Turning Biologic Innovation into Commercial Success (Webcast Recap)

Research-driven biopharmaceutical company Boehringer Ingelheim recently introduced its ‘Life forward’ campaign to highlight its commitment to making innovative medicines. To deliver on this claim, BioXcellence, the biopharmaceutical contract manufacturing branch of Boehringer, provides contract development and manufacturing services at all stages of product creation, including cell-line development, cell banking, fermentation, and purification of recombinant proteins. As such, the organization facilitates full-scale manufacturing of bulk drug substances.

After a December 2023 Ask the Expert webinar, three Boehringer representatives and BPI discussed the company’s work: Nikolaus Hammerschmidt (head of a unit within downstream development), Athelney Woolnough (director of key account management and business development), and Franz Schuster (strategy implementation manager).

The discussion focused on Boehringer’s microbial expertise and how it drives its clients’ biologics manufacturing for supplying innovative medicines to patients in need.

The Presentation

Microbial Protein Production: In recombinant protein production, both mammalian and microbial expression systems are widely used. Proteins produced in microbial systems generally are smaller than those produced in mammalian systems, such as monoclonal antibodies (mAbs) expressed by Chinese hamster ovary (CHO) cells. The demand for CHO-based platform technologies exceeds that for microbial expression systems because mAbs continue to be the dominant format in biopharmaceuticals. Additionally, microbial systems consist of a variety of molecular formats requiring tailor-made solutions from a toolbox of manufacturing technologies, whereas CHO-cell systems have a more standardized approach.

Even so, the market for microbial products is still growing, said Woolnough, with a 9% increase expected between 2022 and 2028. Microbial systems can be used with a diverse array of molecules, ranging from peptides to plasmid DNA (pDNA). The cultivation process for microbes is quicker than that for mammalian cells like CHO cells, with the former taking only a few days compared to the latter’s weeks-long process. Additionally, microbes exhibit high robustness and can be grown to substantial cell densities using relatively straightforward and cost-effective cultivation media. Despite these advantages, the complexity of manufacturing in microbial expression systems may explain why many companies choose not to invest in such systems. For this reason, a contract development and manufacturing organization (CDMO) such as the Boehringer Ingelheim BioXcellence division can assist companies that require microbial manufacturing expertise for their biopharmaceutical medicines. Boehringer has experience with many microbial formats, mainly bacterial and yeast-based. The company focuses on strategies for soluble expression formats and inclusion bodies.

A key element of the organization’s microbial production processes is the Escherichia coli system. E. coli cells have a long history as host cells in the biopharmaceutical industry and have proven to be a reliable workhorse in biomanufacturing operations. Boehringer’s experience in using these cells enables it to efficiently manufacture diverse molecules.

Boehringer’s site in Vienna, Austria, specializes in microbial development and manufacturing. The facility is equipped with 200–6,000-L fermentation systems for commercial manufacturing, enabling it to handle a variety of production volumes and client needs. The Vienna team also has developed efficient strategies for complex downstream processing of microbial products.

Boehringer offers tailored downstream-purification processes for difficult-to-express proteins that require complex refolding strategies. Such processes also may use organic solvents or require chemical modifications. Some of Boehringer’s other techniques address stability or unique molecule formats, such as supercoiled pDNA. “Each phase in a product life cycle has different requirements and challenges that need to be addressed with great flexibility,” said Schuster. He emphasized the importance of cost, quality, and speed during manufacturing to ensure the best outcomes for products and patients.

Boehringer’s development operations team plays a crucial role in the organization’s operations. Boehringer has implemented high-throughput development technologies and created a mature in-house modeling platform, which are both key to maintaining efficiency and quality in developing manufacturing processes. Boehringer’s quality systems are designed to ensure that products, tests, and filings all meet stringent regulatory standards. In addition, the Boehringer team has extensive worldwide regulatory experience, enabling them to cross the complex regulatory landscape efficiently. The company’s multi-product facilities have passed numerous inspections by regulatory authorities.

Customer Approach: Woolnough discussed Boehringer’s approach to customer relations. “It’s a little bit like being an ambassador. It involves weighing our customers’ needs with what we can achieve, respecting our internal processes, operations, and others’ scheduling and client commitments.” She cited honesty, communication, and transparency as the most important aspects of customer service.

Woolnough said that many projects require teams to find creative solutions to customer issues to the strike that balance. In one example, to support a recent customer project, a new scale-up process was needed as the existing process did not meet internal good manufacturing practice (GMP) standards. Significant adoptions had to be made to develop a robust commercial process. Boehringer engineers devised a bridging process that met company quality standards and was fast enough to meet the client’s first clinical batch deadline. The interim solution required a significant equipment investment. The equipment supplier, customer, and Boehringer colleagues from various functions explored options and agreed on a creative solution that met all parties’ needs and ensured that manufacturing did not delay the delivery of medicines to patients.

Hammerschmidt described what customers most want from biopharmaceutical partnerships: product quality and timely delivery schedules. Both aspects require close coordination of manufacturing activities, commitment of team members, and prioritization of all functions involved.

Hammerschmidt, Woolnough, and Schuster emphasized the importance of strong customer relationships. Even during events that limit physical contact, such as the COVID-19 pandemic, Boehringer oversees its projects with open communication. That includes frequent meetings, whether in person or virtual, to understand customer goals and build trust. “Trust is the kickoff to every successful project,” said Hammerschmidt.

Next Steps: When asked about recommendations for sponsors initiating microbial-based manufacturing processes, the panelists stressed the importance of partnering with an organization that has a proven track record in that field. Boehringer is one such organization, with over 40 years of experience in microbial production.

Hammerschmidt broke the partnering process down into three parts. He said that the first step is to reach out to the Boehringer Ingelheim BioXcellence team to discuss your project and the level of support you will need. Second, provide necessary details about your project. Boehringer will draft a comprehensive proposal in response. Finally, review the proposal and negotiate the terms of your partnership. By working with the Boehringer Ingelheim BioXcellence team, you can leverage its expertise in microbial manufacturing to ensure your project success.

“Boehringer has a distinctive character,” concluded Schuster. The company is family-owned, and today’s employees “are invited to be part of that family.” Schuster added that having such a company culture “benefits our microbial business.”

Boehringer is seeking out new partnerships in the biopharmaceutical industry. Inquiries can be addressed to [email protected].

Questions and Answers

Does Boehringer offer drug-product fill and finish services in addition to bulk drug-substance production? Yes, we produce both drug substances and drug products in a variety of formats, primarily at our Vienna site, which houses our microbial drug substance production. Our location in Biberach, Germany, has multiple filling and isolator lines for services.

What is your availability for new products? Our acquisitions team is in close contact with external partners and the industry as a whole to find new products for our production facilities. This means that we are always looking for new products that fit within our capabilities and capacities.

What is the lead time for GMP manufacturing? That depends on the time needed for technology transfer and receipt of client materials. We can make products from scratch and enter the GMP-manufacturing phase within six to eight months. Process duration depends on several factors, but we try to expedite production timelines.

What do you believe is the future of chemical and enzymatic methods for mRNA synthesis, and how might that affect demand for microbially expressed pDNA? In the early 2000s, the biopharmaceutical industry paid much attention to pDNA, although that demand declined over the past 15 to 20 years. With the emergence of mRNA vaccines, we’ve seen a sudden rise in plasmid demand. We have a mature platform for the recombinant production of pDNA at large scales, namely 200 and 4,500 L.

What technology does Boehringer offer for recovery of soluble microbial production streams? We can combine several techniques in the early recovery steps for such cases. For optimization of soluble expressions, we use a molecular-biology toolbox with high-throughput fermentation screenings to boost titers. For soluble-product recovery, we offer all kinds of typical sequences of early recovery steps and can combine centrifugation, filtration, and optional precipitation steps for early impurity reduction. We also have multiple proprietary strategies for expression and recovery that allow for standardization of early recovery steps to expedite timelines and simplify process development.

Find the full webinar online at www.bioprocessintl.com/category/webinars.