Accelerate biotechnology

How to scale your adherent cell culture

Meet the expert: Matthijs, Associate Director Upstream Bioprocessing

Cells derived from mammalian species and cultured under artificial laboratory conditions are used to produce complex biological products. As such cells normally grow as a tissue, most available artificial mammalian cells are originally surface-dependent. They are called adherent cells. Adherent cells will only duplicate and produce a desired product when attached to a surface. Hereto, scientists have traditionally used so called 2D platforms, like roller-bottle and cell-factory formats. Unfortunately, these systems are very labor intensive, need lots of floor space, allow limited process control like pH and Dissolved Oxygen and are poorly scalable. Therefore, these 2D formats are less favorable for a commercial manufacturing process.

For this reason, scientists have developed cell lines capable of growing in suspension. However, in some cases suspension cell lines, like MDCK and Vero, are not fit for commercial manufacturing. Phenotypic changes of these cells lead to either tumorigenicity or lack of productivity. A good alternative for adherent cell culture are microcarrier based processes.

Microcarrier process development

Microcarriers are beads to which adherent cells can attach and thereby retain their ability to proliferate and produce product. Microcarriers made it possible to grow adherent cells in stirred bioreactor systems. This setup results in reduced labor intensity, and a reduction in floor space. These factors in turn result in significantly lower Cost of Goods compared to the traditional 2D formats. Furthermore, microcarrier processes have better process control compared to the traditional systems, allowing production output to be monitored and tweaked.

Developing a microcarrier based cell culture process requires fine tuning of process parameters which is an expert job. A good balance between working volume, pH conditions, Dissolved Oxygen and shear stress is pivotal. Thus, to develop a microcarrier based cell culture process requires an experienced team, but, once optimized, such a process can be smoothly applied in a scalable bioreactor up to 1,000 L.

Latest advances in microcarrier based cell culture

There have been a number of important advances in microcarrier based cell production tools and technology. New surface materials, such as biomimetic surfaces, allow for better cell attachment. Other materials, such as temperature-sensitive surfaces allow for more efficient ways to release adherent cells from the microcarriers and re-attachment of the cells to new microcarriers. This process of release and re-attachment is critical for cell scale-up to large bioreactor volumes or during product harvesting. Other notable improvements are innovations in cell culture media, like the availability of animal component free and thereby very safe raw materials. That said, the optimal production method is known to vary per cell type, product and production scale and therefore needs expert attention to move from bench to clinic.

Design of Experiments

There are many factors to consider with the development of an adherent cell culture-based production process. It is essential to first employ a small scale high throughput screening platform in combination with a Design of Experiments (DoE) approach. This tool allows high throughput optimization of critical parameters with minimal amounts of material prior to scale up to a robust process. My team at Batavia used DoE in combination with small scale screening to develop a novel microcarrier based production process for a customer. The starting point of this project had been a T-flask adherent cell culture process. We were able to increase production output by 2-fold, reduce the footprint by 4-fold and reduced CoGs by 2-fold. Also, the process proved to be robust for scale-up to commercial production. Naturally, we were proud of this result and look forward to our next process development challenge.

 

We are dedicated to help bring biopharmaceuticals to the market at higher speed, with reduced cost, and with higher success rate. Batavia Biosciences has vast experience in transferring adherent cells to microcarriers. Consider this a viable option for your adherent growing cell line that produces your valued product. With our team of experienced researchers, using the newest technologies and techniques, we are well equipped to take on any challenge associated with adherent cell culture.

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Upstream process development

Clinical manufacturing

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