Table of Contents
- Introduction
- Scale out - scale up by unit
- Scale up - scale up by volume
- Disposable or single use bioreactors
- References
Introduction
If you ask 100 people how they would do something, you would hear at least 70 different answers. There are multiple ways you can do things, and the same goes when planning a scale up process for your bioreactor system.
Let’s go through the different approaches of scaling up including a closer look at their advantages and disadvantages!
Scale out - Scale up by unit
Scale out is a method that focuses on horizontal growth of the process, by adding new resources instead of increasing the capacity of current resources. Simply put, it means that bioreactors stay at smaller volumes, but the number of bioreactors used increases.
When using a scale out approach T-flasks or roller bottles can be used as bioreactor units.
T-flasks vary in surface areas and can be filled with different volumes. Gas exchange is taking place through the vented filter caps. They are mostly used for adherent cell culture as T-flasks with treated surfaces allow cells to attach to the bottom. This is useful especially in tissue engineering, and with stem cell lines and primary cell lines.
Roller bottles have a large surface area for attachment, where the medium is put on the bottom while the bottles roll. This way the cells attached to the walls have a constant supply of medium on a larger surface. The turning of the bottle is responsible for mixing and OTR. In the past, this system was used for vaccine production with adherent cell lines.
ADVANTAGES: If you want more product you simply use more bottles. You do not need to build a new bioreactor. It is a proven technology, if it works in one bottle it will work in all of them. If one is contaminated you can just throw it away, but if you have a lot of them, the contamination rate can get higher. In addition, they are disposable and thus easy to use.
DISADVANTAGES: Scale out requires a lot of space and labour. All this makes it cost-intensive. Variations between the flask and bottles mean that samples are not representative for all, which consequently means quality can thus deviate.
Scale up – Scale up by volume.
Scaling up refers to an increase according to a fixed ratio. Instead of adding new vessels, you increase the magnitude and the power of the existing bioreactor.
Stirred tank reactors are the most common to undergo scaling up. Depending on the size of production or R&D you are planning on having, we can divide bioreactors into three scales:
- Laboratory scale, from 0.5 to 10 L
- Pilot scale, from 50 to 200 L
- Industrial scale, from 500 to 5000 L
If the main intention is R&D and you just want to observe how your cells behave, the lab scale bioreactor, benchtop size, is the way to go.
Once you finish the R&D and would like to test the cells’ performance on a bigger scale, you can move on to a pilot bioreactor. These are the last stop before starting full-scale production, usually operating at up to 50% of the predicted full-size production line. It’s the pre-commercialisation stage, the last testing ground before the final step.
The final step is the industrial-scale of bioreactors, offering enough working volume to produce larger quantities of your desired compound.
You scale each bioreactor up by volume while trying to maintain sufficient oxygen supply (more on that in our blog on oxygen transfer) and minimal shear forces (more on that in our blog on shear forces).
ADVANTAGES: The main advantage is having one system with homogenous conditions, meaning that all cells experience the same conditions and have the same quality product. In addition, scaling up to large quantities is possible.
DISADVANTAGES: Scale up is technically challenging and difficult, as well as time intensive. You have to study conditions in the bioreactor at all stages. Even after studying the old conditions and applying them to the new scaled-up bioreactor, there is always a risk of failure at another scale. Gas transfer and mixing have to be sufficient to maintain cell growth. In addition, cleaning and autoclaving for bigger systems takes a lot of time and resources. If contamination occurs, the whole batch has to be thrown away, including the expensive medium and product.
Disposable or single use bioreactors
Currently, in scale-up, disposable reactors are becoming more popular due to the ease of use and lower operating and validation costs. By using disposable bioreactors you save time on cleaning.
For example, a wave bioreactor works by having the medium liquid in a bag. Rocking or turning of the bag is responsible for mixing, which creates wave patterns over a large surface area. These patterns and a large shallow surface area make oxygen transfer very efficient.
ADVANTAGES: As mentioned before disposable reactors are popular because they save time and they have reduced validation. In turn, this leads to being able to do more runs in the same amount of time.
DISADVANTAGES: Disposable bioreactors are expensive, especially if you look at the good quality of plastic. This in itself is very important as plastic components can leach into the medium if the quality is bad. Scaling up is limited at 2000L due to the pressure that builds in the bag.
References
- Scale-up of industrial microbial processes (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995164/)
- Scale-Out Biomanufacturing – A Paradigm Change to Scale Up (https://cellculturedish.com/scale-out-biomanufacturing-a-paradigm-change-to-scale-up/)
- Single-Use Bioreactors: To Scale Up or Scale Out? (https://www.biopharminternational.com/view/single-use-bioreactors-scale-or-scale-out)
- Single-Use Technologies in Bioprocessing: How Far Can They Go? | Technology Networks (https://www.technologynetworks.com/immunology/articles/single-use-technologies-in-bioprocessing-how-far-can-they-go-288520)
