High-Barrier Materials for Blister Packaging
Blister flim and foil converters are making high-barrier formulations more affordable and easier to process, enabling drug makers to package the latest generation of lifesaving drugs safely and effectively.
Healthcare is bustling with a whole new generation of drugs that promise to treat or keep at bay many of today's most threatening diseases. Joining these are other new drugs designed to treat chronic conditions to make life a lot more comfortable for millions of patients. To get these drugs to market quickly, drug makers are increasingly turning toward high-barrier blister packaging materials, either to increase their chances of passing packaging stability tests or simply because the drug is so moisture sensitive that it needs the ultimate in protection. "The trend continues for blister packaging with higher moisture barrier," says Kent Sides, business unit manager for pharmaceutical films at Klöckner Pentaplast of America Inc. (Gordonsville, VA).
To meet such demand, many converters are devising new high-barrier material combinations and versions. Some new products provide barrier at prices more affordable than traditional products, while others offer enhanced capabilities that make high-barrier blister use more attractive than before.
PUSH FOR HIGH BARRIER
To meet requirements established by the International Conference on Harmonisation (ICH), a tripartite effort involving the U.S. FDA and regulatory authorities from both Europe and Japan, drug makers must perform tests that determine a package's ability to keep a drug stable throughout its shelf life. Known as stability tests, the tests involve subjecting packaged drugs to specific temperatures and relative humidity (RH) levels that mimic storage, shipment, and use conditions. The temperature and RH testing levels depend upon whether companies perform long-term, intermediate, or accelerated aging tests (see Table I, below).
|Study||Storage Condition||Minimum Time Period at Submission|
|Long Term||25ºC ± 2ºC/60% RH ± 5% RH||12 Months|
|Intermediate||30ºC ± 2ºC/60% RH ± 5% RH||6 Months|
|Accelerated||40ºC ± 2ºC/75% RH ± 5% RH||6 Months|
|Table I. Requirements set forth by the International Conference on Harmonisation in October 1999 for stability testing of new drug substances and products.|
Because stability tests, even accelerated aging ones, take several months, companies want to maximize their chance of passing the tests and therefore meeting product launch deadlines, so they often employ high-barrier materials from the start. Says Nic Hunt, global product director for Rexam Medical Packaging (Mundelein, IL): "The increased demand for quick time-to-market for new products will see the use of higher-barrier materials to ensure that the accelerated test conditions designed by ICH are satisfied."
As a result, despite the costs of high-barrier pharmaceutical materials like PVdC-coated PVC, Aclar, and cold-formed foil, these materials are in great demand. "High-barrier materials get new pharmaceuticals to market faster," explains Ulrich Frauchiger, executive director of Perlen Converting AG (Perlen, Switzerland). "There is no use taking a risk with lower-barrier materials."
According to R. Michael Cain, sales and marketing manager for Tekni-Films (Flemington, NJ), PVdC can increase anywhere from four to nine times the barrier properties of standard PVC film. In the decades since PVdC's introduction to pharmaceutical packaging in the 1960s, many drug manufacturers have been able to package solid oral-dosage drugs successfully.
Such success didn't come easily, though, says Cain. "This improvement in moisture protection did not appear without significant disadvantages of its own. Though PVdC is an emulsion coating and thus is very economical, the machinery used to thermoform the PVdC/PVC film caused pitting of metal surfaces at a rapid rate. Additionally, prolonged exposure to high temperature altered the crystalline structure of the coating. This expansion reduced the barrier of the film in certain tropical environments."
Over the years, converters have worked to iron out these problems by experimenting with different coating weights and machinery modifications. For instance, in 1999 Klöckner opened a coating and laminating facility called Klöckner Barrier Films. Built in less than one year, the $10 million line doubles the capacity of the plant to produce PVdC-coated and Aclar-laminated barrier films for moisture-sensitive pharmaceutical products. The new line at the facility complements Klöckner's existing line, and it is being used for customer orders as well as for producing prototypes for experimenting with new material formulations. The coating equipment, which can output 90 to 100 meters of film per minute, can be used to produce various PVdC coating weights for PVC.
In terms of aiding drug makers with finding the right barrier, Klöckner's new capability enables customers to experiment with different coating weights during stability studies. For instance, if a firm has already had success with PVdC with other products or has its equipment set up to run PVdC, it may want to put separate PVC films with different PVdC coating weights up on stability tests simultaneously.
Perlen Converting (Hockessin, DE) has made some significant investments in the formulation of PVdC. A few years ago the Switzerland-based converter invested in a four-head coating system called the Explorer that keeps to a minimum the number of times the PVC passes under the PVdC coating heads. "If you use a system with only one or two heads, the material has to pass through the machine a number of times in order to achieve the desired coating weight, and the material could shrink after several passes," says Perlen's area sales manager Dieter Feldberg. He adds that such shrinking could affect machinability.
To reduce the exposure of PVdC to extended cycles, Rexam has developed a special coating system. High coat weights can now be applied at each coating station, says Hunt.
In 1999, EVC Rigid Films (Kensington, CT) opened a state-of-the art coating line in Botzingen, Germany. The new line coats PVC with PVdC at accelerated speeds and can handle wider web widths.
"We also calender and coat materials in this one location," explains sales manager Gene Corcoran.
Recognized as a premium film for pharmaceutical blister packaging, Aclar surpasses PVdC in terms of moisture barrier. According to Cain, materials laminated with polychlorotrifluoroethylene (PCTFE), the chemical name for Aclar, offer barrier properties up to 50 times greater than that of PVC, which is unattainable with PVdC-coated products. Aclar films are composed of homopolymers or copolymers of PCTFE laminated to PVC film or other thermoformable substrates for sealing to foil lid stock as well as for blister card rigidity.
But such high barrier comes at a price. "Fluoropolymers demand significantly higher prices," says Cain. To make Aclar more affordable, Honeywell International (Morristown, NJ), the producer of Aclar, offers Aclar Cx, a downgauged version of its high-barrier Aclar. Efforts with various converters include Klöckner's Pentapharm Aclar 130/02 films as well as a homopolymer Aclar line by Tekni-Plex.
Sandra E. Luciano, healthcare market development specialist for Honeywell, points out that it can cost millions of dollars a day to delay a pharmaceutical product launch if the barrier of the blister package is compromised, so drug companies should really focus on selecting the right material for the product. And Honeywell's healthcare team is set up to help them. "Our expertise allows us to engineer solutions to meet or exceed the needs of the customer," she explains. "Our Healthcare Applications Lab in Linden, NJ, allows us to recreate a laminate, engineer a new laminate structure, and provide form-fill-seal machine expertise on our Klöckner CP2."
In addition, says Luciano, Honeywell's lab has several Mocon units for MVTR flat and blister testing as well as three humidity chambers that allow the firm to conduct testing at accelerated and real-time conditions.
Just as large-scale production facilities for it are being completed, a cyclic olefin copolymer (COC), brand-named Topas by its maker Ticona GmbH (Frankfurt, Germany), has found its way into commercial pharmaceutical applications. Bayer recently employed the new polymer for its relaunch of Aspirin in Indonesia (see the story on page 42).
Topas COC can be extruded into high-quality film and sheet in all customary production processes. Ticona is currently building the world's first commercial-scale COC production plant in Oberhausen, Germany, with an expected annual capacity of 30,000 tn. The plant will come on stream and begin production in September 2000.
Cain likens COC's moisture protection to that of PVdC. "This new material, made up of the same chemical elements as polyethylene and itself a polyolefin, generally provides a moisture barrier level equivalent to PVdC's." Another positive factor is that COC thermoforms similarly to PVC without the need for special tooling.
Rexam has decided to coextrude COC films. This process allows the direct conversion from raw resin granules to the finished product, reducing handling.
Cold-formed foil continues to be the best blister material in terms of barrier properties, and its use is rising. Ernie Gehlert, executive vice president of Gemel Precision Tool Company, Inc. (Ivyland, PA), says that drug packagers are selecting more and more foil in order to extend the shelf life of their products.
Burt Zirin, president of Constantia Packaging (Barrington, IL), both a converter and a manufacturer of foil for pharmaceutical applications, agrees. "Drug makers are choosing foil to meet the packaging needs of worldwide markets," he says.
Hueck Foils LLC (Wall, NJ) is experiencing a similar increase in demand. "For something as important as a new product launch, cost is important, but packaging the product right from the beginning is paramount," explains David Sciubba, healthcare sales manager. He adds that his firm is getting requests for smaller runs, and that Hueck has established a quick turnaround program that keeps material in stock to provide greater flexibility.
Pharma center shelbyville (Shelbyville, KY) has recently expanded, adding a laminator and slitter and a new building with more than 20,000 sq ft, which will more than double al group wheaton's North American pharmaceutical flexible-materials capacity for producing Formpack cold form aluminum base material along with blister lidding. According to pharma center shelbyville's Tim Saarinen, the expansion is the result of increased demand for high-barrier packaging in the pharmaceutical industry. "We offer services that include modeling the performance characteristics of the Formpack for the customer's application and generate the ideal tooling configurations by working with the pharmaceutical company's package-engineering groups. This helps companies save on packaging costs."
About three years ago, Bayer AG (Leverkusen, Germany) decided to relaunch its tried-and-tested painkiller Aspirin in Indonesia and make it one of the leading products in the local analgesics market. However, the region's climate, which is extremely hot and humid, places extreme demands on a blister film's barrier against water vapor. But Bayer couldn't abandon its use of blisters, because local analgesic consumers often preferred to purchase tablets individually.
Consequently, Bayer's Joachim Zander, in charge of international brand management of aspirin, needed to develop a new package with the following requirements:
Zander decided to stay with blister packaging, which could meet these requirements and would be less expensive than sealing the tablets between two layers of aluminum foil. Moreover, the technical complexity of blister packaging and the processing knowledge and capital required for its manufacture offered effective antidotes against product piracy.
Bayer held comprehensive trials and tests comparing a number of different plastic films, including the new Topas, a cyclic olefin copolymer (COC) made in Germany by Ticona GmbH and available worldwide from Ticona (Frankfurt, Germany, and Summit, NJ). Type 8007 for pharmaceutical blister packaging was the version evaluated in the trials. Topas COC is a copolymer of ethylene, a linear olefin, and norbornene, a cyclic olefin. Crystal clear, colorless, extremely pure, and completely halogen-free, Topas COC absorbs virtually no moisture, provides an effective barrier against water vapor in films as thin as 100 µm, and is resistant to hydrolytic degradation.
The glass transition temperature of Topas COC is about 80°C, above which the material begins to soften. At temperatures above 110°C, the shear modulus drops to 20 MPa, allowing the film to be thermoformed within a temperature range of 110 to 130°C, lower than that of any other transparent film, and thereby shortening cycle times. Blister packs manufactured from Topas COC are extremely uniform—the material is stretched uniformly and the thickness of the film remains constant, even in the case of blisters that are deep or that assume complicated shapes. This feature is important in applications requiring an optimum barrier against water vapor—excessive thinness in any part of the blister will inevitably lead to above-average water vapor diffusion. Because of these features and benefits, Zander chose the Topas COC film for the relaunch of Aspirin in Indonesia.
For the new Aspirin packaging, Zander chose a multilayer film with a total thickness of 360 µm. In water vapor diffusion tests performed at 38°C and a relative humidity of 90%, this film demonstrated a permeability of less than 0.1 g/m2/day, a value that cannot be economically attained with either polypropylene films or PVdC-coated PVC films, says Ticona's Ekkehard Beer, who is responsible for worldwide business development of Topas COC.
TOO MUCH BARRIER?
Of course, not every drug needs the highest barrier material around. In fact, some experts believe that many drugs, even newer ones, are overpackaged. To avoid overpackaging at Searle (Skokie, IL), John Bitner, manager of package design, has implemented a program that involves basing material selections for stability studies on careful evaluations of drugs during open-dish testing in order to determine a drug's critical moisture level. The work has helped the drug maker "move away from traditionally relied-upon forms of packaging that are proving to be overprotective and unnecessarily expensive." (To learn more about Searle's approach, see Scientific Approach Removes Guesswork from Package Design in the January 2000 issue of PMP News.)
The use of foil blisters, such as these from Constantia, is rising.
Nonetheless, your product may need one of the highest barriers around, either because it is highly water soluble or because it will be used in tropical regions. Your best bet is to share your drug's needs and your concerns about cost and length of packaging development time with blister material converters, most of which will have a range of barrier products available. EVC and Perlen, for example, offer PVC with PVdC coatings ranging in weight from 40 to 120 g. Converters may also be willing to do some of the thermoforming and sealing evaluations up front, as Klöckner does in its Blister Technology Center.