manufacturing CGTs and tissue-engineered products.

The quality target product profile (QTPP) guides cell therapy development for optimal safety and efficacy. This presentation explores the early implementation of a QTPP, considering product understanding,  manufacturing  experience, and overall control strategy. The presentation will further elucidate how a dynamic QTPP can inform strategic decision-making throughout the development, ultimately mitigating potential risks.

Human pluripotent stem cells (PSCs) offer an unlimited cell source for cell therapies. Major challenges are (1) complexity of bioprocessing, and (2) outdated regulatory guidelines. HebeCell’s proprietary protoNK platform is a first-in-class technology enabling large-scale PSC-derived NK cell production. To translate protoNK platform into clinic, we have (1) successfully established internal manufacturing capability, and (2) identified disease indication. The unique process to manufacture protoNK also eliminates PSC contamination.

Currently available technologies for expanding NK and CAR-NK cells using feeder cells (e.g., K562 cells) and cytokines (e.g., IL-2 ) are invaluable. However, these NK and CAR-NK expansion technologies show several limitations. Previous studies show that a 721.221-mIL21 as a feeder cell can rapidly expand NK and CAR-NK. Based on this technology, we developed a novel, non-feeder cell system to expand NK and CAR-NK cells in vitro.

The rapidly expanding market for regenerative medicines and cell therapies highlights the need to advance the understanding of cellular metabolisms, improve the prediction of cultivation production processes, and support large-scale manufacturing of human induced pluripotent stem cells (iPSCs). A novel Biological System-of-Systems (Bio-SoS) model and risk-based PAT framework is proposed to model cell-to-cell interactions, spatial and metabolic heterogeneity, and cell response to micro-environmental variation.

To address manufacturing challenges of cell therapies regarding product yield, quality, and reproducibility, we designed a digital twin-enabled closed-loop manufacturing platform with automation and feedback controls. This platform integrates process analytical technologies to enable deeper process understanding and provide real-time control of process variables. The digital twin-enabled bioreactor platform was shown to reduce costs, labor, time, and, more importantly, perturbations, and could improve yield while maintaining the quality of the products.

Autologous therapies for HSPCs require manufacturing processes that are high-throughput, scalable, and high-yielding. The Cue is a fully closed and automated platform device that has enabled high accuracy and temperature-controlled cell washing, concentration, formulation and filling for small volumes. Here we show the successful application of the Cue for the preparation of CD34+ cell selection, harvest, final formulation, and filling drug product for HSPC manufacturing at Beam Therapeutics.