Spotlight on VALIDOGEN’s strain and process development program

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Spotlight on microbioreactors supporting Pichia protein production strain selection and bioreactor cultivation process development 15.12.2021
Microbioreactors supporting microscale Pichia strain selection and bioreactor cultivation process development

VALIDOGEN has recently implemented microbioreactors to further advance the benefits of its UNLOCK PICHIA technology platform.

Microbioreactors are used as an intermediate step to support
1. VALIDOGEN's high-throughput microscale strain development and selection procedures
2. VALIDOGEN's bioreactor cultivation process optimization workflows

  • Key benefits of microbioreactors for VALIDOGEN's strain selection and cultivation process development
  • Time- and resource-saving intermediate step between microscale- and bioreactor cultivation
  • Intermediate step to narrow down the number of promising clones identified in microscale screening
  • Tightly controlled bioreactor-like conditions (methanol-induced and methanol-free production)
  • Predictive of bioreactor cultivations
  • Enables simultaneous cultivations with a variety of experimental conditions (DoE)


1. VALIDOGEN`s advanced protein production strain development supported by microbioreactors

VALIDOGEN has recently broadened its strain development capabilities with a microbioreactor system serving as a time- and resource-saving tool for Pichia pastoris strain development. With the company‘s established high-throughput protocols for comparative microscale cultivation in 96-deep well plates, thousands of clones can be screened in minimum time and most promising clones will be reliably identified already at microscale.

However, in cases where a larger number of similarly promising clones are identified in 96-deep well plate based microscale screening, microbioreactor cultivations can be performed to rapidly compare these clones under more tightly controlled conditions as an intermediate step to narrow down the number of promising clones or already select the final producer clone(s). A confirmation of strain performance is then conducted in larger bioreactors.

Therefore, microbioreactor cultivations represent a powerful support for clone selection during early upstream development in microliter scale.

Key benefits of VALIDOGEN`s optimized microscale cultivation and screening procedure

  • Thousands of clones screened in parallel in minimum time
  • Fast and reliable identification of high-performance production clones
  • Results of microscale screening transferable to larger scales


2. VALIDOGEN's bioreactor cultivation process optimization workflows supported by microbioreactors

In addition to the benefits for VALIDOGEN`s Pichia strain development procedures, microbioreactors represent an appealing alternative to larger lab-scale bioreactors for cultivation process development including Design of Experiment (DoE) programs. While results are conclusive for bioreactors, the small reactor volumes and shortened cultivation time as well as the fact that a number of process parameters (such as temperature, pH and feed) can be efficiently controlled, render microbioreactors a powerful cultivation process development tool. This facilitates simultaneous cultivations with a variety of experimental conditions to be carried out in a time- and resource saving manner.

Case study demonstrating the integration of microbioreactors in bioreactor cultivation process development
In order to demonstrate the usefulness of microbioreactors in bioreactor cultivation process development, we performed a DoE based study with a Pichia pastoris strain producing a bivalent VHH. We performed a full factorial design comprising 16 microbioreactor runs (4 factors, 2 levels), each run was carried out in duplicate.

Investigated factors

  • amount of N-source
  • pH value
  • feed composition
  • feed rate

Results and confirmation in lab-scale bioreactors
As a result of this study several parameter sets yielding enhanced productivity were found and interactions between factors depending on their respective levels were elucidated.

Lab-scale bioreactor cultivations applying these optimized conditions confirmed the findings from the microbioreactor DoE. With the time- and resource-saving application of microbioreactors in this study, a ~40% improvement in VHH yield in comparison to standard conditions was achieved, clearly demonstrating the usefulness of microbioreactors for bioreactor cultivation process development as well as the sound transferability of results from microbioreactors into lab-scale bioreactor.

Please contact us if you are interested to learn more about VALIDOGEN's strain development or any other service.

Iskandar Dib - iskandar.dib@validogen.com
Thomas Purkarthofer - thomas.purkarthofer@validogen.com

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