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 operation.

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.

Figure 4. What is best-in-class performance?