biotech bioreactor in lab

Is your bioreactor’s inefficiency impacting your bottom line?

The opportunity: a more efficient bioreactor could increase your operation’s profitability

From the biotech industry to alternative proteins, manufacturers face pressure to increase their bottom line by building more efficiency into their operations. What sets them apart, though, is a unique ace up their sleeve: bioreactors.

Bioreactors create complex environments that rely on multiple conditions to achieve optimal performance. Slight variations in several factors—cell viability, mixing efficiency, pH, dissolved oxygen concentration, and more—could affect productivity. But dialing in the efficiency of your bioreactor can lead to increased productivity, higher product quality, and reduced cost of goods.

Very often, all it takes are a few relatively simple adjustments to achieve better bioreactor performance. The key is to find out where your bioreactor has suboptimal conditions to determine exactly which adjustments will generate positive business outcomes without impacting product quality. Start with these 3 questions:

  1. Could your bioreactor operate more efficiently?
  2. Is your bioreactor completely mixing its contents in an optimal amount of time?
  3. Is the cell culture adequately oxygenated?

For answers, consider the specific challenge in front of you, then assemble the right expertise—with the right tools, including computational fluid dynamics (CFD) simulations—to help you solve it.

Download our bioreactor efficiency guide to get started.

The challenge: how to improve your bioreactor’s productivity and efficiency

There are a number of reasons you may choose to evaluate your bioreactor’s efficiency. In fact, your team may already know there is a problem.

Manufacturers often register an issue inside their bioreactor during periods of transition. Maybe you’ve changed your cell inoculation protocol, or your process utilities have undergone an upgrade, or you’re expanding your product pipeline. It’s especially common for manufacturers to see a drop in efficiency during one of the greatest transitions of all: the transition from lab to commercial-scale production.

Larger bioreactors introduce new geometric and hydrodynamic challenges compared to smaller reactors, which can influence the health and productivity of the cell culture inside. Even details that may seem relatively minor—like the number of baffles in your bioreactor, or the bubble sizes emerging from its sparger—can have a cascading effect on cell culture production, which in turn impacts your operation’s profitability and efficiency. Deviations as small as a few tenths of a percent can make all the difference between achieving your desired yield.

Dialing in optimal operating conditions in a manufacturing environment can be tricky. Traditional approaches that your scientists might try, like bench-scale testing, often fall flat as operating conditions change drastically from bench-scale to a large-scale bioreactor. It quickly becomes impractical to perform testing at a large scale, due to the cost of procuring raw materials, fabricating multiple bioreactors or occupying bioreactors that should be supporting your production line. Rather than troubleshooting your bioreactors, subpar yields sometimes become your operating expectation and production baseline.

Potential causes of low bioreactor productivity

The lack of a single, standard root cause makes the issue of low bioreactor productivity especially difficult to solve. One of the most common issues has to do with selecting the right scale-up parameters. Specific power, dissolved oxygen concentration, oxygen uptake rate, mixing time, shear rates—the range of critical process parameters is broad, and choosing the specific criteria that are appropriate for your project goals is key to future success.

This due diligence helps your team engineer and modify a bioreactor operating environment that’s appropriate for your situation while avoiding many of the conditions that can impair bioreactor productivity, including:

  • Incorrect or sub-optimal bioreactor geometry and impeller configuration
  • Poor mixing and non-homogeneity
    • Dead/stagnant areas within the volume
    • Low cell viability
    • Poor heat transfer
    • Low turbulence
    • High shear rates
    • Flooded impeller
    • Vortex formation
  • Poor gas holdup/residence time
  • Bubble size distribution and surface tension
  • Low volumetric mass transfer coefficient (kLa)
  • Lack of robust pH control
  • Poor gas sparger design
  • Excessive gas entrance velocity (GEV) from sparger
  • Channeling or bubble coalescence from gas sparger
  • Ineffective stripping of carbon dioxide from the culture

The bottom line: While your productivity problem may have a relatively simple solution, identifying that root problem in the first place requires a tailored approach.

graphic of rating your options rating your options: bad, better, best

Strategies for addressing low bioreactor productivity

icon: bad idea; not a desirable outcome

Adjust your business plan

The last resort.

Manufacturers who take no other action toward solving their bioreactor issues must adjust their business plan to accommodate lower productivity targets and address missed targets to shareholders.

icon: just ok; not good, but not bad

Run real-world experiments on equipment

Selectively useful but often costly and insufficient.

While experimentation can be helpful in certain scenarios (and plays an important role in validation), it’s not an effective way to identify and solve the fundamental engineering problems behind most bioreactor issues.

That’s because operators must interrupt ongoing operations, consume expensive raw materials, tie up valuable space and equipment, and put product batches at risk in order to run experiments. Even after all of that, experimentation alone may not be enough to discover and characterize a bioreactor’s core issue, leaving operators with mounting expenses and no real solution.

icon: happy; a good option and outcome

Run simulated experiments in a virtual environment

Ideally suited for complex challenges like this one.

To get more from your bioreactor, you have to understand what’s going on inside of it. Computational fluid dynamics (CFD) is a powerful form of fluid mechanics that allows you to do just that.

By using the laws of physics to accurately simulate the dynamics at play inside a digital model of your bioreactor, CFD specialists can identify solutions to your productivity issues without tying up real-world resources. It’s like having both x-ray vision (to look inside your vessel) and a crystal ball (to test potential solutions). The outcome is a clear set of engineering recommendations, supported by detailed visualizations, that will improve your bioreactor’s yield.

What does a CFD bioreactor study typically reveal?

A CFD study culminates in a detailed description of tailored solutions and recommendations to help you meet your productivity targets. To support and contextualize these recommendations, your CFD team will provide quantitative results supplemented with rich data visualizations captured from their simulations, including contour plots, vector field plots, and animations.

These visualizations provide an up-close view of the environment inside your bioreactor, showing you how that environment responds to different design adjustments. The output of these simulations gives you the data and actionable steps necessary to improve your bioreactor’s operating conditions. Here are two quick examples of how the output of a CFD simulation has increased a bioreactor’s efficiency:

  • We used CFD to optimize the agitation rate and sparge flow rate for a client’s existing 16,000L bioreactor. The adjustments required no additional capital and more than doubled the oxygen mass transfer coefficient, significantly increasing the yield per batch by intensifying cell productivity.
  • In another instance of optimizing processes within an existing bioreactor, we used CFD to reduce virus blend time by 70% while keeping the shear rate low enough to prevent cell damage. Again, we optimized an existing bioreactor’s processes without CapEx by simply adjusting operating settings.

Typically, a CFD study and the visualizations it produces answer the three questions we highlighted earlier:

icon: bioreactor operations

1. Could your bioreactor operate more efficiently?

While planning for scale-up:

A CFD study can help manufacturers prove scalability from benchtop to pilot-scale manufacturing using similar design aspects. This will give you the insights you need to evaluate a particular bioreactor’s efficiency at scale before you commit to purchasing it.

During operation:

Manufacturers can use a CFD simulation to validate current bioreactor conditions, then model minor cost-saving modifications to test their impact on product quality. With these insights, they can make appropriate adjustments to existing units, or plan for efficiency-driven changes to future units.

A typical CFD study helps guide these decisions by modeling variables such as:

  • Dead zones and dead volume
  • Specific power input (P/V) and impeller power number
  • Turbulent eddy dissipation rate
  • Shear rate
  • Turnover rate
  • Axial and radial flow patterns
  • Impeller configuration
  • Gas sparger design
  • Off-gas concentrations, such as carbon dioxide
  • Pressure (for both high-pressure fermentation or anaerobic fermentation)

During cleaning:

A CFD study can also provide valuable insights into your cleaning process, helping you increase your efficiency between production cycles. In addition to modeling off-gasses and pressure, your CFD team can simulate clean-in-place (CIP) variables such as spray coverage, helping you optimize the number and placement of sprayballs.

icon for faster operations

2. Is your bioreactor completely mixing its contents in an optimal amount of time?

Using a non-reacting tracer, the CFD team can run a transient simulation to identify the mixing time required to reach, say, 95% homogeneity.

CFD simulation of a bioreactor's operating conditions

icon for mixing oxygen

3. Is the cell culture inside this bioreactor receiving adequate oxygen?

To understand whether your bioreactor is meeting the oxygen demands of your cell culture—and which adjustments are necessary—your CFD team will quantify phenomena such as:

  • Gas holdup inside your bioreactor
  • Interphase species mass transfer or kLa-hr (i.e., the mass transfer of oxygen from gas to liquid) with a discrete bubble size distribution
  • Effects of bubble breakup and coalescence

What will your CFD specialist need to run simulations?

If your CFD specialist has lengthy experience working with bioreactors in alternative proteins or in biotech, they’ll be able to guide you toward the data and specifications that are necessary to get started. You’ll likely have most of that information at hand already, such as your vessel’s computer-assisted design (CAD) model and details about its current operating conditions.

With this background information to guide them, your CFD specialist can simulate your bioreactor and test different solutions, ultimately uncovering the precise parameters that will generate your target productivity rate.

Need help moving forward?

Download our CFD guide to get started or talk to our team of experienced CFD consultants to take your first step toward more productive and profitable bioreactor operations.

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