Injecting Excitement into Parenteral Drug Packaging

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Injecting Excitement into Parenteral Drug Packaging
April 2005
Jenevieve Blair Polin, Contributing Editor
Medical DeviceLink
Packaging for injectable parenteral drugs is changing its form and function.
Parenteral drug packaging appears to be evolving in three ways. First, alternative materials, specifically copolymers, are replacing glass in certain applications. Next, prefilled syringes are increasingly replacing vials. Finally, for many novel drugs, vials and syringes are giving way to unique drug-delivery devices that deliver the drug via routes other than injection. This article, in which we'll use the term parenteral to refer specifically to injectable drugs, will focus on recent developments in the first two areas. An upcoming article, scheduled for our May 2005 issue, will address novel drug-delivery devices and their packaging.
FROM GLASS TO COPOLYMERS
Borosilicate (type I) glass has always been the standard material for parenteral drug packaging. It is easily sterilized and widely available, and it has low reactivity, high clarity, and excellent barrier properties. What, then, is the appeal of a plastic alternative?
While it has always been considered highly nonreactive, glass contains trace amounts of alkali ions that can be leached out by some solutions, causing a pH shift. In the past, this effect has been considered negligible, except for unbuffered solutions such as sterile water-for-injection, but it has an impact on some sensitive new drugs.
Furthermore, some proteins adsorb to glass. "A key concern with protein adsorption is that it can lead to protien denaturation where the molecule loses its three-dimensional structure and forms partially unfolded intermediates," explains Thomas Petzel. He serves as global marketing and sales manager, toner and injection molding applications, Topas COC, for Ticona (Florence, KY), the technical polymers business of Celanese AG (Kronberg, Germany). Chemical degradation and protein aggregation can follow protein denaturation, he adds.
Robert Hormes, a marketing and sales manager for Schott Forma Vitrum's Competence Center Coating, Pharmaceutical Packaging, says that protein adsorption to glass happens within hours. Schott Forma Vitrum is a world leader in the manufacture of pharmaceutical glass with U.S. headquarters in Lebanon, PA. "The common opinion is that a monolayer of protein is built on the surface, so the adsorption reaches a state of equilibrium quite quickly," Hormes says. "But beyond that, the adsorbed proteins could degrade due to being bound to the glass, and this could help to degrade proteins in the solution, too. This could further decrease the concentration of active protein in the solution." He adds that in former times, bovine serum albumin was added to formulations to saturate the potential binding sites and to keep the active ingredient off the surface. Given the emergence of bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, this is no longer the method of choice, he explains.
Previous generations of plastics were no match for glass in terms of sterilizability, clarity, barrier properties, or leachables and extractables, but cyclic olefin copolymers have changed that balance.
Ticona's Topas COC (cyclic olefin copolymer) is converted into vials and syringes by Schott Forma Vitrum and into vials by Alcan Packaging (Millville, NJ). Topas is also a component in multilayer vials from Owens-Illinois (Toledo, OH). At the Topas COC International Conference on Pharmaceutical Packaging in April 2004 in Oberhausen, Germany, Schott presented data from a University of Munich study showing better recovery of two proteins (bovine serum albumin and interferon-2a) from Topas COC than from type I glass.
Schott is also addressing the pH shift caused by leached alkali ions from type I glass. "The pH shift in water-for-injection in glass, for instance, is a well-known phenomenon," says Guy Sheets, director of marketing and sales, North America, for Schott North America's pharmaceutical packaging division. "Water-for-injection is a very aggressive medium. However, parenteral packaging materials have been developed to minimize the effect," he adds.
Schott offers two solutions: TopPac ready-to-fill COC syringes and vials made of Ticona Topas COC material and the company's Type I plus, a coating technology that the company's Web site says "drastically reduces chemical interaction between your product and the glass container." The coating is an ultrathin layer of silicon dioxide on the container's inner surface, which the company says reduces "loss of active component due to adsorption, degradation, etc."
The Schott Type I plus products are produced by PICVD coating technology, where a pure SiO2 surface is deposited on the inner surface of the container, explains Hormes. This silica surface minimizes the chemical influence of the glass. "This is the reason why we recommend silica-coated containers for R&D of new drugs. You can simply switch off the chemical influence of the glass to the developed formulation," he says. The PICVD technology can be used on different container formats (vials, syringes, or cartridges) and materials (glass, plastics, etc.).
At the Oberhausen conference last year, Boehringer Ingelheim Pharma GmbH & Co. (BI; Ingelheim, Germany) announced the successful launch of a pharmaceutical product prefilled in Schott TopPac COC syringes. The product is a syringe filled with water-for-injection for use as a diluent for reconstitution of a lyophilized product. Because the syringe is part of a kit for use in medical emergency situations, Alexander Haag, a manufacturing specialist in BI's manufacturing science group, told the audience, break resistance and long shelf life were particularly important.
The TopPac syringe has also been designed to meet the company's other process requirements, which include low water-vapor permeability, high transparency, scratch resistance, and the ability to withstand final steam sterilization. Two of the three available grades of Topas?6013 and 6015, but not 8007?withstand steam sterilization.
BD Medical-Pharmaceutical Systems (Franklin Lakes, NJ) this year expanded the range of sizes in which it offers BD Sterifill SCF, a plastic prefillable syringe made of a proprietary BD Crystal Clear Polymer. "We had only offered 20 and 50 ml. This year we added 10 ml, and later this year, we plan to introduce the 5-ml version," says Glenn Thorpe, BD's director, marketing and business development.
Because of the way glass containers are formed, the walls are relatively thick. These characteristics put an upper limit on the size of a glass syringe. Baxter Healthcare Corp. (Round Lake, IL) recently announced the availability of ClearShot prefilled copolymer syringe technology (a trademark of Baxter International Inc.) for development of prefilled parenteral syringes in sizes ranging from 1 ml to 10 ml, says Jennifer Ikeda, director, program management, BioPharma Solutions, for Baxter.
"We attain a high level of accuracy and repeatability of the dimensions by injection molding with a high-quality resin," Ikeda adds. This dimensional accuracy, she says, enhances "the repeatability of closure fit and delivered volume. "We are developing relationships with pharmaceutical companies to put their molecules into this packaging," says Ikeda.
ClearShot syringes are injection-molded, sterilized, and filled in a continuous barrier-isolator in-line manufacturing process in Baxter's Cleveland, MS, facility. This just-in-time system abbreviates the supply chain, obviates warehousing a supply of syringes, and eliminates the potential for contamination by human intervention. The limitation, of course, is that pharmaceutical manufacturers who want this packaging technology must partner with Baxter to have their product filled and finished.
ClearShot syringes are not supplied as components to other contract packagers or to pharmaceutical manufacturers who fill their own product in-house.
Another material option comes from Zeon Chemicals (Louisville, KY), which offers Zeonex 690R cyclo olefin polymers (COPs) for syringes as well as vials. Zeonex features low permeability as well as low interaction with medicines due to its hydrophobic property. Additional product properties include moisture barrier and impact resistance. The material is compatible with steam, electron beam, and EtO sterilization. The firm adds that the transparent material is lighter and less brittle than glass.
FROM VIALS TO PREFILLED SYRINGES
On the other side of this equation is Baxter's BioPharma Solutions business (Bloomington, IL), a major contract manufacturer and packager, where Michael Akers, PhD, is director, pharmaceutical research and development.
Akers describes the life cycle of some injectable drug products, explaining how and why packaging changes occur. "In early development, there are concerns about not only stability but also sterility assurance, and it's sometimes easier to start out with a freeze-dried product," he asserts. "If the product is in the solid form, the potential for contamination is less, and of course, stability is usually better for drugs in a solid state than drugs in a solution state."
Therefore, Akers says, many companies need to lyophilize a product in early development, then proceed to clinical trials and launch. "If it's successful, then people will start looking at line extensions," he says. "Now they're going from a solid to a solution dosage form, and that's where you see people interested in going to the prefilled syringe. If you can formulate a product and have it in solution, even if you have to refrigerate it, a stable solution is still preferable over any other injectable dosage form. They're not only going to have a drug product as a solution, but it's going to be in a more-convenient package."
All the syringes the Bloomington facility currently fills are glass, and many