Special Report

Advances in Cocci Vaccine Production

Briggs and Lomurö

The way Martin Lomurö sees it, protecting poultry against infection from a wide range of Eimeria organisms shouldn't be the only objective of a coccidiosis vaccine. "As a veterinarian, I concern myself with other factors, like whether the product is sterile and free of mycoplasma and other viral, bacterial and fungal contaminants that could introduce a new disease to a flock," he says.

"I want to have a clear head about its safety, consistency and efficacy. I also want a product that's safe to humans and friendly toward the environment."

Few veterinarians in the poultry industry would argue with Lomurö's high expectations for a vaccine. What's unique about Lomurö is that he's not the kind of vet who manages health programs for one or even several poultry companies.

As the manager of quality control at Schering-Plough Animal Health Corporation's coccidiosis vaccine plant in the United Kingdom, Lomurö says his concerns extend to hundreds of progressive poultry operations in Europe, the Middle East, Africa and Latin America that have adopted this approach to vaccination for coccidiosis control with the company's Paracox™ vaccine line.

Meeting the growing demand

Lomurö smiles when asked about the changes he's seen in coccidiosis vaccine production since arriving at the UK plant in 1995.

"Back then I had only one person on staff and we shared facilities with other departments," he says. "Today I have 10 people reporting to me alone and we have a whole QC lab to ourselves. We've also become completely self-reliant in that we hatch our own chicks for potency testing, which gives us the flexibility to retest or conduct additional tests to assure quality.

"Since being acquired by Schering- Plough Animal Health in 1997," he continues, "we've seen a lot of expansion and improvements. The company has invested heavily in our facilities and making sure our equipment and procedures are state-of-the art."

Invested heavily, indeed.

Anticipating the growing demand for coccidiosis vaccine throughout the world, Schering-Plough Animal Health Corporation spent more than €10 million to increase the Paracox production capacity and ensure the highest standards for quality.

"Coccidiosis is all we do here," Lomurö says of the dedicated plant. "For me and everyone else, coccidiosis is our livelihood and we are all very quality driven. There's no room for cutting corners."

Demonstrating quality

But quality is not a feature that's readily apparent with vaccines, concedes Harold Briggs, the plant's quality assurance manager who designs the regimented systems and controls for Lomurö's QC team to implement.

"If you buy a car, you can look at it, drive it, and form your own opinion about how good it is, and you know right away if something isn't right," Briggs says. "It the same with food - you can see or smell whether it's fit to eat."

Rigorous QC Standards Guard Against Mycoplasma, Other Infectious Pathogens

After Paracox antigens have been sterilized, Quality Control produces a small batch of test vaccine to make sure it's free of viral contaminants. According to QC manager Martin Lomurö, this series of tests, which is repeated for every antigen, is different from the plant's sterility test and is subcontracted to the British government's central bacteria laboratory. "If there is a breakdown in the plant's antigens unit during production of a specific lot, we would take blood samples from the birds and do a whole range for serological tests to make sure their status had not been compromised during the period when the antigen was down," he explains. "Those tests alone run from £39,000 to £50,000 (€61,800 to €79,200), but we want producers and vets to be confident they're getting a coccidiosis vaccine that has been tested to the highest standard, free of other infectious agents and immunologically proven."

Reputation takes over

It's a whole different story with vaccines, however, where a certain degree of blind faith needs to accompany every dose. That, he says, is where a manufacturer's name and reputation take over.

"You use vaccine based on the assumption that it was made to certain specifications, it'll do what it's supposed to do, and that it's not going to harm you or your birds in any way.

"So the whole way that vaccines and other animal health products are developed, manufactured, tested, marketed and distributed has to be designed with that in mind," Briggs continues. "Somehow, there needs to be an absolute assurance that what the customer purchases is what it's supposed to be, without fail. Because with vaccines, the consequences of failure tend to be rather severe."

Having confidence in a product also helps veterinarians and producers tackle disease problems with more accuracy and authority.

"When faced with a disease problem, vets and producers can't be second guessing a product's safety or efficacy," Briggs says. "So in order for them to be sure, we have to put in place a lot of checkpoints and think carefully about their design and implementation from beginning to end.

"That's really what quality assurance is about. And that's why I say that quality assurance is a philosophy, not a department or a procedure."

As QA and QC managers, Briggs and Lomurö are, in effect, internal auditors "meticulous, detail-oriented people who play by the book and accept no compromises. It's their job to be fussy and demanding.

"At the end of the day, I'm the guy responsible for saying whether a product meets the specifications and can be released for sale," Briggs says. "And before I make that decision, I will look at all the conditions relating to the manufacture and testing of the product. I have to make sure that the product was manufactured and tested according to specifications and in compliance with good manufacturing practices. Schering- Plough Animal Health has its own set of quality standards, which in many cases are even higher than the government's. If a batch doesn't meet those criteria, it doesn't get shipped to our customers."

Consistency is the key

Consistency from batch to batch is also critical to the performance and safety of a coccidiosis vaccine, explains plant director Sue Bushnell, who supervises 70 scientists and technicians at the company's primary and secondary production facilities.

"Consistency needs to begin with the vaccine's antigens," she insists. "Every batch of vaccine that we produce, because it's come from the master strains, has exactly the same characteristic as those very first experimental isolates that were derived from the field.

"From a product safety standpoint, that is really, really important, because organisms can change and mutate naturally," she continues. "But because we're always going back and making the vaccines from these master seeds, we know that won't happen with Paracox."

Producing coccidiosis vaccine involves infecting mature, specific pathogen-free (SPF) birds with one of eight Eimeria organisms, which in turn reproduce inside the birds and produce oocysts, the eggs of the next generation. The oocysts are then harvested from the feces, sporulated, sterilized, processed and blended in the right proportions to produce the Paracox line of vaccines. (See sidebar, page 12.)

While master seeds are critical for the production of all live vaccines, Bushnell says they are particularly important to the success of Paracox because the seeds are derived from what researchers call "precocious" strains of Eimeria "strains that were deliberately selected for their shorter reproductive life cycle and inability to damage the gut wall.

"Precocious strains of Eimeria produce oocysts earlier than conventional strains, but in fewer numbers," she explains.

This unique feature helps to slow and reduce the level of oocyst infection. As a result, the vaccine stimulates the birds' natural immunity to Eimeria without causing lesions and other short-term damage to the gut of the bird. This in turn means that birds vaccinated with Paracox experience no short-term setbacks in weight gain or feed conversion from the deliberate infection caused by the vaccine.

Keeper of the seeds

As manager of Schering-Plough Animal Health's primary production facility for Paracox, Richard Wood is the keeper of the master seeds, which are carefully preserved in a vat of liquid nitrogen. The slightest change in temperature or intrusion into the highly secure storage area is enough to trigger alarms and send technicians running.

"Anyone handling the master seeds is allowed to handle one species a day," the veterinarian says. "We also have strict time limits for harvesting oocysts from the master seeds. There's only a 15-minute window, which is much less than what we have on the oocysts used when producing the actual vaccine."

Wood notes that each Eimeria species has a different level of reproductive potential. Consequently, some species can be reproduced with only a handful of birds, while others might require hundreds or even 1,000.

"Eimeria necatrix, which goes into our breeder vaccine, is one of the species which is not very immunogenic," Wood explains. "So we need to produce a lot of it to produce the vaccine. Not only do we harvest the material over a 72-hour period, but we have to use over 1,000 birds each time - and that's just to produce 10 million doses or less."

Eimeria tenella, used in both the breeder and boiler vaccines, also presents special production challenges because technicians need to harvest both fecal matter and the guts of the infected birds.

"We've got a high level of control in all our processes," Wood concludes. "The fact that we start off with very dirty material "chicken feces "and produce a sterile, highly efficacious and safe product that's free of mycoplasma and other pathogens is really quite an accomplishment. It takes a lot of experience to make a high quality coccidiosis vaccine."

'Most fantastic achievement'

Technician encased in a half-suit isolator used to protect the smallbatch test product.

Martin Shirley, the coccidiologist at the UK's Institute of Animal Health who helped isolate and develop the precocious lines of Eimeria used in Paracox, says he feels like a proud father anytime he visits Schering-Plough Animal Health's production facility.

"Back in the 1970s, when we were looking at the future and the idea of replacing traditional anti-coccidials with a vaccine, we always hoped it would become big," he says. "But quite honestly, I don't think we really realized that the market would become so huge.

"When I visit the Schering-Plough Animal Health plant, I'm always overwhelmed by the expansion, the stateof- the-art procedures and what it's actually producing.

"Coming up with the master seeds was one thing, but I think what Schering-Plough Animal Health has done to develop the product is the most fantastic achievement," Shirley says.

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