Biomanufacturing is different from other processing industries. It is less able to sustain continuous end-to-end flows because it must contend with unique technical, practical, regulatory, and inertial constraints. Still, biomanufacturing can emulate well-established and far-reaching processing trends such as Six Sigma (for minimizing variability and defects) and Lean Manufacturing (for minimizing waste).

Another trend, one much discussed in biomanufacturing nowadays, is process intensification. Process intensification is already well established in the field of chemical engineering, where it refers to any development that leads to substantially smaller, cleaner, safer, and more energy-nt processing.

In biomanufacturing, process intensification is often taken to mean the same thing as continuous processing. Alternatively, process intensification may refer to approaches that can either move production closer to continuous processing, or lead to semi-continuous operations that approximate the benefits of truly continuous processing.

For example, process intensification may emphasize the integration of multiple processing steps into a single unit operation. Such integration may fall short of the ultimate goal—end-to-end continuous bioprocessing—but it may still conserve space, reduce the need for expensive inputs, and simplify quality control. And it may, of course, increase output.

Continuous processing has been most conspicuous in upstream bioprocessing, but downstream bioprocessing is catching up, particular in purification operations. In fact, downstream processing has little alternative than to move toward continuous processing, through process intensification or other means, if only to cope with ever-swelling upstream flows.

Seeing Connections

According to Tom Ransohoff, vice president and principal consultant at BioProcess Technology Consultants, process intensification involves streamlining, eliminating, combining, connecting, or speeding unit operations through various strategies, mostly hardware-based. Ransohoff believes that with the momentum it has already accumulated, continuous processing is likely to gain acceptance, perhaps sooner than later.

“Vendors are making real progress, from bench to pilot scale, but we’re only in the very earliest stages,” says Ransohoff. “Implementation will take a lot of work, and it’s too early to say how widely continuous processing will be adopted—which, by the way, is how I felt about single-use bioprocessing in the early days.

“At this stage, there are real solutions out there, even at full process scale, and there is clear regulatory support. The FDA has been especially encouraging and cooperative when it comes to continuous downstream processing.” In line with this optimistic view, Ranohoff notes that continuous downstream processing is being pursued by contract manufacturers such as WuXi and CMC Biologics, and by big biopharmaceutical companies, such as Merck, Bayer, and Sanofi.

Ransohoff even suggests that the conventional wisdom about continuous processing—that continuous operations are far more advanced upstream than downstream—may be overstated. “Yes, there are approved continuous cell culture processes,” he concedes, mentioning factor VIII and replacement enzymes as examples. “But these processes are operational because they yield products that are not stable enough to survive a fourteen-day fed-batch process. For those products, continuous processing is a necessity.”

Upstream or downstream, Ransohoff emphasizes, reaping the full economic benefit of large-scale continuous processing will require considerable work. “Plus, fed-batch has been so highly successful, particularly for monoclonal antibodies, that perfusion cell culture may be a hard sell.” Curiously, the upstream success of fed-batch, a less continuous alternative to perfusion technology, actually provides an impetus for continuous processing downstream. Given the improvements in upstream titers over the last few years, Ransohoff notes, “the downstream people are running out of room.”

If one subscribes to Ransohoff’s comparison to single-use processing at a comparable development stage, it is conceivable that continuous downstream processing will continue to advance slowly in this risk-averse industry, but pick up steam as technology improves and new methods for connecting continuous unit operations enter the scene. This scenario is not too outlandish if you remember that what held single-use back for years was the lack of physical connectors.

The big pieces of the puzzle are already in place, Ransohoff tells GEN. “We’re not looking to change process chemistry or the fundamental aspects of purification to gain the benefits of continuous processing,” he asserts. Even if an unconventional technology were to be introduced—for example, crystallization—the disruption might be managed fairly readily. That is, purification via crystallization rather than Protein A capture might generate products with significantly different quality attributes. Regardless, downstream continuous operations could continue to use essentially the same tools that are used with conventional purification.

Doing Two Operations on One Skid

Mary Jo Wojtusik, Ph.D., senior product manager at LEWA-Nikkiso America, notes that there is significant interest in downstream process intensification, particularly in combining two unit operations into one piece of equipment: “An example is combining buffer dilution or prep from concentrates on the same skid as a Protein A or polishing step.”

This strategy consolidates process space and simplifies clean-in-place procedures, but its advantages supersede the conservation of real estate. Since chromatography is a buffer-intensive operation, locating buffers where needed streamlines the overall chromatography step. “It also simplifies scheduling, which for downstream steps can be challenging,” Dr. Wojtusik says, “and the value is even greater for continuous capture, where buffer and media needs are ongoing.”

Dr. Wojtusik is referring to LEWA’s multicolumn EcoPrime Twin LPLC continuous chromatography system with on-board buffer dilution. Such systems may eliminate multiple human interactions associated with buffer dilution. Automation improves formulation accuracy and generally increases walkaway time.

According to Dr. Wojtusik, the progression of upstream operations from batch to fed-batch to perfusion culture has further challenged purification. “The downstream bottleneck is real because titers have risen routinely to the 5–10 g/L range, and cell cultures have become more continuous. That’s the point behind downstream process intensification, of combining multiple operations on a single skid.”

LEWA works primarily with stainless-steel bioprocessing, but the company also uses disposables where they offer value. “If you want to get the most out of modern biomanufacturing technology, hybrid systems are the way to go, where the supply to the skid is entirely single-use,” Dr. Wojtusik insists. “Aseptic connectors and buffer bags reduce clean-in-place time, but at clinical and full production scales you can retain the precision and reliability of stainless steel.”

Doing More in Less Time

In a recent online post about downstream processing, Fritjof Linz, Ph.D., vice president of purification technologies at Sartorius Stedim Biotech, notes that biomanufacturers “will use new combinations of unit operations,” and that “there will be batch processes and those that are operated in a more continuous manner.”1

“We are seeing a move toward companies performing batch operations in parallel and then switching between streams to allow the replenishment of consumables,” he continues. “Whether this is truly continuous processing or not is perhaps not so important if it allows the processing of the necessary product stream volume in the shortest possible time.”

“The common buzzword today is ‘continuous manufacturing’ but I prefer the term ‘process intensification,’” Dr. Linz tells GEN. “Only a few downstream steps today are truly continuous. In some instances (for example, Protein A capture) people run smaller columns in a parallel/staggered way and achieve a more continuous process flow.”

When GEN asked Dr. Linz specifically about process intensification, he mentioned an article by Benoit Mothes, Pharm.D., head of the Global DSP Breakthrough Technologies Skill Center at Sanofi. This article describes Accelerated Seamless Antibody Purification (ASAP), a Sanofi technology that can, according to Dr. Mothes, provide “an innovative path to process intensification by combining the best of current chromatography technologies while keeping the purification process simple and manageable in an industrial environment.”2

Sanofi’s methodology is actually semi-continuous. It involves processing many small aliquots of cell culture harvest to minimize buffer exchanges and product hold steps.

Dr. Linz believes certain downstream unit operations will become more continuous, and some, like flow-through polishing steps, essentially are already. The defining characteristic is the equipment’s dynamic capacity: As long as it is not exceeded, the process continues.

Under this model, virus filtration would not be continuous. This operation’s capacity is exceeded after a certain volume passes through the filter. Once that quantity is exceeded, the process is stopped and the filter is swapped out. Then the process resumes. Switching to a new virus filter by means of sterile valving would qualify as semi-continuous because the process doesn’t stop, but each filter retains its inherent capacity limitation.

The productivity-enhancing potential of process intensification is also emphasized by Demitri Petrides, Ph.D., the president of Intelligen, a provider of process simulation and production scheduling tools and services. Dr. Petrides has spent the last few decades showing how scheduling can be an effective way to intensify a process without investing in new equipment, investigating new process steps, or incurring additional regulatory risk. Scheduling can reduce turnaround time at multiple points in a process, such that even small improvements may, in combination, yield considerably enhanced throughput improvements.

This thought is seconded by Dr. Linz: “Optimizing downstream turnaround times enables manufacturers to process more in a given time for a given process footprint, which may translate into five or six additional batches over the course of a year.” That is, process intensification do more than simply save time. It may also optimize the footprint of unit operations and achieve more separation for a given amount of floor space.

In the online post cited earlier, Dr. Linz also indicates that continuous processing has implications beyond productivity. “Of course, continuous processing makes sense for labile products but it also makes sense for non-labile biopharmaceuticals where the annual production quantities needed by the market are large,” he remarks. “In either case, continuous bioprocessing should improve the quality of biopharmaceuticals because it has the potential to deliver more consistent product.”

Seeking Inner Intensification

Sometimes the spirit of intensification may be achieved not by combining steps but by significantly improving a single operation. For example, in late 2017, GE Healthcare Life Sciences introduced a Protein A chromatography resin that should, the company says, allow its customers to produce more biopharmaceuticals out of their existing manufacturing equipment.

The new resin, MabSelect PrismA, has a monoclonal antibody purification capacity that is up to 40% higher than that provided by MabSelect SuRe LX, another one of the company’s high-performance Protein A resins. PrismA is also significantly more alkaline-stable than MabSelect SuRe LX, which allows cleaning with higher-concentration alkali.

With volumetric titers continuously rising, the potential for a meaningful downstream “capacity crunch” becomes real. Bioprocessors have thus far met the challenge, but at the cost of longer processing times and higher consumption of expensive resins and buffers. MabSelect PrismA addresses these concerns by improving binding capacity.

The dynamic binding capacity of the improved resin is around 80 mg antibody/mL resin at a residence time of six minutes, and around 65 mg antibody/mL resin at a residence time of four minutes.

How did GE Healthcare do it? “This is a result of a major investment for GE Healthcare, which supported one of the largest projects for our Life Sciences’ BioProcess business,” explains Jonathan Royce, business leader for the chromatography resin portfolio of GE Healthcare. “More than 50 people were involved in the project, which took two and a half years and required screening more than four hundred prototypes.”

Royce acknowledges that the downstream capacity crunch has been real, a result of radical improvement in upstream processing, and that longer processing times and higher consumption of chromatography resins have been the result. “Our goal was to address the bottlenecks our customers encounter during production,” he says. “We collaborated with many customers during the project.”

Royce believes that as the market for traditional monoclonal antibodies saturates, the structural diversity introduced by new molecules will usher in new purification technologies. “Downstream processing,” he asserts, “needs to diversify to address these novel purification targets.”

Some of these requirements will be met by traditional chromatography, and some will require improvements such as MabSelect PrismA. “However, some separations will require completely new technology,” Royce points out. “The FibroSelect platform developed by the bioprocessing startup Puridify, which GE Healthcare recently acquired, is a technology that we believe will be an important part of future downstream processing.”


Angelo DePalma Ph.D., is a Writer for GEN.


1. Sartorius, “Continuous Bioprocessing: An Interview with Fritjof Linz, VP Purification Technologies, Sartorius Stedim Biotech,” accessed January 8, 2018.
2. B. Mothes, “Accelerated Seamless Antibody Purification: Simplicity Is Key,” in Process Scale Purification of Antibodies (U. Gottschalk, Ed. John Wiley & Sons. Hoboken, NJ, March 3, 2017), doi: 10.1002/9781119126942.ch20.
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