THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 6

…During upstream process development media composition and bioreactor conditions are studied and optimized using a number of screening and factorial experiments to determine the effects of multiple variables on growth and viability, specific productivity, antibody yields, product consistency, and impurity levels. Upstream process development ends with the definition of a robust cell culture process that is based on the optimal conditions identified to consistently generate high product yield and quality, product homogeneity, and minimal amounts of impurities and contaminants….

…A comprehensive cell culture process development plan consists of a number of related activities, all designed to improve overall production of the monoclonal antibody product in the bioreactor while maintaining or improving the product quality…

…To expedite initial product development, biopharmaceutical companies are adopting the use of defined cell culture platform processes for the production of monoclonal antibody products for preclinical studies and GMP manufacture of Phase 1 clinical trial material. Cell culture process platforms include the use of a common parental cell line to generate the production cell line, defined reactor mode, and favored media compositions and feeds. The use of a platform process provides a high level of assurance during early process development that an appropriate upstream process can be developed within acceptable timelines and at reasonable cost.

..Two basic types of in vitro culture modes, perfusion and fed-batch stirred tank, are employed in the production of commercial monoclonal antibodies today. While both fed-batch and perfusion cultures are successfully used today by companies producing commercial monoclonal antibody products, fed-batch culture has been adopted as the primary method of choice for robust, reproducible, and reliable monoclonal antibody manufacturing. The overall cost of manufacturing for a monoclonal antibody product using either fed-batch or perfusion culture is generally comparable.

…The use of serum-free medium has become standard in industrial production of monoclonal antibodies, and, in a growing number of applications, protein-free media is used as well…

..Integrating the selection of lead clone and basal medium is highly efficient, can save substantial development time, and result in increased productivities and product yields…

..For large scale production, the stainless steel stirred-tank bioreactor is the most common bioreactor type used, ranging in scale up to 25,000 L. Single-use (disposable) bioreactors are increasingly used for inoculum preparation or production of clinical trial material. In order to expedite product development and enable the manufacture of Phase 1 clinical trial material as rapidly as possible, the development of an upstream process for a new monoclonal antibody product is often limited to the implementation of a platform process without full process characterization and optimization.

…To optimize the upstream processes, the use of microbioreactor technology, including high throughput bioreactors capable of conducting large numbers of experiments quickly is likely to increase. Advances on several fronts are rapidly creating the potential to increase monoclonal antibody manufacturing productivity and to reduce manufacturing costs. These potential improvements include methods to increase the maximum concentration of viable cells in a culture, the use of small molecule additives and heterologous transcription factors to enhance specific monoclonal antibody productivity, the prolongation of cell culture processes by controlling apoptosis signaling genes and expressing inducible anti-apoptotic genes, and a variety of other techniques to extend the longevity and productivity of monoclonal antibody producing cultures.

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