Improving Bioprocesses With Fed-Batch Cell Culture

In the world of cell culture, we’re always asking, “what is the best strategy for our particular desired goal?” Is it best to give our cells the best possible conditions for several days or do we want them to grow rapidly and move on to the next stage?

When it’s time to start experimental design, understanding different cell culture parameters and knowing the ins-and-outs of fed-batch cell culture will help you make the choice that’s right for you.

If high cell density is what you’re looking for, then fed-batch cell culture may be the answer to some of your problems. Fed-batch cell culture is essentially the constant addition of substrate or supplements that extend the duration of the cell culture experiment. It forces the cells to switch their metabolism in order to produce proteins of interest. This strategy prevents nutrients from becoming the limiting factor. The constant supply of media, especially if it is buffered for pH, can also help regulate some of the ancillary cell culture environmental conditions.

Though there are millions of variations, there are three standard culturing strategies when it comes to this type of cell culture.

Exponential Fed-Batch
High Cell Density Culture
Constant Fed-Batch
 

Exponential Fed-Batch

Exponential fed-batch cell culture is designed to extend the exponential growth phase of the run. As the cells are starting to grow and reproduce, the feed is increased at a rate that is in proportion to the exponential growth rate of the cells. 

Under this strategy the feed rate is considered the growth-limiting factor. Since the cells are increasing at a non-linear rate, the media feed rate must likewise increase exponentially over the course of the run. You essentially give the cells all they can eat and kill the run before the secondary metabolism stage.

The exponential growth phase needs to be tightly monitored for this process to work.

High Cell Density Culture

High cell density culture is typically designed for industrial applications rather than traditional research purposes. The media is more concentrated, and the feeding profile is more tightly controlled to keep a high concentration of cells in the media. This process is typically more interested in a large volume of cells or heterologous proteins as a product.

Constant Fed-Batch

Constant or continuous fed-batch culture is the simplest type of commercial cell culture and has a constant addition of medium. Unlike an exponential fed-batch cell culture, the media feed strategy is independent from the cell growth and remains constant throughout the entire process. 

There are some distinct advantages and disadvantages to fed-batch cell culture. 

Advantages

The cell culture’s productive stage can be extended.
Environmental conditions may be easily monitored with traditional or optical sensing technologies.
As the process is refined, the cost decreases and greater profits are possible.
Through manipulation of substrate availability there is more control over when cells switch from reproduction to production.
The cell culture can be maximized for productivity by changing feeding strategies.
With larger amounts of cells or proteins it is easier to meet a sudden increase in customer demand.
 

Disadvantages

Feeding strategies can become complicated and the equipment for many of the processes is expensive.
Too many cells or too much protein before you’re ready for it can slow downstream processing and increase costs that may not be offset without increased sales.
It can be prohibitively expensive to start.

 

Conclusion

The fed-batch process is considered to be a discontinuous as opposed to a continuous process though it has been refined over the years and the gap is getting smaller. With the ability to seamlessly integrate new monitoring technology for cell culture conditions, and the advances in optimization of fed-batch cell culture, the bioprocessing industry is closer to the hypothetical closed loop systems we all dream about. 

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