Currently there are 672 cell and gene therapy companies worldwide and 20 products approved by the food and drug administration (FDA). Dendreon’s Provenge autologous cell therapy although approved by the FDA ultimately failed commercially due to a manufacturing and distribution model that was not efficient. Cost of Goods (CoGs), manufacturing process and logistics are critical to the success of cell therapy commercialisation and these need to be considered from the inception of a cell therapy company in addition to the clinical science. Three key enablers for success are manufacturing automation/ single use technologies, a diverse pipeline in modularised facilities, and sophisticated data acquisition/ logistics.
Quality by Design (QbD) is a scientific, risk-assessment framework for process design based on relating product and process attributes to product quality. A risk assessment is conducted to prioritize the study of the most influential critical process parameters and material attributes. In addition to reducing risk QbD also increases efficiency as critical experiments are front loaded (Figure 1). This is particularly important in identifying required changes to the manufacturing protocol early reducing comparability risks.
Cell therapy is facilitated by disposable bioreactors. Single use technologies have many advantages including consistency in the results from batch to batch, simplified handling for operators, time savings, savings of energy and water as well as dramatically decreased cross-contamination risks. Thus, disposable systems are of great interest notably since they reduce the initial capital investments, the process footprint as well as costs linked to the facility design itself.
CoGs analysis is critical to the success of cell therapy commercialisation and can be divided into direct costs, overhead costs, depreciation, and failed batch costs (Table 1). It is particularly important for personalised cell therapies (one patient, one unique batch) which do not have the luxury of economies of scale. Serum source and shipping are major direct cost considerations.
Process Analytical Technology (PAT) which allow real-time monitoring of bioreactor conditions aid both process development and quality assurance during final manufacture. Real-time online monitoring of glucose, dissolved oxygen, pH, and temperature of the bioreactor cell growth medium has been available for some time. In addition real-time automated monitoring of cell viability is now possible measuring the proportion of viable, early apoptotic, late apoptotic and necrotic cell populations in bioreactors using a flow cytometry based method.
Small-scale (2–15 ml) bioreactors are ideal for process development however certain factors need to be taken into consideration for scale up. Once these considerations have been taken into account bioreactors are available at various scales, under 30ml, 30ml – 2L, 2L – 100L, and greater than 100L. Scale-up and industrialisation of autologous as well as allogeneic cell therapy is greatly aided by modular manufacturing facilities.
A QbD approach to manufacturing bioprocess development can greatly aid commercialisation. Cost efficiencies can be found in single use bioreactors integrated into multi-product pipeline automated modular facilities. Scale-up can be facilitated by QbD planning considering serum sources and shipping logistics. Use of innovative PAT in bioreactors with a range of volumes can facilitate process development and monitoring batch to batch comparability. Adopting the approaches outlined here can mitigate risk of commercial failure.