New Strategies Key to the Clinical Manufacturing of Stem Cells for Therapeutic Use

In May, Osiris’, Prochymal, made history by becoming the first approved stem Cell Therapy. The approval was first received in Canada, then New Zealand and is currently under review by the Food and Drug Administration (FDA) in the United States. Prochymal is a treatment for acute graft versus host disease. In addition, there are weekly reports of new stem cell therapies in development and many are showing promising results in clinical studies. With these advancements, it is logical to wonder how these stem cell therapies will progress from small scale manufacturing to large scale manufacturing for therapeutic use.

Over the last few months we have featured three blog series one on CHO production titled “Strategies for Improving Antibody Production in CHO cells,” one on hybridoma production titled “Strategies for Improving Antibody Production in Hybridoma Cells,” and one on vaccine production, “Strategies for Improving Viral Yield in Vaccine Manufacturing.” With the recent successes in stem cell therapies, it made sense that a stem cell series should be published. As research, I conducted some informal polling and asked those in the industry which areas they felt were most important to successful large-scale clinical manufacturing and their responses form the basis of this blog series. This overview will be followed by subsequent blogs where we will examine the following techniques in more detail.

At the beginning of the process, the optimization of cell culture media is one area where improvements need to be made. Stem cell culture, for a large part, still uses serum or animal derived products in manufacturing. This is problematic due to the fact that animal products can be difficult to source, have high batch-to-batch variation and are also a potential source of infectious agents.

Recently the FDA published a guidance that would require a warning label be added to all products containing plasma-derived albumin in their manufacture. The warning would state that due to the plasma-derived source of the albumin, the albumin may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease and the Creutzfeldt-Jakob disease agent. Please see our recent blog “FDA Issues Guidance for Warning Labels on All Drugs Produced Using Blood Products Including Plasma-Derived Albumin,” for more information.

If this recent move by the FDA is any indication of the direction they are moving, then it is clear that a defined, animal-free stem cell culture media should be the goal. However, one challenge is that many stem cell lines do not grow well without the addition of serum or animal derived products such as plasma-derived albumin and transferrin. The good news is that now there are many companies working on animal-free alternatives. These products are defined, animal-free and allow for the reduction or removal of serum and animal products from culture. Today companies including Sigma, Fisher Scientific, InVitria, Sheffield Bioscience, and Mediatech offer cell culture supplements that can be used as alternatives to animal components. These products include recombinant albumin and recombinant transferrin both of which have been successfully used in stem cell applications to replace their animal-derived counterparts. Other companies including TNCBio, Lonza, and Stem Cell Technologies manufacture animal-component free media.

Another area that needs to be addressed is scalability. Several of these potential therapeutic applications will require billions to trillions of stem cells per lot and manufacturing will need to expand to meet these needs. New technologies have been adapted to successful culture large numbers of stem cells at once. Of these, four technologies have the most potential for meeting long term manufacturing requirements. There are three that are applicable to adherent stem cells, planar flask, packed bed bioreactors and microcarriers in large-scale bioreactors. The fourth option is the reprograming of adherent cells to suspension culture and the use of large-scale stirred bioreactors. This technology was covered in a previous blog “Culture and Expansion of Stem Cells in Stirred Suspension Bioreactors Could Provide Key in Large Scale Manufacturing.” To the extent that these systems could be closed, single-use systems would be ideal. Companies manufacturing these systems include Thermo Fisher Nunc, Corning, Millipore, BD, Beckman-Coulter, New Brunswick, GE Wave Biotech, ATMI, and Thermo Fisher Hyclone.

Finally, downstream processing will need to be improved to keep up with large-scale manufacturing and in particular, large cell volumes. New volume reduction and cell washing techniques will need to be adapted to handle large volumes of cells and the specific method will largely depend on manufacturing lot sizes. That said, some of the key processes used in biopharmaceutical manufacturing could be adapted for use in stem cells. The same is true for the finish/fill stage. While biopharmaceutical filling equipment can be adapted for this as well, the act of filling will need to be performed very quickly and the rate of freezing will need to be controlled to ensure successful cryopreservation.

These are just a few examples of work being done to improve stem cell culture production and there are others. Has anyone used any of these methods? Does anyone have any others to recommend?

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