van het hub, 25 sept. 2007:
Posted by: Rajuramas
In reply to: None Date:9/25/2007 9:41:19 PM
Post #of 5090
25 September 2007
Uncorking the biomanufacturing bottleneck
from Nature Biotechnology
Alan Dove
As biomanufacturing capacity becomes strained, several new methods for producing biologics are being investigated by biotechnology companies.
The future for biologics manufacture? Sheep being milked at the dairy of PPL Therapeutics' pilot production plant in Scotland.
© PPL Therapeutics
Molecules produced by organisms or cultured cells—so-called biologics or biopharmaceuticals—are currently the mainstay products of the biotechnology industry. Biologics, which include protein hormones, engineered protein-based vaccines, and monoclonal antibodies, can precisely modify a patient's physiology, often with greater success and fewer side effects than traditional small-molecule drugs or vaccines. Indeed, early biologics—Amgen's (Thousand Oaks, CA) recombinant erythropoietin and Genentech's (S. San Francisco, CA) human growth hormone somatropin—have proven that these drugs can benefit huge numbers of patients and generate handsome profits. But biologics are fast becoming victims of their own success, and a looming deficit in biomanufacturing capacity threatens to restrict the expansion of the commercialization of this group of products.
The manufacturing crunch
In 1998, Immunex (Seattle, WA) launched Enbrel, a soluble tumor necrosis factor (TNF) receptor used to treat rheumatoid arthritis. Demand for the drug rapidly outstripped its supply, forcing the company to make large capital investments in the construction of new production facilities while scrambling for partnerships with companies that might provide additional capacity. When the smoke cleared, Amgen had announced it would acquire Immunex, and Enbrel was monopolizing the worldwide capacity for biologics manufacturing.
Although Immunex has become the poster child for the biomanufacturing bottleneck, experts suggest that the Enbrel story is only the beginning. "There are ten antibodies on the market today, and they're essentially consuming all the [manufacturing] capacity that's available. There may be as many as 500 more in development," according to Tom Newberry, a spokesman for GTC Biotherapeutics (Framingham, MA; previously Genzyme Transgenics). Newberry foresees 20 new monoclonal antibodies reaching the drug market in the next ten years, necessitating a 200% increase in manufacturing capacity for that class of proteins alone. This estimate may even be a conservative one: many biologics are being developed to treat chronic conditions, and proteins, which tend to be broken down in the bloodstream, often have to be given in larger doses than small-molecule drugs.
The current standard technology in biomanufacturing, which uses cultured Chinese hamster ovary (CHO) cells in bioreactors, presents major difficulties for companies seeking to scale up. Because nutrients, heat, and gases must diffuse evenly to all cultured cells, the laws of physics set strict limits on the size of bioreactors. Building more bioreactors multiplies costs linearly. A CHO cell–based biomanufacturing plant can cost upwards of $250 million, and an error in estimating demand for, or inaccurately predicting the approval of, a new drug can be incredibly costly. To compound the problem, regulators in the United States and Europe demand that drugs be produced for the market in the same system used to produce them for the final round of clinical trials, so companies have to build facilities for drugs that might not be approved.
Pursuing a wide range of methods, several companies are now developing new technologies to address this capacity crunch. These include biomanufacturing in domestic mammals, chickens, and plants (see Table 1).
Proteins by the herd
Both GTC Biotherapeutics and PPL Therapeutics (Edinburgh, United Kingdom) have developed herds of transgenic animals that express therapeutic proteins in their milk. April D'Arcy, a spokesperson for PPL, says: "The actual synthesis phase occurs within the animal, under the control of the animal's own physiology. This is clearly an advantage over, for example, cell culture, where the culture conditions themselves have to be controlled within very tight limits."
The mammary "bioreactor" also has the advantage of having evolved for the sole purpose of secreting proteins. "We're dealing with cells that are specifically designed to secrete proteins in a much more packed density. As a result we're able to get much more complex proteins than a standard bioreactor is typically able to get to," says Newberry. As biotechnology research yields greater insights into disease, the ability to manufacture more complex biologics may give transgenic animals a distinct advantage over other biomanufacturing techniques.
There are still bumps ahead for the technology. For example, goat breeding has a turnaround time of approximately 18 months. And some therapeutic human proteins could be detrimental to animals' health when expressed in their mammary glands.
Even with these caveats, animal-based systems have significant advantages over traditional bioreactors in scalability and financial risk. Newberry estimates that a company can get GTC Biotherapeutics to produce a transgenic goat for about a tenth of the cost of that required to build a traditional biomanufacturing facility. If a biologic produced in transgenic animals is successful in clinical trials, a company can enjoy agricultural economies of scale instead of linearly increasing building costs, as traditional breeding can cheaply enlarge the herd.
Or the flock: AviGenics (Athens, GA) is one of several companies working with transgenic chickens (see Table 1), the eggs of which are easily harvested, natural protein-producing systems. Tony Cruz, AviGenics' vice president for corporate development, contends that chickens have a distinct advantage over goats and other dairy animals, as it "takes an egg 21 days or so to hatch after a hen lays it, and a chick will take in the neighborhood of six months to be able to generate her own eggs or reproduce, so you have a very quick turnover." The company has successfully introduced transgenes into chickens using a retroviral system (Nat. Biotechnol. 20, 396 – 400, 2002) and is now developing nonretroviral transgene systems.
According to AviGenics' estimates, a flock of 4,000 hens could produce approximately 100 kg of a biologic drug per year, and each hen occupies about one square foot of space in a chicken coop. "If you want to increase your protein production, it's not a matter of building a new plant, it's a matter of building a new chicken house," says Cruz.
Although chickens may ultimately give goats a run for their money, the production of transgenic birds is still several years behind transgenic mammal technology. "At this stage of the game we are still being looked at as an alternative system," says Cruz, as "anyone who's looking for a biomanufacturing system can't put all their eggs in one basket."
Green proteins
The ease of genetically modifying plants has inspired a few companies to seek bioreactors even earlier in the food chain, a strategy that could eventually produce even greater cost savings (see Table 1).
ProdiGene (College Station, TX), for example, has developed an expression system that produces a desired protein in the ker