PROCESS PERFORMANCE: BIOREACTORS AT SCALE
Q: In the methodology used to assess process performance, you followed the same methods for both the SSBs and SUBs whenever
possible, using the same media lot, inoculum train, and harvest methods. How do the SUBs at scale compare to SSBs from the
product quality perspective?
We carried out an analysis of supply campaigns of six different therapeutic proteins from SUBs. The product was always comparable
to SSBs regarding ion exchange chromatography and glycosylation pattern. Until now, no differences in product quality between
products from classic fermentations and fermentations in SUBs have been observed.
Q: What differences did you see in the performance of SUBs from the different suppliers.
Capability of meeting basic Roche specifications: We worked with vendors on bag design and observed differences in reliability and the control systems. Notably, the user friendliness
of the control systems differs greatly.
Robustness and reliability: This varied considerably from supplier to supplier. We would not expect this to be the case today, but in 2008, there were
quite a few prototypes on the market. Since then, the technology has evolved and in the majority of cases the reliability
Quality systems: There are remarkable differences in the quality systems of different vendors. Some companies have very comprehensive quality
systems mirroring biopharmaceutical operations, in compliance with cGMPs. There are differences in staff resources at the
different companies. These differences impact directly on project timelines and the relative risk of working with a given
Q: Even with the leading supplier, three different bag types were evaluated. Does this reflect the feedback you were giving
Yes, for optimization of some parts of the bioreactor, a different bag design would improve some engineering aspects. Being
able to handle the bag more easily, improving the bag systems to better fit our needs in terms of mixing times, and so on.
Q: You say that to maximize reliability, it is important to minimize connections and use tube welders instead. Can you elaborate?
This is related to the fact that in total we have far more than 100 bioreactors running just in our R&D pilot plants in Penzberg.
As we install the SUBs in stainless steel facilities, the staff, working in shifts, will be working with both SUBs and SSBs.
Operation mode of the tube welders is less operator dependent, and has less risk of errors. Connectors are not an issue for
a company who has only SUBs and is used to these connectors.
Q: Your evaluation showed problems using conventional sensors in an SUB and great potential for single-use sensors. Are you
happy to rely on the single-use sensors?
Yes, there is poor reliability of class in sensors caused by the absence of grounding and harsh autoclaving procedures. We
are working with single-use sensors and the parameters that need improvement with single-use sensors such as DO2, pH, and CO2. A lot of progress has been made in the last year. A lot of new products will be coming on the market.
Q: There are many types of single-use sensors available. What would you recommend in terms of essential key features?
Pre-calibrated, ready-to-use sensors should be drift free, have full USP Class VI certification, and have the possibility
of being recalibrated. Another important aspect is being able to measure pressure. This is very important as a security measure
if, for example, the exhaust filter is blocked because of condensate, clogging exhaust systems, or if you have foaming. A
pressure sensor on an SUB is very helpful in routine use.
Q: What are the big areas for improvement in terms of the overall design of SUBs?
We currently buy the bags with the filter preassembled on the bag, and in most cases the filter could be reused. We should
therefore look at designs that enable us to connect and disconnect the reusable filter to a second single-use bag. We currently
throw the filter away with the bag so there could be substantial cost reductions made here. The other point is that when we
want to connect a single-use system to stainless steel, there are not many connectors that are reliable and available in the
right dimensions, which means working with hybrid arrangements is actually quite difficult.