Risk Management Still Eludes Vaccine Manufacturers

Despite the buzz about "process understanding" and PAT, vaccine manufacturing remains defiantly un-PAT-able and an extremely risky business. Chiron's recent Fluvirin case offers important lessons in due diligence, quality management, and GMPs. However, it also points out an urgent need for incentives and regulatory flexibility.

By Agnes Shanley, Editor in Chief

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Editor's Note: The Chiron Fluvirin case provides lessons in due diligence, but also signals the need for more manufacturing incentives and flexibility. For expert analysis of the Chiron case, read January’s Pharmaceutical Manufacturing.



At a time when drug companies and regulators claim to be striving for greater process knowledge and a better understanding of risk, vaccine manufacturing presents a major challenge. Vaccines are so unlike traditional medicines: they have no true “active ingredient;” in many cases, it’s not even clear exactly how they work. They remain, defiantly, un-PAT-able. Their production is extremely complex and risk-filled, yet primitive — and their manufacturers struggle to meet or improve quality standards while increasing output. Is it any wonder that only five vaccine manufacturers remain in the U.S. today?

Sometimes, regulators have had to step in to force improvements: Consider the multimillion-dollar consent decree imposed on Wyeth four years ago for Prevnar manufacturing. Even after the company had established compliance with the Order — as late as October, 2003 — FDA inspectors continued to find quality problems at the company’s Pearl River, N.Y. facility. Next year, Prevnar will be the focus of a pivotal whistleblower lawsuit that will be tried in Federal Court; the suit may invoke Sarbanes-Oxley, but it focuses on GMP problems at Wyeth’s Sanford, N.C. Prevnar facility — problems that demonstrate the risks and challenges inherent in vaccine manufacturing.

And, if vaccine production is the freak of the pharmaceutical manufacturing world, then the flu vaccine has to be its poster child, since no compound better illustrates the field’s inherent contradictions and complexities. First, oracles decide which strains of flu pose the highest risk; these three strains are then grown and harvested in individual lots of fertilized hen’s eggs; virus is killed, purified and removed; antigen lots are sterile-filtered and tested, made into vaccine, filled and packed. The opportunities for contamination and product failure are almost unlimited, at every stage of manufacturing, from incubation to filling. The timeline for production is short, and any unused product must be destroyed.

In reality, the situation is
far more complex
than due diligence, quality
or increased regulatory scrutiny.
At its core is
a lack of financial incentives
for manufacturers.

Chiron’s recent experience with manufacturing facilities it acquired in the U.K. provides a cautionary tale for any manufacturer. The company bought, in good faith, facilities with past histories of GMP problems from a company that had invested in improvements and had claimed to have resolved any past manufacturing issues.

FDA warning letters and inspection notes relating to the facility and dating back to 1999, when it was owned by Medeva, indicate major systemic quality failures: failure to validate filtration procedures or to establish bioburden limits for the plant; failures involving SOP and documentation; insufficient cleaning or equipment calibration; failure to monitor air pressure in filling operations. More recent FDA inspection reports suggest that some of these problems were passed on to the facility’s next owner, Powderject, which poured nearly $200 million into the facility. Nonetheless, traces of the problems may have been passed on to Chiron.

After paying $878 million for the new manufacturing capacity and announcing a commitment to a market that U.S. companies have all but abandoned, Chiron now finds itself in serious financial jeopardy, facing severe losses in revenues — not to mention lawsuits filed by its shareholders as well as “consumer” class action lawsuits filed by opportunistic lawyers around the country.

It has been argued that Chiron should have been more careful about investing in the facilities — often, all the fresh coats of paint, cleaning, additional equipment and training programs can’t eliminate systemic quality problems at an old facility. It has also been argued that FDA should have been more proactive, and prevented the plant’s previous owners from manufacturing vaccine when the first problems surfaced. But then, where would the Agency have been politically? If FDA had prevented vaccine from being shipped last year, during a severe flu vaccine shortage, how would the public have reacted?

In reality, the situation is far more complex than due diligence, quality or increased regulatory scrutiny. At its core is a lack of financial incentives for manufacturers. Currently, the U.S. government has decided that the flu vaccine should cost roughly $10 — a price that doesn’t perpetuate investment in the latest technology — isolator systems, for example, or the bioreactors required for cell culture production.

What is needed is more coordination between the government, research groups and academia in the area of vaccines. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, recently scoped out some suggestions. The government could guarantee the purchase of unused vaccines, he argues.

Meanwhile, techniques such as “research genetics” under development at NIH could help identify virus strains more quickly. Cell culture production, now in its infancy, may not be a panacea, but could improve the supply situation as well. In the future, plant-based production methods may further reduce risks.

Dr. Fauci also suggests that companies be offered regulatory relief, and that manufacturer liability be limited. These points make a great deal of sense but would have to be addressed very carefully. Risks remain higher with vaccines than any other form of medication, since each person’s immune system reacts differently — even perfectly manufactured vaccines have caused temporary neurological problems or inflammations.

Mention of the word vaccine can strike fear into the hearts of even the most rational of parents. Consider the thimerosol controversy, the growing number of web sites devoted to documenting adverse reactions, or the small but growing numbers of parents who are opting not to have their children immunized. I’ll never forget the stark fear I experienced when one of my children developed an adverse reaction to the DPT vaccine — or my relief when another child’s chronic ear infections appeared to stop a few months after a dose of Prevnar. Clearly, relaxing safety standards is not the answer. Making those standards more attractive and accessible to manufacturers is. E-mail me at ashanley@putman.net to let me know what you think.

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