A number of factors have been responsible for the change, according to Howard Pien, President and CEO of Chiron Corp. (Emeryville, Calif.), who testified on February 12 before the House of Representatives' Committee on Government Reform, in a hearing discussing flu vaccine supply and readiness for potential pandemics. For one thing, recommendations on immunizations have been broadened to include those between 50 and 64 years of age, and between 6 and 23 months. In addition, pricing of vaccines has increased and physician reimbursement rates have increased, encouraging more doctors to recommend immunization.
The most dramatic trend, with the greatest implication for future supplies and products, is the move from egg-based to cell-culture-based manufacturing processes. Although the new cell-culture processes have not yet been approved for use in the U.S., some have been okayed in Europe, where the first commercial cell culture based vaccines are expected to be sold next year.
Cell-culture manufacturing boosts efficiencies
The move from a manufacturing technology based on breeding flu antigen in fertilized hens eggs, then killing and purifying the virus to a cell-culture based process will allow capacity to be scaled up or down quickly, manufacturers say. In addition, cell-culture-based processes will shorten the time between identification of the year's flu virus strains and the rollout of vaccine. The new technology won't require adding proteins or raw materials of animal origin, and will result in a product free of egg protein, antibiotics or preservatives containing mercury, explained Gordon Busenbark, vice president of Baxter AG (Vienna) during a ceremony at a new, partially-completed facility in Austria last March.
The world's leading manufacturers are moving to increase vaccine production capacity. In July, Chiron bought GSK's PowderJect Pharmaceuticals for $878 million. The company currently operates flu-vaccine manufacturing facilities in Liverpool, U.K. (Photo) and Marburg, Germany.
Over the past five years, Pien said, Chiron has invested about $70 million in bulk and fill and finish manufacturing capacity at its FDA-approved facilities in Liverpool, more than trebling the amount supplied to the U.S. from 12 million doses in 2000 to 38 million in 2003.
The company plans to increase capacity to 50 million doses this year, most of it bound for the U.S., he said. The company also expects to spend another $100 million to replace an existing influenza bulk manufacturing plant in Liverpool with a newer plant that would match the new fill and finish plant there, which started up in 1998. Currently, the company manufactures trivalent flu vaccines, harvested in fertilized hens' eggs, for the U.S. market.
However, Chiron has developed a cell-culture based production process using Madin-Darby Canine Kidney cells, and has built a full-scale manufacturing plant using the process in Marburg. The process has been approved in Europe, and the company plans to enter Phase III studies this year. The first commercial vaccine is expected to be sold in Europe by 2007.
Chiron has begun discussions with FDA, and the company plans to file an Investigational New Drug Application, Pien said, to pursue licensure of a cell-culture vaccine in the U.S. Once scaleup becomes necessary, a likely move would be expanding cell-culture production in Marburg, which would offer economies of scale. Developing a new facility on a green field site capable of producing 70 million doses of trivalent cell-culture vaccine and more than 200 million doses of monovalent vaccine, would require an investment of over $200 million, Pien said.
Baxter AG (Vienna), meanwhile, has invested $176 million in a cell culture vaccine facility in Krems, Austria, which is expected to start up this year. The process uses the Vero cell line, which is already used to produce licensed vaccines for human use, including polio and rabies vaccines.
Flu vaccine, meanwhile, figures in two strategic investments that Aventis Pasteur S.A. (Lyon, France) has made: an $80-million expansion in the filling and packaging capacity of its vaccine plant in Swiftwater, Pa., and a $70-million expansion of cell-culture based vaccine production in Marcy L'Etoile, France. The company is partnering with other companies on new cell-culture-based flu vaccine development. In January, it licensed Crucell N.V.'s (Leiden, the Netherlands) PER.C6 technology, based on human retinal cells.
Part of the Swiftwater project has involved installing a new automated manufacturing system, using Wonderware's (Lake Forest, Calif.) InBatch software. The $1.5-million project contract will provide user interfaces to automate batch processing with data-entry screens, a real-time database and visualization layer, as well as batch production execution and reporting systems. The project aims to eliminate paper records, as well as to provide batch sequencing, alarm and notification of adverse conditions, and real-time exception reporting to ease batch evaluations. The new system will permit continuous and comprehensive data collection for historical records and use in process optimization.