Unblocking the Bottleneck

A Conversation with Fritjof Linz

Fritjof Linz is vice president of marketing purification Technologies at Sartorius Stedim Biotech.

With another Upstream–Downstream Processing Forum successfully concluded, BioProcess International caught up with Dr. Fritjof Linz, vice president of marketing purification technologies at Sartorius Stedim Biotech, to discuss the event and discover what trends lie ahead for the bioprocessing industry.

Regarding the event, Linz commented, “The Upstream and Downstream Processing Forum already is an institution in the market and has been organized by our company for many years. All event presentations have been excellent and have provided deep insights. Our aim is to give experts from the biopharmaceutical industry the chance to talk about technologies and products as well as to provide a networking environment in which to talk about the latest industry trends.”

The latter is something that happened during the forum this year, wherein attendees examined how companies could run down-scale models for both upstream and downstream operations. “For upstream applications, our ambr systems are particularly suitable, and a number of speakers included references to those products in their presentations. On the downstream processing side, a key focus area is mitigating the risks of virus contaminations. That work starts at the beginning of a process with culture media preparation and use of specifically designed filters for easy virus removal.”

Another major trend is continuous processing (CM) or process intensification and the need to generate more economical approaches to biopharmaceutical manufacturing. “The primary drivers are higher yields,” explains Linz. “But shorter processing times also reduce costs and labor.” A large part of that (equally well presented by many speakers) is quality by design (QbD). “It’s one of the topics that regulatory authorities are focusing on to ensure that manufacturers gain deep knowledge of their processes.” Regulators advise companies to run tests at a small scale so that when the appropriate data have been collected, manufacturers know how to progress that operation to larger scales. “Again, it’s all about remaining in control of a process, maintaining consistent quality, and ensuring patient safety,” Linz adds.

Industry Demands

“Continuous manufacturing is commonly used as a term for process intensification,” notes Linz. “Depending on the final target volume of a product, different production modes will be suitable. What we’re seeing is a greater diversity of annual production demands. So you have to decide on the best manufacturing method to use. For lower volume products, batch mode may be more appropriate. For larger-scale demands, however, continuous manufacturing often is better.

“Continuous is a single word but comprises a number of elements,” says Linz. “Such factors include improved quality, better process consistency, higher and more cost-effective yields, and downsized facility footprints. Facility footprint has a significant impact on overall cost. Traditional stainless steel set-ups can cost up to €300 million, whereas a single-use, small-scale alternative can be downsized to a range of €50–100 million and offer the same capacity. For industry, that’s important. Manufacturers are challenged to make drug products more cost efficiently because insurance companies no longer want to pay high prices for such products. It’s a key driver,” says Linz.

In such cases, down-scale models can help manufacturers establish relevant information about process economies. But at the end of the day, the method selected will be determined by an annual forecast. Regulatory requirements are another factor to consider in selecting a production method. In down-scale models you can show the performance of a certain mode of manufacturing. Only the process development time needed to collect data will differ between CM and batch mode.

For large-scale production, however, chromatography is still a limiting factor. “If you look at upstream titer development, then resin-based chromatography is limited to a certain size and capacity, says Linz. “Beyond that, from both a management and an engineering perspective, the procedure becomes hard to handle.”

“What we can do is think in terms of our client, which means considering their application — be it an antibody or a vaccine. Such products have very specific but different requirements. We need to fully understand the process and product and fit our solutions to meet those needs. We select out of our portfolio, those products that match our clients’ requirements.”

Single-use technologies are an overarching trend. Manufacturers are using their plant footprints in different ways, reducing interbatch turnaround and preparation times, and making processes more economical, particularly during downstream processing. The use of single-use continuous technologies, such as kSep centrifuges, introduces new opportunities: You can work in closed systems. Sensitive or potent products, for example, need a fully enclosed environment. Of course, eliminating stainless steel components and the associated cleaning times will make any process more efficient.

kSep Systems is a recent acquisition for Sartorius Stedim Biotech. It specializes in advanced centrifugation for the purification of recombinant proteins, cell therapy products, and vaccines. The systems “provide a gentle processing environment for cell separation,” says Linz. “With conventional centrifugation at high cell densities, you often need to sacrifice both recovery levels and product quality because of high shear forces. kSep centrifuges overcome that issue by recovering product from the interstitial space between cells before discharge while reducing host-cell protein contamination by exposing cells to lower shear forces.”

“kSep’s centrifuges are an innovative, single-use cell separation technology that perfectly complements our downstream bioprocessing. Our clients will benefit greatly from the unique ability to collect, wash, and concentrate cells quickly while reducing both the time and cost of high-titer downstream purification.”

Biotech Trends

As Linz observes, one key biopharmaceutical industry, we’re still struggling with product quality indicators that we can’t analyze as well as we can in the chemistry arena. With chemistry, I can analyze a molecule and clearly identify it. That is not yet the case in biotechnology with the same accuracy. With this in mind, using analytical parameters to steer processes to the right quality levels is one of the biggest challenges ahead. The more we think about continuous manufacturing, the more we need to be capable of putting analytics in place — next to or within the process — to fulfill future needs of the drug manufacturing industry.”

At the event, it was suggested that a combined upstream and downstream proposition is where industry should be heading. Linz agrees: “We must always think about upstream and downstream processes together, not as separate procedures. They can’t really be separated from each other or thought of in isolation.Upstream processes affect how we design downstream procedures. Of course, whatever happens upstream will influence downstream. They are clearly interlinked in terms of both capacity and product quality. With increased upstream titer volumes, downstream processing has become the bottleneck!

“One key parameter is that we always have to build a certain level of security into a process. But if I control upstream processes more accurately, then I can better optimize downstream systems to deliver cost savings. Currently, because of upstream variations, we use safety margins of about 30%. With better control, we can improve on that and improve the entire. It’s not upstream versus downstream but rather a combined and better controlled production method. That’s something we’re looking at here at Sartorius.”

Forum Feedback

Linz feels that the forum was well received, and the feedback was very positive. “Our 120-plus guests enjoyed the setting and the fact that the sessions were technologically driven. They also enjoyed the networking opportunities during the breaks and the opportunity to get a first-hand look at some of the new Sartorius equipment. It was a lot of fun, a lot of work, but the organizing team did an excellent job. It was a wonderful opportunity to talk to our valued clients.”

Delving a little deeper into the forum content, Linz notes: “We had speakers from Bayer, for example, who had established single-use antibody– drug conjugate processes that could be performed in a facility that is only typically used for protein purification. That is uncommon in the market. In addition, we had speakers from Boehringer Ingelheim who discussed the challenges surrounding in-house custom manufacturing and whether those procedures met regulatory requirements. It transpires that it’s not always as easy as it looks — and it doesn’t always work out as planned!” “

We also had a very insightful speaker from the US Food and Drug Administration (FDA), who explained that the agency has a research department that looks into the technological challenges affecting the biopharmaceutical industry as well as ongoing and upcoming trends. This means that FDA regulators have a good understanding when they review and audit and are prepared and aware of what’s ahead of them. They must understand and embrace emerging technologies to be able to approve them.”

Looking ahead and commenting on how Sartorius Stedim Biotech can progress downstream processing, Linz says, “If you look at our portfolio and our focus on process intensification, we’re doing a lot of work with membrane-based chromatography. We believe this technology will provide shorter turnaround times and faster set-up times. Also, improving overall system economy is a key driver — not just for unit operations but for an entire manufacturing process. Each step must be optimized to make biomanufacturing more time- and cost-efficient. And, with our current offerings and products in development, we’re well positioned to drive that change.”