This is a guest post from Halina Zakowicz, Marketing Specialist at Biovest International, Inc. Do you have a response to Halina’s post? Respond in the comments section below.
Scaling up cell culture production can be a tricky proposition.
Generating large amounts of cell-secreted proteins is labor-intensive when utilizing traditional cell culture methods. Quality and yields can be inconsistent; these methods are also prone to contamination due to multiple aseptic manipulations. Making the jump to large-scale systems isn’t easy either, often requiring capital expenditures that are not feasible.
Have you been using petri dishes, plates, flasks or spinner bottles for small-scale production of cell-secreted proteins? Are you looking to scale up your protein manufacturing using alternatives to traditional mammalian and insect cell culture?
If so, you should consider hollow fiber bioreactors.
Scaling up poses many challenges
Small-scale cell culture typically requires little more than individual bottles of media, a tabletop incubator and 30-60 minutes a day from a lab technician. However, generating cell numbers that are 100-10,000 fold higher catches many labs short-handed. Lab technicians are usually not hired to perform cell culture as their full-time job; furthermore, lab space is always at a premium.
There are a number of challenges involved in scaling up cell culture, including the following:
Different cell dynamics
What is frequently taken for granted is how the dynamics of nutrient delivery and waste removal change as a function of scale. When expanding and supporting large-scale cell culture volumes, the maintenance of proper pH and temperature becomes challenging, as does the delivery of adequate oxygen, nutrients and growth factors.
Increased labor requirements
Not only do increased numbers of cells require additional passaging, but once the cell-derived products are ready to harvest, they must be purified and concentrated from large volumes of supernatant. Both the additional cells and their derived products require additional labor.
Increased lab space requirements
Many laboratories scale up their production capacity by investing in entire rooms filled with spinner flasks or roller bottles; other labs purchase large stirred-tank bioreactors. Both of these options take up valuable laboratory space.
When expanding cell culture operations, expense and capital budgets are used to purchase extra media, sera and specialized equipment. Additional technician hours must be allotted and budgeted for.
Hollow fiber bioreactors offer one solution
To address the challenges posed by large-scale cell culture, researchers and commercial manufacturing operations are increasingly turning to an established, yet not well known, technology called the hollow fiber bioreactor. This technology addresses the problems outlined above by reducing the following:
The hollow fiber bioreactor system consists of thousands of semi-permeable capillary membranes arranged in parallel and bundled into small cylindrical polycarbonate shells that typically take up the volume of a 12-ounce beverage can.
As a result, two distinct and separate compartments are generated: an intracapillary (IC) space enclosed within the hollow fibers, and an extracapillary (EC) space surrounding the hollow fibers.
Figure 1. A standard hollow fiber bioreactor shown with its enclosed intracapillary (IC) and extracapillary (EC) spaces.
The small size of the hollow fiber bioreactor system means that significantly less media is required compared with stirred-tank bioreactors. Also, growth factors and other high molecular weight nutrients are unnecessary in the IC space, resulting in a reduced need for serum.
Hollow fiber bioreactor systems can be automated for media flow, pH, temperature and oxygen control, and EC cycling. The automation of these cell culture parameters means that less oversight is required to grow large numbers of healthy cells (>109 cells/ml) and to generate large quantities of cell-secreted proteins.
Stirred-tank bioreactors require additional laboratory space for housing and maintenance. Animals used for ascites production must be housed in specialized rooms. In contrast, hollow fiber bioreactor systems have a very small footprint and in many cases can be stored on a lab bench or inside an incubator.
Because cell-secreted proteins such as monoclonal antibodies or vaccines remain with the cells in the EC space of the hollow fiber bioreactor, they automatically concentrate and do not need to undergo time-consuming downstream processing, a required step for most protein manufacturing processes.
Enabling efficient, cost-effective protein production
Due to their technological advantages over traditional cell culture methods, hollow fiber bioreactors are being increasingly used by academic and research laboratories and biotech manufacturing plants for mammalian and insect culture-based protein production. They also have been — for decades — the workhorse of companies that manufacture human and veterinary IVD products worldwide.
In light of the recent influenza outbreaks, for example, there has been particular interest in using hollow fiber technology to rapidly produce viral vaccines not tainted by allergy-inducing animal proteins. Likewise, both price and ethical concerns over using mouse ascites have situated the hollow fiber bioreactor as a more humane method for large-scale in vitro generation of monoclonal antibodies and other cell-secreted proteins.
Because the hollow fiber bioreactor offers a compact, efficient, economical and long-lived method for protein generation, this technology is becoming increasingly employed across laboratories, and especially laboratories that wish to find an easy and cost-effective method for scaling up their production capacities.
About the author:
As marketing specialist at Biovest International, Inc., Halina helps customers understand how hollow fiber bioreactors can be used to scale up traditional cell culture and facilitate novel in vitro applications like vaccine production. Biovest also uses hollow fiber technology in its upstream protein manufacturing and downstream processing services when working with academic, research and pharmaceutical customers.