Traditional academic discovery heavily utilizes T-flasks for both adherent and non-adherent cell culture, however adopting a QbD approach in order to minimize future comparability risks suggests that discovery should take place in culture vessels such as disposable bioreactors which match as closely as possible the target scaled up version to be used in final cGMP manufacture. Disposable bioreactors are also feasible for use in a one patient one bioreactor fashion. With the addition of microcarriers bioreactors are commercially available: Pall Life Sciences’ PadReactor system, XRS 20 bioreactor system, Thermo Scientific’s S.U.B. single-use bioreactors, GE Healthcare’s WAVE bioreactor, Millipore’s Mobius system, Sartorius-Stedim Biotech’s BIOSTAT STR bioreactor.
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. Footprint reduction at commercial scale is critical for the success of autologous cell therapy. Contained systems support automated cell expansion and purification instead of requiring dedicated classified space. Under monitored and controlled conditions, in a multiplexed single-use bioreactor integrated facility, production of a final autologous product in multiple doses from a starting cell population donated by a single patient is possible.
Cost of goods (CoGs) analysis is critical to the success of all life science commercialization and can be divided into direct costs, overhead costs, depreciation, and failed batch costs (Table 1). It is particularly important for personalized cell therapies (one patient, one unique batch) which do not have the luxury of economies of scale.
A major material cost for the cell therapy industry is the availability of bovine serum which is routinely used in cell culture. As commercial scale cell production facilities increase in number the world supply of serum will become limiting to cell therapy manufacturing . Therefore developing a manufacturing process independent of serum is a very sensible consideration for nascent cell therapy companies as this will avoid any issues associated with serum shortage in the future.
Another major direct cost is shipping. The majority of cellular therapies are shipped and distributed under at least -20°C conditions. New technologies that allow higher temperature shipping are becoming available. The World Health Organization (WHO) has dictated that the distribution of pharmaceutical products must be conducted in accordance with cGMP, good storage practice (GSP), and good distribution practice (GDP). Companies are obliged to make use of technology such as temperature monitors during shipping and have contingency plans in place for temperature deviations beyond acceptable levels. Shipping and distribution costs can account for more than 25% of the product cost . This should be considered during QbD planning.
In addition to minimizing cost of materials, savings must be delivered through QbD optimization and automation of the manufacturing production facility in order to reduce overhead costs. Due to the dependence on the patient, autologous cell therapy production facilities can become idle which is a major cost. Companies need to integrate a portfolio of more scalable and predictable products such as allogeneic cell therapies or cellular cancer vaccines that are compatible with the autologous cell manufacturing space available. According to QbD manufacturing capacity should be considered from the outset and the possibility of operating a mixed production facility through the use of contained systems such as disposable bioreactors considered in order to maximize output. The construction of modular facilities can aid the expansion or contraction of certain manufacturing processes as the demand changes. This requires sophisticated logistics to track and predict capacity requirements in the facility. If diversification of the autologous product portfolio is not possible it may be worth considering a contract manufacturing organisation (CMO) that already utilizes a modular system. This could represent a major cost saving compared with a wholly owned but frequently idle single product manufacturing facility.
The post above is an excerpt from our recent whitepaper that outlines the progression towards commercial scale and efficiency in cell therapy bioprocessing. Access the complete whitepaper here.