Cell and Tissue Therapies
Cell and tissue therapies also represent an increasingly significant, although challenging, opportunity for the bioprocessing industry. “Manufacturing and distribution are key to this area,” said Mark Bamforth, senior vp, corporate operations and pharmaceuticals, at Genzyme (www.genzyme.com).
Genzyme has a number of autologous cell therapies, including Carticel, a knee cartilage product for damaged or ruptured knees, and a more advanced product called MACI (matrix-induced autologous chondrocyte implantation), involving cartilage cells on a collagen scaffold. Epicel, Genzyme’s skin replacement, is well-known, but the company also has a cardiac cell-therapy and a renal cell-therapy in development.
The manufacturing cycle for such therapies involves processing a patient biopsy, culture, freezing, and vial storage and shipping. “The normal rules of scale-up don’t apply because one batch serves one patient,” said Bamforth. “Quality is crucial and must be taken into account at the earliest possible stage. Quality cannot be inspected in the usual way in cell therapy—it must be built into all aspects of production.”
There are commercial challenges in cell therapy. Manufacture is costly, there are long clinical development times, and there is a need for training in the clinic. In terms of patient volume, cell therapy is still suboptimal—that is, it only reaches a fraction of the patients who could benefit.
Regulation is another issue, and there is a lack of a clear framework at present, said Bamforth. “Lack of regulation can kill such products.”
The U.K. has a 10-year plan to build a cell therapy industry, as outlined in the recent Stem Cell Initiative. To this end, bioProcessUK coordinated a Department of Trade and Industry Global Watch mission to California. This had U.K. experts visiting over one dozen organizations, including the California Institute of Regenerative Medicine, Geron, Advanced Cell Technology, and Advanced BioHealing. Mission leader Chris Mason, Ph.D., of University College London, explained, “We wanted to look at the state of the cell- and tissue-therapy industry in the U.S., seeking out the technologies that minimize cost of goods and increase effectiveness of these products.”
Mike Leek, Ph.D., vp of operations at Intercytex (www.intercytex.net), said, “Cell therapy presents a number of unique regulatory and quality challenges. There is no rule book.”
Geron (www.geron.com), for instance, has developed a good relationship with regulators during preclinical work on telomerase-modified dendritic cells and has been working to remove animal components from production.
Advanced BioHealing (www.advancedbiohealing.com) is about to relaunch Dermagraft®, a wound-healing product it acquired from Smith and Nephew (www.smith-nephew.com) but won’t be shipping to the E.U. because of concern over patchy regulation. This situation may improve as the E.U. proceeds with its new guidelines on advanced therapies.
Many companies have not yet had to face up to the challenges of GMP because their cell/tissue therapy products were at an early stage.
Angela Scott, head of cell culture operations at Angel Biotechnology (www.angelbio.com), reported on cryopreservation, shipping, and distribution issues. “These should not be considered as separate steps to be added on at the end,” said Scott. Some companies were looking for alternatives to DMSO as a cryopreservation agent for their cells. Various systems were being developed for shipping, which, said Scott, should be regarded as mobile storage. Airport x-ray screening can be damaging for cell/tissue therapy products in transit.
Automation has much to offer the regenerative medicine industry because quality can be operator dependent. Moreover, manufacturing is especially labor-intensive and needs to be done under aseptic conditions. Rosemary Drake, Ph.D., director of business development at The Automation Partnership (TAP; www.automationpartnership.com), said that all the California companies realized the need for automation as a way of decreasing costs, increasing productivity and process consistency, and decreasing errors.
However, few had yet reached a stage of development where automation was a must, and VCs are notoriously reluctant to bear this kind of capital cost. Cytori (www.cytori.com) was using its Celution™ cell-preparation equipment, which separates, isolates, and concentrates cells. Advanced BioHealing and Advanced Cell Technology(www.advancedcell.com) were both using TAP’s Cellmate ™ robot.
Bo Kara, head of expression and cell sciences at Avecia, reported that companies were using fairly standard systems to go from cell bank or tissue sample through manufacturing to product. “In the U.S., they are focused on reimbursement; they will work backwards from this to decide whether it is worth their while to manufacture the product.” Cost of goods is, therefore, a big issue—one that will not be solved by automation alone.
As far as raw materials are concerned, autologous cell-therapies are based on patient tissue samples, which are manipulated and expanded into product to be re-applied to the same patient. Also, there can be growth differences between cells from different individuals, which makes manufacturing unpredictable.
The Cytori adipose cell product being developed as a cardiac therapy involves minimal manipulation and uses a tissue-processing machine provided free to the clinic. This, said Kara, is a potentially important route to return on investment.
Nick Medcalf, bioprocessing manager for Smith and Nephew’s research center, discussed validation issues. Removal of murine feeder-cells, adoption of serum-free media, and the replacement of natural supplements with recombinant versions are all seen as desirable. There is also a need for a better understanding of the impact of environmental variability on cell phenotype.