Dr Peter Levison discusses innovations in upstream and downstream bioprocessing with BPI Europe and shares his insights on the most successful innovations to date and their impact to bioprocessing operations.
Q: What has been the most successful innovation in upstream bioprocessing to date, and how has this innovation impacted bioprocessing operations?
A: This may not seem like the most likely answer, but in my mind the latest generation of depth filters has been a very powerful innovation for upstream processing. Bioprocessing trends have continued to evolve and single-use technologies have become a very mainstream approach to drug manufacturers, particularly when they need to accommodate very shifting drug profiles. Yet this presents a new challenge when you look at the clarification step. In traditional stainless steel facilities where people may be operating bioreactors locked in at about 10 000 liters, then continuous centralization has been probably the mainstay approach, with also some limited use of depth filtration. The challenge with depth filtration is that historically it dealt with cell densities of up to about 20 million cells per mL, but with recent developments in the biotech space with increased cell densities and higher titers, we’re now being faced with processes where cell densities may be 30 million cells per mL. A consequence of that and changes in single-use means that people are moving their bioreactor volumes down to say 2000 liters and when you get to a 2000 liter scale, centrifugation doesn't become the most attractive proposition. It is quite expensive to install, it is a capital item of equipment, and it really does not lend itself to single-use supplications. Depth filtration starts to become the method of choice, but there was then a requirement to improve depth filters. There have been advances in depth filtration in the last two to three years, where new designs of depth filters are developed, with new depth filtration media; an example being our Stax™ mAx clarification platform. These advanced depth filters will enable you to handle feed streams with cell densities more than 30 million cells per mL. That really has been a tremendous enabler to advance upstream processing and hopefully will enable a very flexible platform for processes going forward.
Q: Same for downstream bioprocessing: what has been the most successful innovation and what are its impacts on bioprocessing operations?
A: Downstream is a slightly different situation I would say in that there really have not been any notable innovations in how you do downstream processing. The process, the unit operations that are done in downstream, have remained constant over the last 10 to 20 years. Yes, there are slight differences in modalities, in different types of chromatography products, in different types of filters, but the basic train of unit operations remains constant. I think it's more the integration, the ability to take one unit operation and connect it directly to the next unit operation. That has really been enabled with single-use where one can introduce aseptic connectors, like the Kleenpak™ Presto connectors that we offer and the various single-use manifolds that can be designed to meet the requirements of the process. It is that connectivity that is probably the area, if you like, of innovation. Maybe innovation is not quite that the right word, but it is an incremental improvement to enable you to do things in a more streamlined and simplified manner.
Q: Have these innovations made integration between upstream and downstream processes easier, more useful, more efficient and streamlined?
A: Yes, I would say they have. Traditionally batch processing was the sort of modus operandi, and is inherently more disconnected. They are step-by-step operations, and as I mentioned in the upstream, more effective clarification with these advanced depth filters gives you a flexible solution. Having the ability to be able to handle and process the contents of the bioreactor in a more efficient way, enables you to then integrate with the downstream process. The downstream process can be done continually either through a continuous process or a semi-continuous process, the so-called hybrid operations. I think what people are now doing is looking at where are the real pinch points and bottlenecks in their process and then looking to address them bit by bit, by changing the way that a certain unit operation is done, to optimize the overall productivity of the process. I think that's how people are making the efficiencies were seeing.
Q: What improvements still need to be made in upstream processing technology?
A: One of the challenges with upstream processing is the use of perfusion systems. There is a lot of interest in bringing perfusion systems fully into the commercial space. We have seen a lot of interest and a lot of new processes being developed in perfusion over the recent two or three years. Perfusion by its nature does require the generation and delivery of a very continuous feed stream, and that does require cell retention devices and cell retention technology. Whilst there are technologies available which work and are widely used, I think there are still concerns about the robustness and the consistency of that clarification. So, really, we do need to come up with a very robust, very reliable cell retention technology which enables you to run a perfusion bioreactor for many weeks knowing that every single minute of every day you are getting a consistent feed coming out of that bioreactor, subject obviously to the slight variability of the living system that you're dealing with. This enables you to have a consistent feed going on to the downstream processing steps, so I think that is still a gap that is partially solved.
Q: What improvements still need to be made in downstream processing technology?
A: I think because we are now seeing more of these connected processes, there's a need for real-time analytics and control. There are advances being made, but we need to have a real portfolio of rapid online and at line analytics, so that you know what is going on in the process, in real time. If you are connecting things, then you need to know what is happening. Although we are seeing advances and we are seeing new techniques coming out all the time, I think there is still a ways to go. I imagine the next five years will be quite innovative with many new product introductions coming out as we go further down.
Q: What are "next-generation" biomanufacturing facilities, and what improvements/advancements do they offer?
A: I think with the widespread adoption of single-use with these smaller facilities which need to be quite flexible, then modular designs are coming online where you can build a system facility literally within one or more modules. These modules are preassembled, literally craned into place on your site and set up into operation very quickly. These really do give a great deal of flexibility to the end user. It is much faster to implement once it is installed and operational. You can rapidly interchange and interconnect various components within the module. Also, if you want to scale up your process, rather than scaling up, you simply buy another module and scale out. So, I think that really does give you an awful lot of flexibility. That is an advancement we'll see growing over the coming years. The other area of course is digitalization, with the new automation platforms coming out with the desire to interconnect processes, with the need to have online or at line analytics, then you will be generating mega amounts of data — much more data I think than we really can comprehend and that will need to be managed, it will need to be stored, and it will need to be analyzed. Ideally you want real-time analytics and data. If you can take it to the next logical extension, it becomes real-time release. If you can generate data which is validated and is absolutely accurate and precise in real-time, then there is no reason why you cannot do the real-time release, or certainly shorten the time for release in the critical tests. So, I do think that really is the essence behind Industry 4.0, which we hear a lot about these days. I think you know that there have been proven experiences in other industries and other sectors. The aviation industry has an awful lot of data generated in aircraft which is generated in real-time, and they are thousands of miles away from their home base. There are lessons and best practices from other industries that we can adopt within biotech.