Continuous upstream processing (perfusion) is not a new concept in the bioprocessing industry. Genzyme, Bayer, Centocor, and other companies have been implementing perfusion processes for many years. However, interest is now growing for extending this concept to downstream operations to create fully integrated continuous processing. During the past year, Genzyme has presented on and published about its advancement toward the development of an integrated continuous system (1). The company has completed proof-of-principle development at laboratory scale with different molecules, and the results, says Konstantin Konstantinov (vice president, commercial process development) have been “highly successful and very exciting.” I spoke with him about the technologies involved in a completely integrated continuous process and how it may affect the design of future facilities.
BPI: What are the first steps toward developing a continuous process?
KK: Our starting point is to focus on the process objectives first and then think about the facility. The process is the driver. We want to design a process that is universal, flexible, and very standardized. At the end of the day, we want to have a platform that can be used for any therapeutic protein. This is generally what happens in many industries when they mature: They come up with one harmonized process, often referred to as “the dominant design.” This is what Genzyme is trying to develop — the dominant design of the future.
BPI: How does a continuous upstream process affect downstream?
KK: The downstream conversion into continuous is more interesting than the upstream. I started working on perfusion processes more than 25 years ago, so it is not something that is very unique or that the biotechnology industry recently invented. It is improving, however, because we are using better cell lines, better media, and better cell-retention devices that allow us to operate at very high cell densities.
The newer concepts are in continuous downstream operation. Genzyme has converted the first step (capture) into continuous processing. It is directly integrated with the perfusion cell culture process without any equipment between the two operations. So the harvest hold tanks, microfiltration, and centrifuges, are all removed.
Downstream steps are integrated with the upstream steps; all the flow rates are adjusted to be the same. Integration requires that harvest coming out from the perfusion bioreactor is continuously loaded onto the capture columns directly. It should be compatible with the pH, osmolality, and other parameters without many adjustments. We try to ensure that cycle times and hold times are minimized or completely eliminated for rapid processing, which is especially beneficial for proteins that are sensitive to degradation during any hold steps.
BPI: Continuous processing has been used in other industries. What can biomanufacturers take as “lessons learned” from those industries?
KK: It's a lot, actually. I mentioned that biotech companies have worked on continuous upstream quite a bit. But Genzyme's understanding and vision of integrated continuous processing has significantly evolved over the past three years or so. There are many industries that started as batch, but over the years they have converted to continuous (for example, steel, petrochemical, glass, paper, food, some chemical and pharmaceutical). If you read books and articles related to this, you will discover that despite the diversity of these industries, the driving forces to convert to continuous are always the same. Those industries make changes for same reasons that are completely applicable to biotechnology — with the exception of one in the petrochemical and chemical industries. which cannot include hold steps because some intermediates are highly explosive or toxic. All other business drivers are exactly the same.