The Future of Downstream Processing-2013 - As constant scale up grows out of favor in the biopharmaceutical industry, new—and old—approaches are required. - BioPharm International


The Future of Downstream Processing-2013
As constant scale up grows out of favor in the biopharmaceutical industry, new—and old—approaches are required.

BioPharm International Supplements

Game-changing innovations
Although process redesigns and traditional technologies can contribute to the development of downstream processes, they provide only incremental improvements that marginally increase process efficiency. Incremental or evolutionary technologies have been the mainstay of the bioprocessing industry for the past 20 years, and column chromatography provides one of the best examples of this phenomenon in action (28). These slow marginal gains, however, are already beginning to decline and [the industry is] reaching the stage where it is becoming difficult to envisage how sustainable processing can continue without a major injection of downstream processing capacity. One way this can be addressed is to embrace genuinely novel technological approaches that change the rules of the game. Companies that survive on innovation populate the fringes of the biopharmaceutical industry, and some of these innovations are disruptive in the sense that their influence on the industry is unpredictable and could contribute to a radical change in bioprocessing.

Figure 1a: Mechanistic comparison of solute transport in bead resins (left) and membrane adsorbers (right), where thicker arrows represent bulk convection, thinner arrows represent film diffusion and curved arrows represent pore diffusion. (All figures are courtesy of the author.)
Most technological innovations in bioprocessing have been incremental, but there are several recent examples of disruptive innovations that have challenged the established business model and caused real grassroots change in the industry. Again, many of these changes have affected upstream productivity first (e.g., disposable bioreactors and buffer/media storage bags), but there are examples in downstream processing (e.g., the introduction of simulated moving bed chromatography, expanded bed chromatography, monoliths, and membrane adsorbers) (1, 29). These innovations have taken hold in niche markets but are now beginning to adopt mainstream positions. Disposable modules for downstream processing occupy a more mature status in the development cycle (30). The use of disposable filter modules is now an industry standard, but these are being complemented in more and more processes by disposable membrane adsorbers and innovative combinations that exploit both adsorption and size exclusion as orthogonal separative principles (31, 32).

Figure 1b: Comparison of bed height in columns (left) and membrane adsorbers (right). Using membrane adsorbers is functionally equivalent to shortening columns to near-zero length, resulting in a similarly small pressure drop that allows extremely high flow rates, thereby reducing overall process times up to a 100-fold. In this example, both formats have a 1350 cm² frontal surface; the column has a bed height of 15 cm; and the membrane adsorber has a bed height of 0.4 cm. The height to frontal surface ratio is approximately 100 for the column and nearer to 3500 for the membrane device.
Disposable anion-exchange membrane adsorbers are replacing traditional flow-through chromatography steps for polishing, particularly the removal of host-cell proteins, nucleic acids, and viruses, because of their high flow rates compared to packed resins and the absence of cleaning and validation requirements (32-34). The performance advantage of membranes over resins reflects the transport of solutes to their binding sites mainly by convection, while pore diffusion is minimal (see Figure 1a). These hydrodynamic benefits increase the flow rates and reduce buffer consumption compared to columns, thus shortening the overall process time by up to 100-fold. Polishing with an anion exchange membrane can be conducted with a bed height of 4 mm at flow rates of more than 600 cm/h, providing a high frontal surface area to bed height ratio (see Figure 1b). However, a more diverse range of surface chemistries is now available (see Figure 2). Membrane adsorbers, therefore, are also challenging the hegemony of column chromatography in other biomanufacturing steps, such as bind-and-elute capture steps (35), hydrophobic interaction chromatography (36), and even salt-tolerant chromatography in high-conductivity buffers (37), which broadens the polishing window as shown in Table I. Membrane absorbers have been substituted for both flow through and bind-and-elute polishing steps during the manufacture of various commercial products. These devices are also increasingly viewed as ideal for virus clearance because they interact with both large and small, and both enveloped and non-enveloped viruses, and can easily be combined with other concepts such as irradiation with ultraviolet light (UVc) and dead-end filtration (38,39).

Figure 2. Selection guide for convective media, such as membrane adsorbers. HIC is hydrophobic interaction chromatography. STIC is salt tolerant interaction chromatography.
The flexibility of disposable modules and their capacity to integrate into any stage of the production process is arguably their most important benefit. This reflects the broad industry perspective that manufacturing flexibility is now perhaps at least as important as capacity considering the large numbers of products in clinical development (1,4). Process development can be streamlined and expedited because different modules can be tested in various combinations to arrive quickly at the best overall set of process options, and the absence of cleaning and validation requirements can shorten the time required to develop a finalized process by months or years. The ability to replace each module completely also makes it easier to assemble process trains for new products in existing premises without cross-contamination and to achieve the ideal concept of continuous integrated bioprocessing (40). Continuous integrated bioprocessing has been implemented in upstream production using profusion cultures (4143) and, more recently, in a series of linked downstream operations (4446). Only in the past two years, however, have serious efforts been developed to link upstream and downstream components into a single unified continuous process (40, 47).

Table 1. Broader polishing operation window with salt-tolerant membrane chromatography.
What does the future hold?
Innovations that take into account not only the current state of the industry but also future challenges and demands are likely to be the most successful in the long term, but bleeding-edge technologies always come with risks that must be evaluated by manufacturers looking at major investments into capacity. The perceived bottleneck in downstream processing can be addressed with lower-risk approaches such as streamlining current production processes, with moderate-risk approaches such as introducing technologies that have already proven suitable in other industry settings, or with higher-risk approaches involving the incorporation of novel technologies. In several cases, these novel technologies have already proven their credentials in several processes. Companies following the paths set by the first adopters, the trailblazers of the industry, can be assured that the technologies involved now have established their credibility.

The future of biomanufacturing is likely to rely more on innovation and flexibility than on traditional strengths such as large facilities and the financial muscle to invest in them. Disposable manufacturing is likely to play an increasingly important role as companies maneuver in a crowded market to protect their R&D investments while more and more generics become available. The ability to scale up or down quickly, to switch to new campaigns rapidly, and to produce multiple products in the same facility will be a key metric of success. The future of bioprocessing will require the industry players to embrace the need to change. In the words of US Congressman Bruce Fairchild Barton, “When you are through changing, you are through.”

Uwe Gottschalk, PhD, is vice-president of purification technologies at Sartorius Stedim Biotech GmbH and a member of BioPharm International’s editorial advisory board., This is an updated version of an article previously published in the September 2011 issue of BioPharm International.

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