The need for transformation is a powerful driving force in the biopharmaceutical industry. Opinions and predictions about the best way forward are plentiful. As drug developers seek to enhance productivity, reduce costs, and improve their return on investment in research and development, new ways of doing business are explored, evaluated, and acted upon — with varying degrees of success.

Faced with intense pressure to evolve, the biopharmaceutical industry is smart to leverage approaches that have driven success in other industries. Witness the growing interest among drug developers in applying continuous process improvement strategies that Toyota used to revolutionize automobile manufacturing (1).

In this turbulent environment, what other sources of inspiration can the industry call upon to guide new approaches? Over 20 years ago, the enormously popular self-help book The 7 Habits of Highly Effective People promised “powerful lessons in personal change” (2). Author Stephen Covey offered a blueprint for transformation and encouraged readers to get ready for the necessary paradigm shift. Can Covey’s advice be applied to the drug development industry?

Several habits described in the book — including “begin with the end in mind,” “think win–win,” and “synergize” — offer a framework for thinking about process improvement opportunities and the integration of functional areas to drive gains in efficiency and productivity. A key imperative for developers of therapeutic proteins is more effective alignment and integration of upstream and downstream activities to optimize overall production processes.

Advances in upstream processing such as high-capacity technologies and optimized media have increased protein yields per unit volume coming from bioreactors. Unfortunately, downstream bioprocessing operations capacity designed years ago may struggle to accommodate currently achievable protein titers. Antibody expression levels now routinely exceed 1 g/L, whereas levels of 100 mg/L were commonplace not so long ago. Successful efforts to maximize bioreactor titer levels have put significant pressure on downstream processes, thereby shifting production bottlenecks from upstream to downstream unit operations.

A number of tactics can be leveraged to help downstream processing “catch up” with upstream processing. To address downstream capacity issues, drug manufacturers often resort to increasing physical footprints of their production facilities — an expensive proposition and perhaps not the most practical as the blockbuster era evolves toward a “niche busters” environment.

Taking a more holistic view of upstream and downstream processing can offer new insights to improving overall workflow and suggests alternatives to increasing your manufacturing footprint.

Begin with the End in Mind

One trend in the industry we are observing is a shift from maximizing bioreactor titers to optimizing for “purifyability” — which, in essence, can be equated to optimizing an entire manufacturing process by addressing its production portion. That approach begins with the end in mind as it considers the tradeoff between high titers and purification cost.

Bioreactor titers can increase through improvements in specific cell productivity and/or higher cell densities. In either case, titer increase comes at a cost: reduced protein “purifyability.” Efforts to increase cell productivity can lead to an increased presence of variants, isoforms, and proteins that are not fully formed. Along with higher titers comes reduced cell viability and increased levels of cell debris and organic materials.

With extremely high titers, the cost of production starts to shift downstream, and the law of diminishing returns engages as the overall process yield is reduced. In such cases, the overall minimum cost of production is unlikely to be achieved with the highest titer. Cost synergies realized from producing protein mass at higher titers can be negated by increased purification costs. That increase results from the need to conduct an extra purification step — loss of yield — due to having to run purification processes within a narrower operating window.

The challenge becomes reaching an appropriate balance between bioreactor productivity and protein “purifyability.” An optimized process is needed to encompasses both objectives. A “begin with the end in mind” philosophy must also be adopted by product and services suppliers to the industry.

Drug manufacturers are faced with a dizzying array of reagents and technologies — all intended to optimize a portion of production processes. Novel cell culture media and supplements can drive higher and higher titers, and downstream purification products promise greater capacity and higher throughput.

It is incumbent upon suppliers to adopt a similar holistic view of the process train and understand that maximizing efficiency or productivity of one step doesn’t necessarily optimize the overall process — which must be the intended objective.

Think Win-Win

As both drug developers and their suppliers embrace a more holistic view of the overall production process, their solutions that are mutually beneficial to more than one functional area begin to emerge. In particular, we see a significant opportunity for solutions and technologies that reside at and optimize the interface between process steps. Such advances necessarily take into account the steps before and after the interface at which they reside.

As described above, increased cell densities in bioreactors can be a double-edged sword as higher protein titers are delivered (at the expense of purity). When cell density increases, so do impurities; the pressure on clarification and purification then intensifies as legacy centrifugation and filtration processes struggle to keep pace. To address that challenge, our company is developing novel precipitation technologies that will allow a cleaner product to come from bioreactors into the clarification step while preserving products. Acid precipitation techniques that are beginning to be used may cause protein denaturation. The new technology will help create a win–win in that it will minimize the burden on downstream processes created by high titers without the need to sacrifice titers or risk damage to proteins. Also under development are strategies to ensure that the proteins coming out of bioreactors are the most “purifyable” possible.

Synergize

Continued erosion of the silos that once stratified traditional upstream and downstream unit operations and a broad vision of where resources are best applied to improve workflows should lead to more impressive productivity gains. The ability to identify where resources and new technologies are best applied and which ones should be applied requires both a horizontal view of entire process trains and in-depth vertical expertise about each unit operation. This synergy of horizontal and vertical thinking creates a fresh perspective about how to optimize each functional area — bioreact
or, clarification, chromatography, tangential flow filtration, virus removal, and sterile filtration — to maximize overall process output.

Such an approach is especially useful when considering adoption of single-use technologies, which our industry is increasingly embracing. Adoption has been somewhat limited to certain unit operations such as bioreactors and buffer–media preparation. But interest in single-use technologies in other areas of protein processing has been increasing.

In response, manufacturers of single-use technologies have leveraged their technical expertise to introduce a wide variety of products to support individual unit operations. Those individual components, however, must be optimized to work together with components that reside upstream and downstream. The industry is in need of advanced single-use and hybrid unit operations that combine into solutions that effectively optimize and streamline entire biomanufacturing processes, theregy enabling cost and risk reduction and maximizing the throughput.

Seek First to Understand…

Biopharmaceutical manufacturing is highly specialized and complex because each protein molecule is unique and so requires customized production and purification processes — even in the era of “templated” processes. All manufacturers feel the same pressure: Reduce time to market, cut costs, and facilitate efficient scale-up and technology transfer as manufacturing capacities become more global. Effectively balancing all of those demands and creating a manufacturing process that delivers on corporate objectives requires a multidimensional perspective. The phase of the process, scale, and geographic location all affect decisions about unit operations, analytics, process control, and cost of ownership modeling.

Given that complexity, it is incumbent on suppliers and partners to the industry to adopt another of author Covey’s habits: Seek first to understand. A one-size-fits-all approach to process development and manufacturing will not suffice. Suppliers must first understand drug manufacturers’ objectives and unique pain points to help tailor a successful outcome.

Suppliers, as partners of drug manufacturers, must also engage in informed conversations about the entire production flow and optimizing total cost models — whether those models are driven by needs for rapid production, lowest cost, or both. As we evolve away from the era of blockbuster drugs, new approaches to the entire discovery and development spectrum are critical for driving greater productivity and process efficiency. While specific requirements for individual process steps must always be met, a more holistic view of overall processes with a focus on maximizing outcomes also must be embraced.

Webinar Series

EMD Millipore offers two series of webinars in its “Factory of the Future” program, which expands upon ideas presented here Information is available at www.millipore.com/media/flx2/webinars

• Factory of the Future: Two-Part Clarification Webinar Series

• Factory of the Future: Three-Part Chromatography Webinar Series

We expect that best practices from other industries will continue to be leveraged to deliver breakthrough change. In parallel, some lessons from popular self-help books might also provide a new framework when thinking about and identifying opportunities for meaningful process improvement.

Author Details
Paul Chapman is vice president of Biopharm Process Solutions at EMD Millipore (Paul.chapman@merckgroup.com). Mani Krishnan is director of Single-use Processing Systems at EMD Millipore (Mani.krishnan@merckgroup.com).

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