Cell Therapy Manufacturing: Challenges Remain

If cell therapies are to realize their full potential, manufacturing procedures need to be in place to ensure their safety, potency and consistency at an economically sustainable cost. We aren't there yet, according to a panel at the Alliance for Regenerative Medicine's European Investor Day in London.

Cell therapy continues to attract great interest from both the research community and health care companies, not to mention biotech investors. Although the main focus is cancer, cell therapy products are showing promise in the treatment of diseases as varied as heart failure, osteoarthritis, diabetes mellitus, graft-versus-host disease and Alzheimer’s disease.

According to Informa's Pharmaprojects, more than 300 companies worldwide are developing cell therapy products, and between them they are responsible for more than 500 individual R&D projects. Around 30 of these are in advanced clinical trials. A recent report from market research firm Scalar predicts that the global stem cell therapy market will grow by more than 30% a year for the next several years, rising from a value of around $12 billion this year to just over $60 billion by 2022.

But companies that hope to commercialize cell therapy products face a challenge to develop dependable manufacturing processes that ensure the effectiveness, safety and consistency of cell therapy products at an economically sustainable cost. Meeting current GMP requirements, which were not developed with such products in mind, is especially difficult. Developing new regulatory requirements could be even more difficult, given the scope of potential cell therapy products. For example, autologous cell products would be manufactured using relatively short batch processes before being re-administered to patients, while allogenic cells would probably be subject to much lengthier processes that could however be scaled up to supply multiple patients and thereby achieve economies of scale. A further problem with products manufactured for individual patients is that they must be re-administered within a relatively short time frame, which might not give enough time for sterility and other QC procedures to be carried out.

In short, if cell therapies are to realize their full potential, procedures need to be in place to ensure their safety, potency and consistency. This will be an expensive process, and companies need to ensure that adequate funding is available to support the entire process. Such was the consensus among delegates at the Alliance for Regenerative Medicine’s (ARM’s) fourth annual European Investor Day in London in early November.

According to Thomas Fellner, PhD, head of commercial development, cell therapy at leading custom development and manufacturing company Lonza Group Ltd., the biggest challenge currently facing contract manufacturers of cell therapy products is the large number of research companies with products in Phase III trials that do not have sufficient understanding of how an experimental therapy is translated into a commercially viable product. If they all needed to outsource manufacture of their products at the same time, for example, the CMO (contract manufacturing organization) sector might not be able to cope.

Fellner’s concern was shared by Ryan Guest, PhD, co-founder and director of cell production at Cellular Therapeutics Ltd., an immuno-oncology company specializing in the use of autologous tumor infiltrating lymphocytes to treat a range of cancers. To date the main focus in cell therapy has been getting trials up and running, Guest said, but companies should now be thinking about how to go about scaling up manufacture in anticipation of their products receiving regulatory and reimbursement approval.

Challenge Underestimated

There is a perception in some quarters that the difference between treating 10 or 15 patients in a clinical trial and treating hundreds or perhaps thousands of patients once a product has been marketed is merely a question of scale, which it definitely is not, according to Phil Vanek, general manager, cell therapy growth strategy at General Electric Co.’s GE Healthcare. Currently, insufficient thought is given to manufacturing issues when a product is still in development, he maintained, reflecting what other speakers had said, and nothing short of a shift in mind-set is needed. There is, for example, relatively little awareness of the demands of GMP or other regulatory issues such as how to manage quality control and how to monitor potency of a product. In the latter respect, Vanek said, some sort of international standardization may be needed.

Roundtable chairman Alain Vertès, PhD, director of the European Section at ARM, put the problem in a slightly different way. At present, he said, it is relatively straightforward for a cell therapy product to be made for a named patient by an individual doctor in a single hospital. But how to scale up this process is frequently not at all clear. Too often, Vertès argued, new technology is shoehorned into old procedures, a view shared by GE’s Vanek when he said that most manufacturing processes in use today have been around for at least 15 years and are based on procedures used in other sectors, such as blood product manufacturing.

There was a consensus among the panelists that manufacturing cell therapy products is quite different from traditional pharmaceutical manufacturing. Yet the “drug” mind-set persists, said Vanek, arguing that different types of product demand their own approach to manufacturing.

And it is not just manufacturers that need to rethink their approach: hospitals too need to reassess their procedures the better to deal with cell therapy products.

Communication Is Key

One cell therapy contract manufacturer and process development company that has considerable experience in this area is Roslin Cell Therapies, based in Edinburgh. The company’s CEO, Janet Downie, advised that based on her experience, the secret to successful scaling up of a cell technology from the lab of a research company to a CMO is effective communication, including comprehensive documentation. “The biggest cost is clean room space, and the longer the manufacturing process, the longer the product remains in the clean room and hence the greater the cost,” she warned. Downie spoke of the benefits of using the UK as a manufacturing base, and said that a great deal of effort is currently being expended to make the UK an attractive location for manufacturing. (For a look at one of those efforts, see sidebar, "CGT Catapult Builds Cell/Gene Manufacturing Facility.")

It was, perhaps, an illustration of the newness of cell therapy manufacturing that the four panelists failed to agree on what is the most significant issue the industry currently faces. CTL’s Guest thought it was planning, whereas Lonza’s Fellner opted for strategy and Roslin’s Downie for communication. However, GE’s Vanek was probably nearer the truth when he said “ecosystem,” by which he meant the entire process of scale-up and manufacture. Whoever was right (and they were probably all right to a degree), what is clear is that cell therapy is an exciting new treatment modality that is at the same stage that monoclonal antibodies were 30 years ago. Just as manufacturers then had to overcome a number of hurdles before monoclonal antibodies became an accepted part of mainstream medicine, so too will cell therapy companies have to address a number of challenges before they can ultimately be successful.