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| The
Evolution of Parenteral Drug Packaging
Newer configurations and materials expand the options
for packaging parenteral products. Prefilled syringes are a fast-growing alternative to conventional glass vials and stoppers for packaging parenteral drugs (see “The Ins and Outs of Prefilled Syringes,” PMP News, May 2003). All prefilled syringes on the U.S. market to date are glass. New plastic alternatives may soon make this packaging approach possible for manufacturers of a wider range of sterile products. These new plastics, called cyclic olefins, are manufactured by Ticona, the technical polymers business of Celanese AG (Summit, NJ), and Zeon Corp. (Louisville, KY). Daikyo Seiko Ltd. (Tokyo), the affiliate of West Pharmaceutical Services (Lionville, PA), buys the resin, which is used to make a variety of sizes of vials and silicone-free prefilled syringes. West is the exclusive sales and marketing partner for Daikyo Resin CZ (COP) in the United States and in Europe. Schott Pharmaceutical Packaging (St. Gallen, Switzerland) converts Ticona’s cyclic olefin copolymer, Topas COC, into monolayer vials and syringes. Owens-Illinois (Toledo, OH) incorporates Topas COC into multilayer injection-blow-molded plastic vials and bottles. Glass or plastic? “The barrier properties of glass make it the ideal package for parenteral products,” says Glenn Thorpe, director, marketing & business development, BD Medical-Pharmaceutical Systems (Franklin Lakes, NJ), a leading syringe manufacturer. Glass has always been considered less reactive than plastic with parenteral products. It also has lower levels of leachables and extractables. For some products, however, that equation has changed. “Some newer kinds of drugs have problems with glass,” says Thomas Petzel, marketing and sales manager for Topas COC. “Glass can contain free alkali oxides and traces of metals. Topas COC has a very inert surface and shows no ion or metal release.” “A product that has a high pH potentially will leach alkali components out of glass that could result in either incompatibilities or glass laminate issues,” agrees Michael Akers, PhD. Akers is director, pharmaceutical research and development, for Baxter Pharmaceutical Solutions (Bloomington, IN). He also teaches classes on aseptic processing through various organizations. “All primary package components contain constituents such as ingredients, impurities, contaminants, and degradants that have the potential to accumulate in the product. These constituents are typically referred to as extractables or leachables, although they may also include compounds present on the surface of the packaging that simply solubilize in the product,” points out Dana Guazzo, founder of the consulting firm RxPack LLC (Bridgewater, NJ). Guazzo is an expert on primary package development. Glass and various forms of plastic exhibit very different leachables/extractables profiles, she adds. “The question is: what is your product sensitive to, and can it remain stable when stored in the packages you feel you need to use. And of course the safety of these package constituents must also be evaluated in terms of the risk to the patient population given the route of administration and the duration of the product use.” In the analytical lab,
Schott TopPac syringes are checked under pressure for leakage. “Now we have products in which just a tiny amount of a metal or an antioxidant, a stabilizer, or even a manufacturing or processing contaminant deriving from the packaging can cause real problems with product stability,” Guazzo emphasizes. “Because of the complicated nature of a protein, it is a rule of thumb that proteins interact with almost anything,” Akers explains. “They will interact with any kind of surface or chemical.” If the protein is stressed—by heat or agitation or some chemical substance—the protein may unfold, exposing its hydrophobic amino acids. “That’s when the protein becomes denatured. It forms particles, it gels, it is like an egg that coagulates,” Akers says. “The adsorption effects with proteins and peptides are far less with CZ resin than with glass. We’ve also seen where it makes drugs stable that wouldn’t be stable in glass,” says West’s John Paproski, vice president, product development, pharmaceutical systems. Other products for which cyclic olefin containers are excellent candidates, Petzel adds, include solvents, biotechnical products, contrast media, and toxic products (because of the reduced risk of breakage). Plastic components cannot withstand the heat of the depyrogenation tunnels used to sterilize glass in place immediately before filling. Their manufacturers therefore typically presterilize them. “The question then is, how do you transfer large amounts of sterile plastic into a sterile block? How do you maintain sterility?” Akers asks. It can be done, but not easily. Prefillable vials and
ampules made of Ticona’s Topas COC can protect valuable pharmaceutical
substances. Guazzo adds a cautionary note about the choice of glass or plastic for parenteral packaging. “What is the availability going to be of that plastic down the road?” she encourages her clients to ask. “Because there are various formulations of glass manufactured by several major suppliers that all meet USP Type I requirements, long-term availability of components is less of an issue. The USP standardization of Type I glass makes it easier to make any necessary supplier changes even after market approval. With a few exceptions, compendia standardization of plastics for parenteral product packages does not exist. Therefore, each potential supplier’s plastic components must be demonstrated to be compatible with your product through extensive stability studies. You have to consider the possibility that if something changes in the way the plastic resin is made, or even if the suppliers of some of the ingredients change, a considerable amount of work and time may be required to qualify that new variable.” FDA regulations are no barrier to plastic Rick Friedman says the inability of plastic containers to withstand the heat of depyrogenation tunnels is not a deal breaker from FDA’s viewpoint. Friedman is team leader, guidance and policy, Office of Compliance in FDA’s Center for Drug Evaluation and Research. “Especially in recent times, FDA has been applauded for considering advanced technology and recognizing the advantages of modernization. This latitude permits companies to use various sound approaches to achieve compliance,” Friedman says. He refers to FDA’s revised draft aseptic processing guidance as an example of this open-minded philosophy (see sidebar, page 68). “There is nothing in the draft guidance that would preclude use of novel container-closure systems as long as they are found through our application review and practical day-to-day implementation of good manufacturing practices to be safe and robust systems. We are open to various approaches to assuring a sterile, particle-free, and (where applicable) pyrogen-free drug product.” FDA, Friedman says, encourages pharmaceutical manufacturers to investigate “how well plastic packaging components are protected from the point where the product is manufactured and packaged by the vendor all the way to the drug manufacturer. This of course does not apply to form-fill-seal operations, as all those three processing steps occur within seconds of each other. But for other plastic packaging components, which will not be dry-heat depyrogenated, a company may want to pay particular attention in their audits of the vendor to make sure that they hold the plastic component, once formed, in good environmental conditions to minimize presterilization bioburden, and that they protect it so that it is not subjected to a low-quality environment in which it might be objectionably contaminated.” Hypak syringes from BD
Medical-Pharmaceutical Systems can be prefilled for self injection. Silicone A far more likely reactant than traces of alkali or metal leachates in glass container-closure systems is silicone. Glass syringes, unlike glass vials, are siliconized to enable plungers to glide smoothly through them. The silicone applied to the glass syringe, however, is polymerized to a relatively inert substance by the heat of depyrogenation. The silicone oil on elastomeric parts is free to interact with product. “A lot of our customers are anxious to get out of silicone,” says West’s Paproski. Daikyo Seiko combines CZ resin with FluroTec-coated stoppers to produce a silicone-free syringe. “To our knowledge, it’s the only silicone-free syringe system that meets the needs of the injectable market,” Paproski says. Later this year, West will introduce vial stoppers with a silicone-free coating called TrakStar. TrakStar will provide vial filling line processability without silicone. Because silicone is typically present on the glass, prefilled syringe fillers are often concerned about minimization of silicone rather than total elimination. TrakStar benefits those users by eliminating the silicone needed to feed the plungers. “The customers that I’ve worked with have been more concerned with knowing consistency of silicone content than with eliminating silicone,” says Guazzo. “They want to quantify it, understand how it is being applied and cured, and verify the amount available for product interaction. They want to make sure that what they see in their research studies and in their clinical studies is going to be typical of what the marketed product is going to see.” West Pharmaceutical Services’
FluroTec coating is used as a barrier between rubber stopper and drug product,
and in some cases, on the top of the stopper to enhance lyophilization processing.
Customization While prefilled syringes offer a leap forward in convenience for the user, in the hands of pharmaceutical packaging engineers their designs continue to evolve. One example is Humira (adalimumab), which was the most successful product launch ever for Abbott Laboratories (Abbott Park, IL) when it hit the market in 2003. This monoclonal antibody for the treatment of rheumatoid arthritis is supplied in a prefilled syringe customized for ease of use by patients with this crippling disorder. BD supplies the prefillable syringe, the plastic wings, and the oversized plunger. Another customer uses a modified BD Hypak syringe to forego the injection route completely. That customer is Wyeth Pharmaceuticals (Collegeville, PA), which in 2003 in cooperation with MedImmune Inc. (Gaithersburg, MD) introduced the FluMist vaccine for nasal administration. BD’s Thorpe explains that the device is a Hypak glass barrel with a nasal aspirator instead of a needle or luer lock at the tip. Basing the design on the Hypak body, Thorpe says, “simplifies the filling process and the regulatory process, and its economics are based on a large volume of existing capacity.” “We like to call them sprayers because those who are afraid of syringes may like the term sprayer more than syringe,” says Edward Smith, PhD, manager, package testing, for Wyeth. A further modification is
the dose divider. “This is an add-on component to the plunger rod,”
Thorpe explains. “It allows the user to deliver one dose, then remove
a clip and deliver another dose, because with most nasal products, you want
to give half in one nostril and half in the other.”
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