The complexity of modern vaccines breeds manufacturing challenges for pharmaceutical companies working to meet a growing demand.
Keeping the world’s population safe from many diseases depends on vaccines, and lots of doses of them. In fact, the demand appears primed to multiply. On November 7, 2007, Datamonitor in London predicted that the market for vaccines for children and adolescents will quadruple, growing from $4.3 billion in 2006 to $16 billion by 2016. Keeping up with that demand requires making vaccines in large batches.
“Vaccine manufacturing is challenging; and the larger the scale, the greater the challenge,” says William Reed, PhD, vice president, industrial operations, USA, sanofi pasteur, Swiftwater, Pa. In part, the challenge arises from the nature of vaccines, which are produced by biological processes. Instead of simply mixing chemicals to make a small molecule, pharmaceutical companies grow vaccines in a series of steps, including fermentation. As Reed says, “These are biological processes that are very difficult to characterize and control. Therefore, they are part science and part art.”
In the past, scientists made vaccines by growing bacteria or a virus in a fermenter, killing the microorganism to attenuate it, and then bottling it, more or less. Many modern vaccines, however, rely on more-complicated processes. For example, Merck’s Gardasil—a vaccine against human papillomavirus (HPV)—was derived in a series of steps. “The genetic information for the outside coat of the HPV virus was inserted into yeast,” explains Barry Buckland, PhD, vice president, bioprocess research and development at Merck Research Labs, West Point, Pa. “As the yeast cells multiply in a fermenter, they make virus-like particles, or VLPs, which look like the real virus but have nothing inside.” After fermentation, the yeast cells are collected and ruptured to release the VLPs. “These are purified and then used as a vaccine,” says Buckland.
Consequently, scaling up vaccine production requires more than a bigger vat. Indeed, keeping a vaccine effective while increasing production requires a broad range of skills, including manufacturing, development, and efficacy assays. “The ultimate challenge is to be able to make tens of millions of doses,” says Buckland.
A sterility problem at a manufacturing facility prompted Merck & Co. to voluntarily recall on December 12, 2007 more than a million doses of a common vaccine for children. The involved vaccines were the Haemophilus influenzae type B vaccine, PEDVAXHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)], and its combination Haemophilus influenzae type B/ hepatitis B vaccine, COMVAX [Haemophilus b Conjugate (Meningococcal Protein Conjugate)].
In a statement, the company said it is conducting this recall because it can not assure sterility of the specific vaccine lots. The potential contamination was identified as part of the company’s standard evaluation of its manufacturing processes. Sterility tests of the vaccine lots that are the subject of this recall have not found any contamination in the vaccine.
The potential for contamination of any individual vaccine is low, and, if present, the level of contamination would be low, the company said. The recalled doses are considered potent, so children who got vaccine from the recalled lots will not have to be revaccinated, said Dr. Anne Schuchat, director of the CDC’s National Center for Immunization and Respiratory Diseases.
Health officials believe most children will experience, at worst, a skin irritation around the vaccination site if they received a vaccine that later proves to be contaminated. Children with compromised immune systems could face more serious problems.
Merck supplies about half of the U.S. 14 million doses of the vaccine. The company plans to change its manufacturing process, gain FDA approval, and resume production in the fourth quarter of 2008.
Scale-up sensitivity
“In chemical processes, conditions are fixed and well-researched,” says Dave Zisa, MS, vice president, Wyeth Biotech, Collegeville, Pa. “With the biological processes involved in vaccine production, the variables are magnitudes greater because of using living organisms.” As a result, vaccine production does not always scale geometrically. “To a point, you can scale that way,” says Zisa, “but processes must be specific to the scale you are operating at.”
For example, very small changes in the reagents can produce large changes in the efficacy of the resulting vaccine and the efficiency of producing it. “There are many minor components present in any number of media reagents at levels below the level of detection of existing analytical methodologies,” says Reed. “Some of them could increase several fold before they could be detected. These changes in minor components of raw materials can result in significant changes in the vaccine-manufacturing process.” If such changes decrease the quality of the product, scientists at sanofi pasteur create a “process excellence team” to determine what caused the change. “Then the analytical teams attempt to determine specifically what has changed,” says Reed. “At the same time, the procurement teams attempt to identify specific lots of raw materials whose introduction match up with the event.”
Making scale-ups even more complex, regulatory agencies view the entire manufacturing process as part of the product. “So if you make changes to that process, you need to know what the effect will be,” says John Picken, BSCHe, vice president, North American industrial relations at GlaxoSmithKline Biologicals, Rixensart, Belgium. “But sometimes we just don’t know what will happen, and you either need more information from the development team or you just have to try things.”
Scaling-up a vaccine’s production can also be sensitive to time. For instance, influenza vaccines are limited in terms of when they can be used. “At the end of the year, the strains change,” says Picken. “So you race to make a new product every year.”
Trials versus sales
To some extent, how a vaccine gets manufactured depends on its intended use, say for clinical trials versus market sales. “Still, all vaccines we manufacture are produced with the highest regard for safety for both the patient and the manufacturing personnel,” says Reed. But clinical trials require less product. And that can change a company’s approach.
“A Phase 1 clinical program may involve hundreds of vaccine doses, and a Phase 2 study can involve thousands,” says Buckland. “As we make the first few hundred doses at small scale, it is important to do this in a process that can easily be increased in scale.”
Once a company brings a vaccine to commercial scale, it is already well-characterized and validated. “The objective then becomes to maintain and monitor the process to avoid any process drift and deliver a product that is consistent with that which was used in the clinical trials and ultimately approved by the regulators,” says Reed.
So, in general, companies keep manufacturing consistent across clinical trials, especially late-stage ones, and commercial-scale production. “You want to be certain that throughout the development, scale-up, and product-manufacture phase that you have similar and consistent product characteristics. This is absolutely critical,” explains Zisa.
Successful scale-ups
Wyeth had to scale-up the production of Prevnar—a pneumococcal vaccine for children—because it was launched at a scale that could not meet market demand. To increase available quantities of Prevnar, Wyeth developed a multiple-site, process-improvement program. “Our biggest challenge was making sure that improvements at one site did not affect the next operation at another site,” says Zisa. So fermentation, biochemical, and analytical processes had to be integrated and managed across sites, and one person actually manages the cross-site teams to keep things working smoothly. So far, this change increased production by five-fold, and Wyeth expects that to grow several fold further.
Companies can also increase capacity by adding more pieces of equipment, essentially making more batches. GlaxoSmithKline Biologicals took that approach with manufacturing its influenza vaccine in Quebec, Canada. “We multiplied the pieces of equipment, keeping the scale the same,” says Picken. “We already understand the process, which limits the likelihood of changes in the vaccine and makes for an easier regulatory pathway.” As a result, the company tripled its capacity for that vaccine in 2007.
Other companies also keep producing vaccines in larger quantities. In 2006, for example, sanofi pasteur produced more than 985 million doses of vaccines, an increase of 11.6% over its 2005 production.
Beyond manufacturing a vaccine at several nearby sites, companies can spread production around the world. For example, Merck recently agreed to establish a $280 million vaccine facility in Ireland, and it will be that country’s first standalone, human vaccine project.
“In the past, vaccine manufacturers had one worldwide center,” explains Picken. In the future, he expects companies to have sites around the world to leverage the best technology and people. In 2005, for example, GlaxoSmithKline invested $2 billion to expand globally. “Time-to-delivery is becoming more critical,” he says, “and local capabilities are the most effective way of dealing with that.”
About the Author
May is a publishing consultant for science and technology based in Minnesota.
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 1, January, 2008, pp. 38-40.
Filed Under: Drug Discovery
