In Part II of our series on “Strategies for Improving Viral Yield in Vaccine Manufacturing,” we will examine the use of bioreactors to improve virus production. With a large number of cell culture based viral vaccines in the pipeline, manufacturing capacity will need to be maximized and the best way to achieve this is to increase yield and make manufacturing more efficient. Another advantage in increasing yield is cost reduction, which means that vaccines are more accessible to the developing world. In addition, manufacturing time is also decreased, which is critical in the case of a pandemic. Improving cell culture media is one way to increase virus yield, which was examined in Part I titled “Improving Media to Increase Virus Yield in Vaccine Production.” Now we will examine the role of bioreactors and accompanying technology as another way to achieve higher yield.
Bioreactors provide many benefits in vaccine manufacturing compared to static culture or roller bottle technology. While many vaccines are still manufactured using these older technologies, several studies have shown that manufacturing can be greatly improved by employing bioreactors. For one, bioreactors provide a larger vessel for manufacturing and in turn can handle much larger batches at one time (in some cases 2,000 liters per batch). This large-scale production reduces costs by lowering the total number of batches necessary to meet demand. In particular as the influenza vaccine is moved from egg-based production to cell culture-based production, the need for large-scale virus manufacturing will be increasingly essential.
Bioreactors also offer the advantage of optimal culture conditions. Cell lines used for virus production are notoriously difficult to grow and bioreactors offer more options for optimizing growing conditions to maintain cell health and increase productivity. Companies manufacturing bioreactors for use in viral systems include Thermo Fisher Hyclone, GE Wave Biotech, FiberCell, Xcellerex , ZellWerk, ATMI, Refine Technology, AmProtein, Sartorius Stedim, and Biovest. Most commonly stainless steel, stirred-tank bioreactors are used for this application although there has also been an increase in the number of single-use disposable options available for vaccine production.
Single use systems offer another attractive option in the area of bioreactors with similar advantages and some additional benefits that are particularly well suited to virus production. They offer similar growth and productivity to stainless steel bioreactors but are more flexible. Single use systems have a faster turnaround time between batches because there is much less cleaning and validation necessary than with stainless steel tanks. Cleaning and validation can be costly and time consuming steps in the manufacturing process and can delay the next manufacturing run.
The annual demand for some vaccines can be unpredictable. For example, influenza vaccine demand is often based on how bad the previous year’s flu season was. If it was a bad flu year, more people will want to be sure that they get their vaccine the next year, but if the flu season was relatively mild, then people may hold off on getting the vaccine. By using single use systems, vaccine manufacturers have more control over increasing or decreasing production based on demand. For instance, a company only needs to purchase and operate the number of single use bioreactors necessary to meet demand and if demand grows they can add more single use reactors. This also reduces upfront capital investment. Companies that manufacture single use systems for viral systems include, Thermo Fisher Hyclone, Xcellerex, Sartorius Stedim, GE Wave Biotech, Refine Technology and ATMI.
Bioreactors can support both suspension culture and attached culture, with the use of microcarriers. Before recent improvements in microcarrier technology, bioreactors were largely limited to suspension culture – i.e. CHO cell manufacturing. However, microcarriers allow attachment dependent cells used for vaccine production such as Vero, MRC-5, and WI-38 to be propagated in bioreactors. With an increase in the use of stirred-tank bioreactors, microcarrier innovations have been necessary to allow adherent cells to be cultured in these conditions. For example, new low-density matrices can be positioned in bioreactors and allow for efficient adherent culture in stirred-tanks.
Microcarriers enable more cells per milliliter of culture. More cells in culture increases overall titer yield. In addition, the use of microcarriers allow manufacturers to increase the number of cells that can be cultured in one tank enabling more efficient large-scale production and permitting the use of greater than 1,000 liter bioreactors. New microcarriers are now making it possible for adherent cultures to take advantage of the use of bioreactors and optimize their manufacturing.
Whether companies are interested in stainless steel tanks or single use systems, bioreactors can offer a way to improve virus production and increase yield and improve efficiency. These improvements can lead to reduced costs and manufacturing time both critical goals for vaccine manufacturing. Do you use bioreactors for your vaccine manufacturing? If so, what system do you use and how does it work for you.