ABSTRACT
There has been a rapid uptake of disposable technologies in the biopharmaceutical industry over the last decade, including
disposable modules for chromatography. Disposable membrane chromatography has proven to be a powerful alternative to polishing
columns, particularly for process-scale monoclonal antibody purification, because of advantages such as high throughput, faster
processing time, reduced buffer consumption, and elimination of column packing and packing testing activities. Disposable
technologies also allow facilities to run multiple products in a single plant without the risk of cross-contamination between
batches. This article demonstrates through, a case study, the practical and economic benefits gained from replacing reusable
column chromatography with disposable membrane chromatography. The study looks at the whole process and evaluates the production
costs for the stainless steel option, in which all unit operations are performed using stainless steel equipment items, and
the disposable option, in which column chromatography is replaced by disposable membrane chromatography and all other unit
operations are based on stainless steel equipment items.
SARTORIUS STEDIM BIOTECH
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Significant upstream process advancements in the biomanufacturing industry have led to high cell culture titers producing
a large mass of proteins. But we haven't seen the same improvement downstream, which now has to handle the elevated protein
concentration and contaminant level. It has been much discussed in the literature that specific unit operations, such as traditional
chromatography, can represent technological bottlenecks caused by dimension limitations.1,2 The improvement in titer affects production and material costs as the buffer, cleaning, and sanitization solutions required
for downstream operations increase in proportion to the mass of product being purified.3 Therefore, large upstream protein production levels combined with the large scale demand of antibody-based therapeutics
have driven the biopharmaceutical industry to search for alternate technologies to surmount the bottleneck downstream and
fulfill the requirements for high-throughput production while delivering a product with high purity.2,4
Manufacturers are exploring multiple ways of streamlining product recovery and purification processes. Strategies include
standardized platform approach to downstream processes,5 and the evaluation of alternatives to chromatography separations to overcome the physical limitations of traditional chromatography.6,7 Among the novel technologies developed, membrane chromatography has already proven to be a robust alternative to columns,
especially anion exchange chromatography (AEX) for polishing.
AEX chromatography is perhaps the most powerful tool to remove a variety of viruses, DNA, and endotoxins.8 In most cases, AEX chromatography is carried out using flow through (FT) mode, with the impurities binding to the chromatographic
support and the product and the product of interest flowing through.
Replacing AEX column chromatography with AEX membrane chromatography has resulted in similar viral clearance at a much higher
flow rate and load density compared with columns. Arunakumari, et al., recently reported >4 logs of minute mouse virus (MMV)
and murine leukemia virus (MuLV) removal using Sartobind Q membrane adsorbers (Sartorius Stedim Biotech) in monoclonal antibody
(MAb) processes at a load density of up to 20 kg MAb/L of membrane.9 The diffusion dependence and pressure limitation associated with column chromatography significantly limit throughput at
large scales and lead to column oversizing in traditional polishing scale up. Because of the hydrodynamic benefits, membrane
chromatography involves much smaller devices than columns with a similar output and no bottlenecks.1,2,10 Such disposable technology offers the added advantages of reducing buffer volume, processing time, and floor space requirement.
Membrane chromatography is a disposable operation system; there is no need for column hardware, packing-related studies, resins
life studies, carry-over studies, cleaning-in-place (CIP) and steaming-in-place (SIP) procedures, and validation. Membrane
chromatography offers easy solutions to biomanufacturing, increases flexibility, and lowers capital requirements—all of which
are benefits derived from disposable technology.
Whereas the disposable approach has been accepted for many years for operating certain unit operations in upstream and downstream
processes such as cell harvest, filtration, and buffer and media storage, an increased trend toward disposable technologies
only has been observed in the last five years in response to the needs of biopharmaceutical companies. In an effort to increase
capacity without exposure to excessive investment risk, biopharmaceutical companies are considering disposable manufacturing.11 The economic benefits of single-use membrane chromatography for polishing as a single unit operation has been demonstrated.12 In this paper, we analyze the cost impact of replacing reusable chromatography technology with single-use membrane chromatography
technology in the FT mode for the AEX polishing step, looking at the overall cost of goods (CoG) and the breakdown of the
CoG into different categories (i.e., capital charges, materials, and consumables). The FT AEX polishing step was implemented
as a unit operation in the whole process at a production scale of 2,000 L. The study evaluates the production costs for the
whole process based on all stainless steel equipment and compares it to the process in which the Q column is replaced by the
Q membrane capsule.
