Biotech Manufacturing Under Scrutiny

Last year was a difficult one in the biotech-manufacturing arena. The H1N1 vaccine shortage in October and November brought home the perils of influenza vaccine development and production, especially when working with new viral strains each year. A leading biotech manufacturer suffered major losses caused by serious problems on the production and compliance front. Despite several decades of experience in monitoring bioreactors and refining cell culture operations, the production of safe, pure, and potent biologics remains a tricky business.

Jill Wechsler

DEBACLE AT GENZYME

The troubles at Genzyme began two years ago when it sought to scale up production of its new treatment for Pompe disease, Myozyme (alglucosidase), at its flagship Allston Landing facility in Massachusetts. With six large bioreactors, that plant produces Genzyme's lead product, Gaucher disease treatment Cerezyme (imiglucerase), along with Fabrazyme (agalsidase) for Fabry disease. Unfortunately, initial commercial batches of Myozyme made at Allston Landing differed from those made at Genzyme's smaller Framingham facility, requiring the company to conduct additional clinical trials and submit a new license application for the product.

In addition, an inspection of the Allston Landing plant by the US Food and Drug Administration in the fall of 2008, found deviations from good manufacturing practices (GMPs), including inadequate procedures for preventing contamination, equipment maintenance, maintaining in-process controls, and for computer systems validation. Genzyme thought it had addressed all these deficiencies by February 2009, but an FDA warning letter requested additional actions and information, as did another FDA communiqué in May.

As Genzyme struggled to address the FDA's concerns, in June 2009 it discovered viral contamination of a bioreactor used to produce Cerezyme in-process material. The company had to close the Allston Landing facility altogether for several weeks for decontamination. Almost all of the starting material used to make Cerezyme was scrapped, and several thousand patients were left with limited access to therapy for these very serious conditions.

As the cleaning process concluded, Genzyme then discovered problems with its fill–finish process at Allston; evidence of metal particulates, fibers, and other minute particles in certain batches of Cerezyme and Fabrazyme prompted a shutdown of those operations. Genzyme transferred those activities to facilities in Waterford, Ireland, and Geel, Belgium, along with all large-scale bulk production for Myozyme. Genzyme also contracted with Hospira to perform fill–finish work for its major drugs to support what it hoped would be expanded production in the coming year. The company is anxious to ramp up output because the FDA has moved to alleviate the Cerezyme shortage by fast-track approval of alternative therapies made by UK-based Shire and by the Israeli firm Protalix Biotherapeutics, which has linked up with Pfizer to commercialize its Gaucher treatment.

By the end of 2009, Genzyme was beginning to ship new lots of Cerezyme and Fabrazyme. But by then, revenues had slumped, along with the company's standing with investors. New competition was on the horizon, and the company had to implement a two-year corrective action plan to address the FDA's concerns about manufacturing processes and controls. Prominent stockholders raised questions about the leadership of Genzyme CEO Henri Termeer, who moved to deflect these challenges by bringing in new senior executives to oversee manufacturing, operations, and regulatory affairs. It remains to be seen if these responses are too little, too late.

EGGS VERSUS CELLS

Despite the perennial risk of contaminated cell cultures, there's a big push underway to switch influenza vaccine production from eggs to cellular methods. The campaign accelerated after vaccine makers failed to deliver some 100 million doses of the new H1N1 influenza last summer as expected; industry and government officials lost considerable credibility when only 40 million doses were available in September, and some 20 million Americans already were hit by the new flu. Health and Human Services (HHS) Secretary Kathleen Sebelius said she relied on industry predictions that turned out to be wildly overoptimistic, although manufacturers claimed they kept health officials informed of their technical problems.

Manufacturers have used fertile chicken eggs to grow flu vaccine since the 1930s, because the influenza virus grows well in eggs, an important feature for fast production of a viral strain that changes every year. But with the H1N1 flu, production took longer than expected because the yield in each egg was much lower than with seasonal flu viral strains. The resulting delays have prompted government officials and manufacturers to accelerate the shift to cell-culture flu vaccine production. Such methods have been used for decades to produce vaccines for mumps, measles, polio, rubella, and other diseases, explained Jesse Goodman, FDA chief scientist, at a December 2009 seminar on advances in influenza vaccine technologies at the National Institutes of Health (NIH). But that approach has not been adopted for influenza because it can take a long time to get a good yield out of cell cultures.

The change will not transform influenza flu vaccine production, said Goodman, but could lead to more reliable products and faster scale-up. Anthony Fauci, director of NIH's National Institute of Allergy and Infectious Diseases, agreed that shifting to cell culture doesn't cut off that much production time, but could establish a more flexible surge capacity. Making the transition from egg- to cell-based production "will take some time," Fauci said, "but eventually we will get there."

Support for this transition comes from HHS' Biomedical Advanced Research & Development Authority (BARDA), which funds efforts to expand manufacturing capacity for influenza vaccine as part of its mission to expand research and production of public health countermeasures. BARDA has awarded grants and contracts to construct new facilities and retrofit existing plants with an eye to creating more robust, flexible, and scalable manufacturing systems, explained BARDA Director Robin Robinson at the NIH seminar. A big winner is Novartis, which received $487 million (of $1.3 billion in grants to manufacturers) to construct a cell-based pandemic and seasonal flu vaccine manufacturing facility; the new plant opened a few months ago and is scheduled to be operational in 2011.

Potency has been another issue with H1N1 vaccine production. Even though clinical trials indicated that the new vaccine was effective with a single dose in adults, manufacturers found some lots inadequate: Astra-Zeneca's MedImmune had to recall nearly 5 million doses of its nasal spray vaccine in December, and Sanofi Aventis pulled 800,000 doses in prefilled syringes for young children. But by then, the pandemic was ebbing, and manufacturers faced a new problem: more vaccine than anyone wanted. Last month, the French government moved to sell off millions of doses to countries in the Middle East and Latin America, and to cancel sizeable orders from Sanofi, Glaxo, Novartis, and Baxter.

The real "endgame answer" to pandemic and seasonal flu vaccine production problems, according to Fauci, is to develop a universal influenza vaccine that could be administered in childhood and last a lifetime, as with most vaccines against infectious disease. Such a discovery could reduce the need to produce 120–150 million doses of a new influenza vaccine each year in the US, at a cost of $2.8–4 billion. "And it is doable," Fauci said, noting that researchers already are identifying possible vaccine targets that don't change with every different influenza virus.

Even though the FDA received some of the blame for the pandemic flu vaccine manufacturing woes last fall, Commissioner Margaret Hamburg prefers to regard the response from the FDA and from the industry as "quite remarkable in terms of how much has been mobilized in response to a previously unrecognized strain of flu virus." Some of the disappointment may stem from over-optimism in predicting how much vaccine would be available when. "Sadly, we know that it's the nature of manufacturing vaccines to have some unexpected delays, and it's the nature of science to have unanticipated problems emerge."

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com