Disposable Biopharmaceutical Processes–Myth or Reality? - - BioPharm International


Disposable Biopharmaceutical Processes–Myth or Reality?

BioPharm International

Cellulosic depth filters for cell harvest and clarification are available in completely disposable capsules, eliminating the need for housing cleaning and validation.3 They can be simply and directly connected to the downstream processing line or to disposable bags, thereby minimizing product contact by the operator, reducing contamination risk and operator safety concerns. Depth filter capsules are available from small- to large-scale, in a range of pore sizes up to 20 mm. Cell-free and clarified harvest is typically then pumped through a sterilizing grade filter capsule to the subsequent integral unit operation or storage bag.

Centrifugal separation also allows for disposable product contact surfaces, but has direct scalability problems and is best suited for volumes smaller than those seen at production scale.

Figure 8. Load capacity 10 kg/L (source: BioPharm Services, London)

Figure 9. Load capacity 2 kg/L (source: BioPharm Services, London)

Robust chromatographic separation using membrane adsorption is proving to be an economical alternative to traditional resin and column-based operations.4 Microporous membrane with pore sizes of >3 mm drastically suppresses diffusion-related mass transfer effects and enables purification of large biomolecules (capturing), or the adsorptive removal of contaminants such as HCP, DNA, endotoxin and viruses in flow-through mode (polishing).5 Membrane-based chromatography allows for far accelerated flow rates and very low nonspecific product binding. In a typical polishing application, a 1.5 L disposable membrane chromatography capsule can remove the contaminants downstream of a 10,000 L bioreactor, replacing a resin column that is >100 times larger.6 While reusable resin columns require a complex periphery, including a packing station and a chromatography skid, this is not the case for disposable membrane cartridges, the impact of which can be substantiated with process cost models. Comparisons of a polishing step in a flow-through operation with anion exchange chromatography are shown in Figures 8 and 9. Unit operation costs of a reusable resin-based chromatography (100 cycles) were compared to disposable membrane chromatography. The maximum antibody load was limited by the contaminant levels in the feed. Figure 8 shows the typical scenario of polishing after cation exchange intermediate purification, where the load capacity was 10 kg/L. Figure 9 shows polishing after initial capture with Protein A, with a load capacity of 2 kg/L. (One liter of membrane corresponds to 3.6 m2.)

In addition to cost advantages, however, there are many additional benefits, including significantly shorter cycle times and superfluous carryover studies in process validation, making adsorptive virus clearance much more straightforward.

A broad range of functional chemistries, including various ion exchange and affinity ligands, is currently available in disposable membrane formats with typical dynamic binding capacities of 30 g/L for proteins and up to 10 g/L for DNA. Protein A chromatography, while possible in membrane format, remains economically practical at production scales using traditional resin-based columns until small Protein A mimetic ligands allow for disposable alternatives.

The trend towards disposable chromatography has only just begun; it will lead to a complete replacement of reusable systems in polishing, with membrane capsules as part of the final filtration train.6 New formats of membrane chromatography include disposable direct capture devices allowing for processing of unclarified fermenter offload.

Disposable mixing systems, described previously, are ideally suited for buffer mixing, while filter capsule/storage bag manifolds systems are ideal disposable solutions for column wash, equilibration, sanitization, elution, strip, and storage.

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