CHOOSING THE BEST OPTION
In the early stages of development, laboratory technology such as cell stacks or flasks is perfectly adequate to produce a
sufficient amount of cells for preclinical and clinical studies. But once Phase I and II trials have succeeded and the product
moves down the development pipeline, these methods are impractical, and some form of scale up or scale out is necessary. This
process is further complicated by the fact that GMP standards also require that safety and process reproducibility be considered
When choosing the best bioreactor, a number of questions need to be asked. These questions include looking at whether shear
stress, pH, and dissolved oxygen levels need to be controlled. This is mandatory with fragile cells such as stem cells. Another
important question is related to the scale of batch. When a very large number of cells is required (i.e., hundreds of billions
cells per batch), microbeads in suspension or a high-cell-density bioreactor (i.e., fixed bed) may be the best option. On
a more limited scale, cell stacks can be used if the scale remains extremely small—millions of cells. A multiplate bioreactor
will probably be more appropriate for mid-scale production (i.e., hundreds of millions of cells per batch).
Overall, the scale-up from R&D to industrial production must preserve the integrity and quality of the cells. It is important
to be able to control the physicochemical parameters, minimize change in the cell surface, and monitor cell density. The process
must meet GMP standards within a closed system, be reproducible, and require minimal operator intervention.
For an autologous therapy, the most practical option may well be a 2D multiplate system such as the Xpansion bioreactor which
has a much smaller footprint and operator requirement than laboratory-scale devices. The biggest advantage of this bioreactor
is that the microenvironment in which the cells grow remains close to the environment in the cell stack or flask, and therefore,
the way in which the cells behave is much more likely to remain the same as in small-scale culture. As such, it requires less
process development effort and decreases risk, because of the similarity to laboratory-scale systems. Automation of the system
can be a solution to support scale out, and can enable running several cultures in parallel to supply large volumes for commercialization.
For an allogeneic therapy, where the volume requirements may be much larger, switching over to using microcarriers in a stirred
tank bioreactor could, in the long run, be the best solution. An intensive process-development program would be essential
to ensure that the stem cells that are grown remain substantially the same as those made in the laboratory, and that neither
the changed microenvironment nor the harvesting process affect the final product. Packed-bed technologies would be even more
efficient, but innovative and specific scaffolds must be developed if they are to become a practical solution. A mixed scale-up
and scale-out process using Xpansion might offer a route to push forward clinical development and the early commercialization
scale while more efficient large-scale technologies are being investigated.
When working on a larger scale, microcarriers in a stirred-tank bioreactor and packed-bed bioreactors can enable larger batches
to be made, but may require much more development work to ensure the cells grow with the correct morphology. Multiplate bioreactors
address this challenge by mimicking the laboratory-scale equipment in which the cells are initially developed.
In the long run, industry needs to develop a new solution that simplifies the scale-up process. The perfect technology will
minimize the time and energy required in the development process, while ensuring the production of stem cells with the correct
morphology in reproducible batches. The multiplate design is practical in the earlier stages of development as an enabling
technology for the industrialization of cell therapy process. Future technological development will ultimately be required
to support and sustain the mass commercialization of stem-cell therapies.
Mattieu Egloff is product manager and Jose Castillo is global director of cell culture at ATMI Life Sciences.
1. B. Nafzinger, "Regenerative Medicine to Be a $20 Billion Industry by 2025," April, 2010,
http://www.dotmed.com/news/story/12382?p_begin=0 accessed Oct. 22, 2012.