For almost 40 years, bioprocess engineers have been indoctrinated with the technology of the stirred tank bioreactor. But many have concluded that a plastic bag can be effective and that the results achieved with cultures in a single-use bioreactor are comparable with the results achieved in the glass or stainless-steel stirred tank bioreactor. This article describes experiments performed in the bag type single-use bioreactor that suggest it can yield results that are comparable with those as achieved in the traditional stirred tank bioreactor.
An increasing number of therapeutic candidates, including monoclonal antibodies, biotherapeutic proteins, and vaccines, are currently entering early-stage process development. At the same time, biologics are being introduced onto the market or have recently been introduced. In this competitive market, time-to-market, cost-effectiveness, and manufacturing flexibility are key issues that all must be achieved while maintaining product quality.Traditionally stirred tanks, glass vessels, and stainless steel tanks have been used at laboratory and pilot scales for process development and production of research grade, toxicological, and Phase I clinical material. Stainless steel tanks dominate large-scale manufacture (> 1000L) of bio-therapeutics. However, fixed plant equipment is costly, requiring long lead times for installation and qualification. There is also a high burden from validation efforts related to sterility and cleaning, as well as for maintenance. The risk for cross contamination in standard steel or glass equipment leads to strict rules for cleaning and cleaning validation.
During the past decade, industry has been switching to disposables in medium preparation, storage of buffers, and even for cell culturing and downstream operations. For cell culture, various types of disposable technologies have been introduced, all with specific benefits and drawbacks.
Advanced cell-line engineering and process development have resulted in more productive cell cultures. During the past 15 years, cellculture titers in fed-batch processes have increased from 0.05 to over 10 gL-1 today, allowing the use of smaller scale bioreactors.
Smaller bioreactors are gaining popularity, and this again has led to increased implementation of disposable technologies. While the industry is looking for high cell densities, high productivity, cost-effective process design, and speed to reach market introduction, the bioreactor demands are increasing, too. This is especially relevant for mixing and mass transfer but also for measuring and control of essential parameters, such as pH, dissolved oxygen (DO), glucose, lactate, and viable cell density.
High-cell density culture—including perfusion cultures—generate greater demands with regard to mixing and mass transfer. Microbial fermentation processes are even more demanding in terms of mass transfer when compared with a cell culture process. The currently available disposable bioreactor systems are less suitable for high-density cell culture processes and are not suitable for microbial fermentation processes. The exception here is the CELL-tainer bioreactor (CeLLution Biotech, Assen Netherlands). The performance of this bioreactor is comparable with the stirred tank and thus covers the complete range of applications from cell culture to microbial fermentations, from adherent cell cultures to more viscous fungal fermentations. This article will discuss a rocking-based disposable bioreactor that can be used in a wide range of biotechnological processes.