Thus, efforts to improve downstream technologies should focus more on the ability of the downstream process to handle an ever
increasing mass of drug product rather than on the raw material or step costs. We believe that this interpretation will remain
relevant until there is a paradigm shift to entirely different unit operations that offer similar overall purification performance,
safety, and robustness without constraints in mass and volume handling and at a cost of ownership below current costs for
membranes and resins.
Emerging Reference Process for MAbs
Initial data about the design of a reference process were recently published and are used for research purposes of GE Healthcare
Life Sciences (Figure 6).2,4 This is a second generation process using similar purification principles and step sequences to the current, most widely
used platform process used to manufacture today's MAbs as described in the literature and at recent scientific conferences.
The current most popular process may use resin and membrane products from different suppliers, but almost all are from the
same generation as Sepharose Fast Flow. Consequently, for the most part, the latest generation of downstream purification
technology is not being used.
Figure 6. Schematic overview of consensus process design (left), resins for the generation 2 process (middle), and other options
that have been tested by the industry (right).
The purpose of the development project is to address challenges such as the increase in upstream productivity of monoclonal
antibodies in an integrated fashion (not solely in selected step improvements), and to remove downstream process bottlenecks
now and in the near future. Notwithstanding other development projects and their possible outcome, it is our goal that the
resin technology selected for this process will remain relevant for most processes developed in the next 5–10 years and be
able to remain in full scale production for the next two decades with no need to alter the fundamental design. This goal coincides
with the need to avoid major process changes that delay development and increase regulatory costs in the industry. Improvements
offered by the new reference process compared with current popular practices can be described by two categories: process robustness,
and productivity and costs.
In any downstream process sequence, the capture step dominates robustness in many ways. Capture transfers the drug product
into a stable environment, concentrates the dilute feed ~10 fold, and ideally removes most impurities that could compromise
the stability of the drug throughout the remainder of the process time. It also minimizes the level of impurities to a low
level handled reproducibly by subsequent polishing steps, independent of feed stream quality variations. The robustness period
can be extended to include robust performance between various development projects, covering a wide range of monoclonal antibodies
Figure 7. The stability of a novel Protein A resin ("MAbSelect SuRe," GE Healthcare) following several hundred clean-in-place
cycles with 0.1 M NaOH..