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... there is a huge manufacturing challenge involved in bringing cell therapies (especially stem cell therapies) from the lab bench into the clinic.
Stem cell researchers are often in the news as governments and the general public debate which experiments should be allowed to proceed. They often say — usually with the support of industry groups and patient charities — that cells could one day provide cures for degenerative brain disorders, such as motor neurone disease and Alzheimer's. Of course, this work should be supported, but it is important not to raise false expectations because there is a huge manufacturing challenge involved in bringing cell therapies (especially stem cell therapies) from the lab bench into the clinic.
Cell therapy is part of a new approach called regenerative medicine, which involves using cells, tissues, and possibly whole organs, to heal and repair the human body. Regenerative medicine may be able to achieve what conventional pharmaceuticals have not — effective, long-term treatments for chronic diseases involving tissue damage. Besides brain disorders, these would include arthritis, diabetes, stroke and heart disease — all of which are increasing as the population ages.
There are two ways of performing cell therapy, each involving different manufacturing issues. Autologous cell therapy uses the patient's own cells; a biopsy is taken, the cells are manipulated and expanded in the lab, and then returned to the patient. In allogeneic cell therapy, donor cells are used as a source of therapy. Conducting autologous cell therapy on a commercial-scale involves 'scaling out' rather than scaling up; it is similar to procedures that already take place in hospital, such as blood transfusion, and may fit as a 'bedside' procedure into the healthcare system. Allogeneic therapy is more akin to conventional (bio)pharmaceuticals in its manufacture. Scale-up is an issue and one that is made more complex by the end-product being a living cell rather than an inert chemical.
So far, cell therapies have been applied to more than 250000 patients using products either on the market or in clinical trials. Companies such as Organogenesis, Genzyme, Advanced BioHealing and Intercytex have shown how to manufacture cells for applications as skin substitutes and in-joint cartilage repairs. This, however, represents only a fraction of the potential market, even for well-established indications such as skin and bone. If the market is to achieve its potential, then automation must start to play a much larger role in cell manufacturing.
"Currently, cell therapy is reliant on the manual 'green fingered' approach," says Professor Chris Mason of the regenerative medicine bioprocessing unit at University College London (UCL). "It has given us a great start, but it won't give us an industry." Automation will give cell therapies better quality and consistency, but the technology needed will be more complex than the robotics used in biopharmaceuticals, and the capital outlay may put investors off. However, some companies are beginning to automate small parts of the manufacturing process, while Advanced Cell Technology and Intercytex have built-in automation from the start.
In manufacturing a small molecule drug, you can at least be sure of the quality of the starting materials. This is not the case in autologous cell therapy. There is no standardized procedure for surgeons to take the biopsy that starts the whole manufacturing process, and there is always the danger of contamination, which means discarding the product. The growth characteristics of cells also vary with the patient's age and state of health — a factor that no precautions can guard against. Therefore, autologous cell therapy has intrinsic unpredictabilities that manufacturers must deal with.
Meanwhile, the maturation of the industry depends upon recruiting and retaining people with the right skills, which is proving difficult. There are specialized bioprocessing courses at UCL and some companies offer in-house training. "GMP experience is always transferable," comments Dr Paul Kemp, founder and chief scientific officer at UK company Intercytex, which is pioneering cell therapies for applications as diverse as venous and diabetic ulcers, and hair and skin regeneration. He thinks people from pharma may find adopting a nurturing, 'horticultural' approach to cells difficult; they are more used to regarding them as sources of contamination to be eliminated. Nursing cells can be both tedious and stressful.
However, Mason argues that increased automation may go some way to addressing this problem. He adds that more needs to be done, for both kinds of cell therapies, on cryopreservation and distribution, if the industry is to reach its potential. At present, products are used 'fresh' and have a limited shelf-life, therefore, creating much wastage.
There is also the issue of regulation. Currently, the EU is working out its new Advanced Medicinal Product Directive and it should come into force sometime over the next year. "The directive will be good for the industry," says Kemp. "We can jump the regulatory hurdles once we know what they are. With more clarity, we will be able to plan our clinical strategy." In the US (presidential vetos of federal funding of human embryonic stem cells [hESCs] aside) the regulation of the cell therapy industry is ahead of the EU position. One of the market leaders, Geron, has been working with FDA on regulation and is poised to begin the world's first ever clinical trial of hESCs later this year.
There are also significant scientific barriers to overcome before cell therapy becomes a clinical reality. Much more needs to be known about how to expand and differentiate stem cells. It is also unclear how far allogeneic cell therapies will be immunogenic; that is, whether patients will need to take immunosuppressant medication for life (as with transplant recipients). Some of these issues are being addressed by initiatives such as bioProcessUK, which is creating a research interface between academia and industry to solve these problems.
"In cell therapy, the product is the process — the health and quality of the cells are mission critical," says Mason. Ultimately, the challenges of cell therapy manufacture can only be resolved by realising the unique nature of the product.