Vaccine Manufacturing Reborn - Pharmaceutical Technology

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Vaccine Manufacturing Reborn
Drugmakers hatch new manufacturing paradigms in the wake of the 2009 H1N1 influenza pandemic.


Pharmaceutical Technology
Volume 10, Issue 34, pp. 40-46

A long tradition

Influenza vaccine has traditionally been manufactured by a pretty dowdy process, one that has remained largely unchanged for the past 50 years. The process begins when the Centers for Disease Control and Prevention (CDC) identifies the specific strain of virus causing a particular outbreak and makes "seed" virus available to vaccine manufacturers.

In the most basic manufacturing scenario, seed virus is introduced into fertilized chicken eggs, where it reproduces in large numbers and is secreted into the allantoic fluid—essentially the white of the egg. The fluid is collected after a few days and purified, and this purified fluid forms the basis of the vaccine. (Because some egg-related matter remains in this formulation, people with egg allergies often experience adverse effects with this vaccine, an additional motivation to move away from egg-based manufacturing.)

The traditional vaccine contains either live, attenuated, or killed virus particles. Live, attenuated virus can replicate in the vaccine recipient, and can confer immunity without causing disease (at most, it may cause some limited respiratory symptoms). In contrast, killed virus cannot replicate in the recipient, but still confers immunity.

For the most part, this process with few innovations has reliably produced influenza vaccine for decades—as long as the demand for vaccine is predictable. Most experts estimate that it takes one to two eggs to manufacture each dose of vaccine, so producing some 100,000 doses of vaccine requires a lot of eggs and a lot of advanced planning. Amassing that number eggs can be difficult, to say the least. "It's a scramble every year," says James Gombold, director of testing services for Charles River Biopharmaceutical Services (Wilmington, MA).

The difficulties don't stop there. The seed virus is replicated many times in the course of manufacturing. But viruses are notoriously sloppy in their replicative fidelity, so the virus in the vaccine can potentially differ from the infective strain—which can result in a less protective vaccine than required

"It's a dirty little secret," says Alan Shaw, chief scientific officer and chairman of the board of VaxInnate (Cranbury, NJ) "that you get mutants during passage."

To circumvent this problem, stringent analytical testing is required—DNA and protein analysis, primarily—to demonstrate homology between the virus in the vaccine and the infective strain, says Gombold, who directs the testing program for Charles River. Additional testing is required to ensure that avian pathogens lurking in the eggs do not end up in the vaccine, although Gombold says that this is probably more a precautionary measure than a response to any known incidence of contamination. Nevertheless, the additional testing adds time and costs to egg-based manufacturing.

Eggs have been the preferred system for vaccine manufacturing because in general, the virus grows well in them—but not always. H1N1, for example, did not, in spite of what Shaw calls manufacturers' "heroic effort...to make vaccine quickly and appropriately."

But even if the virus does grow well, says, Shaw, egg-based manufacturing can take longer than expected. "It's an egg-by-egg process," he says. "There's not much of a surge capacity for egg-based business. You can't ramp up by a factor of 20, which you essentially need to do [in a public health emergency]. The point is, the egg system has its days numbered." Many people think cell-based systems may take its place.


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