Manufacturers Face New Challenges Battling Global Threats

Although new drug development usually focuses on clinical and preclinical research, moving innovative products from clinical testing to market mainly involves overcoming manufacturing capabilities and production challenges. Ensuring access to consistently high-quality critical vaccines and therapies needed to counter bioterrorism attacks is a topic frequently debated. Product shortages are leading to policies that expand US drug and vaccine manufacturing and ensure that US regulatory and healthcare policies avoid erecting roadblocks to high-quality drug production (see sidebar, "Signs of progress").

Jill Wechsler

Warnings of a global flu pandemic and of bioterrorist attacks in the next few years are increasing the focus on drug manufacturing. The World Health Organization (WHO) advises that the avian flu virus is likely to mutate and spread to humans, which could kill millions worldwide. Congress is weighing new "BioShield II" legislation to spur the development of countermeasures to biological threats and to fight infectious diseases. Such crises would stress national healthcare systems as well as international capacity to produce needed vaccines and medicines. Government agencies are looking to encourage research and development of new vaccines and other drugs to protect and treat influenza patients, a process which would involve new methods for testing and producing great quantities of new treatments.

A key issue is whether the United States has sufficient capacity to produce vaccines and medical treatments needed to meet domestic needs in the event of a health emergency, particularly a global pandemic. This past year's flu vaccine shortage, precipitated by manufacturing problems at Chiron's United Kingdom vaccine production facility, focused national attention on vaccine quality control and regulation. Federal officials also acknowledge that in the case of a global flu pandemic, foreign governments very likely would curb exports of vaccines and drugs to the United States until the needs of local populations are met. Some manufacturers are looking to expand US production capacity of critical drugs and are developing more-efficient production methods for vaccines, but such undertakings are expensive and may take several years to accomplish.

Signs of progress

Seeking more antivirals

To prepare for a potential global influenza crisis in the near future, the Department of Health and Human Services (HHS) plans to finalize its Pandemic Influenza Preparedness and Response Plan by fall. In the wake of this past year's highly disruptive flu vaccine shortage, plus regular supply problems with routine children's vaccines, policymakers are very nervous about how the nation will deal with such a global health crisis.

A major flu pandemic would increase demand for medications to treat patients stricken by influenza, particularly during the period when vaccines are under production. At the forefront of this effort is rising international demand for Roche's antiviral Tamiflu (oseltamivir), which was approved by the US Food and Drug Administration and recommended by WHO for influenza treatment. In 2003, more than 1 million prescriptions were written in the United States for this neuraminidase inhibitor, which prevents flu virus replication. Roche reports that foreign governments are ordering millions of doses of Tamiflu for national stockpiles. The company is urging the Centers for Disease Control and Prevention (CDC) and other US agencies to follow suit or face shortages in the case of an international emergency.

Last-minute orders will be difficult to fill because Tamiflu involves a complex manufacturing process that takes 8–12 months to progress from raw material to finished product, explained Roche Medical Director Dominick Iacuzio at a hearing in May before the House Energy and Commerce Committee on pandemic preparedness. The production process involves many intermediate steps, including use of a unique starting material and "a potentially explosive production step that may be carried out only in specialized and costly facilities," Iacuzio pointed out.

Roche doubled production capacity at its European facility in 2004 and plans to increase production in 2006. One initiative would expand US output by shipping active ingredient to US manufacturing sites to produce finished drug product. In the United States, Roche also is adopting special packaging for stockpiled Tamiflu to extend expiration dating. These plans, though, may be blocked if Gilead Sciences follows through on its June announcement to end its 10-year licensing agreement with Roche for Tamiflu manufacturing and marketing.

Meanwhile, Roche is advocating an increased Tamiflu order from HHS, which so far has purchased only 2.3 million courses of Tamiflu, enough to treat less than 1% of the US population. Other nations are stockpiling enough of the drug to cover up to 40% of their populations. Without further purchase commitments, the manufacturer might find itself in the uncomfortable position during a global pandemic of having to export Tamiflu to countries with advance orders.

The Infectious Diseases Society of America (IDSA) recommends that the United States stockpile antivirals sufficient to treat 50% of the nation's population. It notes the need to support the development of antiviral production capacity in the United States as well as a strategy for distributing antivirals and vaccines to states, local health departments, and points of care. CDC is enhancing systems for monitoring adults hospitalized with influenza to detect signs of resistance to current antiviral drugs and to guide its policy for distributing scarce supplies of these medications.

The National Institute of Allergy and Infectious Diseases (NIAID) is supporting research on new antivirals to precisely target viral proteins and to inhibit their functions as well as studies of new broad-spectrum therapeutics that might work against many influenza virus strains. IDSA points out that such innovation could be important in light of the potential for a pandemic influenza strain to become resistant to Tamiflu.

Fragile vaccine production system

A major obstacle in preparing for an influenza pandemic is a lack of domestic vaccine manufacturing capacity. Only five manufacturers produce vaccines for the US market, and only one company makes conventional seasonal flu vaccine entirely in the United States, according to a report from Congress' Government Accountability Office (GAO), (GAO-05-760T, May 26, 2005). At the House Energy and Commerce Committee hearing in May, Julie Gerberding, CDC director, described the US vaccine manufacturing system as "fragile" and noted that pandemic flu vaccine produced in other countries probably will not be available in the United States because other governments "may prohibit export of the vaccines produced in their countries until their domestic needs are met."

The National Institutes of Health (NIH) are supporting research into new vaccine production methods as well as disease analysis, and FDA is developing policies to facilitate new vaccine approval and ensure that manufacturing facilities meet all quality standards. Although vaccine manufacturing is a tricky process in any situation, fast production of a vaccine for a novel virulent influenza strain raises additional challenges. For seasonal flu vaccine, it usually takes six to eight months to identify prevalent flu strains, to develop effective vaccines, and to ramp up production of millions of doses.

Policymakers recognize that efforts to expand the nation's vaccine manufacturing infrastructure and to stabilize the market for routine and seasonal vaccines will lay a foundation for responding to a national or global pandemic. This past year's shortages, to some extent, may help improve the process by boosting funding for new programs and reducing regulatory and legal obstacles to vaccine development. NIH and CDC are providing funds for manufacturers to develop cell-based vaccine production methods. Such methods eliminate the need for using eggs, which are the basis of traditional vaccines in the United States and Europe. Additional support is available to improve vaccine manufacturing processes at existing facilities through the development of more-efficient methods for viral master seed production; egg inoculation; growing, purifying, and harvesting vaccine; formulating the vaccine product; and filling vials or syringes.

Sanofi-Pasteur has received grants from HHS to test cellular and recombinant vaccine production methods, as well as to develop a year-round supply of eggs suitable for full-capacity flu vaccine production under current systems. Sanofi has committed to expanding its current manufacturing operation to produce as many as 300 million doses of monovalent pandemic vaccine, a process that will take at least five years. To move forward now in developing a vaccine against the existing avian flu viral strain (H5N1), Sanofi has produced pilot lots of the new vaccine for testing in clinical trials and has a contract to produce 2 million doses of the vaccine, an unusual move to ensure that manufacturing techniques and conditions that would be used for large-scale production are satisfactory.

Stepping up oversight

In the event of a pandemic outbreak, manufacturers and regulators also will be looking to shift production capacity from other therapies to produce vaccine to attack that influenza strain. In anticipation of such a move, FDA's Center for Biologics Evaluation and Research (CBER), which has put vaccine licensing and quality assurance at the top of its priority list, says it will regard a vaccine for a pandemic flu strain from a licensed manufacturer as a product undergoing a routine change and thus require only a supplement application for approval. The agency also may offer accelerated approval to new vaccine sponsors, using antibody levels as surrogate markers for efficacy.

Another CBER goal is to be more aware of possible manufacturing problems that could curtail vaccine production, as seen at Chiron's UK facility this past year. The agency now plans to conduct good manufacturing practices inspections of flu vaccine manufacturers annually instead of every two years. This recognizes that complex manufacturing issues may arise when producing new influenza vaccines each year. The hope is that recently inspected manufacturers will be well positioned to quickly develop and produce a vaccine in the event of a pandemic.

FDA also has signed information-sharing agreements with British and other regulators from countries where vaccines are produced for US distribution. The aim is to facilitate access to information on problems that arise from manufacturing inspections and to better communicate information on new technologies in manufacturing operations.

One sign of progress is that GlaxoSmithKline (GSK) announced in May that it has filed a license application for its Fluarix vaccine, which is produced in Europe. GSK plans to provide 10 million doses of the product for the 2005–2006 flu season once the application is approved.

At the same time, Chiron recently acknowledged that it probably will not meet earlier predictions for resuming full production of flu vaccine at its UK facility. The company now expects to produce 18–26 million doses of its Fluvirin vaccine for the 2005–2006 flu season, instead of the 25–30 million doses predicted a few months ago. Chiron attributes the reduction to delays in ramping up production of the third of three prevalent flu vaccine strains. Chiron must retrain more than 100 production workers involved in quality control activities plus integrate hundreds of manufacturing process changes into its newly overhauled production system. FDA was scheduled to inspect the re-engineered facility in July, which will determine the company's ability to begin shipping vaccine in September.

Countering bioterrorism

Many of the challenges confronting vaccine manufacturers during an influenza pandemic also affect the development of treatments to counter potential bioterrorist attacks. Congress approved Project BioShield legislation in July 2004 after months of debate. That bill provides funding for government purchase of vaccines and therapies for national stockpiles and supports R&D funding for biopharmaceutical companies developing new treatments. It also allows FDA to authorize emergency use of unapproved new products and permits the agency to approve countermeasures on the basis of animal testing.

The policy has generated little enthusiasm among pharmaceutical companies, however, primarily because it fails to shield manufacturers from lawsuits related to anti-bioterrorism products. In response, members of Congress who want to spur industry investment in this area have been crafting BioShield II legislation. Senators Orrin Hatch (R-UT), Joe Lieberman (D-CN), and Sam Brownback (R-KS) introduced a bill (S. 975) that aims to assure the biopharmaceutical industry that the government will be a reliable partner in this high-risk R&D field. Key provisions expand liability protections, boost tax incentives for countermeasure development, and support FDA fast-track approval of such treatments. Manufacturers have called on Congress to remedy the "valley of death"—the gap between funds available for basic research to document scientific proof of principle and actual procurement orders from federal agencies—in financial support for countermeasures. Small biopharmaceutical companies interested in pursuing counter-terrorism projects maintain that they need public funding to move from the lab into commercial production because they cannot raise private capital for such high-risk projects without purchase agreements in hand.

New BioShield legislation also aims to be more explicit about offering R&D incentives for dual-use medical products that combat infectious diseases as well as bioterrorist chemicals. Although the proposed bill primarily encourages government funding for medical countermeasures, it recognizes that many new treatments will be appropriate for the civilian market for antibiotics and could be important in combating diseases in the developing nations, where malaria and tuberculosis have become resistant to current drugs.

Even though proposals to indemnify pharmaceutical companies have drawn fire, the big fight is over proposals to enhance intellectual property protections. A highly contentious provision would award companies that develop biodefense products "wild card" patents (i.e., up to two years extended exclusivity on another company product). Generic-drug makers as well as pharmacy benefit managers insist that such legislation will delay competition from low-cost generics and raise pharmaceutical costs for public and private healthcare programs.

The wild card provision is likely to be dropped as Senate leaders move to combine more acceptable provisions of this and other biodefense measures into a bill with sufficient bipartisan support to gain approval. With six Senate committees evaluating various sections of Bioshield proposals, there will be ample opportunity to debate whether the legislation is a giveaway to pharmaceutical manufacturers or a reasonable approach to spurring new countermeasure development.

Jill Wechsleris Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com