Downstream Processing: Promising Technologies are on the Horizon - The new technologies being developed to improve downstream systems go beyond traditional chromatography. - BioPharm International

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Downstream Processing: Promising Technologies are on the Horizon
The new technologies being developed to improve downstream systems go beyond traditional chromatography.


BioPharm International
Volume 23, Issue 3


Eric Langer
Downstream processing used to be the Rodney Dangerfield of biopharmaceutical manufacturers ... cleaning up crude bulk product got no respect, especially after the relatively glamorous upstream manufacturing from living organisms. Today, that's changing because outdated filtration, chromatography, and purification steps are creating real bottlenecks.1 As a result, both manufacturers and vendors are looking hard at new technologies to improve their downstream systems. This is the first column in a series that will discuss new technologies for downstream processing.

Most manufacturers agree that the cost and complexity of chromatography steps are the real sticking points, and our current 7th Annual Biomanufacturing Survey data shows that 53% of biopharmaceutical managers feel it's the biggest downstream problem today. Yet, even as internal company pressures to reduce operating costs grow, most managers still concede that major breakthroughs are unlikely in the short term. On the other hand, they also accept that small, incremental improvements are unlikely to dramatically lower overall costs. The technical change that led to the downstream bottlenecks is, of course, the increase in upstream fermentation and cell culture yields. This is unlikely to slow, and the continuous yield improvements for target proteins continue to burden downstream operations.

So, where are we going to find relief? There's an increasing push to move away from traditional Protein A as an affinity chromatography ligand and find solutions that are cost-effective and readily acceptable to regulatory authorities. And even though few companies want to be the first to blaze the regulatory approval trail, many are considering the move. In fact, for new production units, 35% of the industry is considering alternatives to Protein A today.2

WHERE ARE THE IMPROVEMENTS?

At present, few real commercial options exist, but promising technologies are on the horizon or entering commercial production. We do expect to see improvement, including membrane processes, monoclonal-fragment technology, and more specialty resins and synthetic affinity matrices that are priced near Protein A.

It's a matter of time before an alternative to traditional chromatography for antibody purification becomes an industry norm. Eventually, the industry and the FDA will move away from tried-and-true methods of purification, but when that happens, simpler, cheaper, and FDA-approvable alternatives are likely to take hold rapidly.

Our survey data show that most companies are already investigating new technologies. Those not paying attention may get stuck with manufacturing processes for their pipeline products that are simply not competitive.


Table 1. Downstream technologies that iopharmaceutical companies are currently examining
So it's not surprising that most are not sitting still on the issue. Our current study illustrates the dramatic changes now emerging. Nearly two-thirds (65%) of respondents are increasing their budgets for acquisition of new downstream processing technologies in 2010. This shows that adoption of new purification technologies is a distinct trend. Table 1 includes some of the technologies from our study that biopharmaceutical companies are currently examining.2

Even as end-users are investigating broad technologies, specific alternatives to Protein A and traditional purification are becoming commercialized. Some of these are listed below.

  • Single-use downstream chromatography: Novozymes's new patented Dual Affinity Polypeptide technology platform replaces Protein A process steps with similar, but disposable, technology
  • Stimuli responsive polymers enable complexation and manipulation of proteins and allow for control of polymer and protein complex solubility, which results in the direct capture of the product without centrifuges or Protein A media, from Millipore Corp
  • Mixed mode sorbents to replace traditional Protein A and ion exchange, for improved selectivity and capacity with shorter residence times. These media, with novel chemistries, include hydrophobic charge induction chromatography, such as MEP, and Q and S HyperCel from Pall Corp
  • Monoliths, involving chromatography medium as a single-piece homogeneous column, such as Convective Interaction Media monolithic columns from BIA Separations
  • Simulated moving beds, involving multicolumn countercurrent chromatography, such as BioSMB from Tarpon Biosystems
  • Protein G (multiple vendors)
  • Single domain camel-derived (camelid) antibodies to IgG, such as CaptureSelect from BAC
  • New inorganic ligands, including synthetic dyes, such as Mabsorbent A1P and A2P from Prometic Biosciences
  • Expanded bed adsorption chromatography systems, such as the Rhobust platform from Upfront Chromatography
  • Ultra-durable zirconia oxide-bound affinity ligand chromatography media from ZirChrom Separations
  • Fc-receptor mimetic ligand from Tecnoge
  • ADSEPT (ADvanced SEParation Technology) from Nysa Membrane Technologies
  • Membrane affinity purification system from PurePharm Technologies
  • Custom-designed peptidic ligands for affinity chromatography from Prometic Biosciences, Dyax, and others
  • Protein A- and G-coated magnetic beads, such as from Invitrogen/Dynal
  • New affinity purification methods based on expression of proteins or MAbs as fusion proteins with removable portion (tag) having affinity for chromatography media, such as His(tidine) tags licensed by Roche (Genentech)
  • Protein A alternatives in development, including reverse micelles (liposomes), liquid–liquid extraction systems, crystallization, immobilized metal affinity chromatography, and novel membrane chromatography systems
  • Plug-and-play solutions with disposable components (e.g., ReadyToProcess), process development ÄKTA avant with design of experiments capability, and multicolumn continuous capture, from GE Healthcare.


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