Raising the Bar for Upstream Processing

A Conversation with Stefan Schlack and Christel Fenge

Stefan Schlack is senior vice president of marketing and product management at Sartorius Stedim Biotech.

Christel Fenge

Sartorius Stedim Biotech (SSB) has developed the first fully integrated upstream platform. It connects a top-performing expression system with outstanding equipment and process control for the rapid development and scale-up of robust, high-titer commercial manufacturing processes.

With more than 20 years of experience in the biopharmaceutical industry, mainly in upstream processing, Christel Fenge is responsible for SSB’s fermentation business. She moderated the company’s European Upstream and Downstream Forum, which she describes as a place where customers can discuss topics that are relevant to their own bioprocess challenges — including those in development, manufacturing, and upstream and downstream processing. “We’re offering an opportunity for people to talk about their experiences and challenges and to share them with their peers in a technical and scientific environment,” says Fenge.

Summarizing the event, Fenge notes that the first day focused on early process development such as getting drugs into the clinic. It covered topics such as continuous processing, scalability, and predictive scale-up models. On the second day, the presentations concentrated on production-related matters, including vaccine manufacturing, large-scale preparation of biosimilars, and implementation of single-use production techniques. “On the third day, we looked at downstream processing. Throughout the forum, however, quality by design (QbD) and process analytical technologies (PAT) played key roles. Speakers from the US Food and Drug Administration (FDA) discussed the benefits of PAT, presenters from Fortune Engineering talked about risk assessment, and representatives from GlaxoSmithKline (GSK) addressed the issues surrounding converting big data into usable knowledge.”

Key Themes
“What was critical was linking early development to manufacturing, discussing speed to clinic, and taking a more QbD approach to bioprocessing,” says Fenge. “It’s about the issues that are important to our customers right now, including accelerating process and product development.” Robust production was another recurring theme during the forum as well as increased titers, media optimization, and process intensification.

“At SSB, we see that more and more companies are trying to reach the clinic as fast as possible. But at the same time, they have quite significant pipelines. So they struggle to complete all the work that needs to be done to get ready for clinical trials within a framework of acceptable costs and resources. Another issue is that companies are increasingly considering QbD when they’re filing. That allows them to incorporate a certain level of flexibility and accommodate future process changes and improvements,” observes Fenge.

Larger companies often operate within a global manufacturing network, with facilities all over the world. When you transfer a process from one site to another, reproducibility is key. The best way to achieve that — beyond using exactly the same equipment — is to understand your process as well as you can. That is when QbD comes in. It’s important to establish a design space to fully comprehend how your production or purification process functions within a given range of parameters to ensure product quality. With this knowledge, process transfer is much easier, and it enables companies to apply a principle of continuous improvement that is compliant with the current regulatory environment.  

"From our perspective, our fully automated ambr250 bioreactors (high-throughput or modular) enable our customers to run parallel experiments to establish a design space and optimize process performance in a relatively short time frame using few resources," says Fenge. "And our BIOSTAT B-DCU benchtop bioreactor (which can be fully qualified) can help companies to generate process characterization data that can be included in documentation for filing. My advice would be to establish a design space as quickly as possible by using design of experiments (DoE) and our ambr technology. Then in late-phase development, use our BIOSTAT benchtop systems with DoE and multivariate data analysis to compare results with clinical runs. And finally, use a safe and reliable data hub such as our MFCS SCADA system from early stage research to commercialization. It facilitates process data storage, access, and analysis.  

"A key consideration is scalability, particularly to ensure that data generated at small-scale are representative of production-scale," says Fenge. "Using our bioreactor solutions, for example, not only can we supply single-use bioreactors from 250 mL to 2,000 L that use the same design principles and a comparable sensor technology, we can also support our customers to convert scale-dependent process parameters such as stirrer speed or gassing rates between scales to ensure that the data generated at small scale can be transferred to large-scale operations."  

Equally important is the issue of high titers. There is an almost linear relationship between titer and cost of goods (CoGs). If you have a low titer of <1–2 g, for example, your drug CoGs will not be competitive, so companies want to reduce this as much as possible. What we see in the antibody arena is that a number of really good expression systems are now available, including ours, which offer titers of up to 10 g/L. But, beyond the expression system, we also see optimized media and feeds for cell lines playing a more prominent role. Companies are often reticent to hand over their proprietary cell lines to a third party. So having access to a supplier who can provide a structured approach to media and feed optimization is an advantage. Our DoE-enabled media optimization approach in a high-throughput bioreactor that´s predictive of large-scale production together with consultancy and analysis services offer complementary options to our offering of a reliable, high-titer cell line.   

Market Trends
Also, in attendance at the European Upstream and Downstream Forum was Stefan Schlack, senior vice president of marketing and product management at SSB. He was keen to support Christel’s comments. "An important sector topic that is becoming increasingly prominent is speed to clinic," says Schlack. "If you look at today’s drug development pipeline, there are a huge number of therapeutics in development and numerous companies working on new applications; but, these companies are well aware that the success rates of novel (candidate) therapies have decreased. Only one in 10 monoclonal antibodies actually make it to the clinic. Just 10 years ago, it was one in four!" 

When you consider large companies with huge pipelines, they want to spend their investment on the most promising candidates. Often, that’s derived from patient feedback, so they act as fast as possible to get new drugs into patients — into the clinic — to assess the feasibility of the candidate molecule. For smaller companies, the value of their product (and the company) increases as soon as they reach a clinical milestone. Here, speed to clinic is vital to secure further funding to progress the product, conduct larger trials and, perhaps, make them a more appealing acquisition proposition. Whether large or small, though, reaching the clinic is a financial imperative.

“Drug producers need to realize that if they have a drug that is worth spending money on and getting to the market, they must establish a regulatory package that accommodates process changes. You might need to implement tech transfer or shift production sites, for example. A QbD filing will make these process changes — or subsequent late-stage improvements — easier,” he adds.

“Another very important trend is the move towards more intensified and even continuous manufacturing. Intensified processing allows companies to make more efficient use of their production assets. Enabling technologies, such as the KSep centrifuge, are allowing the harvest of single-use bioreactors in a high-cell density fed-batch mode. This reduces the scale of production, manufacturing footprint, and requirement for capital expenditure. Potentially, it’s the future of pharmaceutical production,” says Schlack.

Supporting the Industry
In the last few years, Sartorius Stedim Biotech has focused on bringing its upstream portfolio together and enhancing it with new additions and acquisitions, such as Cellca’s cell line and media development and BioOutsource’s analytical services, and also enhancing the company’s singleuse bioreactor offering with ambr technology to support their customers, from concept to commercial production, to accelerate product development and scale-up, and provide analytical support. “This very much ties in with our Connect Upstream campaign, in which we’ve brought different technologies together into a single, holistically aligned platform — from cell line development to commercial production — to get our customers into the clinic and onto the market in a time- and cost-effective way,” says Schlack.

Sartorius Stedim Biotech has a strong technical focus, observes Fenge, and collaborates closely with its customers to understand their challenges. “We can help with speed to clinic, particularly with our ambr products (the ambr15 for clone screening and media optimization and the ambr250/ambr250 modular for process optimization), and with our recently acquired expression technologies that facilitate scale-up.”

“Sartorius always has had a very comprehensive understanding of membranes and membrane modification,” Stefan adds. “We see opportunities to integrate intensified downstream processes that use membrane adsorber technology to purify the increased quantities of proteins and viral vaccines being harvested from cell cultures.” Our integrated solutions department is here to help customers to identify the most appropriate facility layout and design of the upstream and downstream process train, and how to qualify it.”

“We not only have the equipment and the consumables,” says Christel “We also have the software solutions to deal with all the data. When we work with a customer, our main remit is to make their lives easier, either by solving existing technical problems — such as providing a novel solution to deal with media virus filtration — or we improve or simplify a process. Our aim is to be a total solution provider.And our main focus is to help our customers. We take a holistic approach to, for example, coming up with a cell line and process that takes a client’s product all the way to commercial production. That’s what drives us forward.”

Innovation
Tackling the thorny issue of innovation, Schlack believes that it is hard to copy the creativity of the market. “I believe, at Sartorius, we need to get the right balance of innovating ourselves, based on our strengths while at the same time being open to integrating third-party innovation” says Schlack. “We need to be out there, looking for new technologies, developed by other companies, and bring that in-house to improve our overall offering.
“It might start with a collaboration with an innovative company that leads to an acquisition, such as with the integration of Cellca,” says Schlack. “Or take TAP, the ambr systems were a perfect fit for our portfolio. So the acquisition of complementary technologies represents a good approach for Sartorius Stedim Biotech, and I believe we have done that rather well. There are a number of other projects in the pipeline and we always keep a keen eye on developments in the industry. We don’t believe in the ‘not invented here’ philosophy and always keep an open mind.”

On Reflection
Looking back on the event, Fenge reflects on more than 20 excellent presentations during the forum and that SSB was proud to host more than 120 guests. “It’s the most successful conference we’ve run to date,” she says. “We’ve never had so many delegates in attendance, from all over Europe, including Germany, France, Spain and the UK; we even had people from Korea, China and India, demonstrating a wide diversity and the breadth of the industry.

“I should also thank our outstanding speakers, as well. Everything went exceptionally smoothly and it’s very satisfying when the topics are especially relevant to our visitors,” says Fenge. “You know that people are engaged and interested when they ask a lot of questions. There was a great buzz around the meeting and I know the discussions continued long after the sessions had finished.”