Regulatory Beat: Federal Regulators Weigh New Biotech Controls

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BioPharm International, BioPharm International-05-01-2004, Volume 17, Issue 5

Government agencies examine the need for more regulation of ?bio-pharming,? biosecurity, and BSE.

The recent discovery of "mad cow disease" in the US has sparked a call for tighter controls on the use of bovine-derived substances in pharmaceuticals and biologics. At the same time, fears about the spread of genetically engineered (GE) plants and animals have prompted a review of regulations governing GE organisms used to produce pharmaceuticals. These developments may further complicate biotech manufacturing processes but ultimately increase confidence in product quality.


With "bio-pharming" on the rise throughout the US and the world, industry is supporting the federal government's reexamination of regulations in this area. USDA announced plans in January to re-evaluate and update its 1986 rules governing GE crops — a process that promises to be contentious but could lead to more rational oversight of this field. Manufacturers developing these technologies hope clear government rules will guard against inadvertent release of genetically altered crops and consequently defuse some of the anti-GE rhetoric.

USDA's Animal and Plant Health Inspection Service (APHIS) is heading the review effort, which will involve preparing an environmental impact statement on the potential effects of GE crops on plant and animal life. One topic on the agenda is the risks and benefits of increased use of GE plants to produce pharmaceutical and industrial compounds not intended for food or animal feed. Government officials aim to develop a risk-based regulatory scheme involving increased regulation of GE organisms that pose the greatest risk to plant and animal health and reduced oversight for low-risk categories. Pharma and biotech firms plan to participate actively in the review process with an eye to demonstrating that GE plants used to produce medical treatments can be tightly controlled and should be considered low-risk compared to GE food crops.

USDA's announcement came on the heels of a study from the National Academy of Sciences that describes confinement technologies for preventing GE organisms from escaping into the natural ecosystem. The report generated some controversy by indicating that complete confinement may not be necessary in all cases.

The Biotechnology Industry Organization (BIO) favors strong regulatory oversight of bio-pharming to prevent any inadvertent contamination of food crops that could lead to a "doomsday" regulatory approach. The organization supports a government permitting system for field testing and commercial planting of pharmaceutical-producing plants, and it urges companies to prepare detailed confinement and handling plans and to agree to mandatory audits and inspections.



The realization that the US no longer qualifies as a BSE-free country is prompting government regulators to take a new look at policies to control the spread of infection. Up until a few months ago, there was no evidence of US cattle infected with bovine spongiform encephalopathy (BSE), or mad cow disease, which can cause variant Creutzfeldt-Jakob disease (vCJD) in humans. This changed dramatically in December when tests confirmed the disease in a cow imported from Canada.

In addition, prior to a death in the United Kingdom related to a blood transfusion from a donor with vCJD, scientists were uncertain that the disease could be transmitted through human blood, as well as by ingesting BSE-infected beef. FDA already had imposed restrictions on blood donors living in Europe and required blood banks to perform additional screening of donated blood to detect any prions linked to this disease. These practices may have prevented transfusion of infected blood, but they also have reduced blood donations, increased the cost of collecting blood, and further stressed the nationís blood supply system.

These developments are important for manufacturers of drugs, vaccines, and biotech therapies because they regularly use bovine-derived materials in production, including certain active ingredients and many common drug excipients such as gelatin, glycerin, and amino acids. In addition, bovine blood and blood products commonly serve as reagents in the production of monoclonal antibodies and vaccines. Fetal calf serum and other beef extracts are important elements in establishing cell banks, bacterial and viral seed banks, cell cultures, and fermentation operations. Extracts and gelatins and other materials are important in purification and formulation of many biological products.

Federal officials aim to prevent the spread of BSE among the nation's 35 million cattle primarily by expanding and stiffening the ban on feeding rendered beef parts to cows. The possibility that pharmaceutical products could be contaminated by BSE-infected materials was discussed at a February meeting of FDA's Transmissible Spongiform Encephalopathies (TSE) Advisory Committee. Because statisticians and experts still agree that the risk of vCJD infection through use of a drug made with bovine-derived materials is minute, the panel held off on recommending new regulations pending further assessment of the scope of the BSE cattle problem in the US.


The main FDA strategy for preventing BSE contamination via regulated products has been to limit sourcing of bovine materials from most of Europe. The TSE advisory committee recommended in 2000 that vaccine manufacturers use materials from non-BSE countries and re-derive working cell banks and viral seed banks that were established using materials from questionable sources. The panel acknowledged, though, that master cell banks did not have to be re-derived due to the risk that such changes could alter a vaccine. (FDA BSE policies are available at

.) However, with the US and Canada now on the at-risk list, this limited sourcing policy is very difficult to maintain. Only Australia and New Zealand now appear completely BSE-free, and they cannot meet industry'ís demand for bovine-derived materials alone.

FDA is continuing to encourage manufacturers to switch to non-animal-derived ingredients where possible. However, such changes often are impractical: adopting a new excipient can have a major impact on a product's safety and efficacy profile, and it often is impossible to replace a bovine-derived active ingredient.

In addition, FDA has worked with industry to develop processes to completely deactivate the prions linked to BSE. Such processes can ensure the quality of gelatins used in oral and topical products and tallow derivatives. However, BSE risk cannot be totally eliminated for most injectibles and vaccines that use bovine materials. FDA officials would like additional research on whether cell banks propagate BSE agents and if additional processes could purify vaccine and biological products.

Meanwhile, industry is looking for other innovative approaches, such as establishing select, closed cattle herds to produce safe bovine products for injectibles, using fish-derived and plant materials for biotech fermentation, and developing new filtration processes better able to remove infectious prions from red blood cell concentrate in animals. Even though these strategies are expensive, manufacturers are considering them seriously to avoid any liability problems that would arise from BSE contamination.


One offshoot from the war on terrorism is a fear that bioterrorists might gain access to biomedical research and materials that could be misused by hostile parties. Last October, the National Academy of Sciences (NAS) issued a report recommending actions for scientists and government agencies to safeguard beneficial research involving pathogens and other potential dual-use life sciences projects. In March, federal officials implemented one proposal of the NAS panel (called the Fink Commission after its chair, Massachusetts Institute of Technology geneticist Gerald Fink) by establishing the National Science Advisory Board for Biosecurity. The research community is pleased that the panel is designed to be advisory; it will not impose an additional layer of regulation over research activities.

The biosecurity board will be housed at the National Institutes of Health (NIH) and may operate similarly to NIH's Recombinant DNA Advisory Committee, which oversees gene therapy studies. The panel will establish guidelines for what kinds of research warrant biosecurity review, develop a code of conduct for scientists, publish guidelines for journal editors to avoid inadvertent publication of sensitive information, and seek international standards in this area. Instead of actually reviewing research activities, the board will work with some 400 institutional biosafety committees that already examine security issues related to biomedical research. The board's standards and guidelines will apply to all federally funded research, including NIH grantees, but it also is expected to shape activities and attitudes in the private sector. Some national security experts believe that this approach is inadequate to prevent harmful release and exposure and advocate stronger efforts to develop international standards. Federal officials continue to review the Fink Commission's recommendations and may propose additional policies.