Abstract
Allogeneic cell therapies provide a new tool to regrow, repair, or replace damaged tissues for large populations of patients by using cells derived from unrelated donor tissue. Lower back pain is the most prevalent cause of disability and is frequently characterized by the breakdown of intervertebral disc tissue, making it a prime candidate for regenerative cell therapy. Our team is developing an allogeneic progenitor cell therapy to treat painful disc degeneration called IDCT (rebonuputemcel). Unfortunately, regenerative cell therapies have seen limited commercial success due largely to unclear regulatory expectations, high levels of variation in product quality from unrelated donor tissue, and difficulties culturing therapeutic cells at a commercially viable scale. Quality by Design is an approach employed by the biopharmaceutical field to build quality into a product by first defining a quality target and then building biomanufacturing methods around the ability to match that quality target. Herein we discuss the primary challenges in the bioprocess development of IDCT using a Quality by Design approach. The first chapter introduces the challenges associated with identification and management of variability for cell therapies in a commercial context. The second explores the challenges, successes, and failures we had with transitioning our cell sphere process to a large-scale bioprocess modality. The third chapter shows our use of QbD and Design of Experiments to build a multi-dimensional process design space where the impact of media, donor, and process variability on our final quality target is quantified. In the final chapter, we significantly improve upon a linear regression-based process model using artificial neural networks. By exploring regulatory pathways, scale-up of cell spheres, media, process, and donor variability, as well as modeling and optimization approaches, we illustrate a practical approach to bioprocess development and characterization for a cell therapy product.