Stimulating Manufacturing Innovation: Can FDA Walk the Talk?

March 15, 2004
Antiquated approaches to vaccine development challenge the agency, and government, to become more flexible

Vaccines represent one of humankind's greatest scientific achievements, but the way they've been regulated and distributed in the U.S. has driven most drug makers out of the business and stymied new manufacturing technologies. Over the past 30 years, the number of vaccine manufacturers in the U.S. has dropped from 25 to 5, according to "Financing Vaccines in the 21st Century," an August report by the National Academies' Institute of Medicine. In fact, the study says, there is currently only one supplier for the six critical vaccines used to immunize children against diphtheria, tetanus, and other diseases.

Shortages of flu vaccine this winter, and new strains of avian flu developing in Asia, have underscored vulnerabilities. Operation Bioshield, proposed by the Bush Administration, would streamline vaccine R&D and commercialization, and provide funding for state and local governments to buy and, where possible, stockpile vaccines. Further legislation has been proposed that would provide vaccine manufacturers with tax breaks, patent extensions and liability protection.

How these new initiatives will shape actual legislation and change the overall vaccine supply situation remain to be seen. At a February 12 hearing before the U.S. House of Representatives' Committee on Government Reform, the focus was on the nation's readiness for a flu pandemic. Despite an aggressive buildup of flu-vaccine manufacturing capacity and new technology, the country is unprepared. Manufacturers suggested that lawmakers take a more flexible, cooperative approach to supply and regulation.

MedImmune, Inc. (Gaithersburg, Md.), whose intranasal vaccine, FluMist, received FDA approval in June, illustrates the challenges facing any new entrant to the market. It took the company 30 years, $1 billion, and three FDA advisory committee meetings to get that approval, said Dr. Jim Young, president of R&D. The product is the first live attenuated vaccine available in the U.S. and is delivered in nasal spray, rather than injection form. MedImmune plans to extend its use to higher-risk groups (i.e., children under five and adults over 50)

However, he said, the company faces a double standard. "To simply achieve parity with the approved labeling of old-line, inactivated vaccines, we must spend at least another $200 million to achieve safety and efficacy standards that the other vaccines were never required to achieve, or have ever independently proven," he said.

Bring On the Soothsayers

The method used to match flu vaccine supply with demand each year is primitive at best. Forecasts are based on prior years, and, since the flu changes form every year, whatever vaccine isn't used is destroyed. In 2002, some 12 million doses had to be disposed of, said Howard Pien, President and CEO of Chiron Corp. (Emeryville, Calif.), the world's second largest flu vaccine manufacturer, who also spoke at the hearing.

Manufacturing technology is unwieldy. Based on forecasts, vaccines are produced in fertilized hens' eggs. Individual lots of each of three virus strains are grown in the eggs and harvested, Pien explained. Harvested virus is then killed, purified and separated from egg proteins by ultra-centrifugation. The concentrated virus is further purified; monovalent antigen lots are sterile filtered and tested for quality and potency, then formulated into trivalent vaccine, filled and packed.

The process begins early so that product can be released by October or November. However, it is inflexible and does not allow for changes, for example, when original estimates are found to be low.

Manufacturers have high hopes for alternative production routes based on cell culture. Chiron has developed such a process, which has undergone Phase II clinical trials and been approved for use in Europe. A full-scale production facility for the vaccine is onstream in Marburg, Germany, and the company plans to apply for FDA approval. Baxter AG also has cell-culture capacity in Austria, while Aventis-Pasteur and other manufacturers are also developing cell-culture flu vaccine processes.

Cell-culture production would not depend on egg supply and could be scaled up or down quickly. It would also allow continuous manufacturing to begin sooner, would reduce production lead time by six to eight weeks, and could produce vaccines for "avian flu," strains of which won't grow on eggs unless they have been genetically modified, Pien said.

To be ready for a flu pandemic, Pien says, it will be critical to move to cell-culture based technology. A flexible approach to regulation and supply will make this move possible.