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because outdated filtration, chromatography, and purification steps are creating real bottlenecks.1 As a result, both manufacturers and vendors are looking hard at new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
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.
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
Table 1. Downstream technologies that iopharmaceutical companies are currently examining
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
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
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.