Principal Scientist Anders Cai Holm Hansen explains how CDMO AGC Biologics uses its global, single-use network and a strategy emphasizing “scale-out” manufacturing, to derisk demand uncertainty, speed timelines and conserve cash for emerging drug developers.
The clock is ticking for both drug developers and CDMOs to get biologics to market quicker and in a more capital-efficient manner while maintaining high manufacturing standards. However, traditional manufacturing scale-up approaches often spur bottlenecks, delaying time to commercialization and increasing spending.
A better solution is scale-out development, said Anders Cai Holm Hansen, Principal Scientist, Customer Solution Design at AGC Biologics, in an interview with BioSpace.
Standard scale-up design involves moving to larger stainless-steel reactors as production needs grow. Anders notes that this alters internal parameters like mixing and gas transfer, which can affect the cell environment and performance.
By contrast, scale-out methods utilizing single-use reactors keeps vessel size consistent and adds mirrored bioreactors operating in parallel, avoiding those environmental changes. This also provides a growing opportunity to expand the range of molecules that can be brought to market, including those with limitations that are particularly tough to produce in mass quantities during late-phase trials or at commercial scales.
How a Flexible Scale-Out Model Adapts to Your Needs
Early in drug development, uncertain demand and unknown project success add complexity to decisions on how to best proceed. Ideally, the resource investment correlates with the probability of success, but if projections are wrong, it could lead to locking a process into large, expensive stainless steel production too early.
Traditional scale-up mandates considerable investment in large-scale process development and equipment. In addition, a recent article highlights the difficulties developers face, such as inaccurate demand forecasting and challenging accelerated regulatory pathways. These issues could be addressed by the flexibility and consistency scale-out processes provide. This method also allows for the reduction of raw materials and removes the need for extensive cleaning validation studies required for stainless-steel equipment.
AGC Biologics’ solution is to have single-use 2,000 L units as the basic building blocks, then scale-out via its 6Pack System™ lines to reach up to 12,000 L per suite without taking on classic large-scale stainless steel comparability risk, Anders said.
The 6Pack System™ is AGC Biologics’ proprietary large-scale, mammalian manufacturing platform that allows up to six 2,000 L single-use bioreactors to be run in tandem or individually, providing scales of 2, 4, 6, 8, 10 or 12,000 L batches. As high-level data in Figure 1 shows, this can be a very effective strategy that can be optimized to increase or maintain titer and yield over the lifecycle of a product.
Figure 1: Overview of key process parameters - harvest titer and overall downstream yield - from a commercial project at AGC Biologics. The project was scaled out from a 2,000 L single batch scale to a multipack in response to better-than-projected demand for material. The values have been normalized with respect to initial process performance and batches maintained their harvest titer or downstream yield after scaling out.
Simplifying Comparability and PPQ/Validation Strategies
AGC Biologics ensures the same bioreactor scale, while scaled out, does not negatively impact comparability expectations and the PPQ/validation strategy across its network of sites. These include Copenhagen, Chiba and Seattle, and the new site coming online in Yokohama, Japan with multiple 5,000 L single-use reactors for large-scale manufacturing.
By having similar equipment, the CDMO can minimize validation requirements for individual equipment units, while building in more flexibility around final manufacturing scale, Anders said.
Sites operate under a global quality system with aligned procedures and similar equipment. Their similarities facilitate transfer processes and shared capacity, which directly support mirrored bioreactors/6Pack strategies across the network. Additionally, there are regular global alignment meetings, which underpin effective methods, efficient tech transfer and multi-site PPQ.
In one case study, Anders shared how AGC Biologics initiated a project at a site with available capacity to meet an urgent timeline, then later moved it to another site in response to geographic needs of the developer partner. This work was enabled by shared infrastructure, a global supply chain and standardized processes and methods for producing the molecule in single-use platforms.
The move aligns with the CDMO’s broader capabilities of multisite drug substance sourcing, ease of transfer and process sharing to derisk supply across the product lifecycle.
Easing the Path to Regulatory Approval
Aligning on a scale-out, single-use strategy early positively impacts the overall timeline from first-in-human through commercial launch, particularly for accelerated or conditional approval pathways, Anders said.
AGC Biologics can move faster by reusing process knowledge already generated at smaller scales instead of developing intricate, new scale-up studies. In addition, scale-out allows output to be adjusted to meet changing sponsor needs, avoiding unnecessary production of large material volumes during high-risk, uncertain stages.
“This streamlines the flow of material and helps our partners manage resource expenditure along the development path,” Anders said. “This is especially important when accelerated regulatory paths compress development timelines and raise pressure on supply readiness.” There are several commercial processes already running in scale-out configurations with no regulatory concerns, he added.
Innovation is happening with advanced process and analytical technologies to expedite manufacturing and release, giving customers more efficient, higher-quality manufacturing as the scale-out model continues to mature.
Ultimately, for smaller/midsized biotechs keeping an eye on cash flow, Anders proposed that single-use scale-out lets them allocate financial resources responsibly. They can avoid expensive, large-scale infrastructure until necessary while still having a path to commercial capacity by utilizing AGC Biologics’ global network and extensive scale-out capabilities.
Maximizing Output
In addition to scaling out, there are also alternative intensification strategies for single-use technology. While the standard fed-batch approach remains an industry staple for producing drug substance with single-use bioreactor systems, according to Anders, the demand for perfusion capabilities is increasing, particularly for complex molecules. Perfusion allows for continuous, high-efficiency manufacturing where fresh medium is constantly exchanged in/out of a bioreactor, encouraging high cell densities.
For atypical or complex molecules that may not reach the titers seen with standard monoclonal antibodies, AGC Biologics can utilize their scale-out framework with full perfusion process at production scale, generating much more material even from relatively low -titer processes.
This provides a growing opportunity to expand the range of molecules that can be brought to market with single-use systems, including those with limitations that are particularly tough to produce in mass quantities during late-phase trials or at commercial scales.
Perfusion and modular single-use suites – like the 6Pack System - also generate more material from a smaller footprint and considerably increase material supply from existing processes. This is crucial as sponsor pipelines shift toward more complex and personalized therapies.
“Perfusion or N-1 perfusion can also be combined with traditional fed-batch process as an intensification of the seed train to reach higher cell density before inoculating production,” Anders explained. “This is valuable for sponsors wanting more material without jumping to larger stainless-steel vessels.”
A Strategic Path Forward
As demand increases for greater speed and capital efficiency, single-use technology and scale-out methods are filling the need. This model enables drug developers to match production with demand by utilizing global networks of standardized, single-use bioreactors. It reduces financial risks inherent with large stainless-steel production and eases regulatory approval by ensuring process consistency and easier comparability. When combined with strategies like perfusion, the scale-out method maximizes output from a smaller footprint. Ultimately, this flexible, modular approach redefines capacity and risk, enabling faster, cost-effective development of vital therapies.
