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Volume 32, Issue 1
Automation in cell-line development and cell culture is leading to more consistent quality while improving efficiency, and, ultimately, speed to market.
A stable, high-expressing cell line is a must for commercial biopharmaceutical production, but cell-line generation and cell culture have traditionally been manual processes, requiring hours of repetitive, meticulous work. Not only are these processes low throughput, they are also vulnerable to human error (1,2). Nurturing living cells requires optimizing and controlling process conditions throughout the cell culture cycle, during cell growth, harvesting, reseeding, and analysis. This requires careful control of media conditions as well as freezing and thawing rates to ensure viable and consistent cell lines (1).
Automating mammalian cell-line development and cell culturing can not only speed up processes and offer consistent operation but can free up time for technicians to focus on other tasks. It also allows the date and time of cell growth as well as cell type to be scheduled, so that researchers and developers will know when the cells will be available for screening or for research projects (1).
For technicians, automation reduces the risk of injury caused by the repetitive strain that is often associated with continuous manual tasks, thereby improving overall efficiency. Robotics can achieve a level of consistency in procedure and sterility that is difficult for even the best-trained technicians to reach. This consistency results in less batch-to-batch variability, and removes the lag time typically experienced at the beginning of a week because cells are not usually cared for over the weekend. Automated systems also allow the production timeframe to be shortened, enabling quicker scale-up.
In order to be fully automated, however, a system should be able to provide both an environment within which cells will grow as well as the capability to monitor that growth without the need for human interaction. In addition, automated cell culture systems should be able to run unattended over the course of days or weeks while allowing technicians to evaluate pH, nutrient/waste levels, and cell concentration and viability (1).
A number of automated platforms for cell line development have been useful in reducing development costs and increasing throughout for biopharmaceuticals. One platform based on the Cello robotic system developed by The Automation Partnership-now known as TAP Biosystems-screens for colonies and expanding static cultures.
In a study in which Lonza Biologics’ glutamine synthetase expression system was used for therapeutic monoclonal antibody (mAb) production in Chinese hamster ovary (CHO) cells, the automated approach resulted in cell lines that were of equal quality to traditionally generated cell lines. According to researchers involved in that study (3), the automated system permitted a three-fold increase in the number of development projects that could be done, while maintaining the same manual workload.
Automating cell assays facilitates quality cell-line development by improving the quality of assay results and enhancing throughput. Recently, biopharmaceutical developers have been focusing on compact and scalable automated low-to-medium throughput systems that are flexible enough to adapt to changing needs (4).
Various factors can still limit productivity in cell-based automation, including:
No single factor predominates, so improving productivity may involve improving multiple parameters (4).
One example of recent automation advancement has been the establishment of an integrated high-throughput, automated platform for developing the cell lines used to manufacture protein therapeutics. The integrated approach combines a cell sorter, a clone cell imager, and a liquid handling system, enabling high-throughput screening and a more efficient process for developing cell lines, according to a study. (2). The integrated process can screen approximately 2000–10,000 clones per operation cycle.
According to the study, the integrated process has been used to manufacture high-producing CHO cell lines, which are then used to produce therapeutic mAbs and their fusion proteins.
By using different types of detecting probes, the method can be applied to the development of other protein therapeutics or be used in other production host systems (2). The platform offers the advantages of significantly increased capacity, ensured clonality, traceability in cell line history with electronic documentation, and much less opportunity for operator error.
Automation is beneficial in that it allows biomanufacturers to take advantage of the latest cell culture technologies. Manual operations, no matter how efficiently carried out, will always be limited by throughput, according to Bhagya Wijayawaredena, senior applications specialist, Beckman Coulter Life Science, in a webinar (5).
“Most screening experiments require you to look at thousands of cultures at one time. It is impossible to achieve that throughput manually. Also, automation allows you to use low-region values, using 384-well plates instead of 96-well plates. This could drive your reagent cost down,” Wijayawaredena said in the webinar.
Another compelling reason to use automation in cell culture is to address the long workflows involved. “Cell-culture workflows take weeks, sometimes even months, to complete. Timing is very important,” Wijayawaredena affirmed. “Instead of coming during the weekend to check the confluence of your cell culture, for example, you can program the liquid handler to do that,” she said. There is only so much that one can do manually, especially with a limited staff, she said, adding, “You want your staff members to [perform] more productive tasks than protein pipetting. Furthermore, by using automation, you eliminate the human-to-human variation in pipetting, thereby improving [overall] reliability and the quality,” Wijayawaredena said.
Among the advancements in automation for cell culture are 3D cellculture techniques, which have been receiving much attention from scientists in recent years, Wijayawaredena noted in the webinar. These 3D techniques provide more accurate models of tissues. Most recently, the cell-culture field has been moving more toward continuous cell culture, which includes continuous feed addition, cell maintenance, and process control, she said.
1. M.E. Kemper and R.A. Felder, The Journal of Laboratory Automation (formerly The Journal of the Association for Laboratory Automation) online, DOI: 10.1016/S1535-5535-04-00183-2, April 1, 2002.
2. S. Shi, R.G.C. Condon, L. Deng, et al., J Vis Exp. online, DOI: 10.3791/3010, Sept. 22, 2011.
3. K. Lindgren, A. Salmén, M. Lundgren, et al., Cytotechnology online, DOI: 10.1007/s10616-009-9187-y, Mar. 21, 2009.
4. J. Comley, “New options for Cell-Based Assay Automation,” www.ddw-online.com, 2005.
5. B. Wijayawaredena, “Advances in Cell Culture Technology,” webinar on www.labmanager.com, Aug. 3, 2018.
Volume 32, Issue 1
When referring to this article, please cite it as F. Mirasol, “The Role of Automation in Cell-Line Development,” BioPharm International 32 (1) 2019.