Closing the Bioprocessing Gap

As the divide between upstream output and downstream capability in bioprocessing expands, it is becoming necessary for the biopharma industry to address plant capacity, process intensification, digital connectivity, and business feasibility.

Bioprocessing is undergoing a transformation as various technological and process advancements help to improve yields, efficiency, and safety for drug developers and manufacturers. Driven by innovation in cell line development, media formulation, and bioreactor design, upstream operations have achieved unprecedented productivity gains; however, this rapid upstream evolution has exposed operational imbalances across the bioprocessing continuum.

Operational Pressure Points 

“The most significant operational friction in today’s bioprocessing workflows occurs in downstream processing, quality control (QC), and the handoffs between upstream, downstream, and data systems,” remarks Jean-Marc Cappia, Head of Marketing Development, DSP Intensification & Digitalization, Separation Technologies, Sartorius. “While upstream process intensification has successfully increased cell culture productivity and product titers, downstream purification and QC activities often struggle to keep pace.” 

Significant bottlenecks are commonly experienced during purification — chromatography, virus inactivation and filtration, and final product recovery steps — as a result of “capacity constraints, process complexity, and the need to maintain high product purity and yield,” Cappia continues. “At the same time, lengthy analytical testing and batch release activities can delay product availability even after manufacturing is complete.”

Increasingly complex manufacturing needs and fragmented workflows and data silos are key drivers contributing to this operational friction, Cappia confirms. “Many organizations still optimize upstream and downstream operations separately, resulting in bottlenecks when higher upstream productivity overwhelms downstream capacity or creates new scalability challenges,” he says.

Novel therapeutic modalities, such as bispecific/trispecific antibodies and fusion proteins, raise additional challenges as a result of their complexity, reveals Abijar Bhori, Associate Vice President, Enzene. “These molecules often generate a greater number of product-related variants, increasing the impurity burden and making downstream purification more challenging,” he adds.

For Alex Toda, Vice President, Technical Operations at Prolific Machines, the main pressure point impacting the current bioprocessing workflow is from a business perspective rather than a technical one. “From a business standpoint, the therapeutics landscape may overall be shifting from blockbuster-volume mAbs toward targeted, biomarker-defined, and increasingly personalized therapies — smaller patient populations by design — which, in turn, increases pressure on the development and manufacturing units to ‘make more in less time’,” he specifies.

“In addition, limited integration between process development, manufacturing, quality, and digital systems reduces process visibility and slows decision-making,” Cappia notes. “As a result, companies are increasingly focusing on end-to-end process integration, digitalization, automation, and connected data strategies to improve throughput, accelerate technology transfer, save costs, and reduce operational risk.”

Technology Versus Capacity

According to Toda, both technology and capacity are factors in the downstream bottleneck issue. “From the technology point of view, it’s essentially resin cost driven by column sizing required by plant capacity design,” he says. “Protein A chromatography is still the dominant capture platform and is fundamentally a batch process that is limited by resin capacity. There are numerous efforts underway to improve these costs or employ alternative methods, but I think they’re behind the upstream technology gains.”

Focusing on capacity, Toda points out that, for most biopharma companies, it is financially unfeasible to simply buy a way out of capacity limitations. “Upstream technologies — both those that have improved cell productivity and processing throughput power — still fundamentally take place in the same footprint,” he specifies. 

“Downstream isn’t quite there yet,” Toda remarks. “Since it’s highly unlikely that a biotech company (which, in this market, must do more with less money to drive products to market) will have the appetite or CAPEX flexibility to change their plant on an ongoing basis, the root cause solution most likely lies in technological improvements such as continuous/connected processing, higher-capacity/alternative capture chemistries, and membrane-based polishing.”

While agreeing that both capacity and technology contribute to the downstream bottleneck challenge, Cappia also asserts that currently, companies are primarily faced with a capacity issue that is being exposed by technological limitations. For example, technological advances in cell culture, media optimization, and process intensification have led to increased upstream titers and hence production of more material from the same bioreactor footprint; however, downstream operations, particularly chromatography, have not kept pace, leading to contraints and longer processing times, he highlights.

“Over the past decade there have been significant improvements in upstream mammalian cell culture processing, particularly in achieving higher titers. However similar improvements have yet to be made in downstream processing, particularly in resin capacity,” concurs Bhori. 

“As a result, many companies, despite benefitting from higher upstream productivity, are struggling to process these increased titer-containing harvest volumes downstream,” Bhori states. “Facilities built over the past two to three decades were not designed to accommodate the higher titer in downstream, larger hold tanks, and increased processing demands associated with today’s higher-titer processes.”

Given that many current downstream technologies have been developed for lower titers and, as such, are approaching their practical limits, particularly for complex biologics, the solution is not simply to add more equipment, Cappia points out. “Traditional chromatography, multiple purification steps, and extensive QC requirements can limit productivity, increase costs, and reduce facility flexibility,” he says. “This suggests that while capacity is the immediate pain point for many manufacturers, the long-term solution will require technological innovation, including higher-capacity resins, membrane chromatography, continuous downstream processing, automation, and better integration of upstream and downstream development."

Emerging Paradigms

“To counter the potential bottlenecks we see in bioprocessing, one technology that is emerging, and which regulators also support, is the continuous manufacturing process,” Bhori notes. “We [at Enzene] believe that a fully connected continuous manufacturing process will be a game changer due to its flexibility across various modalities and throughout the product development lifecycle.”

Another innovative approach to resolving operational friction involves actively controlling cell biology during upstream processing through optogenetics. Rather than treating productivity as a fixed attribute locked in during clone selection and media formulation, optogenetic control uses light as a precise, reversible, and externally addressable control input over the cell itself, he reveals.

“The philosophical shift is what matters more than any single titer number,” Toda explains. "You can decouple growth and production phases with precision, tune expression timing and intensity mid-run, and in principle dial productivity to match what downstream and the facility can actually absorb, rather than always pushing upstream titer as high as biology allows and letting downstream absorb the consequences.”

Crucially, optogenetic hardware can integrate into existing facilities without requiring costly bioreactor retrofits or structural overhauls, Toda specifies. Light delivery systems can attach directly to single-use bag holders, functioning as standalone modules or integrating seamlessly into established process control systems, minimizing financial and adoption barriers while providing dynamic control over cellular output, he adds.

From an infrastructure perspective, digitalized, integrated bioprocessing driven by real-time analytics, AI, and predictive process control offers comprehensive gains, Cappia notes. While individual hardware innovations like continuous chromatography improve specific steps, the largest efficiency gains stem from unifying data streams across the workflow, he stresses.

"Many of today’s bottlenecks are not caused by a lack of equipment but by limited visibility into process performance, delayed decision-making, and disconnected workflows," Cappia asserts. “Digitalization enables predictive monitoring, faster root-cause analysis, improved process optimization, and more efficient technology transfer across the product lifecycle. Equally important is the shift toward an integrated process development philosophy, where upstream, downstream, manufacturing, and quality considerations are designed together rather than optimized independently.”

The Bioprocessing Facility of the Future

As process intensification, continuous processing, and digital architecture mature, the physical and operational design of biomanufacturing facilities will shift dramatically. Facilities built around massive, fixed assets and siloed operations are giving way to agile, connected, and footprint-efficient environments.

"Future bioprocessing facilities must have smaller footprints, support multi-product manufacturing through single-use technologies, focus on intensified and integrated processes, reduce carbon emissions, be flexible to meet customer needs, and be PAT [process analytical technology]-enabled and digitally integrated for process control,” Bhori outlines. “These capabilities can all be achieved through the design of continuous manufacturing facilities.”

According to Cappia, facilities of the future will shift toward fully integrated digital ecosystems, moving biomanufacturing from reactive monitoring to dynamic, self-optimizing control. “Rather than relying on large, fixed manufacturing assets and manual interventions, future facilities will operate as digitally integrated environments where equipment, sensors, analytical systems, and manufacturing execution platforms continuously exchange data in real time,” he states. “Advanced PAT, digital twins, AI-driven analytics, and automated control systems will enable operators to predict deviations, optimize process performance, and make proactive decisions before bottlenecks impact production."

Additionally, Cappia believes that physical footprints will become more compact and modular, relying heavily on platform-based approaches to accommodate multiple modalities on demand. By designing upstream and downstream operations as a single, integrated system, biomanufacturers can prevent localized productivity gains from overwhelming adjacent steps, he specifies.

Toda anticipates that economic market pressures will continue to push facilities toward modular, intensified, and highly automated designs, while emphasizing the need for adaptability over rigid future-proofing. “I’m admittedly curious to see if the so-called 'lights-out' (fully automated) production vision will make inroads into bioprocessing,” he reflects. 

"We all somewhat dream of an autonomous, closed processing facility that mixes robotics, intelligent control, and predictive interventions — however, we’re also not interested in making manufacturing more expensive to build and/or maintain,” Toda summarizes. “My hope is that the new facilities being built in the single use/modular space can be more adaptable to change and therefore be more able to realize justified technology benefits. Instead of betting on a future final end stage, I hope that we aim for a cadence of change that allows the plant and people to pivot, adapt, and flex, rather than stay fixed and unyielding."

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