Sales of biopharmaceuticals reached $214 billion1 in 2017 and are growing by 8% per year2, compared with 4% for all pharmaceuticals. Biopharmaceutical patent applications have risen by 25% per year since 1995, as reflected in the 200 approved biological drugs, and 1500 in clinical pipelines3. By comparison, global sales in 2003 were less than $30 billion4.
This remarkable growth would have been impossible without technological innovations in the forms of disruptive technologies and continuous productivity gains of existing unit operations. As the biopharmaceutical industry grows it continues to look to technology and service providers for products that enable operation at desired scales and economies. Since those needs are often shaped by available bioprocessing tools, the relationship between biopharmaceutical companies and their suppliers is deep, complex, and in some ways symbiotic.
Technical innovations take many forms and originate from multiple sources. Many arise within biopharmaceutical development groups, while others emerge from small and large technology companies or academic labs.
However, innovation only reaches full acceptance at commercial scale through collaborations between inventors, end-users, and large suppliers, who alone possess the resources for integrating innovative products into complex production systems, for both new and existing processes. End-users and suppliers further create technologic meta-entities from technology innovations, for example platform processes. This has been particularly enabled by the widespread success and growth of monoclonal antibody biologics and their fusion proteins.
As the technologies of platform processes and their integration improved, large suppliers created even higher-order systems -- modular facilities -- that further support the application of innovation to larger issues of supply and facility flexibility.
Regardless of the mechanism, the principal driver for technologic innovation -- productivity within the context of existing capacity -- remains constant, although other factors come into play.
Markets are one such impetus. In the early days, biopharmaceuticals were introduced with relatively low expectations, but by virtue of addressing critical, sometimes unmet medical needs, many succeeded beyond prediction. Success (and manufacturing issues) resulted in shortages, for example with the rheumatoid arthritis drug Enbrel. Therapeutic biotechnology thus faces continuous pressure, due to its successes, to resolve supply challenges.
Technical innovations also arise from regulatory constraints, where regulators push back with demands for deeper evaluation or characterization -- process understanding in the current parlance. Serum-free cell culture was originally a response to concerns about the risks of animal pathogens infecting patients. In the process of eliminating serum, scientists at supplier organizations were forced to examine media composition for ingredients that were essential for cell growth and productivity. Although initial serum-free results were mediocre, eventually media manufacturers discovered that serum-free led to more in depth process and cell line knowledge opening new opportunities for improving fed-batch cultures.
Like individual technical innovations, their integration into platform technologies, and ultimately into flexible facilities, follows a collaborative, integrative commercialization path, but always toward the goal of enhanced productivity.
Single-use bioprocessing is a prime example of a technology which, while undergoing its own continuous improvement, facilitates application of platforming to a wide range of products and manufacturing environments, and thus makes possible flexible, multi-product, modular biomanufacturing facilities.
Single-use bioprocessing has been a disruptive driver for efficiency and cost reduction, at both process and facility levels, but without dramatic improvements in product titers the strong uptake of single-use systems at all scales would likely not have occurred, or been as rapid. Related as they are, rising titers and single use evolved gradually and in parallel since the early 2000s, mostly through the effort of both end-users and suppliers to upgrade cell lines, expression systems, media/feeds, and on the single-use side to improve mixing, mass transfer, gas handling, and bioprocess monitoring and control.
Note how single-use technology itself has evolved. In the early 2000s suppliers still needed to convince users that plastics were compatible with bioprocesses. Having achieved that, today’s concerns center on safety issues. Here the collaborative environment of groups like BioPhorum Operations Group (BPOG), composed of users and suppliers, will be instrumental in mitigating the potential safety issues surrounding single-use bioprocessing.
Pharmacia’s (GE Healthcare’s Life Sciences predecessor company) coining of the terms capture and polishing was perhaps the first step in recognizing the value of what came to be known as platform processes. Platforming reinforces its relevance as its individual components, through the efforts of GE and other major suppliers, continue to meet industry needs through continuous improvement.
Improving the chromatography resin’s dynamic binding capacity for protein A chromatography, arguably the defining operation in platform monoclonal antibody purification, illustrate how a component step validates the larger concept of platform. Protein A has experienced constant improvement since the concept of capture platform was first introduced, from less than ten grams of bound protein per liter to fifty or more grams.
While improving protein A binding capacity, GE has also improved the resin’s tolerance for caustic cleaning. Current GE resins, for example MabSelect™ PrismA, withstand cleaning with 1 N sodium hydroxide, which enhances bioburden control. The usable life of columns for manufacturing campaigns thus extends to the point where resin costs are almost trivial. Long-life resins further strengthen the case for platform processing.
As noted, commercialized process innovations often originate within biopharmaceutical sponsor laboratories, who then hand them off to suppliers. Behind the scenes suppliers improve their stock media and hardware products, and sometimes specific contracted-in products. An example is virus filtration, which fifteen years ago had a reputation for low capacity and high cost, but today satisfactorily meets industry needs. Similarly, the capacity of stock chromatography resins has risen four- to five-fold during that time.
Yet even stock products do not emerge through the efforts of suppliers alone. GE engages industry partners in the development of most of its major products, each of which go through several iterations of testing, feedback, and re-engineering. Innovative products usually originate from specific needs, but sometimes they anticipate expected or future needs.
Lonza’s GS Gene Expression System®, launched in 1992, is an example of step-change innovation from a supplier (in this case of contract manufacturing services). More than 35 licensed products, and upwards of 500 drugs in clinical trials, use GS, which Lonza continues to improve. The latest iteration, GS Xceed®, claims titers as high as ten grams per liter. GS was a disruptive technology but its continuous improvement has been incremental.
Disruptive technologies also result through the corporate route. GE’s acquisitions of Wave Biotech in 2007 and Xcellerex in 2012 occurred at junctures where single-use bioprocessing was by no means a slam-dunk for, respectively, development/seed train and large manufacturing processes. Both companies were founded by visionary entrepreneurs working for large pharmaceutical companies. Commercialization of their technologies followed a similar path of invention, proof of principle, refinement, acquisition, and further refinement. GE’s global reach and broader supply chain capability thus became the enabler for wide-scale adoption of what already were well-respected products.
At times, acquisitions anticipate future needs that lack an already established user base, for example, Pall’s 2015 license agreement of acoustic wave separation from FloDesign Sonics. Single-use acoustic wave separation uses acoustic forces to trap cells and debris during harvest. It achieves clarification without the limitations of scale, operational footprint, and buffer consumption associated with either depth filtration or centrifugation, and greatly reduces the need for these cumbersome, expensive operations. More recently, GE’s acquisition of Puridify was driven by the opportunity to use nanofiber technology to develop small, high-productivity purification devices that could alter the approach and scale of downstream purification, or facilitate the rapid purification of challenging entities such as labile viruses.
As monoclonal antibodies and their rising titers energized adoption of single use, and (with the aid of constant improvement) of the platform concept itself, platform processes now enable the meta-structure of versatile, flexible, modular, multi-product facilities.
In the early 2000s, processes used stainless steel almost exclusively for product contact surfaces, including bioreactors, storage vessels, tubing and piping. As a consequence, constructing a biomanufacturing facility was a long, costly endeavor. Genentech completed the first phase of its Vacaville, California manufacturing facility in 1998 at a cost of $150 million5; the Vacaville expansion six years later cost $600 million. By 2012 a typical biomanufacturing facility took about five years and cost $200 to $500 million6 to build. At the time a comparably-sized small-molecule facility could be had for as little as $30 million.
The size and complexity of biopharmaceutical facilities at the time was dictated by the productivity of upstream processing, but productivity has been a moving target in the best sense of the term.
Product titers for cell culture-based processes has been rising steadily7 since the dawn of therapeutic biotechnology. Average yields for monoclonal antibody production were about 200 milligrams per milliliter in 1985, about 1.2 g/L in 2003, and 3 g/L today, with one in eight processes claiming productivity of up to 6 g/L (and a few claiming ten or more).
Facilities were large and expensive in 2003 because productivity was low, particularly on the expression side. Downstream purification, while also quite inefficient by today’s standards, was sufficient for extant production titers.
Back then the cost and complexity of biomanufacturing facilities was a given: Opportunities for process efficiency and streamlining of operations and facilities, as a consequence of high titers and single-use processing, were beyond the horizon of anticipation. Hence the predicted continuation of the “capacity crunch” for biomanufacturing never materialized. The emergence of single use at all production scales, again made possible by rising titers, has led to platform processing for both upstream and downstream operations, which in turn has allowed biopharmaceutical firms -- with the assistance of large suppliers -- to consider modular facilities not as one-off supply solutions to temporary crises like influenza pandemics, but as a general strategy for building production capacity worldwide.
The expansion of therapeutic biotechnology into developing markets has added a new dimension to leading suppliers’ relationship with users. As demand grows in developing countries, so does the need for flexible, easily commissioned facilities to serve these consumers. Such facilities are only possible by virtue of technology commercialized by large suppliers, and on technologic meta-structures like platform processes and beyond.
Thus, the meta-structural nature of bioprocess innovation is illustrated in fixed-tank and single-use platform processes, which represent the aggregation of dozens of individual technical innovations and integration efforts. Platform processes serve as the components of GE’s FlexFactory platform, which in turn has become the building block for flexible facilities worldwide.
FlexFactory enables the rapid construction of new biopharmaceutical facilities, for example Clover Biopharmaceuticals’ proposed facility in Changxing, Zhejiang, China.
We now find ourselves in the next phase of maturation for single-use technology, during which further design improvements, expanded capabilities, and improvements in materials of construction meet current end-user requirements for productivity and safety. During the next few years we expect further improvements in the physical/mechanical properties of single-use products, how these products are manufactured and supplied, and a deeper understanding of how they interact with processes and, ultimately, with patients.
These improvements will occur not just for bioreactors but for other critical single-use product surface components like flow paths, filtration, and chromatography, which as downstream components still lag behind cell culture in terms of capacity.
Future opportunities to expand the application base for single-use will arise through the introduction of new therapeutic modalities, or novel ways of manufacturing established products. Cell culture-based vaccines, highly potent antibody-drug conjugates, bispecific antibodies, antibody fragments, and the anticipated successes of gene and personalized therapies, will entail unique production challenges to be sure.
Downstream processing, particularly in single-use formats, will likely require further improvements as long as titers rise. Upstream efficiencies have, to a degree, stressed purification, leading to what has been termed an “upstream-downstream capacity mismatch.” Note that the mismatch is less severe, and some would say not problematic at all, for larger traditional stainless-steel purification systems. GE’s FlexFactory installations, for example, are often designed as hybrid platforms with single-use upstream and stainless steel downstream based on scale requirements.
Capacity mismatch suggests to the potential for a disruptive technology, such as continuous chromatography, to improve downstream operations in a way that more closely matches upstream and downstream capacities.
The responsibility for commercializing continuous chromatography will likely fall to early adopter biotechnology companies working closely with suppliers. We expect that, until robust and broadly applicable continuous chromatography is commercialized, continued improvements in protein A binding capacity and cleanability will handle at least some of the slack.
By relying on many small columns instead of one large one, continuous chromatography could theoretically utilize protein A resins to their full theoretical extent, such that the resin effectively becomes disposable, thus enabling further efficiencies.
Clarification is a downstream operation that is ripe for innovation as products designed for low gram-per-liter titers are now expected to handle product and cell concentrations two to three times as high. Several ventures to improve clarification are underway, recently reported by a number of biotechnology companies and technology providers.
Another area with huge potential to improve productivity is QC analytics. The industry term “testing in quality” refers to the antiquated but standard biopharma practice of assessing quality after a product is manufactured, rather than during production. FDA’s 2004 Process Analytic Technology guidance notwithstanding, progress in real-time monitoring has been slow. It therefore behooves industry to move as many quality assays as possible to real-time manufacturing, as Amgen has done at its new Singapore plant.
The commercialization and production-level scaling of bioprocess innovations entail risks and investments that drug sponsors typically avoid, hence the critical role of suppliers in development, scaling, and ultimately commercialization. Implementation is moreover evolutionary, such that an industry-wide initiative (e.g. PAT) assumes a radically different thrust five years on.
In the past, the inexorable rise in product titers has been met with a sometimes exceedingly slow overall pace of innovation, interspersed with the occasional appearance of disruptive technologies. In this environment suppliers serve the unique role of gatekeeper or nexus where invention, need, and commercialization intersect. We expect the relevance of this role to continue as therapeutic bioprocessing enters new realms and continues its quest for value through productivity.
AuthorsAmit R. Dua – Global Marketing Strategy Leader, Bioprocess – GE Healthcare
Nigel Darby, PhD – Senior Advisor, Life Sciences – GE Healthcare
Guenter Jagschies, PhD – Strategic Customer Relations Leader, Bioprocess – GE Healthcare
Parrish Galliher – Chief Technology Officer – Upstream, Bioprocess – GE Healthcare
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