rapid turnaround to increase the chance of being first in the marketplace with a product that will probably have a short life span.

Commercial mAb production requires more than the culturing of large batches of cells or their injection into large numbers of mice. It requires considerable preproduction effort to ensure that the cell line is stable, can produce commercially appropriate quantities of a stable antibody, and can produce an uncontaminated product. Commercial production also involves building a high-quality facility for in vivo and in vitro production and for processing of the antibody. There is a need for quality control and quality assurance departments to meet the requirements of good manufacturing practices that are required for commercial products. Product-lot testing is necessary to ensure product reproducibility. Production-process verification and documentation are necessary to protect the consumer and are required by FDA in its regulatory "Points to Consider in the Manufacture and Testing of mAb Products for Human Use" (FDA 1997).

In Vivo and In Vitro Methods for Commercial Production of mAb

Commercial mAb production uses both the mouse ascites method and in vitro methods. Cost is usually the major consideration in determining the method except for marketed therapeutic products.

When all fully-loaded production and pre-production and post-production costs are considered for a commercially viable line, economics usually favor in vivo production. However, as the amount of mAb increases, existing in vitro production technology can become more economical because high, fixed optimization costs (costs associated with selecting a subclone with the best growth and mAb production characteristics and grow in low-serum or serum-free conditions) associated with in vitro production are spread over a larger production amount, making cost per gram competitive with in vivo production, which has a higher and more variable cost structure (figure 2). When production costs are compared for small-scale production, in vitro methods are 1/2 to 6 times higher, depending on the cell line (Hendriksen and de Leeuw 1998; Jackson and others 1996; Peterson and Peavey 1998; Marx 1998; Lipman 1997). However, these costs might not include all factors, such as animal housing costs and technician time. In large-scale production runs, in vitro systems are economically competitive and are usually selected because they reduce animal use and decrease the presence of contaminating foreign antigens if serum-free media can be used. When the time of mAb production is critical and small amounts are required, in vivo production is selected because it takes only 6 weeks. For in vitro systems, time requirements vary considerably. Production time depends on the amount of time required to optimize the hybridoma to the system being used and on the quantity of mAb needed. Commercial-quantity in vitro production of mAb requires more time



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