Cell cultures are not homogenous, despite process best efforts. Understanding how inconsistencies impact drug quality is vital for efficient, large-scale manufacturing. Unfortunately, it is also challenging says Roman Zakrzewski, PhD, a process development scientist at uniQure.

“At large scale, the kind of scale that large drug companies will be producing their biologics, it is still unclear whether the environment within a cell culture vessel is truly homogenous,” he continues. “However, it is generally agreed that heterogeneities do exist in these large vessels and studying them at that scale is very expensive and so no one does it.”

Nevertheless, understanding culture heterogeneities is vital for drug makers, maintains Zakrzewski, citing the findings of a research study conducted with former colleagues at University College London.

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

Culture pockets

The study used a miniature bioreactor—an ambr15 from Sartorius—to model a production reactor at small scale. However, rather than try and recreate the entire culture Zakrzewski and colleagues were more selective.

“My approach was to effectively mimic a pocket of cells within a large-scale vessel. The miniature bioreactor was this 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 the industry and are commonly used for cell line screening and process development. What made my approach unique was using them to study fluctuations or heterogeneities. Previous work used larger cumbersome lab-scale equipment that was not high-throughput.”

The next step of the research would be to combine the data into a computational model to predict the performance at large-scale, according to Zakrzewski, adding the aim is to create a tool to assess the likelihood a cell line would be impacted by fluctuations in pH or DO.

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

“Companies are already using these miniature bioreactor systems so implementing my approach within their existing workflows would not be difficult,” he tells GEN. “The time and cost advantages of using miniature high-throughput bioreactor systems for process development are well known the documented. Bottom line: you can test a lot more, faster, and cheaper.”