June 15, 2017 (Vol. 37, No. 12)

Celebrate the Downstream Improvements That Have Been Achieved, Even If They Fail to Match Upstream Improvements

The first step in solving a problem is admitting there is one. So, let’s put aside the idea that a downstream bottleneck isn’t a real problem, but just a matter of perception—specifically, a way of perceiving a capacity mismatch. This idea, always agreeable to the defensive biomanufacturer, might be expressed as follows: “It looks as though downstream processes—cell culture harvest, buffer management, and chromatography—are slowing production, but you must realize that downstream processing is actually much faster than it used to be.”

In other words, we shouldn’t complain about downstream bottlenecks. Instead, we should celebrate the downstream improvements that have been achieved, even if they fail to match upstream improvements.

Alternatively, we could acknowledge that downstream bottlenecks often result in equipment or facility under-utilization, product instability, reduced efficiency, and higher process-related costs. These are real problems, and they need to be solved, or at least mitigated. That’s where this roundup can help. It relates the thoughts of bioprocessing experts who are familiar with downstream processing issues.

GEN’s Expert Panel

GEN: To what extent are biomanufacturers still constrained by downstream bottlenecks?

Mr. Sanderson: Improvements in resin capacities and better implementation of downstream technologies, such as inline buffer dilution, have caught up with upstream titers; hence, many of the bottlenecks in larger facilities are disappearing. Downstream bottlenecks persist, though, especially at smaller biomanufacturers. And the “holy grail” of a robust, continuous downstream process is still years, if not decades, away.

Mr. Whitehead: It is a significant problem. Cycle times for downstream processing have not drastically improved. Titers have improved for most upstream processes and have had a positive effect on downstream volumes.

Dr. Bulpin: There are significant improvements being made in upstream processing, with the move to higher titers through the implementation of improved expression platforms and defined media. However, these improvements in the upstream space can lead to bottlenecks in the downstream space. Unless biomanufacturers take a holistic view of production, and thereby ensure that upstream improvements are accompanied by downstream improvements, the benefits and efficiencies of moving to higher titers can go unrealized.

Dr. Levison: Batch chromatography has long been a bottleneck, but it can be eliminated if continuous multicolumn chromatography technology is used. In a batch process, the efficient use of chromatographic sorbents requires very large columns or the cycling of a smaller column. Either option results in a bottleneck; neither is needed in a continuous process.

In the case of mammalian cell-derived proteins, another bottleneck can result if purification includes a virus-inactivation step, which often requires that bulk eluate be treated prior to subsequent processing. Continuous virus inactivation systems are under development to eliminate this bottleneck.

At present, single-pass tangential flow filtration technology, such as that provided by Pall Life Sciences, enables the traditional ultrafiltration/diafiltration stages of the formulation process to be carried out in continuous mode rather than in recirculation mode, which helps to eliminate process bottlenecks.

Dr. Linz: Managing the higher yields from upstream is still the challenge for biomanufacturing. Currently, a 2,000 L bioreactor can provide as much product as was once provided by a 10,000 L bioreactor. The limited efficiency gain in the downstream process is reducing the cost advantage that biomanufacturers derive from higher yields. This limits access to potential indications, especially those with high patient populations, the very indications that one might expect reimbursement systems to favor for economical reason.

Dr. O’Donnell: For an innovative biological therapeutic, companies rush to be first in humans. But when “speed to clinic” is emphasized, companies may neglect downstream process efficiency, and biopharmaceutical production may encounter unexpected bottlenecks.

The ubiquitous demand to reduce manufacturing costs later in drug development will always identify bottlenecks as significant no matter how much the operation actually impacts the overall process. New technologies are always thought to be a solution to bottlenecks, and these technologies will be evaluated for their ability to reduce time and costs while still maintaining or, even more important, improving product quality.

GEN: What are the main downstream challenges?

Mr. Sanderson: Today’s downstream challenges go beyond the simple ‘how to reduce protein A costs’ conundrum. A lack of commonality among single-use connectors drives complexity in the supply chain and discourages standardization. Decisions on whether to universalize platform processes (and simplify the resin/filter supply chain), or instead to optimize a process for, say, a challenging molecule, are not simple ones for management. How to manifest a continuous downstream process will remain a challenge for the foreseeable future, which means that we continue with small, incremental improvements in the near term rather than achieve any sea-change efficiency gains.

Mr. Whitehead: Liquid volume constraints for low-concentration buffers not only tax buffer making/holding systems, but also strain utility systems. The desire to reduce resins expenditures and the costs of goods have forced many manufacturers to create cycling strategies that lessen downstream efficiency and create complications with continuous processing strategies.

Dr. Bulpin: Two of the biggest downstream challenges that accompany high-titer processes are the capture of protein A and the management of overall process volumes. The productivity of protein A with higher titers is insufficient when executed in traditional batch mode. Additionally, for customers with an existing facility, high-titer processes can result in downstream process volumes which exceed the capacity of their intermediate hold tanks.

Dr. Levison: With continuous bioprocessing gaining acceptance in the industry, many of the current downstream challenges have been eliminated. However, new challenges will always appear, and these relate more to process intensification, integration of unit operations, process automation and control, and the opportunities presented in terms of process analytical technology to measure the critical quality attributes in real time.

Dr. Linz: Downstream unit operations—specifically, cell harvest for high cell densities and the affinity capture steps—struggle to keep up with increasingly efficient upstream processes. For downstream processing, capacity and single-use applications are not yet able to provide appropriate solutions for economical and flexible manufacturing facility designs. Fully closed single-use systems, such as those for vaccine downstream processing, pose abiding challenges for biomanufacturing.

Dr. O’Donnell: Initial process development strategies utilize traditional and sometimes discontinuous unit operations. These are time-consuming operations and are often the challenge most discussed; however, buffer consumption and specialized equipment are also critical cost and efficiency considerations.

Continuous chromatography operations are a logical evolution to downstream processing. Most companies are evaluating this technology in some form. Continuous chromatography is an inherently more complex operation that will require a more educated production team. Also, the resins utilized in continuous chromatographic operations were not developed with continuous chromatography in mind; therefore, they may give rise to a new class of bottlenecks.

GEN: What can be done to address these challenges and improve downstream efficiency?

Mr. Sanderson: Standardization is the key, and it needn’t limit innovation. Typically, suppliers won’t move toward a common standard on their own if they aren’t sure the market is on board. Therefore, biomanufacturers will need to work with suppliers to develop standards that can be leveraged for the supplier’s future product development.

Some of this work has already been started through industry consortiums, such as the BioPhorum Operations Group (BPOG), but continued progress requires corporate leadership. The incremental efficiency improvements that have been made over the past decade—such as single-use, just-in-time buffer makeup; single-pass tangential flow filtration technology; and improved resin and virus filter capacity—should be institutionalized.

Mr. Whitehead: Inline dilution technologies could be implemented. By facilitating the use of concentrated buffer solutions, inline dilution technologies could help biomanufacturers address volume constraints.

Other efficiency-promoting actions include reducing resin costs or developing technologies to allow for an increase in protein-binding capacities. Such actions could expedite simple load and elution chromatography schemes and even push continuous downstream processing into the mainstream.

Dr. Bulpin: There are several ways to address these challenges. Flocculation in the bioreactor, continuous multicolumn chromatography, and single-pass tangential flow filtration have all been shown to improve downstream efficiency. These technologies can help to capitalize on the benefits of high titers through increased productivity of the protein A capture step and reduction of downstream process volumes.

Dr. Levison: Integrated single-use systems should include appropriate process analytical technology tools and robust automation platforms for process control. Such systems would drive improvements in downstream efficiency. Coupled with cell culture intensification and greater adoption of continuous cell culture, improved process control should improve overall productivity and process economics.

Dr. Linz: Several new solutions are on the horizon. They include parallel processing/ “continuous processing” for the chromatography step; single-use approaches for affinity chromatography; single-use centrifuges (rather than sensitive filtration approaches) for addressing cell-density challenges; expanded bed absorption for unifying unit operations; and more consideration and equipment for continuous—flow-through—downstream processing (specifically, non-resin-based chromatography polishing steps).

Dr. O’Donnell: A strategy that incorporates continuous chromatographic operations will require resin manufacturers to redevelop the basic physical properties of their resins. Along with higher capacity, the resins must have superior binding and elution kinetics; otherwise the anticipated increases in efficiency will be cancelled by more unit operation complexity.

For example, a process that uses an ordinary resin, one characterized by slow binding kinetics and elution behavior, may require a four- to six-column system, whereas a process that uses a newer, better resin may require only two or three columns in the system. The transition to better resins must be accomplished without compromising the chromatographic selectivity, robustness, or pressure/flow parameters already established in downstream processes.      

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