A tough sell for cells?

Cells are the natural targets for viruses, so it makes sense to exploit that relationship to manufacture them. Viruses cannot reproduce on their own. They contain the requisite genetic information, but not the replicative machinery. Cells, on the other hand, do. In order to reproduce, viruses penetrate and co-opt the replicative machinery of dividing cells. Fertilized eggs contain dividing cells, but in limited numbers. Dividing cells don't occupy in the entire volume of the egg, so space isn't optimized, in contrast to cells in a bioreactor.

A bioreactor containing enough cells to produce 50,000 doses of vaccines occupies far less space than do the number of eggs required to produce a comparable batch. Notes George Kemble, senior vice-president and head of research for MedImmune (Gaithersburg, MD), whose FluMist vaccine is currently manufactured in eggs, "Try to make 2000 L of cell culture fluid versus 2000 L of egg fluid. Not to mention the personnel needed."

Among manufacturers, Novartis was the first to use this cell-based system. The company already produces two vaccines in cells in its Marburg, Germany, facility. Recently, Novartis opened a cell-based facility in Holly Springs, North Carolina, in which says Matthew Stober, Novartis's global head of technical operations, the company hopes to be able to produce up to 150 million doses of pandemic influenza vaccine as early as 2013.

"The regulatory pathway to achieve FDA licensure for vaccines is a long and complex one, particularly if clinical studies are involved. However, because Novartis accelerated the investment of this facility under the current pandemic threat, bulk prepandemic vaccine [against H5N1] could be produced from the site as early as late 2011 under an emergency use authorization," says Stober. Other drug manufacturers, including GlaxoSmithKline (GSK, London) and MedImmune are exploring cell-based programs.

So why aren't all manufacturers embracing cell-based facilities? For one thing, manufacturers with facilities geared toward egg-based manufacture can't retrofit them to produce vaccine in cells, says Gombold. But the real hesitation is economic. A dose of vaccine currently sells for under $10 says Shaw, and that's "not good for a producer that has to stay in business." Nor does it provide the kind of revenue that justifies the investment required to build a cell-based facility. "Only an external subsidy makes it feasible," he says.

Indeed, the US government provided approximately 40% of the $1 billion for Novartis's Holly Springs facility. MedImmune can consider the move because it already has bioreactors. "It would be different if we had to build the factory anew," says Kemble. Like Novartis, MedImmune has also received government funds that Kemble says, "help enormously." Once a facility is built, cell-based production should cost much less on a per unit basis than egg-based manufacturing, he adds.

GSK currently produces its vaccine in eggs and will for the foreseeable future, says Martine Wettendorff, vice-president, Influenza Vaccines Development Leader. But the company is not insensitive to the problem of scale up for a pandemic. GSK's answer is to make the existing vaccine more potent through the use of adjuvants, thereby reducing the amount of antigen required for each dose.

The company markets pandemic influenza vaccines in Europe and Canada that contain its proprietary ASO3 adjuvant and plans to seek FDA approval to supply an adjuvanated H5N1 vaccine in the US. Nevertheless, the company is researching cell-based technologies, which Wettendorff describes as "not yet a fully mature technology. The cost of goods remains a challenge," she says, but GSK is "always looking around at what's happening to lower that cost as well as at recombinant technologies." She reflects the attitudes of many who feel the cell-based technology is not yet an economically viable proposition.