ABSTRACT
Improved feedstream titers are driving a demand for increased downstream processing productivity as manufacturers seek to
lower the costs of monoclonal antibodies (MAbs). The unique selectivity of Protein A has enabled platform technologies for
MAb purification. Platform technologies and chromatography resin improvements can help manufacturers achieve rapid and economical
process development and scale-up. A multiprong approach can enable downstream process scientists to enhance productivity.
Antibody-based therapeutics are expected to continue to be a major source of new therapies for the next decade. However, monoclonal
antibodies (MAbs) are among the world's most expensive drugs. Pressure from healthcare providers is driving the need to lower
the costs of manufacturing MAbs by as much as an order of magnitude, from $1,000 per gram to $100 per gram.1
Table 1. Upstream productivity increases from 1994 to 2004
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So far, the most significant improvement is the increasing titers from concentrations of low milligram- to multigram per liter
(Table 1).2 This increased upstream productivity has subsequently created a demand on downstream processes to provide enhanced capacity
and speed. In addition, because only a small proportion of biotherapeutics that enter clinical trials make it to market, companies
tend to populate the candidate pipeline quickly, meaning more processes require development in shorter timeframes.3
To solve these multiple demands, several solutions have been developed, including, among others, the use of platform technologies
and chromatography resin improvements.
PLATFORM TECHNOLOGIES
A downstream platform technology is based on experience with purifying a class of products with similar properties. With more
than 500 MAbs currently in preclinical studies, monoclonal antibodies represent the greatest number of biotechnology products
to which similar purification processes can be applied. In particular, the unique selectivity of Protein A has enabled the
development of platform technologies for the purification of monoclonal antibodies.
Figure 1. A typical platform technology for production of a monoclonal antibody
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Platform technologies facilitate rapid and economical process development and scale-up, potentially allowing evaluation of
a larger number of product candidates, speeding market entry, and even reducing the validation effort. Familiarity with a
process also can result in more robust processes and better technology transfer from development to manufacturing. Platform
technologies create predictable activities and durations that result in a generic timeline.4 Further advantages are the use of established vendors for raw materials and standardized waste disposal procedures. Platform
technologies are composed of a number of unit operations and methods, and not just purification steps. An example of a platform
technology for a monoclonal antibody is shown in Figure 1.
Monoclonal antibodies usually differ from one another in surface charge and glycosylation. By selecting and adjusting unit
operations, selectivity is achieved for each MAb. Typically, the order of anion and cation exchange steps might be reversed,
hydrophobic interaction chromatography might replace cation exchange chromatography, or hydroxyapatite columns might be used.
Before adding or substituting a chromatography step, it is usually advisable first to try optimizing the process by evaluating
column load, wash and elution buffers, and pH. Of particular importance is pH, as some proteins tend to aggregate when exposed
to low pH. Downstream platform technologies thereby simplify development across the breadth of MAb products.
