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Advances in Large-Scale Biopharmaceutical Manufacturing
and Scale-Up Production*, 2nd Edition

    Maximizing Productivity in Biopharmaceutical Manufacturing

    Abstract:
    Recent progress in biopharmaceuticals has been led by the rapid growth in development of monoclonal antibody (mAb) products; thus, mAb will be a major focus of this chapter. Significant progress has been made on both the molecule and process fronts leading toward greatly improved manufacturing plant productivity. Biotherapeutic molecules have always been selected for the target clinical properties, but now also may be engineered for stability and suitability for productive production processing. More tools are available to select and manage the mammalian cell lines to achieve higher specific productivities. Better balance of media components and feeds has allowed higher cell densities and higher viability late in cell culture processes. Product recovery and purification have been substantially standardized and optimized. The combination of these advances has resulted in a 3- to 10-fold decrease in costs of goods for a modern mAb and much higher output for a standard plant. Current business pressures are for speed in development and commercialization. Scaled-down experimental cell culture models promise to provide optimal process conditions faster. Production plant models, such as Extend or Batch Plus, are improving plant design and operation before the processes are fully developed. Selective use of disposable vessels and modularization of stainless hardware are accelerating the speed to build and expand manufacturing plants. On the horizon are technologies that could change the rules for what we see as an ideal biotherapeutic molecule and the ideal biotherapeutic process.

    About the Authors

    Matthew D. Hilton, Ph.D.
    Research Fellow, Bioprocess Research & Development, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN

    Dr. Hilton received his BS from the University of Iowa, followed by a Ph.D. in 1985 from the Department of Microbiology and Immunology at the University of Washington, Seattle. This basic education was followed by two years of postdoctoral training in the Industrial Fermentation Labs of MIT with Professor Arnold Demain and four years of fermentation process research with Pitman-Moore, Inc. (an animal pharmaceutical company) where his basic education was complemented with experience in strain development (genetic engineering, random mutagenesis and selection) and exposure to the product development cycle. He joined Eli Lilly & Co. in 1990 and has had diverse responsibilities for discovery and development of biotechnology and fermentation products. Overall, Hilton has 19 years of experience with pharmaceutical fermentation process development and scale-up including 15 years with biotech fermentations. His projects have included one therapeutic protein now registered for sale worldwide (Humalog™ insulin), two enzymes used in commercial biotech manufacturing and additional proteins that have failed in the clinical evaluations. He has had additional responsibilities for process improvement efforts and technology transfer to new sites for several commercial therapeutic proteins after their launch. His experiences include chemical bioconversion processes, production of secondary metabolites, expression of protein therapeutics and catalysts and scale-up to fermentors as large as 40 cubic meters. Biotechnology development and scale-up experiences include proteins expressed by the bacterium Escherichia coli and the yeast Pichia pastoris and more-limited experience with the slime mold Dictyostelium discoideum and mammalian cell culture processes.

    Parviz A. Shamlou, Ph.D.
    Senior Engineering Consultant, Lilly Engineering Technology Center, Eli Lilly & Company, Indianapolis, IN

    Parviz Shamlou is responsible for innovation and technology evaluation for commercialization of biotherapeutics. He works closely with manufacturing operations organization on registered products and with the process development organization in design and development of pipeline molecules. Projects have included insulin, human growth hormone and several antibody molecules currently in development. Shamlou joined Lilly in 2003. Prior to that, he served as Deputy Head of Department and Co- Director for Research in the Biochemical Engineering Department at University College London (UCL). Parviz received his first academic appointment at UCL in 1983. He was appointed Professor of Biochemical Engineering in 2001. In addition to his work at Lilly, Parviz is the Editor-in-Chief of the peer-reviewed Journal of Biotechnology and Applied Biochemistry, a Fellow of the British Institution of Chemical Engineers, and an AIChE Member of ABET responsible for chemical engineering course program evaluation. He also serves as a Board Member of the European Federation of Biotechnology. During his tenure at UCL Parviz supervised 35 Ph.D. students and postdoctoral researchers and has over 145 publications in peer-reviewed journals, chapters in books and presentations at national and international conferences. He received his Bachelor of Technology degree and Ph.D. in Chemical Engineering at the University of Bradford in UK.


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