July 25, 2021
Scaling up a bioprocess can be challenging, but thorough preparation for scale-up early in the process can mitigate some of the associated risks. Here are three tactics that can help reduce some of the common issues encountered during scale-up.
1. Run experiments at bench scale first
Running experiments at bench scale will help you better understand how scaling up will affect your results. Securing additional bioreactor capacity specifically to simulate conditions at scale in order to test process robustness can be helpful in de-risking scale-up. Whether it’s mimicking the number of generations in case of strain instability or viability issues, or testing the robustness of each step, running experiments at bench scale can tell you a lot about your expected results. For example, you may want to find out the maximum amount of time between fermentation steps that will still yield optimal results.
One common challenge that bench scale experiments can address is that mixing times are longer in larger reactors. Materials that take seconds to mix at bench scale may take minutes at a larger scale. This can be an issue because there might be times when organisms are more exposed to a certain substrate (periods of excess) and times when they are not exposed at all (periods of starvation), which can have a detrimental effect on strain performance. Mimicking this phenomenon at a small scale is beneficial in helping to understand how mixing at a larger scale can affect the process. We recommend using a pulse-feeding strategy to do this most effectively as this can help mimic how strains may respond to cycles of substrate excess and depletion at scale.
Concentrations of gas in liquids vary with scale sizes as well. Changes in scale lead to changes in pressure, which can change the solubility of gas and in turn expose organisms to different levels of a gas. Recreating this phenomenon at bench scale can provide important understanding of how scaling up will affect strain performance at production scale.
Troubleshooting experiments and scale-up can be a difficult process, but Culture can help. Culture's guaranteed bioreactor capacity can be used to support studies that provide insight into the robustness of the process and potential issues that may be encountered during scale-up before you reach that point. Check out this scale-up data from our customer Modern Meadow, who scaled up to 50,000L tanks from Culture's 250mL cloud bioreactors.
2. Prepare for limitations in large-scale fermentors
When running your initial smaller-scale experiments, it’s important to pay close attention to limitations, such as physical constraints, that you may face during scale-up.
A common limitation to anticipate is oxygen transfer rate. Smaller tanks often have higher oxygen transfer rates, whereas larger tanks usually have a limit to the amount of oxygen that can be transferred. If a process is developed at bench scale with high oxygen transfer rates, there is a risk that it won't scale. You can mitigate this risk by understanding mass transfer rates and capping oxygen transfer rates when you run your experiments at bench scale.
When conducting a fermentation process, another potential limitation is feed rate. At larger scales, the slower rate of continuous sterilization of feeds can limit the upper bounds of feed rates that are feasible. This should be factored into feed rate design when developing a bioprocess at bench scale.
A third limitation is the cooling capacity of large-scale fermentors. The metabolism of microbes can generate significant heat, and at a larger scale, the process might not be able to cool down quickly enough, or at all. It is therefore important to design the bioprocess to limit heat production in a way that is compatible with commercial scale facilities.
Additionally, the cost and availability of feedstock can be crucial limitations. If your scaled process requires an amount of feedstock that is beyond your budget, you may not be able to scale the bioprocess in a commercially viable manner. It’s also important to ensure that the feedstock is available at scale.
Lastly, if there is variability in feedstock used at production scale, this could affect bioprocess performance. Factors that could affect feedstock include seasonal variation and inhibitory components in less refined substrates. Testing different lots of feedstock that reflect the variations you might encounter at commercial scale can help inform whether this will be an issue down the line.
3. Communicate with downstream processing partners
Another challenge of scaling up is that several different teams and possibly even companies can work on a single project. When there are many groups involved, it can be difficult to see how distinct parts of the process affect each other. Thus, it’s important to communicate with downstream processing partners to keep them informed of the likely properties of the broth at the conclusion of the bioprocess. For example, factors such as compounds in the fermentation broth from media and feeds as well as biomass concentration can impact downstream processes. By communicating with downstream processing partners ahead of time, you can ensure you’re not negatively affecting their future processes. Culture's Workspaces feature on our Cloud Console makes it easy to collaborate with colleagues at any point in the process.
How to scale your bioprocess
Now that you know some tips for de-risking scale-up, how should you go about scaling up your process? One way to get started is by partnering with Culture, where we provide the bioreactor capacity you need to run experiments at bench scale, and the data visualization tools to analyze your experiments and plan for the next ones. Our team executes your experiments in our cloud bioreactor lab - and you see the data in real time - so that you can understand the robustness of your bioprocess under conditions relevant to larger scales. This, in turn, can mitigate any potential process challenges before costly scale-up runs.
Ready to de-risk scale-up? Start running bioreactor experiments with Culture in less than one month.
An interview with Hardware Engineering Manager and first employee Collin Edington about the new capabilities you can expect from Culture's bioreactors.
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