To shorten time to market for new therapeutic proteins, new and fast methods, such as high throughput screening, are needed
to speed up downstream processing. The platform technology discussed in this article includes a structural approach that can
be used as a general procedure to purify therapeutic proteins. The approach starts with ligand screening and selection-on-a-chip,
with the Surface Enhanced Laser Desorption Ionization–Time of Flight (SELDI–TOF) mass spectrometer system. Next, resin screening
and supplier selection are performed using robotics, followed by scouting studies under dynamic conditions to select the best
resin. Finally, optimization studies of critical parameters are carried out with statistical design approaches (design of
experiments). Examples are presented to explain the platform approach for purification development in more detail.
Downstream processing is the most costly part of biopharmaceutical production and there is considerable demand to reduce the
costs involved. Also, an increase in the throughput of downstream processing instrumentation is needed to cope with upstream
developments such as high throughput screening.1 In the drug discovery area, rapid systems for one-step protein purification are already common, such as fast methods to
isolate new tag proteins or to develop new constructs of monoclonal antibodies.2,3 In light of these advances, it would be beneficial if related methods could be established to isolate therapeutic proteins
in the process development area. Therefore, a platform technology for purifying new biopharmaceuticals was developed (Figure
1). This approach can be applied at the initial screening stage through to the development of a controlled, robust process.
The downstream processing platform technology described here is a collection of current techniques used in a structured approach
to develop purification processes. For a new purification step in a downstream process, the procedure is summarized as follows.
First, ligand selection (i.e., ionic, hydrophobic, hydrophilic, or affinity) is carried out using the Surface Enhanced Laser
Desorption Ionization–Time of Flight (SELDI–TOF) system and ProteinChip Array technology.4 Second, resins from various suppliers with the specified ligand are selected and screened using robotics. The most promising
resins obtained from these studies are dynamically tested by performing scouting experiments to select the preferred chromatographic
resin. Finally, the most important parameters (binding capacity, flow rate, pH, salt, etc.) for a given purification step
are optimized with experimental design. Figure 2 outlines this platform technology approach when going from small to large
Overall, this structured method for developing new purification processes can speed up overall process development, and also
may provide a scalable process. It may also be particularly helpful for process development scientists who are not specialists
in downstream processing. However, note that certain parameters (bead size, scalability, reuse, pressure, cleanability, price,
binding capacity, etc.), may influence the screening procedure, such as whether certain resins will be tested for use in capture,
intermediate, or polishing steps. For example, resins with larger beads and high binding capacity are preferred for capture
to increase throughput and prevent clogging, whereas smaller beads are preferred in the polishing phase for better resolution
and purity. The following is a detailed description of the various parts of the platform technology.