May 1, 2017 (Vol. 37, No. 9)
The Factory System Will Help the Stem Cell Industry Standardize, Integrate, and Automate Unit Operations
Stem cell therapies hold extraordinary potential to revolutionize human medicine. Indeed, the global market for cell-based therapies is expected to surpass $20 billion by 2025, with an annual growth rate of 21%, as estimated by Scientia Advisors. Because stem cells have the ability to transform into a variety of cell types, stem cell therapeutic targets include cancer, neurodegenerative disease, heart disease, autoimmune disease, and musculoskeletal disorders.
The choice of which stem cells to pursue for clinical applications depends both on their potential clinical risks and accessibility. Stem cells can be isolated from many sources. For example, multipotent adult mesenchymal stem cells (MSCs) are readily harvested from the bone marrow of patients or donors for use in autologous or allogeneic therapies. MSCs can also be derived from blood, fat, placental and umbilical tissue, and other tissues.
Stem cells of another type, pluripotent stem cells (PSCs), are isolated from preimplantation embryos. Also, somatic cells may be coaxed to return to a more primitive state, and become induced pluripotent stem cells (iPSCs), through the application of specific transcription factors.
Various ways of developing therapeutic stem cells are of interest to stem cell manufacturers, who hope to make large-scale production of stem cells more efficient and economical. Production issues, as well as basic biology and application possibilities, were discussed at the Stem Cell Product Development and Commercialization Conference, a recent event that took place in Boston and was organized by GTCbio.
Stem cell specifics addressed at the event included the necessity of developing more cost-effective manufacturing solutions, ranging from altering media formulations and vessel types to utilizing automated, closed systems in place of traditional cleanrooms. Other solutions described newly available plug-and-play systems for rapid cell expansion and included advice for when to consider outsourcing processes to knowledgeable partners.
Thinking Outside the Vial
MSCs were discovered more than 30 years earlier than PSCs, and have many more total publications behind them. This depth of MSC knowledge, conference presenters argued, makes MSCs an attractive target. “Since there are over 500 clinical trials today using MSCs, and less than 10 active trials using PSCs,” said Jon Rowley, Ph.D., chief technical officer, RoosterBio, “we have focused our products to solve the challenges of the largest market.”
According to Dr. Rowley, while MSCs are the workhorses of regenerative medicine, they have run up against stubborn challenges, particularly scaleup costs: “RoosterBio is a very market-focused company that is solving manufacturing challenges for stem cell-derived therapeutic products. We have likened the process to the microchip industry. When microchips were offered off the shelf, and no one had to make their own, the computer industry grew exponentially. We are hoping to have the impact on the regenerative medicine industry that Intel had on the computer industry.”
This sort of impact could be achieved by various means. “First, you need starting cell stocks and bioprocess media,” suggested Dr. Rowley. “Second, you need to work out efficient processes to streamline scale up that also maintain the critical quality attributes of the starting materials.”
“To meet these challenges, our company has developed ready-to-use cellular starting stocks (cell banks) and bioprocess media systems that are designed for manufacturing scalability,” he asserted. “These products provide the only scaleup cell banks on the market and the only bioreactor-specific media systems for fed-batch processes.
“We also offer plug-and-play bioreactor kits (including small reactors and microcarriers with protocols). Our ‘Ready-to-Print’ thaw-and-use cells are targeted for bioprinting applications. Thus, we have extremely differentiated product lines that are engineered to generate more high-quality cells to reach complex applications faster.”
Dr. Rowley insisted that RoosterBio is unique in this regard: “None of the stem cell products on the market have a characterization profile relevant to cellular therapy. Since these starting materials have not been available, everyone has had to develop similar processes to get to a MSC working cell bank, and then the processes to scale up the expansion. This has created extreme redundancy in the field that we are hoping to address. With our plug-and-play systems, anyone can now quickly implement highly sophisticated, scalable, and economical MSC production processes.”
Pluripotent Stem Cell Scaleup
PSCs also have garnered much enthusiasm for their potential to provide advances such as for drug screening, disease modeling, and cellular therapies. However, PSC manufacturing scaleup remains a bottleneck.
“Laboratory-scale PSC expansion strategies require costly complex media and regular handling by highly trained scientific personnel,” noted Gary M. Pigeau, Ph.D., development manager, cell therapy, GE Healthcare. “There has yet to be a demonstration of a truly scalable solution for PSC production.”
Dr. Pigeau says that the industry needs to make some key changes: “Cost-effective manufacturing of PSCs will require scalable suspension-based cultures; minimal (and xeno-free) medium formulations; and automated, closed, and integrated unit operations.”
GE Healthcare is developing such solutions, according to Dr. Pigeau. “The field is currently working at the 1 L scale, and a suitable solution to meet near- and long-term clinical requirements is needed,” he explained. “One of the primary challenges in scaling to larger volumes is the difference in vessel configurations, geometries, and mass transfer.
“The GE Xcellerex portfolio of single-use, stirred-tank bioreactors is a scalable, modular platform spanning the 10 to 2,000 L range. The key in this scaling trajectory is the maintenance of vessel attributes, which enables the transfer of operating conditions across the product line. By demonstrating PSC expansion in the XDR-10 and beyond, we are intent on enabling the next generation of PSC-derived clinical trials.”
Further, GE Healthcare is partnering with the Federal Economic Development Agency for Southern Ontario and the Centre for Commercialization of Regenerative Medicine (CCRM), a leader in developing and commercializing regenerative medicine technologies and cell and gene therapies, to build a Centre for Advanced Therapeutic Cell Technologies (CATCT) in Toronto. This initiative plans to “BridGE” the gap of industrialization for cellular and gene therapies.
“The BridGE group is working toward developing the processes and products that will enable clinical trial sponsors to meet their manufacturing needs with respect to efficiency, scale, cost, and quality,” reported Dr. Pigeau. “We are currently executing on projects in the most active areas of cell and gene therapy to build and demonstrate our best-in-class solutions to manufacturing challenges in this emerging industry.”
With respect to the PSC manufacturing initiative, the group recently demonstrated the production of 8 billion cells in one 8 L batch. “These cells met our potency quality specifications throughout the manufacturing workflow and were successfully differentiated to high-quality cardiomyocytes,” stated Dr. Pigeau. “To my knowledge, this is the first successful PSC manufacturing endeavor at this scale. It represents a paradigm shift in modern medicine.”
One of the biggest challenges in stem cell manufacturing and scaleup is cost, suggests Kevin Murray, vice president, global sales BioSpherix Medical. “These high costs are largely due to the use of cleanrooms to grow cells,” he declared. “Cleanrooms are simply not a viable option for the production of cell therapies. They not only are inflexible, time consuming, monolithic, and expensive, they also cannot provide the sizing necessary for scale up.”
According to Murray, the industry needs a paradigm shift in thinking to adapt to future technology: “Current cGMP guidelines and FDA input indicate an increasing regulatory preference for advanced aseptic processing, specifically isolators for future facilities. BioSpherix already is focusing on such a ‘cytocentric approach.’ Instead of using cleanrooms that leave people in the same space as the cells, we developed an efficient, closed, and modular approach that provides a cell-centered, flexible platform able to interface with automation.”
The company’s Xvivo System includes incubators and hoods, all integrated together as co-chambers and sub-chambers to provide aseptic conditions.
“Additionally, all common cellular tools such as microscopes, centrifuges, and sorters can be integrated,” Murray elaborated. “You name it, and we can enclose it and allow proper access. Thus, for the first time, all cell needs can be met by one very efficient system.”
An added benefit is that cost plummets. “Cleanrooms typically cost between $300,000 to $400,000 per year to operate,” noted Murray. “Our cytocentric system operates at one-tenth of that cost.”
Murray’s take-home advice is that a change of vision is needed in the industry: “Traditional thinking about mass production in cleanrooms may be suitable for the manufacture of pills, but it does not make sense for the manufacture of gene and cell therapies. Contemporary manufacturing must incorporate flexible, closed, and automated systems. This greatly lowers cost, enhances scale, and provides much greater safety. Sticking with the old school is not going to be cost effective for the future.”
Building a Cell Therapy Supply Chain
There are many links in the supply chain for regenerative medicine and stem cell products. Partnering with skilled experts may enhance the process.
“It is important for companies wanting to build a cell therapy supply chain to select partners fully versed in all aspects from collection to administration,” advised Beth Shaz, M.D., chief medical and scientific officer of Comprehensive Cell Solutions (CCS), a division of the New York Blood Center (NYBC).
“We not only provide cell banking and tissue therapy services, we dialog and interact with each company about their specific needs,” detailed Dr. Shaz. “No two companies want exactly the same thing.”
According to Dr. Shaz, critical issues include apheresis collection, tailoring procedures relevant to each cell therapy product, quality management systems, and navigating the regulatory environment. Further, the care and treatment of each patient also matters. “Since products come from autologous related donors or volunteers,” she explained, “we work hard to provide good donor management and personalized care to keep them safe and well informed about all aspects of what we are doing.”
Another issue is that not all stem cells are alike. For example, hematopoietic progenitor cells (HPCs), unlike embryonic stem cells, are collected from sources such as peripheral blood, cord blood, and bone marrow. HPCs can develop into any component of the bone marrow and immune system, including red blood cells, white blood cells, and blood platelets.
NYBC’s newly commercialized HPC product, Hemacord™, is the first FDA-approved and licensed allogeneic HPC-cord cell therapy. Following infusion, the cells migrate to the bone marrow, mature, and move into the blood stream, partially or fully restoring normal blood cells and their functions. The product can treat certain blood cancers and some inherited metabolic and immune system disorders.
“The ability to supply high-quality cells under rigorous manufacturing requirements is critical to success of cell therapies,” concluded Dr. Shaz. “Expertise exists in all the critical areas companies require. It is important to create partnerships for the product to succeed. Our goal is to get new therapies for patients, and we are part of that process.”