January 15, 2013 (Vol. 33, No. 2)

Scientists working in stem cell research and on cellular therapies are in real need of new biotools and reagents to more effectively move these fields forward.

That was one of the key messages delivered last month at the Genetic Policy Institute’s “World Stem Cell Summit” in West Palm Beach, FL.

Recombinant proteins have been around the halls of research labs for a long time but in their current form they won’t stand the muster in a regulated environment. The current requirement is for improved efficiency of production and more chemically and biologically defined reagents with a better understanding of their mode of action.

It is critical that there be consistency across rounds of manufacture such that everything used in a clinical trial is well-defined and documented. This is a significant change from “reagent” to “regulated reagent.”

Unlike the market for small molecule therapeutics, stem cell and other biological therapies carry stringent temperature requirements. These products must be maintained at specific temperatures, from the manufacturer to patient administration, to preserve their therapeutic integrity.

Fisher BioServices, part of Thermo Fisher Scientific, saw an opportunity to provide regulatory-compliant cold chain logistics, storage, and distribution of cell-based drugs.

“As a first step, we work with our clients to understand the specific temperature and other requirements for their products and clinical trials” said Bruce Simpson, director of commercial operations.

“We also offer customized solutions for ancillary supplies, specimen collection kits, cold-chain transport, lab processing, biobanking and repository services that ensure our customers’ success and their peace of mind. We are driven in our work by the knowledge that there is always a patient waiting.”

Fisher BioServices provides regulatory-compliant cold chain logistics, storage, and distribution of cell-based drugs.

Unique Challenges

The temperature requirements associated with biological therapies create unique challenges in the storage, handling, and transport of these products. The solutions offered by Fisher BioServices vary, and may involve just-in-time delivery, stocking programs at clinical sites, or a hybrid approach to enable timely, temperature-compliant delivery of a therapeutic dose to the patient.

Stem cell therapies are transported using a “dry shipper” (charged with liquid nitrogen [LN2]) that will maintain the product temperature from -150°C to -196°C for more than 10 days. Fisher BioServices’ trains cryogenic technicians at the clinical site who can then receive and transfer the products from the shipper to an on-site vapor phase LN2 freezer. The shipper includes a full set of labels and excursion-monitoring devices, including a USB-based temperature data-logger, to allow the technician to quickly determine whether the product has been compromised during transport.

Life Technologies has historically been a broad research tool provider for the life science community. A small, rapidly growing business for the company has been stem cell research and regenerative medicine. By repurposing existing reagents and tools and continually developing new products specific for cell-based therapies, Life Tech has put together a portfolio that provides support for this community.

“We have specialized culture media, cryopreservation media, media supplements, growth factors, and cell matrices,” noted Mark Bonyhadi, Ph.D., director of the cellular medicine group.

“But in addition, we can also provide the stem cell researcher with a variety of molecular and protein-characterization tools, such as qPCR/digital PCR platforms, gene and RNA sequencing platforms, flow cytometric and cellular imaging systems, as well as advance platforms for safety testing of cellular material.”

When current work-flow solutions aren’t ideal for a given application, the company can also provide customized or optimized services such as creating serum-free media, or GMP magnetic beads for removing unwanted cell types, according to Dr. Bonyhadi.

Production Processes

EMD Millipore is another company that chose to make an investment in the emerging area of stem cells. As progress is made to move this biological material into the clinical trial process the need for large numbers of stem cells and large-scale production processes will be recognized.

“Stem cells and stem cell products will be used in a regulated way,” said Robert Shaw, director of the stem cell initiative at EMD Millipore, echoing a familiar refrain.

The company is working on providing products for large-scale production of stem cells that customers can use in a validated environment. The primary focus is on bioreactors and bioreactor-based processes.

EMD Millipore’s model stem cells are mesenchymal and they are grown as adherent cells on micro-carriers to make the production of cells scalable from 10 L up to 100s or 1,000s of liters. This has been a collaborative effort, with EMD Millipore working with scientists at Athersys and at the Fred Hutchinson Cancer Research Institute.

The company is developing a platform of products that can be used to facilitate the scale-up and industralization of stem cell production regardless of the stem cell type or the disease focus. It is their view that the process to produce stem cells can be similar, but each system must be optimized in make the most efficient production possible.

As the product is very much dependent on the process, much attention is paid to QC/QA. This can be done using panels of markers that indicate upregulation or downregulation to guarantee that the growth conditions don’t perturb the cells and keep them in their pluripotential state.

According to EMD Millipore, the Mobius CellReady 3L Bioreactor combines the predictability of a stirred tank design with the flexibility of single use.

GE Healthcare Life Sciences also has signed on to the emerging cell therapy business. It believes that the next logical step is an industrialized bioprocessing workflow. Its approach is to leverage expertise in protein and monoclonal antibody production to develop specialized separation and analytical tools. While cell therapy is a nascent market with some risks from a business point of view, GE is willing to invest based on its previous experience in biologics. Regardless, the most expedious path for GE to enter this market is through partnerships.

The company already has established two: one with the Canadian Centre for Commercialization of Regenerative Medicine on new product development and the second with the Karolinska Hospital in Sweden.

“We are working on three projects at the Karolinska,” said Firman Ghouze, Ph.D., director of the cell therapy group at GE Healthcare. “We are initiating several R&D activities to optimize stem cell growth using GE tools and Karolinska’s clinical know-how. We also are capturing the clinical workflows associated with the cells and clinical processes. Finally, we are working on a framework to address regulatory and reimbursement challenges from the customer’s standpoint.”

GE is taking an agnostic approach to developing technologies for cell therapy. It is building a process that is broad and independent of a particular customer’s stem cells and approach. The key steps in the process have been defined as separation of cell populations, expansion of cells with desired biological function, quality control, and administration, i.e., injection and sample tracking.

During the course of this activity GE is looking to develop new products and adapt existing bioprocess platforms, optimized for stem cell production. An example of the latter approach is the use of the WAVE bioreactor.

Also for monitoring and QC processes, GE just launched a small footprint cell analysis imaging platform (Cytell) that can be used to image cells throughout the workflow process.

According to officials at Akron Biotech, their goal is to utilize the firm’s knowledge and expertise to supply and manufacture raw materials and provide technologies and validated services for the regenerative medicine industry.

Claudia Zylberberg, Ph.D., president and CEO, said the company is working to enable a better transition from the preclinical research bench to the clinic under a well-documented manufacturing process. Their portfolio includes serum-free growth media, supplements, and cryopreservation media, human growth factors and cytokines, cellular scaffolds (e.g., human fibronectin, and human fibrinogen).

In addition to “regulated” products, Akron also offers assay development services and works closely with start-up cell therapy companies to help them move their cellular therapeutic products into clinical trials.

GE Healthcare is optimizing existing platforms, like the WAVE bioreactor, for stem cell production.

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