Without a doubt, stem cell manufacturing plays a critical role within the rapidly expanding stem cell sector. Progressing a cell-based therapeutic from pre-clinical stage production through later clinical stages and into commercial production requires scale-up.
Historically, the production of adequate quantities of stem cell based therapeutics has been a major challenge and bottleneck for the industry.
Thankfully, a growing number of technologies are now being adopted to support the production of emerging cell therapies.
Choice of stem cell technologies for scale-up is determined by cell type (stem cell, immune cell, primary cell), growth conditions (adherent vs. suspension), donor source (autologous vs. allogeneic), and phase in development (early or late).
During the manufacture, stem cells are expanded in sufficient numbers to reach the desired doses for either individual patient treatment or the establishment of cell banks.
Stem cells are also manipulated by stimulation with specific factors, co-culture with other cell populations, or genetic alterations. Finally, cell expansion and manipulation are performed manually, by using an automated system, or through a combination of these methods.
Scale-Up of Stem Cell Manufacturing
Today, the methods for scale-up production of stem cell therapeutics include:
- planar technologies (flasks, plates)
- bioreactors (stirred tank, perfusion systems, rocking motion
- suspension platforms (microcarriers)
Usually, for scale-up, the surface area and volume of the containers are increased to accommodate a greater number or density of cells. For instance, in planar systems, scale-up is attained by increasing the size and number of layers per vessel (e.g. stacked plate cell factories).
Likewise, scale-up of bags and bioreactor technologies also necessitates an increase in size and number of vessels. Some bioreactors use substrate scaffolds (hollow fibers, fibers or porous structures) for the cells to adhere and increase the surface area to volume ratio, and hence, cell density.
The same principle applies to microcarriers and small beads that are placed inside bioreactor systems as a scale-up method for adherent cells.
Closed Automated Systems
For scale-up manufacturing, automation and greater capacities for parallel processing within closed systems are essential. A number of closed and automated systems have been launched into the market. These systems employ robotic arms to perform various cell culture operations.
They may use traditional cell culture flasks or a specifically designed plate, flask or other bioreactor design. The high-end automated systems also possess plating and harvesting capabilities, media reservoirs and incubators, and enable automated detection of cell parameters, such as cell numbers and viability.
Unfortunately, many of the systems lack capabilities for early stem cell growth and selection. Nearly all are lacking automation of the final stages of high-throughput harvesting, freezing, and storage. However, Miltenyi CliniMACS Prodigy System is an exception and it has more automated features. However, this system has the disadvantages of a small capacity, long process times, and no options for scaling up without the purchase of additional units.
Today, leading companies that specialize in stem cell manufacturing equipment include:
- Aplikon Biotechnology
- BD Bioscience
- EMD Millipore
- FiberCell Systems Inc.
- Global Cell Solutions
- Nunc A/S of Denmark
- Pall Corporation
- Terumo BCT
- Thermo Fisher Scientific / Gibco
Many of these companies are giant multinational companies, although smaller competitors exist as well.
Of course, there are also many companies specializing the manufacture of stem cells and their differentiated cell types, such as FUJIFILM CDI, Ncardia, REPROCELL, TakaraBio, RoosterBio, Cynata Therapeutics, and numerous others.
Future of Stem Cell Manufacturing
If stem cells are to be used routinely within drug discovery and therapeutic applications, it is essential that stem cell manufacturing become easier and more affordable. To achieve this, a number of changes have to occur in the next 20 years.
First, the harvesting of stem cells needs to become routine so that obtaining starting material for stem cell production will be less invasive.
Second, stem cells should be produced in automated systems with rapid in-line analytics with little human input for the culture, testing and production.
Third, the cost of reagents and media for the culturing and production of stem cells has to become lower and these cell culture products should be designed to deliver consistent results in automated systems.
Currently, the expenditures involved in the manufacture of cells include:
- capital (facility, equipment)
- materials (media, growth factors, supplements, buffers, QC tests)
- consumables (bags, pipettes, tubes, vials, culture flasks, bottles)
- labor (human activities)
- other expenses (such as insurance, maintenance, utilities, etc.)
In total, labor accounts for approximately half of the total cost of stem cell manufacturing.
Thus, a final step toward lowering the cost of stem cell research and development will be to streamline the labor involved with stem cell manufacturing.