Xcellerex XDR MO Fermentor Systems
Xcellerex XDR MO Fermentor Systems from GE Healthcare come in two sizes: 50 L and 500 L. (The 500-L system, the Xcellerex XDR 500 MO, is shown here.) According to the company, these single-use stirred-tank fermentors provide powerful mixing, high oxygen transfer capacity, and efficient temperature control, allowing microorganism growth performance that is comparable to that obtained with conventional stainless-steel fermentors.

Bioreactor design must satisfy user demands, which vary from user to user. For example, a developer of cell-based therapeutics may prioritize certain bioreactor features and capabilities, whereas a manufacturer of monoclonal antibodies may prioritize others. Yet even disparate users deal with common drivers. In bioreactor design, these common drivers are at least as important as the drivers that are specific to different users.

“One common driver is the need to support modern, intensified, high-cell-density processes that require high oxygen transfer as well as excellent carbon dioxide removal,” says Christel Fenge, PhD, head, bioprocess R&D, GE Healthcare. “In continuous operations, bags need to be designed to connect readily, with the appropriate tube diameter, to cell retention devices. Also, an integrated control approach to bioreactor and cell retention control is preferred.”

Ease of use is another near-universal need. “Users expect that system interactions be as intuitive and self-explanatory as they are with any modern software application, and that they not require a lot of training and prior knowledge,” she explains. “This also applies to tube management, bag installation, or any other aspect of handling. It is all about plug and play.”

Monitoring tools improve process control

The ability to check culture conditions is also something all drug firms want. Real-time tracking lets developers optimize production and follow quality regulations, says Karl Rix, PhD, vice president, business unit bioprocess, Eppendorf.

BioBLU line of single-use vessels,
One dimension of bioprocessing flexibility is the ability to accommodate a range of working volumes. To support this ability, Eppendorf developed the BioBLU line of single-use vessels, which are suitable for small, bench, and pilot-scale cell culture applications. A range of adaptor kits is offered as well. Such a kit can ready an existing bioreactor system for single-use operation without the expense of replacing the whole system.

“In upstream bioprocess development, the economic pressure is high,” he explains. “Important drivers are the pressure to reduce time to market and development and manufacturing costs. And of course, the regulatory pressure for consistent product quality is enormous.”

Rix adds that regulators want companies to use a quality-by-design (QbD) approach for all production processes, including those inside the bioreactor. Such approaches incorporate real-time monitoring and control of process parameters, and they require, Rix emphasizes, “advanced solutions for online process analytics, data analysis, and process control.”

An increase in demand for in-bioreactor monitoring technologies has also been seen by GE Healthcare. These technologies include improved sensors that can help users satisfy their process control needs, says Fenge, who adds that better process control can lead to more favorable metabolite profiles, higher cell densities, and greater product concentrations—as well as higher quality.

Additional confirmation of the growing demand for monitoring-enabled bioreactors is supplied by Alex Chatel, EngD, product manager, Univercells. “In general,
manufacturers want to be able to enhance the monitoring of key culture parameters, such as pH and dissolved oxygen, within the reactor. They also want to be able to track parameters such as biomass, metabolites, and product titers,” he points out. “In practice, this means bioreactors usually combine a variety of process analytical technology (PAT) tools that vary depending on the customers’ needs.”

Univercells has developed the scale-X™ carbo, an automated cell culture system for expression and concentration of viral drug substance. It features a scalable, fixed-bed bioreactor designed for enhanced upstream processing of viral products. According to the company, the system can enable rapid process development and cost-effective clinical production.

Single-use systems enhance flexibility

The first bioreactors were large, stainless-steel tanks. Early producer cell lines made only small quantities of product, so cultures tended to be large. This necessitated the use of large vessels.

Until very recently, most commercial biomanufacturing was still done with stainless-steel reactors. Today, more manufacturers have started to adopt single-use systems, which are relatively cheap and disposable.

Among commercial producers, single-use facilities outnumber stainless-steel facilities, both in volume and in number of installations. “Applying intensified, continuous manufacturing processes,” Fenge points out, “a 2000-L manufacturing train can produce the same amount of drug substance as previously produced in a 20,000-L facility.” She adds that the adoption of single-use bioreactors is also being increased because industry is improving production cell lines and focusing on niche, low-volume drugs.

More and more indications require lower manufacturing volumes. This trend, says Fenge, reflects the availability of higher titers and, especially, the rise in personalized medicine, where individual patients’ genetic patterns determine which drugs will deliver the best outcomes. The need for large stainless-steel manufacturing facilities is very limited, she continues, among producers of cell and gene therapies.

Deliberations between steel and plastic are often influenced by efficiency considerations. According to Rix, one dimension of efficiency is the ability to respond to market dynamics. “The need for faster turnaround in development as well as production favors the adoption of single-use technology,” he maintains. “Scalable systems are required to streamline process transfer from research and development to manufacturing.”

Keeping suspension culture in the mix

Mixing is another area of innovation in bioreactor development. In early biomanufacturing, cells were immobilized to promote economic viability.

Fixing cells minimizes the nonproductive growth phase of cell culture, and it improves yields as well as overall volumetric productivity. It also protects cells against shear forces and environmental stresses. But immobilizing cells limits mass transfer of both substrate and product, which is a problem for some developers, says Fenge.

“In antibody or recombinant protein production, or in viral vector or cell therapy manufacturing processes, mass production and scalability are critical, even if the route of scale-out or multiparallel culture is chosen,” she explains. “Hence, well mixed suspension culture is the method of choice offering the best results.”

Sticking by adherent culture

For other types of biomanufacturing, immobilization is the preferred option. This point is emphasized by Chatel, who notes that demand from firms that use adherent cell lines is a major driver of Univercells’ bioreactor R&D activities.

“Choice of bioreactor is a function of cell type,” he says. “Companies using adherent cells want bioreactors that can be used for laboratory-scale development through to commercial production. They want to keep cell culture conditions consistent throughout the development process. They want to use the same equipment and production processes.”

Producing vectors for cell and gene therapies

Viral vector production, which often relies on adherent cell technology, is unable to keep up with demand. Finding a way to improve production is a major focus for industry. Viral vector shortages, it is feared, will hinder developers hoping to develop drugs that could follow Kymriah® (tisagenlecleucel), Luxturna® (voretigene neparvovec-rzyl), and Yescarta® (axicabtagene ciloleucel) to market.

“The lack of viral vector capacity is a problem for developers of cell and gene therapies,” Chatel insists. “Adherent cell lines produce only limited quantities of viral vectors, but to create a cell therapy, a significant quantity of vector is required.”

Adherent cell lines are improving, and in recent years, researchers have developed “stable producer” cell lines that can make vectors on a continuous basis. Despite such advances, the major challenge remains the lack of specialist bioreactor technology.

“Many small-scale current viral vector production technologies are based on static technologies,” Chatel explains. “Adherent cells need a physical support matrix to grow, typically embodied in the industry by multitray plasticware. Media is introduced and the cells are passaged.

“The processes are labor and resource intensive. And scaling up is a challenge because the systems being used are lab-scale platforms that have been scaled out, rather than up.”

Alternatives are being developed. For example, some systems use porous beads as the attachment surface for the adherent cells. Other systems, such as the one developed by Univercells, use a microfiber bed as the growth surface to better protect the cells against environmental stress and shear forces.

Another approach to improve adherent cell growth has been developed by Eppendorf. This approach is also focused on cultivating cells in a protective environment. “The three-dimensional environment certainly plays an important role in the cultivation of adherent cells, which are particularly shear sensitive,” Rix points out. “One example for a bioreactor design taking this into account is packed-bed bioreactors filled with Fibra-Cel disks.

“Fibra-Cel consist of a fibrous matrix made of polyester and polypropylene. The disks are electrostatically pretreated to support cell attachment. The matrix provides a three-dimensional growth environment, which protects the cells from damaging shear forces.”

Respecting the sensitivities of stem cell lines

Bioreactor design is also being influenced by novel therapeutic approaches such as regenerative medicine, which often involves the cultivation of stem cells and stem cell–derived differentiated cells. According to Rix, such cells cannot be cultivated as single cells in suspension. He adds that the cell lines that are used are more sensitive than the average producer cell line.

“Such applications,” Rix suggests, “may require specific adaptations of the bioreactor design—for example, new impeller types.”

Future bioreactors

Bioreactor design will continue to accommodate the biopharmaceutical industry’s demands. These demands, in Fenge’s estimation, will be fairly diverse. “In the future, users will expect robust single-use systems that do not require any training,” she predicts. “Upstream and downstream processing [will need to be] fully integrated with process automation at a completely different level. I also envisage that there will be systems in place taking care of the plastic waste. Innovation will come from process automation, ease of use, and ecological considerations.”

According to Fenge, bioreactors of the future will also accommodate evolving biopharmaceutical R&D priorities. “The industry,” she insists, “needs to stay on top of novel molecular modalities and their specific production requirements, both regarding biology and bioreactor technology.”

Global Bioreactor Market to Hit $2.2 Billion by 2025

The U.S. bioreactor market was valued at over $230.0 million in 2018. It is anticipated to witness significant growth over the coming years due to increasing number of biopharmaceutical companies focusing on new drug development processes and growing number of strategic collaborations with academic institutions and venture capital firms.

So reports Global Market Insights which goes on to state that the worldwide bioreactor industry is projected to achieve 17%+ CAGR to surpass $2.2 billion by 2025 owing to technological advances in bioprocessing technology and equipment industry. Rising chronic disease prevalence and growing research in the field of biopharmaceuticals will drive the global market size. Increased focus of biopharmaceutical companies to develop effective treatment options for the most common orphan diseases should fuel industry growth.

Personalized medicines are changing the way many diseases are identified, classified, and treated. Increasing number of personalized medicines targeting a specific population will further boost the industry expansion. A new manufacturing technology has evolved to provide more personalized drug products such as 3D bioprinting.

Biopharmaceutical products are individualized products with highly specific manufacturing requirements. Advanced biopharmaceutical manufacturing technologies have enabled development of effective drug delivery systems and drug device combination products. Increased collaboration in biopharmaceutical industry through partnerships with medical device manufacturers, diagnostic developers, academic institutions should propel business growth.

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