To assess current trends in fermentation and cell culture equipment, BioPharm International turned to Gregory Hermetet, a single-use bioreactor specialist, ATMI LifeSciences; Lyle Peshek, national sales and corporate accounts manager, Nova Biomedical; Falk Schneider, PhD, executive vice president, DASGIP AG; Brad Stasny, product manager, New Brunswick Scientific; and Millie Ullah, PhD, product manager, disposable bioreactors Sartorius Stedim Biotech North America.
Q: Increased titers appear to be leading the industry toward smaller bioreactors for commercial scale MAb manufacturing. Yet there is still a lot of existing capacity with very large bioreactors. How long will it take for the move to smaller bioreactors to play out for commercial production?
Hermetet: It will take years, because processes and platforms need to be altered and redeveloped.
Schneider: We foresee this change happening in the next 5 to 10 years.
Ullah: We do see the industry moving to smaller-scale bioreactors. There are still very large system installations which also have a seed train attached to them, so customers are just not using the larger tanks and continue to use the smaller vessels they already have in place.
Q: What is the current level of interest in perfusion systems?
Hermetet: The same it has always been. I am not hearing about many companies trying to make a move to perfusion. It has its niche, however.
Schneider: From what we see, interest in process development using cell culture perfusion systems is low.
Stasny: Currently, there is strong interest in perfusion systems. The perfusion process increases the product output that is normally achieved from batch-style processes without increasing the overall system capacity. Perfusion processes are currently being used in the development and manufacturing of vaccines in many global markets.
Ullah: We see perfusion to be a growth area at the moment. The market has increased about 30 to 40% in the last few years.
Q: Scale-up always presents challenges for cell culture. Are we making any significant advances toward making scale-up easier?
Hermetet: Yes, there now exist different models that can analyze data and better predict a process at scale. New technology for rapid processing and scaling systems down will aid in making scalability a more predictable piece of the development process.
Schneider: There has been a lot of progress in the last few years. More precise small-scale bioreactor systems, better control, and extensive data logging lead to a much better process understanding. Parallel setups and systematic design of experiments (DoE) approaches help bypass the 5–20 L scale and allow rapid scale-up from 1-L bench-top bioreactors directly to pilot scale.
Ullah: Yes, we offer multi-use systems, and customers can purchase one system with additional vessel accessories and different gas flow rates, which allow them to do both cell culture and fermentation in one system. Additionally, we are developing single-use vessels that can be interchanged very easily.
Q: Currently, there is a lot of interest in applying Quality by Design (QbD) methods such as DoE and multivariate data analysis (MVDA) to bioprocess development. Is this having any effect on the decisions manufacturers make about cell culture and fermentation equipment?
Hermetet: Single-use technologies allow for more rapid development. When combined with QbD, DoE, and MVDA methods, there will positive impacts on development timelines.
Schneider: Yes, today's laboratory equipment is used to support QbD and MVDA. For this reason, open information exchange and (software) interfaces are in high demand.
Ullah: Yes, we sell a lot of small-scale screening systems that allow multiple replicates to be developed at the same time. These small-scale systems offer process monitoring and control so growth parameters can be modeled.
Q: What is the current state of monitoring and control systems for cell culture operations? Are there still significant gaps, either in the ability of available systems to meet industry needs or in the industry's application of existing methods?
Hermetet: The options on the market are good; gaps may still exist with respect to data collection and finding convenient methods to use that data in process analysis.
Peshek: Historically, methods for understanding and controlling bioprocesses consisted of instruments from multiple vendors pieced together to form an improvised closed-loop system. Only recently are systems available that automatically sample and measure key process variables such as pH, gases, nutrients, metabolites, waste products, cell count/viability and osmolality, with bi-directional communication to any OPC-compatible controller. The trend is certainly moving toward single, integrated systems that can reliably monitor multiple process variables in real-time from an online sample and provide real or near-real-time process control.
Schneider: Information management and online data exchange for fermentation and cell culture equipment is essential for state-of-the-art industrial applications.
Ullah: Yes, there are still some gaps. The main one is in situ analysis. For example, online sensors for glucose and lactate currently are not available.