also be a surveillance system that uses animal sentinels for health and serologic screening. These programs need to be continually updated as other adventitious viruses are identified by the FDA.

Protocols for ascites production require specifics on the animals used for manufacturing—such information as sex, age, and species. There are requirements for volume of pristane, cell concentration of the inoculum, and timing for priming, inoculation, and harvesting of ascites. Other requirements are strictly related to the well-being of the animals, such as bedding, feeding schedules, and general housing conditions of the facility involved in manufacturing.

FDA has approved 13 mAb for clinical use, two of which must be produced by the ascites method. Most new-drug applications to FDA are for mAb that are produced in vitro. It is likely that large-scale manufacturing of mAb will use in vitro methods as systems and technology are optimized to reduce the final cost per unit. FDA is encouraging using in vitro methods for producing mAb. In Europe, Germany, the Netherlands, Sweden, Switzerland, and the UK have restricted or prohibited the use of mice for production of ascites and more countries will probably join them.

More important than regulatory differences between the two modes of manufacturing of mAb are requirements that must be met when the mode of manufacturing is changed during product development before licensing. Changes in manufacturing often occur in clinical development of a product. The FDA requires a plan for demonstrating that the products made in different ways are similar. The requirement also applies if there is a scaleup without substantial changes in the manufacturing process during or after completion of phase 3 trials. As presented by the FDA Center for Biologics Evaluation and Research Division (Stein 1998), it could take 3–8 years to obtain data needed to approve a product formerly produced by the ascites method and later produced in vitro. There have been cases in which the two methods of production have yielded similar antibodies that are not comparable. As stated in Stein's presentation, the earlier in the development of the process the changes are made, the better the success of the product. She stated that investigators should adapt the hybridoma to in vitro conditions early when developing mAb for clinical applications.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement