Traditionally, scale-up of biopharmaceutical manufacturing has been a straightforward process: Makers of protein products would perform 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, the latter handling potentially tens of thousands of liters of cells and growth media. If a drug developer did not have the requisite equipment to scale up, it leveraged the bioreactor capacity of a contract manufacturing organization (CMO). But production strategies have changed significantly during the past ten — and even five — years. Process improvements, novel cell-culture technologies, effective single-use components, and innovations in continuous biomanufacturing now enable biopharmaceutical companies to scale out processes of intermediate production volumes instead of pursuing maximum volumes in stainless steel. Technologies for production of advanced therapies are experiencing similar gains, such that developers of such products now can consider scaling up to suspension culture systems. This featured report explores the newfound possibilities and complexities of scalability strategy.

Introduction: Navigating New Options
for Commercial-Scale Biopharmaceutical Production
by Brian Gazaille
Scaling needs are changing in the biopharmaceutical industry. Rather than designing blockbuster therapies that address multiple conditions for many patients, companies are developing biological products for targeted indications and small patient populations. Thus, many biopharmaceutical companies are finding it technically easier and economically more efficient to “clone” processes of moderate scales instead of scaling up to cultures of 10,000-L and 20,000-L volumes in stainless-steel bioreactors. Technological advances, including developments in single-use cell-culture formats, also are enabling the shift to scale-out strategies. In this article, BPI’s associate editor explores those trends, then describes ongoing needs for optimizing production scales, especially in the realm of cell and gene therapies.

Boosting Yield and Preserving Quality: Increasing Production of Induced Pluripotent Stem Cells for Cell Therapy and Regenerative Medicine
by Brian Gazaille, with Maxime Feyeux
Significant obstacles remain in the manufacture of advanced therapies based on induced pluripotent stem cells (iPSCs) — even for allogeneic processes. A primary factor is the difficulty of controlling iPSC differentiation during expansion steps. BPI’s associate editor speaks with the chief science officer of Bordeaux-based TreeFrog Therapeutics about strategies for maintaining the genomic stability and desired phenotypes of cultured iPSCs when scaling up to commercial production scales. The conversation features TreeFrog’s C-Stem technology for iPSC encapsulation and its role in preserving iPSC quality. Feyeux also provides insight into the limitations of scale-out strategies for cell therapy production, especially when they depend on two-dimensional bioreactors and adherent cell culture.

Reducing Downstream Scale-Up Needs:
Advances Toward Continuous Downstream Processing
by Brian Gazaille, with Margit Holzer
The biopharmaceutical industry readily acknowledges that significant increases in upstream productivity have added pressure to downstream operations, which have not experienced corresponding gains. Many companies are exploring options for continuous downstream operations to address increasing demands imposed by high-density cell cultures, perfusion-mode operations, and other upstream scalability solutions. BPI’s associate editor herein speaks with industry consultant and new editorial advisor Margit Holzer about the state of continuous downstream processing. The discussion emphasizes that recent technological advances have facilitated implementation of continuous unit operations — and now are setting the stage for fully continuous processing.

Scaling AAV Production: Easing the Transition
from Laboratory Scales to Commercial Manufacturing
by Brian Gazaille, with Barbara Kraus
Although demand continues to grow for gene therapies based on adenoassociated virus (AAV), production processes for such vectors continue to generate low expression titers and low ratios of full to partial/empty capsids. BPI’s associate editor interviews a scientist from Takeda Pharmaceuticals about strategies for optimizing production of AAV vectors and for facilitating the transition from laboratory-scale processes performed in academic centers to commercial-scale manufacturing of gene therapy products. The conversation provides practical advice for optimizing AAV culture and transfection. It also highlights the importance of analytical method development and of strong communication across teams responsible for process development; chemistry, manufacturing, and controls (CMC); and analytical sciences.