Manufacturing on a Grand Scale

TECHNOLOGY TO THE RESCUE

Source: BioPlan Associates

Respondents were asked: When do you believe drug production using plant or animal systems will be a viable alternative to traditional bioproduction methods?

Some manufacturers hope that changes in the cells and equipment used to make biologic drugs will rescue them from cost pressures. Indeed, another survey of over 600 biopharmaceutical scientists by Eden Biodesign found that many believe new technology is key to reducing manufacturing costs in the long term.

Many biologics are manufactured using mammalian cell lines that provide the postprocessing modifications, such as glycosylation, that complex biologics require. Mammalian cell culture is used more than any other system, and biomanufacturers plan to expand this type of production by 2008.³

Compared to yeast and Escherichia coli, however, mammalian cell lines are expensive and inefficient, says Tillman Gerngross of Dartmouth University. Microbes can reach a greater cell density, enabling manufacturers to pack more into a smaller space. Gerngross predicts that over the next few years, more biomanufacturers will switch some of their production over to yeast. He says it's already happening: Currently, one-fifth of today's biologics are produced in yeast, as is one-half of the world's supply of insulin.

In his laboratory at Dartmouth, Gerngross and his team have also engineered yeast to produce human patterns of glycosylation on each biologic, by knocking out the processes that introduce unwanted sugars and replacing them with human analogs. "You get a very defined human glycan structure attached to that protein," he says. Gerngross can produce several grams of protein per liter of broth in three days when using yeast. By comparison, producing 5 grams of protein per liter using mammalian cells can take three weeks.

Gerngross has created a New Hampshire startup company called GlycoFi around this technology. As chief scientific officer, he says he is now collaborating with Biogen IDEC, Eli Lilly, Bayer and others to transfer their biologics from mammalian cells into yeast.

Some companies are considering the use of disposable bioreactors and other throwaway parts such as tubing, mixing bags, and waste bags, in order to reduce costs. Being able to simply discard a tube, rather than clean it, might speed up production and streamline the overall process, says Eric Langer, managing editor at BioPlan Associates, a biotechnology market research firm in Rockville, Md.

However, any change in the manufacturing process faces one major hurdle: getting approval from regulatory bodies such as the FDA and the European Medicines Evaluation Agency. Unlike small-molecule manufacturing, biomanufacturers get approval for both the drug and the process used to make it, and that approval can take years. It also can be expensive, says Langer, since the FDA requires manufacturers to validate every step. "There's a huge burden on the producer to document every stinking little piece of equipment," he says.

Courtesy of Genzyme Corporation

Changing any step in the manufacture of an already-approved product often requires that the entire validation process be repeated to make sure the new technology doesn't change the final product, notes Langer. This is done for good reason, as even minor manufacturing changes can alter a drug's safety. For example, the incidence of a rare complication known as pure red-cell aplasia began to increase in patients taking a Johnson & Johnson product called Eprex, despite 20 problem-free years on the market. After four years of investigation and $100 million, the company learned that a new stabilizer had interacted with the syringes' rubber stopper. "Any change in the process can end up with the product being changed in a way that impacts its clinical safety," says Audrey Phillips, executive director of bio-pharmaceutical policy at the company.

Langer says the rigorous system of regulation can discourage manufacturers from ever introducing any changes, even improvements, to the already existing system. This level of regulation "seriously reduces the creativity on the manufacturing side," he notes. "To propose a change requires a lot of guts. There has to be a reason for making a change that outweighs the cost associated with it."

Gerngross says his yeast technology, which has not yet been approved, has an edge over other new techniques because the FDA has already accepted yeast. New technologies such as transgenic plants or animals may have a more difficult time, he notes. "Anyone who goes in first, the agency is going to look at very carefully," says Gerngross.

TRANSGENICS STILL UNTESTED

No transgenic plant products are commercially available, but expression systems using corn, tobacco, potato, rice, and duckweed have already emerged. Some companies are testing the use of transgenic plants to produce treatments that target cystic fibrosis, pancreatitis, and the bacteria that cause tooth decay.

Transgenic animals can be genetically modified to produce human recombinant proteins in milk. According to Kalorama Information, small farm animals such as goats and sheep can each generate up to 900 liters of milk per year, and dairy cows can produce more than 10 times that amount. Moreover, animals require a lot less money to operate and maintain than stainless steel bioreactors.

However, experts agree that barriers must be overcome before transgenics are a viable alternative to traditional systems. Transgenics can take a long time to go from gene to protein, Gerngross says, and even if they cross the regulatory hurdle, which is high, transgenics may end up costing the same amount as traditional methods. Manufacturers need to purify, fill, and finish the proteins after they are produced in plants or animals, which adds to the cost, he says.

LOOKING OVERSEAS

Source: BioPlan Associates

Respondents were asked: What is the single most significant barrier to biopharmaceutical manufacturing?

Like other industries, biomanufacturers are considering shifting production to countries where it costs less to build and operate a facility. By 2008, the percentage of biomanufacturers who plan to outsource some production will increase by 12%. Countries such as India, South Korea, Singapore, and China, among others, "will eventually become major players in the industry," says Patrick Lucy, business leader for microbial biopharmaceuticals at Dowpharma in San Diego, Calif.

However, some obstacles must be overcome before these countries can compete with facilities in the United States and the European Union. Out-sourcing production of a biologic also means giving up some control over the product, a step companies may be hesitant to take. "You're betting the drug on your ability to manufacture it," and developing countries will need to prove themselves before companies will entrust them with a potential blockbuster, says Roger Wyse, managing director at Burrill and Company, a life sciences merchant bank in San Francisco.

Some companies also have logistical concerns, says Fox, such as the ability to conduct business when the company and its manufacturing plant are in different time zones. David Smolin, vice president of protein-therapeutics development for pharmaceutical research at Bristol-Myers Squibb, notes an additional concern. If a company builds a facility in a country with less stringent intellectual property laws, a citizen might discover how to make the drug and produce generic or less expensive versions.

Bamforth notes that outsourcing to developing countries "certainly has its place," but he argues that companies gain a lot by making the drugs themselves rather than outsourcing to contract manufacturers, regardless of location. He says in-house production enables companies to make their own production decisions. Moreover, they can retain any workers who develop additional skills from making the drug. In-house manufacturers may also be more motivated to make technological improvements that increase yield, since it's their money, says Bamforth, while contract manufacturers are mostly concerned about filling up extra space. "We believe that manufacturing is core to what we do."