Scalability remains a critically important topic for biopharmaceutical companies. For conventional protein products, the strategy once was straightforward: Drug makers would scale up, beginning with cultures in flasks and roller bottles to grow enough cells to inoculate laboratory-scale (often glass) bioreactors, then again to pilot- and commercial-scale, stainless-steel, stirred-tank bioreactors. At their highest volumes, such reactors can handle tens of thousands of liters of cells and growth media. If a drug developer did not have the requisite equipment to scale up, then it needed to leverage the bioreactor capacity of a contract manufacturing organization (CMO).
By contrast, scalability possibilities have been limited for cell and gene therapies (CGTs). Many of their developers have scaled out rather than up, expanding sensitive, anchorage-dependent cell cultures in multiple small-volume vessels. Even when production could take place in suspension culture, as is the case for gene therapies based on viral vectors, production volumes and expression titers have remained low.
However, production strategies have changed significantly during the past 10 years. Technological advances and increased process knowledge are encouraging some biopharmaceutical companies to scale out processes of intermediate production volumes instead of pursuing traditional scale-up options. And CGT production technologies have evolved to the point that developers can consider scaling up to sizeable batches in suspension culture systems. This featured report explores the newfound possibilities and complexities of scalability strategy.
Working Smarter, Not Harder
The biopharmaceutical industry has yet to move fully beyond the days of producing vast quantities of “blockbuster” biologics to treat a wide range of conditions (1–3). But developers are designing biologics for more targeted indications and smaller patient populations than were produced even a decade ago. Regulatory approvals of blockbuster biologics have diminished during the same period, driving shifts in commercial and regulatory strategies (3).
Scaling needs are changing, in turn. Some developers find it easier and more efficient to “clone” processes of modest scales (with single-use (SU) equipment) than to scale up processes for 10,000-L batches (usually in stainless steel). Scale-out runs fewer risks of diminishing product quality at high scales. It can facilitate development of a common process to be executed in several regions and markets. Alternatively, the strategy enables concurrent manufacturing of multiple products in the same facility — and the need for multiproduct environments continues to increase as companies produce greater numbers of drugs for orphan indications (4, 5).
Technical innovations are helping to frame bioreactor scale-out as a viable commercial strategy for production of conventional proteins. Cell culture processes have improved substantially. Average expression titers of monoclonal antibodies (MAbs) from Chinese hamster ovary (CHO) cell cultures have increased from 1.95 g/L in 2008 to 3.5 g/L in 2020, with some yields exceeding 10 g/L (3).
Process knowledge also continues to increase for perfusion systems, which hold promise for increasing culture densities and yields further still. Although the biopharmaceutical industry for more than a decade has acknowledged such systems’ potential productivity gains and cost savings, perfusion operations are more difficult to implement than fed-batch cultures (6, 7). Among the complications are increased needs for culture media, risks for batch contamination, potential for operator error, and difficulty aligning upstream and downstream activities (7). Some of that complexity remains, especially regarding downstream bottlenecks. But perfusion systems are improving, and many companies today are leveraging them to increase expression titers and product quality.
One thread running through all these innovations is increased availability of SU culture technologies. I vividly recall walking through the exhibition hall of the September 2019 BioProcess International conference in Boston, MA, and finding materials promoting ABEC’s 7,500-L CSR (custom single run) bioreactor, the first disposable reactor to feature a working volume of 6,000 L. Scientists from Thermo Fisher Scientific were describing development work for the 3,000-L and 5,000-L HyPerforma DynaDrive reactors that the company would unveil just a few months later. Several other companies were showcasing vessels for anchorage-dependent cells.
Such systems represent important advances in negotiating the pressure and oxygen-transfer limitations that have limited cell-expansion potential in SU equipment. A potential reason for improvements in disposable reactors is a shift in scalability priorities. The Thermo Fisher team at the 2019 BPI Boston event noted that HyPerforma DynaDrive systems are designed with the volumetric mass transfer coefficient (kLa) as the most important scaling parameter (8). Traditionally, bioreactor scale-up to commercial volumes has prioritized power-to-volume (P/V) ratios, even in SU applications. As Thermo Fisher’s scientists suggested, though, kLa quickly is becoming a more meaningful metric for SU bioreactor design than had been supposed.
The breadth of disposable options also embodies a growing preference for versatile scalability solutions. As SU bioreactors handle increasingly high culture volumes, developers are finding SU equipment to be a productive investment, especially because such technologies enable variable-scale production in multiproduct environments.
The following articles continue the scale-up/-out discussion. In my interview with Maxime Feyeux of TreeFrog Therapeutics, we discuss the need for scalable three-dimensional (3D) bioreactor solutions for induced pluripotent stem cells (iPSCs) used in several cell-therapy production processes. Next, BPI editorial advisor Margit Holzer describes scalability advantages of continuous downstream processing for MAbs and other protein products. Finally, Barbara Kraus of Takeda in Austria speaks about best practices for scaling up production of gene therapy products based on adenoassociated virus (AAV) vectors. Together, these accounts indicate what scalability strategies are possible and what concerns remain in different parts of the biopharmaceutical industry.
1 Oxtoby K. How Biologics Have Changed the Rules for the Pharmaceutical Industry. Chem. World 7 May 2019; https://www.chemistryworld.com/molecule-to-market/how-biologics-have-changed-the-rules-for-pharma/3010301.article.
2 Stanton D. Biomanufacturing Capacity: 45% Growth But New Blockbusters Could Leave Shortage. BioProcess Insider 4 November 2019; https://bioprocessintl.com/bioprocess-insider/facilities-capacity/biomanufacturing-capacity-45-growth-but-new-blockbusters-could-leave-shortage.
3 Langer ES, et al. Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, 17th ed. BioPlan Associates: Rockville, MD, April 2020; https://www.bioplanassociates.com/17th.
4 Sargent B. Scale-Out Biomanufacturing: A Paradigm Change to Scale-Up. Cell Culture Dish 24 January 2018; https://cellculturedish.com/scale-out-biomanufacturing-a-paradigm-change-to-scale-up.
5 Chen J. Evaluation of the “Scale-Out” Biomanufacturing Strategy from Early Clinical Stage to Commercialization. BioProcess Int. (Ask the Expert webinar) 3 November 2017; https://bioprocessintl.com/ask-the-experts/evaluation-of-scale-out-biomanufacturing-strategy-from-clinical-to-commercial.
6 Pollock J, Ho SV, Faird SS. Fed-Batch and Perfusion Culture Processes: Economic, Environmental, and Operational Feasibility Under Uncertainty. Biotechnol. Bioeng. 110(1) 2013: 206–219; https://doi.org/10.1002/bit.24608.
7 Jorjorian P, Kenyon D. How to Set Up a Perfusion Process for Higher Productivity and Quality. BioProcess Int. 15(4) 2017: 48–52; https://bioprocessintl.com/upstream-processing/perfusion-cell-culture/set-perfusion-process-higher-productivity-quality.
8 Scott C, Gazaille B. Bioreactor Scale-Up: From Pilot to Commercial Scale in the Modern Age. BioProcess Int. eBook 17(9e) 2019; https://bioprocessintl.com/upstream-processing/bioreactors/ebook-bioreactor-scale-up-from-pilot-to-commercial-scale-in-the-modern-era.
Brian Gazaille is associate editor of BioProcess International, part of Informa Connect, PO Box 70, Dexter, OR 97431; email@example.com; 1-212-600-3594.