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As a trusted partner in the life-sciences industry, Sartorius has contributed significantly to the evolution of biopharmaceutical manufacturing. To reflect on the rich history of the industry, we arranged a virtual roundtable. Based on shared questions, we corresponded about what we considered to be the most important scientific, technological, and operational developments in the past 20 years of bioprocessing. We also reflected on the emergence of new modalities and how such products are likely to shape the future of the biopharmaceutical industry.
What Scientific and Technological Advances Have Been Most Formative to the Biopharmaceutical Industry’s Development?
Horry: Many innovations have been implemented to increase upstream yields, improve product recovery, enhance product purity, and streamline manufacturing processes. In the early days of monoclonal antibody (MAb) production, for instance, protein yields from perfusion-mode cell-culture campaigns were around 100 mg/L.
Now, perfusion has become the cornerstone of upstream process intensification, with process volumetric productivity reaching on average 6 g/L/day.
Dixit: Even 10 years ago, there was significant impetus to set up large-scale stainless-steel equipment — e.g., stainless-steel production bioreactors of >10,000 L — to produce several tons of MAbs annually. That strategy was meant to address indications with large patient populations. But the need to produce at such high volumes has transformed, with development pipelines showing greater numbers of MAbs and MAb variants with less annual demand (e.g., 50–200 kg). Approval of several biosimilars in the European Union and in US markets has reinforced the need for drug companies to manufacture several products in smaller quantities out of each facility.
Nestola: Over the past 20 years, we also have witnessed strong uptake of single-use technologies (SUTs). That has helped the biopharmaceutical industry to become more efficient and flexible than ever before, especially by enabling multiproduct manufacturing environments. The shift to disposable equipment has been particularly recognizable in facilities for new modalities such as cell and gene therapies. The question of whether to go with single use or stainless steel is not asked anymore in that forum; SUTs have become the standard.
Horry: The biopharmaceutical industry generally has been conservative when implementing new technologies. But the status quo is being challenged today by the development of computational technologies, artificial intelligence (AI), and machine learning (ML). This revolution is happening while the biopharmaceutical industry is still in its infancy.
We already are witnessing significant acceleration in process development (PD) activities. In-depth understanding of critical process parameters (CPPs) and critical quality attributes (CQAs) through design-of-experiments (DoE) approaches and advanced analytics has enabled the construction of representative models that are paving the way to autonomous and predictive processes.
Nestola: Also of note is the industry’s increased focus on process understanding and quality by design (QbD), prompted by pushes from the US Food and Drug Administration (FDA). This development has led to increasing investment and adoption of process analytical technologies (PATs), mainly for upstream production, but also increasingly for downstream processes. Process understanding and reproducibility both have improved dramatically because of closed-loop control of bioreactors using data collected by Raman spectroscopy probes.
Improved analytics programs have changed how data are collected and analyzed to monitor or control processes, both at PD and good manufacturing practice (GMP) scales. The industry also has much more data available than ever before thanks to adoption of high-throughput technologies, some of which have become standard equipment in even PD laboratories.
What Role Has Sartorius Played in the Industry’s Development?
Dixit: Sartorius has expanded its bioprocessing solutions portfolio significantly over the past 20 years. That stems from a combination of internal development work based on our core competencies in SUTs and separation membranes and strategic acquisitions that have complemented those strengths. We have developed an extensive line of single-use products for mixing, aseptic connection/disconnection, and freeze–thaw applications. We also have offered filter membranes for dead-end and tangential-flow filtration as well as scalable membrane-chromatography devices for MAb polishing steps and viral vector capture.
Our Ambr 15 and 250 automated minibioreactors are considered to be industry standards for early stage process development (PD) for microbial and mammalian cell cultures, and they are known to reduce PD timelines and thus decrease time to market. Our Biostat STR line of scalable single-use bioreactors (2–2,000 L) have been implemented at many biomanufacturing facilities to produce not only MAbs and other recombinant proteins, but also viral vectors that are used in vaccines and gene therapies.
We have strengthened our chromatography offerings through select acquisitions, such as that of BIA Separations. Now, Sartorius can provide chromatographic monoliths that can address a number of separation needs with solutions that already are available for commercial manufacturing. Sartorius also has acquired BioSMB and Novasep BioSC multicolumn chromatography (MCC) systems with single-use and reusable flow paths to address MAb process intensification needs. We plan to launch protein A affinity membranes later in 2022. Those could improve MAb capture significantly by providing solutions with capability for rapid flow, high dynamic binding capacity (DBC), good NaOH stability, and consistent performance over several hundred cycles.
Today, Sartorius also provides predictive and even prescriptive process monitoring tools. SIMCA software for multivariate process analysis has helped save many batches through early warnings about process perturbations.
How Has the Pandemic Changed Things?
Dixit: The COVID-19 pandemic has ushered in a new era in the biopharmaceutical industry, with mRNA-based vaccines that hold much promise for changing the drug development landscape. Several million doses of a vaccine can be manufactured from a single batch with starting volumes of tens to hundreds of liters. Several biopharmaceutical companies are exploring this modality not only for vaccines against infectious diseases, but also for other indications such as certain cancers. Many leading companies in the mRNA space will have diverse pipelines focused on indications with few or no therapies available. Many drug companies will need to build PD expertise across different modalities, from MAbs to viral vectors to cell therapies and now mRNA.
Nestola: Although the biopharmaceutical industry has worked mainly with MAbs and other antibody products for the past two decades, we now are experiencing remarkable changes in the molecules that we work with. That development is causing a shift in mindsets and innovation pipelines of biomanufacturing suppliers, as well. Workflows for new modalities are quite different from those for MAbs. Thus, customer requirements for biomanufacturing equipment are changing, too. New products must be designed specifically for new modalities. As a process technology manager, my team needs always to stay up to date, reading the latest trends and anticipating customer needs to prepare the company for the future.
Horry: It’s important to consider how the COVID-19 pandemic has influenced our work. It’s difficult to present a general comment because everyone is experiencing the pandemic differently. But I observed that modern communication and networking tools — computers, internet capabilities, shared cloud-based working spaces, and video conferencing tools — kept the whole biopharmaceutical industry connected. Fortunately, communication and to a certain extent networking never stopped. Information continued to flow, and that kept the industry in motion. That was not necessarily the case for other sectors.
The pandemic forced us to pause and step aside from the work-related “storm” in which we found ourselves. Traveling stopped for many of us. That was significant for employees who spend 50–60% of their work time taking flights, waiting in lobbies, and experiencing jet lag. Simply by being less tired, many people realized how exhausting our working style can be. That recognition has forced some of us to reconsider why we travel and network, how often, and where we might like to invest our time and resources instead. Simply put, we have become more selective.
We also have rediscovered the power of global capabilities, with colleagues from all around the world attending local events (when possible) and then sharing internally what they learned. We have remembered the importance of internal networking, work delegation, and empowerment of collaborators.
As we return to a relatively normal and stable work situation, companies need to find the right balance between local and external activities. I’ve seen significant changes already. Now that we are visiting customers and suppliers again, we know how much we missed in-person interaction. We’re also recognizing how valuable such interactions are for our companies. Business is not just numbers, facts, strategies, and tactics.
Habib Horry is manager of process technology at the Sartorius site in Strasbourg, France; [email protected]. Piergiuseppe Nestola is manager of process technology at Sartorius in Zug, Switzerland; [email protected]. Mandar Dixit is head of value-chain services at Sartorius in New York City, NY; [email protected].
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