Baxter Tackles Insoluble Solutions

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Baxter Tackles Insoluble Solutions
April/May 2004
Agnes Shanley, Editor in Chief
Pharmaceutical Manufacting
After less than three years in the contract manufacturing business, Baxter Pharmaceutical Solutions, LLC is tackling some of the pharmaceutical industry's most challenging--and expensive--manufacturing problems. Its niche? Formulating and delivering insoluble or unstable drugs, and offering alternatives to the hated hypodermic needle.
The company has integrated R&D and pilot production in Round Lake, Ill., with lyophilization, filling and packaging at a new manufacturing facility in Bloomington, Ind. A $100-million expansion project, including a brand new manufacturing plant due to start up next spring, will double overall capacity.
Baxter's not alone in targeting formulation and delivery problems, as explosive contract manufacturing growth entices more companies to offer their expertise. Nearby Abbott Laboratories (Abbott Park, Ill.) is expanding its One 2 One outsourcing business, including aseptic filling, while Dow Chemical Co.'s (Midland, Mich.) Dowpharma subsidiary has launched its BioAqueous services for custom drug solubilization, and is now working with Bristol-Myers Squibb Co. At this point, though, there appear to be enough challenges to go around, as more drug manufacturers outsource key development or production processes. "The philosophy of 'doing it yourself' has given way under FDA pressure and the fact that pockets aren't as deep as they'd been," says Bill Anderson, director of new ventures at Baxter Healthcare Corp. in Round Lake. Demand for outsourcing is growing by 20% per year, Anderson says.
"We're seeing more demand for our services than we had expected five years ago," adds Joel Tune, Baxter Healthcare vice president and general manager of global drug delivery. "We've had to expand twice in the last two years, and we are talking about expanding facilities here as well as in Puerto Rico."
Drug solubilization and delivery is a persistently troublesome issue. Currently, one third of all the medicines listed in the U.S. Pharmacopoeia are poorly soluble, posing oral bioavailability problems and, for injectable formulations, often result in development delays and suboptimal cosolvent formulations. In addition, an estimated 40% of all drugs currently in development are insoluble--many cannot be formulated successfully, wasting millions of dollars in drug company R&D budgets each year.
Minimizing adverse side effects from excipients is another challenge facing drug manufacturers. The billion-dollar cancer treatment, Taxol, for example, typically uses cremofor (phytomenadione), a polyoxyethylated castor oil, as an excipient. The compound can cause severe swelling, so patients often require antihistamines when taking the drug.
Then there is the matter of unstable materials. Proteins and peptides and even some mainstays such as penicillin and cephalosporins can be very difficult to work with.
A $100-million expansion project is poised to double capacity at Baxter Pharmaceutical Solutions' Bloomington, Ind., manufacturing facility.
Acquisitions Round Out Options
Strategic technology acquisitions, refined in-house, now permit Baxter to troubleshoot a broad range of formulating, delivery and filling problems. The Nanoedge process, for example, based on technology that Baxter licensed from RTP Pharma, Inc. (now SkyePharma, London), addresses solubility and excipient side effects in formulation. Drug particles are reduced to 100 nanometers in diameter then coated with a thin layer of proprietary excipient, creating drug particles that dissolve more rapidly when injected or infused. "It's similar in effect to the difference between confectioners' sugar and coarse sugar," Tune explains. The resulting dispersion can then be freeze- or spray-dried, if necessary.
So far, Nanoedge has allowed Baxter to solve seemingly intractable formulation problems. Consider a solid that would ordinarily take 1 part drug to 10,000 parts of water to dissolve. Instead of requiring the poor patient to infuse 10 L of fluid, Tune explains, a manufacturer could use Nanoedge to formulate the drug in a 10-mL dose. "We had one customer who had tried for three years to formulate an insoluble drug," says new ventures director Anderson, whose team at Round Lake focuses on formulation and delivery challenges. "With Nanoedge, we provided a formulation in a few months."
ProMaxx technology, acquired from Epic Therapeutics in 2002, allows Baxter to encapsulate sensitive biopharmaceuticals in uniform, high density microspheres, the size and release capabilities of which can be closely controlled. Release time can be varied from one day to three months, and compounds can be incorporated into prefilled syringes. The system is also water-based.
The company is betting that this time-release platform will help it take clients closer to the Holy Grail of injecteable drug delivery. "Getting away from frequent needle delivery for large molecules will be a huge trend in the future, with explosive growth," Anderson says.
For high-end biotech drugs, Baxter has already developed new cartridges and high-speed filling systems in the Bloomington facility, based on technology that was pioneered in the dental field. The filled and finished product would allow patients to use one cartridge to administer several doses of medication, or to vary dosages, instead of having to measure a single dosage into a single syringe each time--a major advantage for those with chronic diseases such as MS and diabetes. "We're migrating from vials to prefilled applications and from multidose vials to multidose cartridge forms," explains Lee Karras, vice president of operations at Baxter's manufacturing facility in Bloomington.
The company is also freezing drugs in a ready-to-use presentation to handle aseptic filling of unstable compounds such as cephalosporins and pencillin. Drugs are frozen within within their final containers then thawed out in a simple device at room temperature in five minutes, Tune says.
Baxter had worked closely with specialist Mike Akers, now the company's director of pharmaceutical R&D, to improve lyophilization cycles for proteins and peptides. In one case involving a well-known molecule, the company was able to halve the time required, Anderson recalls.
With these key technologies, Baxter expects to offer an integrated approach to formulation and delivery. "Nanotechnology may not be new, but the ability to work with nanoparticles in an aseptic environment without toxic excipients, and to keep the material stable, is a plus," says Tune.
Baxter's new lyophilization unit features fully automated, PC-controlled loading and unloading equipment developed by BOC Edwards (Wilmington, Mass). Operator contact is eliminated, improving safety and cleanliness while increasing output. Photo courtesy of Pharmadule.
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