An aggressive perfusion strategy can dramatically increase the required harvest volume—potentially an order of magnitude higher, or even more—compared to a facility designed for fed-batch operation. This substantial increase in volumetric load places greater demands on several aspects of biomanufacturing infrastructure, including buffer preparation, surge capacity, and capture throughput. Consequently, many biomanufacturers are currently assessing the impact of this higher volume on their existing facilities.
With pipelines being so unpredictable, margins so tight, and capital expansion limited, process intensification is becoming absolutely necessary for operations.
Dr. Mark Schofield, Director of Science at Cytiva, emphasizes that the response cannot be one-size-fits-all. “Every company and every molecule follows its own path".
That reality explains why intensification looks different across organizations. “Some teams are trying to get more output from the facilities they already have,” Dr. Schofield observes. “Others are working with unstable molecules and need to move quickly from the bioreactor into purification,” he adds. In biosimilars, cost dominates. “Reducing cost per gram will require a step change in how we process these molecules.”
Working in analytical science?
Register for a FREE Separation Science account to subscribe to the Separation Science Newsletter.
Perfusion: Higher Output, Higher Downstream Load
Intensification rarely happens in a single leap. Early decisions shape downstream architecture. Many manufacturers begin with N-1 perfusion because, as Dr. Schofield explains, “It represents low-hanging fruit that increases cell density and shortens production timelines without requiring a full facility redesign.” Moving to production-scale perfusion represents a deeper structural shift with broader downstream consequences.
He contrasts the models directly: “In a traditional fed-batch campaign, you might achieve around 21 harvests per year. With perfusion, you can produce substantially more material per litre of bioreactor per year. Perfusion commonly runs at about two bioreactor volumes per day, and leading processes can achieve roughly four grams per litre per day—about 2 g/L steady-state titer at two BVD per day—while fed-batch titers may reach around 10 grams per litre,” explains Dr. Schofield.
The result is a volumetric imbalance that defines the downstream challenge. “You may generate six times more product, but you are processing close to 30 times more volume,” emphasizes Dr. Schofield. That ratio reshapes facility economics: media demand escalates, capture throughput must increase, buffer preparation scales sharply, surge capacity becomes critical, and automation requirements expand.
The financial implications are equally sensitive. “Nothing in this process is free,” Dr. Schofield cautions. “Small adjustments in cost assumptions can significantly change the outcome of a model,” he observes, noting that high-volume perfusion scenarios may require careful choice of cell culture media to manage cost.
Continuous Capture: Designing for Synchronization
A continuously producing bioreactor does not pair well with stop‑start chromatography. “If upstream and downstream drift out of alignment, you either need a much larger surge tank or you risk deviations,” explains Dr. Schofield.
Continuous capture addresses that mismatch. With alternating twin columns, “one column loads while the other completes wash and elution, and then they switch,” he describes. Loading remains continuous, and synchronization tightens.
Periodic countercurrent chromatography (PCC) extends this logic. “By loading columns in series and capturing breakthrough from the first onto the second, you gain additional intensification and higher usable capacity,” Dr. Schofield observes. “This improvement reduces resin volume and buffer consumption.”
The following choices alter core design principles:
- Column sizing becomes flow-driven rather than purely capacity-based.
- Resin lifetime reflects higher cycling frequency.
- Breakthrough monitoring shifts from verification to active control.
- Automation becomes integral rather than supportive.
Once a team commits to perfusion, downstream flexibility narrows. “You’ve chosen a path,” exclaims Dr. Schofield. Continuous capture often becomes the logical extension of that decision.
Interpreting the Claims
In clinical settings, reductions can be dramatic. Dr. Schofield notes that at a commercial scale, where campaigns may run hundreds of cycles, the decrease may be closer to 20 or 30 percent.
Trade-offs are unavoidable. “You cannot maximize all performance metrics at once,” he asserts. Analytical teams should pressure-test the assumptions underpinning cycle counts, resin lifetime models, the burden of cleaning validation, buffer and WFI projections, and the new risks introduced by higher volumetric load.
Facility Fit and Technical Boundaries
For many organizations, the driver remains a physical constraint. “Process intensification is fundamentally about facility fit,” states Dr. Schofield. “The objective is to produce more within the same footprint.”
However, technical limits remain. He observes that, in perfusion, some cell retention systems are less scalable at very large reactor volumes. Upstream gains must remain mechanically and biologically sustainable. At the same time, the industry has adjusted expectations. Rather than pursuing fully continuous end‑to‑end processing, many manufacturers focus on key integration points. “Integrating the bioreactor directly with capture chromatography delivers the greatest impact,” explains Dr. Schofield. “That focused island of continuity often delivers the most practical return.”
Start With the Right Question
When asked where manufacturers should begin, Dr. Schofield jokes, “Why haven’t you come to Cytiva already?” before clarifying, “What specific problem are you trying to solve?”
Before process redesign begins, that objective must be clear. Identifying the constraint—whether footprint, cost per gram, pipeline flexibility, or molecule stability—structures subsequent technical decisions and prevents reactive redesign. It also allows suppliers to bring a broad toolbox of solutions tailored to each facility's limitations.
Implications for Separation Scientists
Process intensification requires separation science to shift from optimizing isolated steps to designing integrated systems, demanding that downstream scientists prioritize synchronization over resolution. This involves balancing economic factors, understanding breakthrough under dynamic loading, and discerning true value-add versus fragility. While targeted intensification boosts capacity and flexibility, overextension risks making the process brittle. Future competitive advantage lies not in the extent of intensification, but in intelligently synchronizing upstream and downstream processes. Success belongs to teams that engineer integration, balancing throughput, control, and resilience, not just productivity.
