Baxter Tackles Insoluble Solutions

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.

Added Capacity Is Flexible, Modular

Baxter has taken a modular approach to its Bloomington site that will allow it the flexibility to expand its capacity as needed. Pharmadule Emtunga AB of Sweden has engineered and built cleanrooms for the facility, and is currently building them for the new plant "A parallel approach allows us to build cleanrooms while we're developing the building infrastructure, getting permits and validating the whole package, says vice president Karras. It will also shave 10 months off the time required to complete the plant.

The modules are quite different from those that are typically "dropped in" and built onsite using the owner's equipment. Instead, each cleanroom, including piping, is custom engineered and built in Sweden, then taken apart, shipped and reassembled on the site. This approach may add some complexity to preliminary engineering, but it pays off in the final stages. Since all modules are pre-tested, validated and qualified, users save a significant amount of time, explains Par Almhem, president of the company's U.S. subsidiary, based in Bedminster, N.J. The company has recently completed projects for Eli Lilly, Astra Zeneca, Merck and Pharmacia.

Raymond Engineering's (Chicago.) Professional Group designed the overall site layout, the support building structures and the utilities infrastructure, while Turner Construction handled purchasing, value engineering and construction. Raymond and Pharmadule had worked on Baxter's first new plant in Bloomington, and agree that the experience helped improve efficiency. "Onsite management helped greatly in narrowing and finalizing the project's scope," says Raymond Engineering architect and project manager Tom Hofmaier.

The existing Bloomington plant, which came onstream in 2001, features 48 modules for preparation, formulation, filling and utilities, with a combined filling capacity of 200 million units/year. Similar to the existing facility, the new expansion is designed so that formulation takes place on the second floor, with a layout that has people, material and equipment flowing to progressively cleaner areas. Also like the first plant, the new addition will feature duplicate capping, vial- and syringe-filling rooms, so that each activity can continue in one room while the other room is unloading.

Baxter already uses barcoding at the case level in Bloomington, but will soon extend its use to raw materials and finished goods. The facility is also benchmarking the use of smart tags for temperature profiles, critical to optimizing refrigeration for high-end drugs. "We eventually plan to use RFID," Karras says.

Moving to a new enterprise planning system from J.D. Edwards (recently acquired by PeopleSoft, Pleasanton, Calif.) will facilitate the tracking and management of materials throughout the manufacturing process, according to Karras. The platform features a production scheduling module that will monitor constraints and anticipate potential problems--a task that already requires six full-time managers at the plant. It will also be 21 CFR Part 11 compliant, Karras says, requiring password controls and maintaining data trails. Baxter is also using the compliance document-management system Qumass (Florham Park, N.J.), and plans to have a new laboratory information management system in place by the end of the year.

High Speed, Low Waste

On the back end, new filling equipment has raised speed and accuracy limits. In cartridge filling, Karras says, equipment has traditionally "overfilled" containers, using vacuum to remove excess--an extremely wasteful process when you're dealing with expensive biologicals costing hundreds of dollars a milliliter.

Instead, Baxter is now using a filling machine designed by the German equipment manufacturer Bausch+Stroebel (based in the U.S. in Clinton, Conn.) that fills each container up to 80% in the usual way, then uses a new sensor to control filling closely for the remaining 20%. So far, the new system has reduced filling line waste at the existing Bloomington plant from 5-7% to essentially zero. Karras expects it to allow Baxter to run bigger batches and reduce changeovers.

Baxter also will be the first pharmaceutical company to use a new high-speed syringe-filling system developed by Optima/Inova of Germany (U.S. offices in Green Bay Wis.). The new machine can fill 500 syringes per minute, well above the 300/min limit with existing technology. "We worked closely with Optima, and they increased the base machine's capacity by 50%, just by improving the unit's tub handling system--tubs are now handled in parallel rather than sequentially, improving throughput," Karras says.

Not only will the machine increase throughput, it will save Baxter capital and facility costs. "For the same output, we'd have had to install two 300-per-minute machines, which would have required two new cleanrooms and one additional gowning room," says Karras.

The new facility also will use machine vision systems developed by Frakes Engineering (Indianapolis) to track syringe production. Each of four machines is designed to count syringes in a nested configuration and generate a label containing both barcode and human-readable lot number, tub number and count information. The algorithm used for the system was designed by programmer Bob Emery, who worked on the vision system for the Mars Rover.

In addition to the Frakes system, Baxter uses automated systems for inspecting defects in their syringes and vials. Manufactured by Eisai Equipment Co. (Hackensack, N.J.), the machines sort out defects such as particles in the solution, glass and stopper defects. Each machine can inspect 300 syringes per minute, something that would take 70 people, at the rate of 4 syringes a minute each, to achieve.

As pharmaceutical companies continue to focus on cutting costs, Baxter expects more of them to demand one-stop capabilities from contract manufacturers, to avoid losing time during project hand off. "Our clients are facing tough decisions today--do we invest to upgrade or do we outsource," Anderson says. "Large clients still struggle to strike a balance between delegation and control." But for Baxter, he says, the challenge is different: "Can we expand fast enough?"

 

Fast-Track Construction Demands Front-End Clarity

One of the biggest challenges with Baxter's Bloomington, Ind., expansion has been the project's accelerated schedule. Construction began last summer, and the deadline for completion remains the fourth quarter of this year.

The overall site plan had to allow for a smaller scope now while providing space for a more rapid build-out of the remainder of the original scope, says Tom Hofmaier, project manager for engineering firm Raymond Engineering (Chicago). It also required that additional modular expansions be made without major disruptions to ongoing operations.

During the preliminary design stage, frequent meetings defined the scope, and the quality of data that Baxter provided early in the preliminary engineering design sped up the process, Hofmaier says.

"Weaving together two existing buildings, some 70,000 square feet of stick-built construction, and 37,000 square feet of industrialized modules has been challenging," Hofmaier says. Working with prebuilt modules complicated project logistics, dictating early design deadlines and unique approaches to utility supplies. Support buildings, for example, have been designed to allow site access and approach from at least two sides, Hofmaier says.

Modular construction is allowing Baxter's new manufacturing to be brought on line almost a year earlier than traditional construction would allow. Units fabricated at Pharmadule's manufacturing facilities in Sweden (above) are re-assembled an ocean away (below) in Indiana. Images courtesy Pharmadule.

 

Tec Transfer hOptimized

Baxter's Bloomington, Ind., production facility is closely tied in with its R&D and pilot plant operations, and associated staff of 100, in Round Lake, Ill. Typically, the feasibility of any new project is determined and managed by the R&D group, then a pilot study is done, and two or three experimental batches are run.

Once a formula is ready for clinical trials, Round Lake staff is sent to Bloomington to ensure proper tech transfer, according to Bill Anderson, Baxter Healthcare director of new ventures. "The secret is for R&D and scale-up teams to work closely together. Clients typically stay to learn more about the process, and good rapport ensures there are no conflicts," says Monte Wisler, manager of engineering for Baxter's medication delivery business. At any one time, he says, the R&D facility is handling formulations for 20 clients, involving some four to five projects per day.

The facility is modular, with formulation areas set up with long rows of isolators. VHF homogenizers in a range of capacities essential for Baxter's Nanoedge process are found throughout the plant. Both Class 100,000 and Class 100 isolators are used, with double HEPA filtration, and homogenizers with a range of capacities. This range is essential for all equipment at the plant. "Clients may have only one gram of material to work with initially, but results on the smallest level can be scaled up to the 1000 L per hour level," says Wisler.

Crystallization kinetics and models developed in-house are used to optimize pressure and temperature before any material is placed in a homogenizer. "Precipitation occurs very rapidly, so the kinetics are challenging," Anderson says, "but having a handle on the models is very useful when scaling up."

The facility is using a solvent removal prototype based on diafiltration supplied by GEA Niro, to augment centrifugation capacity. The new device will will offer tremendous labor savings, as operators won't have to remove supernatant, Anderson says

 

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