Process analytical technologies in cell therapy manufacturing: State-of-the-art and future directions

Abstract

Cell therapies have the potential to effectively treat and even cure complex, currently untreatable diseases with unprecedented success. The cell therapy industry has been growing rapidly since the Food and Drug Administration approval of the first product in 2017. Despite tremendous promise, there are significant and unique challenges that must be overcome to make cell therapy manufacturing reproducible, scalable, high-quality, and cost-effective. Discovery and implementation of critical quality attributes (CQAs) and critical process parameters (CPPs) to the complex cell therapy manufacturing processes is one such grand challenge for the field. The role of process analytical technologies (PATs) in CQA/CPP discovery and eventual in-process, or at-process monitoring to maintain consistent process and product quality, is indispensable. Here we discuss the major challenges and the strategic framework for optimizing process development and related PATs for various cell therapies, with a focus on upstream processes. We introduce relevant approaches, such as quality-by-design (QbD), and the implementation of PATs to enable QbD in current biomanufacturing processes. We examine state-of-the-art PAT implementation on standard physicochemical parameters in biopharmaceutical operations and consider potential cell therapy-related parameters that may be instrumental in overcoming the challenges of the current cell therapy manufacturing landscape. Current innovations applied to the field, such as high-throughput and high-dimensional analyses, machine learning, and novel sensor technologies, are also discussed. We conclude that advances in PATs are necessary to identify CQAs and CPPs, overcome limitations in current operating processes, reduce overall product cost, and significantly accelerate the translation of laboratory discoveries into commercialized cell therapy products.