Pocket heterogeneity models to improve cell culture performance

Cell cultures are not homogeneous, despite the best efforts of the process. Understanding the impact of inconsistencies on drug quality is essential for efficient large-scale manufacturing. Unfortunately, it’s also a challenge, says Roman Zakrzewski, PhD, process development scientist at uniQure.

“At large scale, the kind of scale at which big pharma will produce their biologics, it’s still not clear if the environment in a cell culture vessel is truly homogeneous,” he continues. “However, it is generally accepted that heterogeneities exist in these large vessels and that studying them at this scale is very expensive and therefore no one is doing it.”

Nonetheless, understanding cultural heterogeneities is vital for drugmakers, argues Zakrzewski, citing the findings of a Research study conducted with former colleagues from University College London.

“There are many reasons why it is important for pharmaceutical companies to fully understand the environment within their vessels. My work focused on understanding the impact of heterogeneities on the performance of cell culture and the quality of the biological they produce. By understanding this impact, companies can design or select better cell lines that would be more robust or resistant to these heterogeneities,” he explains.

Cultural pockets

The study used a miniature bioreactor – an ambr15 from Sartorius – to model a small-scale production reactor. However, rather than trying to recreate the whole culture, Zakrzewski and his colleagues were more selective.

“My approach was to effectively mimic a pocket of cells in a large-scale vessel. The miniature bioreactor was that pocket. I fluctuated pH and DO to test the effect this had on cell culture performance and product quality,” he says. “Miniature bioreactors are quite ubiquitous in industry and are commonly used for cell line screening and process development. What made my approach unique was to use to study fluctuations or heterogeneities.Previous work used bulkier and larger laboratory equipment that was not high throughput.

The next step in the research would be to combine the data in a computer model to predict large-scale performance, Zakrzewski said, adding that the goal is to create a tool to assess the likelihood of a cell line being affected by fluctuations. of pH or DO.

And, for the industry, the potential benefits are worth the investment, Zakrzewski believes.

“Companies are already using these miniature bioreactor systems, so implementing my approach into their existing workflows wouldn’t be difficult,” he said. GEN. “The time and cost advantages of using miniature, high-throughput bioreactor systems for process development are well known and documented. The result: you can test much more, faster and cheaper.

Helen D. Jessen