I had the pleasure of meeting Dr. Eytan Abraham over lunch on the first day of the Till & McCulloch Meetings, held last month in Ottawa (October 27-29). After some discussion about cell therapy manufacturing, I learned that he is the new Head of Research and Technology at Lonza, based out of Walkersville, Maryland. Eytan spent several years with Pluristem in Haifa, Israel, where he was Manager of the 3D R&D team, focused on development and optimization of Pluristem’s 3D bioreactor platform and, subsequently, a Product Manager focused on the development of novel cell therapies in the areas of degenerative, ischemic, and immune disease.
Dolores Baksh’s presentation, a birds-eye view on the industrialization of the cell therapy industry, set the stage for Eytan’s lunchtime workshop, the following day, which focused discussion on the challenges associated with commercializing cell therapies, specifically those around transitioning cell cultures into bioreactors.
Both Dolores and Eytan stressed the need to make this transition as early as possible in clinical development. Without a path to scaling a cell therapy, there is no way of making it commercially viable. Parallel processing of planar cell culture systems, like 10- or 60-layer cell factories, paired with extensive automation, has allowed for the routine production of 10s of billions of cells. This, however, is not enough to support future needs, which is why bioreactors and packed-bed systems will play a critical role in the future of cell manufacturing.
In order for the cell therapy industry to produce doses for hundreds of thousands of patients, its infrastructure must be able to support batch sizes of approximately 100 billion to one trillion cells. To put this into perspective, even at the low end of the therapeutic dose range of 100 million to 1 billion cells, this is the equivalent of ~1700 10-layer cell factories. These single-use planar culture systems, composed of plastic, have commonly been used for scale-up for research activities, and as far as mid- to late-stage clinical development in the case of some allogeneic therapies.
Dr. Abraham provided insight on where we currently stand with cell manufacturing technology in terms of available manufacturing platforms and doses that can be achieved with each. This data is detailed in a whitepaper he co-authored in 2012.
Doses per batch will obviously change with the cells per dose, but these figures give a general sense. A single 10-layer cell factory can produce around 40 doses of cells for humans, at a dose of 250 million cells. Cell factories can have as many as 120 layers and produce anywhere from 500 – 3000 doses. Bioreactors, which currently top-out around 1000L – 2000L, can produce 20,000 doses or more. Increasing scale greatly improves process efficiency and reduces cost. Bioreactors have 80x the efficiency of 2D culture systems and can produce a million cells at half the cost.
There are many other advantages of suspension systems beyond efficiency and cost, including more control over the culture environment, optimized feeding of cells, reduced time between harvest and freeze, less batch-to-batch variation, and smaller overall footprint. However, the cell therapy industry must be vigilant in selecting the most appropriate conditions in which to scale-up cellular products.
Putting a spin on a familiar saying, “the product is the process.” There have been instances in the past when cell therapy products have changed over the course of scale-up, resulting in cell populations with different identities. 3D environments add layers of complexity to the cell culture process. Vessel design and volume, choice of microcarrier (if necessary), media choice, growth factors, and feed strategy (batch vs. perfusion) are all considerations that must be tailored to specific cell types.
So, how can researchers show that a cell-based technology is scalable? The spinner flask is a good start. While it is not a bioreactor in the true sense, it gets cells into suspension and will help inform commercial viability. Dr. Abraham pointed to a paper recently published in Cell by Doug Melton and his lab at the Harvard Stem Cell Institute that discusses the generation of functional beta cells from human pluripotent stem cells (hPSCs). As opposed to seeding hPSCs on to a planar surface to carry out the differentiation protocol, Melton’s protocol calls for seeding into spinner flasks followed by the addition of a series of growth factors over the course of 35 days.
Dr. Abraham’s advice on the successful commercialization of cell therapies is as follows: understand your indication, required dose, and target cost of production. The latter will delineate whether a cell therapy can be produced cheaply enough to secure reimbursement. Identify a suitable suspension platform for scale-up early in development and transfer over to this system before Phase 2. Finally, know the mechanism of action of your cells such that their identity and potency can be monitored throughout the scale-up process for a quality end product.