IMPACT OF INCREASED MAMMALIAN CULTURE PRODUCT TITERS
One development that will impact production scenarios and may also change common practice is the increasing product titers
achieved in mammalian cell culture, the dominant method of biopharmaceutical manufacturing. Because of low product titers
of one gram per liter or even less, some protein drugs require large bioreactors and many batches to yield the required quantities.
However, many projects currently in the clinic have reached product titers of three to five grams per liter.
This development opens up two options, both with potentially significant effects on the facility of the future. These options
are: producing only a few batches with very large cell-culture volumes, or producing many batches with a reduced scale of
Few Batches, Very Large Cell-Culture Volumes
A company may decide to manufacture the same product quantities in fewer batches using large cell-culture volumes, producing
between 50 and 125 kgs of protein in one batch. This set-up could create facility time in the plant for manufacturing additional
products or, in a less positive situation, it could create a problem with unused facility time. In addition, this scenario
challenges downstream processing because the batch sizes envisioned here require high-capacity resins for all steps. Although
such products are either under development or have only recently become available, the biopharmaceutical industry is concerned
about downstream processing becoming a bottleneck.
Many Batches, Reduced Scale of Operation
As the second option, a company may reduce the scale of operation and manufacture the product at a 500- to 1,000-L bioreactor
scale in many small batches. In principle, this option would allow much of the production to be run on disposable equipment—albeit
at the cost of replacing such equipment for every batch. However, such a small-scale operation could be advantageous by requiring
relatively low upfront investments and smaller plants, and by allowing more flexibility to add capacity or move production
to other sites.
FIXED FACILITIES ARE UNDER PRESSURE
The classic fixed facility is coming under pressure. No longer is it sufficient for companies to demand that processes be
adapted to a facility design that is "cast in steel." To get full value from its facility investment, a company should realize
that rethinking its facility design is just as important as carefully creating a process design. In the changing business
landscape, technical process improvements are providing new ways of operation.
Whether homemade or contracted, the custom engineering of production plants suffers from a lack of standardization in both
hardware and automation. Wheels are re-invented, and available standard solutions are ignored. This situation often exists
because, in making short-term decisions related to costs, companies ignore the long-term savings of standardization. The results
are facilities that are adequate but too specific; thus, cost issues arise when a new process must be accommodated or a site
transfer takes place between two facilities. Moreover, in a maturing biopharmaceutical industry that faces significant economic
challenges, both the cost and time for completing an entirely new plant or a major reconstruction are viewed as heavy burdens.
What, therefore, has the biopharmaceutical industry achieved in performance and in manufacturing? Figure 4 summarizes a "best-in-class
performance" study conducted at GE Healthcare BioSciences during the last two years. When this information is compared with
GE Healthcare BioSciences' own performance-related data, the conclusion is that most companies can further improve their technical
frameworks. Few companies have achieved full success. Those that have succeeded have multiple products in their facilities
already and can look back on a decade of successful large-scale antibody manufacturing.
Figure 4. What is best-in-class performance?