Table 1.

Clinical and manufacturing approaches for cell therapies. The table summarizes the development stage of the cell-therapy technologies with their current manufacturing technologies and key remaining clinical and manufacturing challenges.

cell technology	development stage	remaining clinical challenge(s)	manufacturing technologies	remaining manufacturing challenge(s)
somatic cells	many therapies in phase 2; some reaching later stages	demonstration of compelling efficacy in large randomized controlled studies	manual and automated multi-planar flasks and stack systems; microcarriers within disposable stirred tank systems; hollow fibre growth systems; membrane and contraflow centrifugation systems	scale up and control of large batch sizes. Recovery of cells from microcarriers. Downstream large volume handling, fill finish at scale using enclosed technologies. Suitable potency assays
gene-modified cells (ex vivo)	mainly small clinical trials of gene-modified T cells or HSCs; adoptive T-cell therapies reaching large-scale trials	multi-centre trials; treating larger numbers of patients; accelerated development strategy; maximizing efficacy signal while minimizing toxicity	manual processes often not fully enclosed using static bags, gas-permeable pots plus lateral movement bioreactors for higher cell yields. Positive or negative cell selection process steps often used. High cell purity becoming a possibility with smaller footprint sterile cell sorters	adapting systems to deal with variation in quality of incoming patient material. Lack of product stability pressurising manufacturing and distribution models. Lack of real time final product release assays. Low rates of transduction with non-replicating virus. Enclosed and automated solutions are becoming available for the entire process train
gene modification (in vivo)	mainly small clinical trials but some proceeding along phase-less accelerated development	consolidation of promising early data into significant long-term efficacy and safety	processes follow a traditional vaccine/biopharma model of upstream (USP) growth of producer cell lines and downstream (DSP) harvesting of replication-defective viral vectors. USP currently limited to manual multi-planar systems but immediate scale-up possibilities exist with commercial automated multi-planar solutions and hollow fibre systems	USP and DSP process scale up currently limiting systemic clinical utility of this technology as yields too low. Step changes needed in USP through scale up adherent systems including microcarriers and disposable dynamic bioreactors. DSP limited by current methodologies so new chromatography and filtration approaches needed for clarification, purification and polishing steps
cell plasticity	mainly pre-clinical with first pluripotent cell-derived therapies reaching clinical trial	demonstration of safety and potential for efficacy in the clinic	current processes are extremely manual, seamless with no intermediate step and rely on small scale culture and harvest technology. High risk processes with QC assays resembling product characterization tests	a bi-phasic process of pluripotent scale up prior to differentiation needed. Intermediate holding step to reduce process risk and increase production options. Dynamic culture systems to expand pluripotent cell numbers. Robotic scale-out of current plate-based technology is also being explored. In process controls deterministic of culture outcomes essential
three-dimensional technologies	mainly pre-clinical tissue engineered therapies with some small-scale trial or clinical case studies	demonstration of safety and potential for efficacy in the clinic	a complex manufacturing interplay between (bio)materials, cells and biological coatings. Incorporates de-cell/recell therapies such as trachea, oesophagus and veins through to smart bandages incorporating cells into an applied external matrix	enclosed bioreactors to control cell and material interface. Improved stability and delivery systems. Robust product to ensure as widespread clinical use as possible