As cell-line optimization continues to push bioprocess productivity limits, several “loose end” issues persist. These include the use of design of experiment in clone selection, viral contamination, automation, and cell-level engineering.
Automation plays an increasingly significant role in cell-line development, particularly during clone screening and selection. When paired with the appropriate culture ware, liquid-handling systems provide consistency, fewer errors, and rework, and they free lab personnel from repetitive pipetting and sample manipulation.
At Informa’s upcoming “Cell Line Development and Engineering” conference, Jochen Schaub, Ph.D., associate director for cell line and cell culture development at Boehringer Ingelheim, will make the case for automation-driven cell-line screening with his company’s BI-HEX® platform, comprising BI-HEX expression system, cell-line development, and process development including a cell culture media platform.
As a platform, BI-HEX incorporates highly efficient vectors with novel genetic elements, serum-free operation throughout, FACS-based automated single-cell cloning, and high-throughput screening—which, according to the company, enables simultaneous analysis of more than 1,000 candidate clones. Boehringer Ingelheim employs imaging systems for automated cell counting.
“To cover the whole variety of today’s molecule formats, we apply different technologies for product titer determination such as homogeneous time resolved fluorescence or biolayer interferometry,” Dr. Schaub points out. Analyses are integrated within automated, robotic platforms to maximize sample throughput.
Greater insight into mammalian cell biology in the form of advanced systems biotechnology and knowledge of cell-line stability provides a scientific rationale for high-throughput cell-line development. “Despite the considerable scientific progress in these areas, the availability of robust and broadly applicable predictive tools in cell-line screening currently is still limited,” says Dr. Schaub. “Hence clone screening still relies on high-throughput workflows.”
Besides the benefits noted above, automation provides flexibility depending on specific project needs. “Examples are the optional incorporation of alternative single-cell cloning technologies or the early assessment of bioactivity measurements,” says Dr. Schaub.
In addition to continuous optimization of its cell-line development workflows to improve performance and to reduce timelines, Boehringer-Ingelheim has been focusing on early integration of process development ideas into cell-line development.
“Here, the aim is to perform screening in a representative cultivation environment through controlled, miniaturized bioreactor systems versus uncontrolled systems such as deep-well plates or tubes,” Dr. Schaub explains. Cell lines developed in this manner are selected not only for productivity and product quality, but also for performance during scaleup, process development, and for manufacturing.
“Through this combined approach, we recently obtained an increase in product titer by 85% in a 10-day fed batch process in clone selection without any further process development compared to a standard workflow.”