In this podcast and accompanying article, we interviewed Dr. Aline Zimmer, Head of R&D, Advanced Cell Culture Technologies at Merck about the importance of optimizing fed batch cell culture for successful biomanufacturing. Aline discussed how her team has developing new tools and methods for optimizing fed batch culture and the impact this has had on productivity and product quality.
I began the discussion by asking Dr. Zimmer about some of the current tools that help with optimization. She explained that there are three strategy options when it comes to optimization. The first involves analyzing and characterizing spent medium then creating a feed that replenishes the depleted nutrients throughout the 14 day run. The second strategy involves testing a large number of different feed formulations using high throughput screening to find the components that have a positive (or negative) impact on the productivity and critical quality attributes. Then this data can be used to mix a custom feed.The last strategy is great for smaller companies or companies that don’t want to spend the resources on extensive screening. This strategy would be to screen commercially available pre-made feeds to see which provides the best productivity and product quality outcomes.
Next, I asked Aline about the concerns with amino acid solubility and how that has required the use of additional feed steps. She explained that two of the most critical amino acids, L-Tyrosine and L-Cysteine both have solubility issues that make adding them to media a challenge. Her team wanted to create a solution for the difficulty of adding these amino acids to feeds at high concentrations. They began with a literature search, which soon informed them that there was no way to improve the solubility without altering the chemistry of these amino acids and essentially creating a replacement.
I then asked how they went about developing the new and improved amino acids. She said that they began with a brainstorming meeting with the chemistry team and they began to throw new components onto a whiteboard. They then proceeded to test several of these new components in a fed batch system. They evaluated each based on critical quality attributes and selected the best to move forward with.
I followed up by asking her if there was anything during development that surprised her. Aline said that L-Tyrosine was very straight forward and creating a suitable replacement was not difficult. However, L-Cysteine was much more challenging and her team was very surprised to find that after testing more than 50 derivatives that very few were capable of supporting growth and titer. She added that it was very exciting to follow this project all the way from the whiteboard to commercial manufacture of the new products.
Next, I asked what impact did the modified amino acid products have on productivity and product quality? Aline said that there was no impact to productivity or product quality, but added that concentration is important and that titration should be conducted to optimize the correct concentration.
Then I asked her how these new products be used to further optimize cell culture for bioprocessing? She said that they enable the development of a single feed instead of multiple feeds due to solubility issues. This simplifies operations and is more convenient. It also permits the use of highly concentrated formulations, which provides more flexibility.
I ended the interview by asking if there was anything else that she would like to add for listeners? Aline said that she was excited about the new products developed to optimize fed batch culture. MilliporeSigma is committed to developing new tools to improve biomanufacturing processes and create new processes for the future. This includes both fed batch and perfusion applications.