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Bioprocess Optimization

Reducing batch variability and improving yield

Biologics production is a complex process that relies upon the interplay of several bioprocess parameters to influence yield and quality. As a result, batch-to-batch variation can become an issue. Many of the factors contributing to batch-to-batch variation begin in the upstream process. Upstream refers to the generation of product via cell engineering and cultivation. Cell culture conditions must be tightly controlled at this stage to ensure consistent results. Bioprocess optimization through enhanced control can help to improve reproducibility, reduce batch-to-batch variations, and increase yields and product quality, helping to save time and money in biologics production. This is especially important when seeking to scale up or for performing a process validation. Here, we will consider the factors that can contribute to inconsistent results and offer strategies to increase the reproducibility and productivity of cell culture bioprocesses.

How can bioprocess reproducibility be improved?

Find information on how to achieve consistent cell quality and process conditions.

Fine control of process conditions

Fine-tuning the control of your bioprocess is critical to ensure quality, yield, and batch consistency of the product produced. You can automatically gain information about your process by implementing Process Analytical Technology (PAT). PAT can provide real-time monitoring of critical process parameters (CPPs), such as pH, DO, temperature, cell density, cell viability, nutrient concentrations, by-product concentrations, and help to keep these within a defined range. When incorporated into bioreactor control systems, PAT can be used to acquire data in real-time and use it to leverage feedback loops, for automated, in-process parameter control. For example, it is possible to automate culture feeding based upon the glucose concentration in the medium. By automating bioprocess control, stress on the cells can be reduced significantly, and form a sound foundation for optimal performance.

Robust calibration of sensors

In order to deliver reliable readings, the sensors in your bioprocessing equipment need to be well-maintained and frequently calibrated to ensure high precision. Failure to do so will result in inconsistent cell culture conditions and could lead to batch-to-batch variability or batch failure. One solution to increase reproducibility is the use of bioprocess software for guided calibration. For example, the Auto Calibrate software feature of the Eppendorf BioFlo® 320 and BioFlo® 720 bioreactor control systems can automatically calibrate DO sensors according to the preferred calibration methodology, providing reliable and reproducible results every time.

Interested in how to increase the reproducibility of cell culture bioprocesses? Check out our e-book .

Ensuring consistent cell quality in bioreactor culture

When it comes to establishing cell cultures, the first challenge is the variable status of cells used to inoculate the bioreactor - known as the inoculum - at the beginning of a bioprocess run. Before the inoculum is added to the bioreactor, it is important that cells have been maintained in their optimum state throughout each stage of the upstream process, from cell thawing, right up to the bioreactor culture phase. The inoculum quality can have a large effect upon the product quality and yield. When culturing cells in flasks, remember to
  • Monitor cell growth in your shake flask culture – Take note of your flask culture data, including cell density and metabolites. Creating a growth curve can be an effective way to see if your culture is on track.
  • Optimize your passage schedule – Ensure that you split your cells at the optimal time point in their growth phase. Too frequent passaging can hinder cell density, while too infrequent will cause metabolite build up and affect viability.
  • Keep your flask in optimum conditions – Ensure that flasks are kept in an incubator with optimized temperature, plus CO2, oxygen, and moisture levels. Make sure that flasks spend minimal time outside the incubator for monitoring/passage.
  • Keep track of pH levels – Try and keep the pH level in the flask and in the bioreactor medium at a standard level to avoid pH shock. In-flask pH monitoring systems is useful for this.
Keeping up with each of these steps ensures that the cells remain in optimal conditions at the time of inoculation.

Want to learn more about inoculum optimization in a cell culture scale-up workflow? Check out our application note.

Application Note
PDF 1.4 MB

How can bioprocess yield and productivity be improved?

Find out more about choosing the right process mode.

Choose the best process mode for you

One of the best ways to improve yield is to consider the optimal process mode for your bioprocess. A variety of culture strategies including batch, fed-batch, and perfusion culture exist to help you optimize quality and yield. Read, how process modes for antibody production were compared at bench scale.

Optimize cell culture perfusion at small scale

Bioprocessing in perfusion mode is a powerful tool to increase the volumetric productivity of your bioprocess. Read more about how to optimize perfusion using alternate tangential flow filtration (ATF) at small scale and how to set up a perfusion process using a packed-bed bioreactor.

Solutions for bioprocess optimization

It may seem obvious but ensuring that your cell culture conditions are optimized throughout your bioprocess is a powerful way of ensuring that you gain the best yield possible. By following the steps mentioned above, you can ensure that your cells are kept in the most optimal conditions possible and are in perfect conditions to produce strong yields of high-quality product every time.

Eppendorf has a range of bioprocess control solutions to help you with optimizing your process, including but not limited to:

  • DASbox® Mini Bioreactor System : Designed for small working volumes and parallel experimentation, it can boost your bioprocessing research and early process development.
  • DASware® control bioprocess control software : Enables bioprocess monitoring and control and the integration of analytical devices to your bioreactor system. Along with the DASware® software suite, this is a valuable tool for experimental design.