For many years, biopharmaceutical manufacturers have worked to increase capacity, address upstream production issues, and improve product yields. Notable successes recently achieved in upstream technology have significantly increased expression rates and therefore, upstream production capacities. Successes in generating higher titers combined with increasingly stringent quality and regulatory requirements have led to a number of challenges in aligning the efficiency of downstream processing with upstream titers. It is generally recognized that downstream processing costs account for about 70% of the total biomanufacturing cost (
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). As a result, improvements in product recovery and purification are urgently needed. In trying to overcome this challenge, companies analyze where the best solutions lie: in streamlining operations, exploring emerging technologies, and/or using disposables.
Biomanufacturers are showing increasing interest and seeing strong development in single-use technologies and devices bot...
+1Over the past 10 years, disposable bioreactors have grown from a niche tool servicing small-scale projects to a common and essential component in the CGMP production of human therapeutics (
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). Recent advances in filter integration, aseptic connectors, and disposable sensing allow entire cell culture processes to be performed using only single-use components. However, harvest and clarification operations remain largely dependent on centrifugation, cross-flow filtration, and depth filtration (
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), which are all techniques that have not been widely adapted to single-use implementation. Their use in harvesting from disposable bioreactors can lead to process bottlenecks (
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), especially when large numbers of relatively small bioreactors are in use (e.g., for clinical and research laboratories). In such cases, the advantages of ease-of-use, disposability, and turn-key processing often outweigh the need for optimized, molecule-specific processes.
Here I report the results of a three-phase, nine-month–long st...
Biopharmaceutical manufacturing is divided into two areas: upstream fermentation or cell culture and downstream purification processes. Each area contains multiple unit operations. A unit operation is defined as a step in processing using a particular type of equipment. Here, we focus on downstream process development, which must reliably produce a highly purified drug substance (often >99%). Downstream processing includes recovery, capturing, and polishing steps.
The primary downstream unit operation is chromatography because of its simplicity and high resolving power (
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). Most process trains involve at least two distinct, orthogonal chromatography steps chosen from the number of chromatography supports available with various ligands attached to solid matrix. Affinity, cation-exchange (CEX), anion-exchange (AEX), ceramic hydroxyapatite (CHT), and hydrophobic-interaction chromatography (HIC) are the main types of chromatography modes used in large-scale bioseparations. The mode used for polishing depend...
+4 Much has already been written lately about addressing the so-called “downstream bottleneck(s).” A number of companies are leading the way toward developing products and platforms for reducing both the costs and the time required for downstream processing. Our task with this special issue was to provide a state-of-the-art update on these activities — but as always, within a limited number of pages allotted.
The primary issue behind this bottleneck debacle is to address purification challenges posed by aggregation in cell culture supernatants after cells are pushed to high antibody titers. This special issue therefore touches upon trends in single-use purification options, single-stage and turn-key harvest solutions, and cutting-edge innovations in chromatography.
Knowing that our coverage would only scratch the surface of the work being done, I polled members of BPI’s editorial advisory board. I asked them what sorts of articles they want to see more of related to current trends in downstream processing. T...
Manufacturing processes for biopharmaceuticals have undergone significant changes over the past decade. One of the most striking results of improved process sciences is the dramatic rise in expression levels from animal cell cultures. Figure 1 shows how some monoclonal antibody titers have increased about 30-fold over the past 15 years. These increasing titers have allowed current biomanufacturing facilities to produce larger product quantities than anticipated at the time they were designed and built.
Figure 1:
As a result of those increasing titers, the “bottleneck” in biopharmaceutical production has shifted from upstream production processes toward downstream processes (
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). In particular, chromatographic capture is currently presenting significant challenges in terms of facility throughput. The mass of product that needs to be captured during each batch has often exceeded the maximum binding capacity of a single column, so capture columns generally are being cycled multiple times during a single bat...
+2 What’s keeping senior biopharmaceutical executives awake late at night? According to BioPlan Associates, Inc., which publishes an annual comprehensive survey of the state of worldwide biopharmaceutical manufacturing, capacity constraints are among the key issues at hand (
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). And one of the most important constraints is the lack of physical capacity in purification equipment. Bioreactors are producing a lot more protein than current downstream purification steps are designed for. Overcoming the resulting bottlenecks may require increasing the productivity of downstream unit operations and turning over processing equipment faster to handle each consecutive batch.
Many biopharmaceutical manufacturers are turning to single-use systems to increase product throughput. Recent advances extend the use of disposables from the typical bioreactors and buffer or media storage bags to clarification and chromatography steps – and even to viral filtration and drug formulation. With such advances, the industry is on the...
