Fixed Bed Bioreactors: Bridging the Gap from Bench to Market | Corning

Enormous strides have been made in cell and gene therapies. Many potential treatments are now in development, in clinical trials, or even on the market for health conditions that have traditionally been difficult to treat. Much of this research is performed on adherent cells grown on traditional 2D surfaces, which produce relatively small quantities of cells and viruses. Procedures performed on these 2D surfaces often don't scale efficiently, leaving a big gap between obtaining exciting research results and manufacturing enough product to bring a therapy to market at a reasonable cost. Fixed bed bioreactors are helping to close that gap by dramatically increasing capacity and yield without requiring the time-consuming and costly conversion to suspension systems.

Increasing 2D Surface Area

In operations involving adherent cells, methods for scaling up have often focused on increasing 2D surface area without increasing the footprint of the vessel used. For example, the Corning® HYPERFlask® vessel offers 1,720 cm2 of growth area with the same footprint as a traditional T-175 flask by providing 10 interconnected growth surfaces made of a gas-permeable polystyrene. The Corning HYPERStack® vessel also uses ultra-thin gas-permeable layers to produce a closed system with 12 or 36 layers (6,000 cm2 or 18,000 cm2, respectively). They can be manifolded together to increase production and reduce handling time. The Corning CellCube® modules are available with 10 to 100 layers to provide 8,500 cm2 to 85,000 cm2 of surface area. The CellCube system also provides a perfusion-based method to supply oxygen and nutrients, and to remove waste, which mimics the constant fluid flow of in vivo systems. These modular vessel scale-up innovations help to make these adherent platforms highly effective for many applications and as seed train. However, space and manipulation requirements can become challenging when scaling out 2D cell culture vessels to achieve significantly higher cell or vector production targets.

Modern Fixed Bed Bioreactors Offer Flexibility, Speed, and Scalability

A fixed bed reactor (FBR), such as the Corning Ascent® FBR system, consists of a cylindrical vessel, packed with a substrate on which adherent cells attach and grow in 3D space. Culture medium is supplied through a conditioning vessel. While some fixed bed bioreactors are reusable systems that require cleaning and sterilization, disposable, single-use fixed bed bioreactor vessels, introduced in the past decade, offer improved flexibility, speed, and scalability.

Early single-use bioreactors were small-scale, with a maximum cell culture area of between 1 m2 (or 10,000 cm2) and 20 m2 (or 200,000 cm2). The main option for commercial scale manufacturing provided between 0.5 m2 (or 5,000 cm2) and 500 m2 (or 5,000,000 cm2) of cell culture area. However, assessment of these early systems using fluorescent microscopy revealed that many cells form 3D clumps on the growth surface, which reduces viral production compared to cells grown in 2D monolayers.

Improvements in Fixed Bed Bioreactors

The Corning Ascent FBR system uses a specially woven polymer mesh that allows even fluid flow throughout the bioreactor bed. This enables uniform cell distribution and efficient delivery of nutrients and oxygen, and removal of waste. As a result, cells grow in uniform 2D monolayers at high densities. The Ascent FBR system includes a system controller to promote hands-off operation, and single-use bioreactor components that come pre-assembled and irradiated, saving valuable time. Disposable sensors monitor pH, dissolved oxygen, and temperature.

The Ascent FBR system is available in a benchtop PD system with 1m2, 2.5 m2 and 5 m2 bioreactors. A Pilot system that scales from 20 to 100 m2 and a Production system that scales up to 1,000 m2 are in development and expected to be commercially available in 2023. The system exhibits true scalability, demonstrating transfection efficiency of greater than 90% independent of vessel size. This helps smooth the path from process development to production, reducing the time to market.

Reducing Costs

Mammalian cells are used for production of monoclonal antibodies, retroviral vectors for gene therapy, and cultivation of tissue cells for artificial organs. A major challenge in manufacturing adherent cells for advanced therapies is producing the large quantities of cells and viruses needed in a cost-effective manner.

The Ascent FBR has produced eight times more viral genome per surface area and higher titers of viral genome per cell compared to a competitive FBR. It also has demonstrated potential to reduce overall cost of viral genome production through savings on media consumption and labor as fewer runs may be required to achieve production goals.

Unlike most FBR systems, the Corning Ascent FBR system also enables efficient cell harvest. The system has achieved greater than 95% cell recovery and 90% cell viability, which is necessary for stem cell therapy development, regenerative medicine, and other applications that require large quantities of viable cells.

Bridging Gaps

Fixed bed reactors are bridging the gap from bench to market for cell and gene therapy. By drastically increasing surface area and cell density, FBRs are making it possible to increase efficiency, reduce costs, and produce the large quantities of cells and viruses needed for therapeutic applications in an adherent cell culture platform. By offering single-use bioreactor components and an automated process, FBRs can reduce handling time and opportunities for errors and contamination.

Learn more here about the Ascent Fixed Bed Bioreactor System and how it can help produce large quantities of cells in a cost-efficient manner.