Strategies for Improving Viral Yield in Vaccine Manufacturing

A recent article in Pharma Times titled “US biopharma: nearly 300 vaccines in R&D,” points out that there are currently 300 vaccines either in clinical studies or under review by the Food and Drug Administration (FDA). While not all vaccines are cell culture derived vaccines, it does indicate that a large number of cell culture based viral vaccines are in the pipeline and that perhaps viral vaccine manufacturing should be examined. One area under consideration is how to improve viral yield so that vaccines can be made at lower cost and therefore available to more people. Viral yield is also very important when dealing with a pandemic because the higher the titer the more available the vaccine becomes to needy people. . During the last pandemic, the H1N1 outbreak in 2009, most vaccine manufacturing was egg-based and reports of low yields were common. When yields are low, it leads to shortages and delays in distributing vaccine to prevent significant public health risks. This indicates the critical importance of maximizing viral yield, regardless of the manufacturing host system. Now that cell culture based flu vaccines have been approved in Europe, cell-based viral yield will be crucial to prepare sufficient doses in case of another influenza pandemic.

Over the last couple of months we have featured two blog series one on CHO production titled “Strategies for Improving Antibody Production in CHO cells” and one on hybridoma production titled “Strategies for Improving Antibody Production in Hybridoma Cells.” It is logical, based on the volume of vaccines in the pipeline, that our third series focus on strategies to improve viral yield in manufacturing and will be followed by subsequent blogs where we will examine the following techniques in more detail.

The optimization of cell culture media is one area where improvements can be made in vaccine manufacturing. The removal of animal products and creation of a robust, customizable media, which maximizes output per cell and earlier harvest times, would be ideal. Additional improvements can be achieved with the move to a defined medium that avoids the use of variable components such as protein hydrolysates. While CHO manufacturing has made continual improvements over the years, including advances in media formulations to remove fetal bovine serum (FBS), vaccine manufacturing has maintained many of the same practices including the use of animal products in media. One challenge is that manufacturing practices for many current vaccines were developed decades ago, before the rise of serum-free media technology. Cell lines used for vaccine manufacture (Vero, MDCK) were not amenable to being grown without FBS and cell health and productivity was often compromised when serum was removed.

It is important to note that animal products are undesirable not only because they are a potential source of infectious agents but because they are undefined and have unpredictable performance leading to high batch-to-batch variation. Variation hurts consistency and causes low yielding or failed batches. There may be a solution in a new class of recombinant media supplements that are animal-free and defined and allow for the reduction or removal of FBS from virus cultures. Today companies including Sigma, Fisher Scientific, InVitria, Sheffield Bioscience and Mediatech sell these recombinant supplements and many including recombinant albumin and recombinant transferrin have been successfully used to improve cell viability and yield of cells used for biomanufacturing under animal-free conditions.

There is also an opportunity to improve virus production by using bioreactors. Bioreactors can provide cells the optimum environment, which can lead to an increase in productivity. While many vaccines are still manufactured using static culture or roller bottles, several studies have shown that manufacturing can be greatly improved by employing bioreactors. Companies manufacturing bioreactors for use in viral systems include Thermo Fisher Scientific, GE Wave Biotech, FiberCell, Xcellerex, ZellWerk, ATMI, Refine Technology, AmProtein, and Biovest.

Bioreactors can be used when cells are in suspension or adherent by employing another technology – microcarriers.

Microcarriers enable more cells per milliliter of culture by expanding the surface area for cell proliferation. More cells in culture increases overall titer yield. 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. 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.

These are just a few examples of work being done to improve viral vaccine production and there are others. Has anyone used any of these methods for improving their Vero or MDCK production? Does anyone have any others to recommend?

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