The Evolution of Parenteral Drug Packaging
Newer configurations and materials expand the options for packaging parenteral products.
Jenevieve Blair Polin
Prefilled syringes are a fast-growing alternative to conventional glass vials and stoppers for packaging parenteral drugs (see ï¿½The Ins and Outs of Prefilled Syringes,ï¿½ 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 Ticonaï¿½s 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?
ï¿½The barrier properties of glass make it the ideal package for parenteral products,ï¿½ 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.
ï¿½Some newer kinds of drugs have problems with glass,ï¿½ says Thomas Petzel, marketing and sales manager for Topas COC. ï¿½Glass can contain free alkali oxides and traces of metals. Topas COC has a very inert surface and shows no ion or metal release.ï¿½
ï¿½A product that has a high pH potentially will leach alkali components out of glass that could result in either incompatibilities or glass laminate issues,ï¿½ 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.
ï¿½All 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,ï¿½ 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. ï¿½The 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.ï¿½
|In the analytical lab, Schott TopPac syringes are checked under pressure for leakage.|
Why are potential package-product interactions receiving more attention now than in the past? The answer is the growing number of proteins and peptides used as therapeutics.
ï¿½Now 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,ï¿½ Guazzo emphasizes.
ï¿½Because of the complicated nature of a protein, it is a rule of thumb that proteins interact with almost anything,ï¿½ Akers explains. ï¿½They will interact with any kind of surface or chemical.ï¿½ If the protein is stressedï¿½by heat or agitation or some chemical substanceï¿½the protein may unfold, exposing its hydrophobic amino acids. ï¿½Thatï¿½s when the protein becomes denatured. It forms particles, it gels, it is like an egg that coagulates,ï¿½ Akers says.
ï¿½The adsorption effects with proteins and peptides are far less with CZ resin than with glass. Weï¿½ve also seen where it makes drugs stable that wouldnï¿½t be stable in glass,ï¿½ says Westï¿½s 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. ï¿½The question then is, how do you transfer large amounts of sterile plastic into a sterile block? How do you maintain sterility?ï¿½ Akers asks. It can be done, but not easily.
|Prefillable vials and ampules made of Ticonaï¿½s Topas COC can protect valuable pharmaceutical substances.|
ï¿½The traditional vial and syringe processing approach doesnï¿½t work for CZ,ï¿½ agrees Paproski, ï¿½because most glass is processed through vial washers and depyrogenation tunnels. That has been the challenge for the pilot customers we are working with to use CZ. In Japan,ï¿½ he adds, ï¿½many pharmaceutical manufacturers have developed processes to handle the material.ï¿½
Guazzo adds a cautionary note about the choice of glass or plastic for parenteral packaging. ï¿½What is the availability going to be of that plastic down the road?ï¿½ she encourages her clients to ask. ï¿½Because 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 supplierï¿½s 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.ï¿½
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 FDAï¿½s viewpoint. Friedman is team leader, guidance and policy, Office of Compliance in FDAï¿½s Center for Drug Evaluation and Research.
ï¿½Especially 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,ï¿½ Friedman says. He refers to FDAï¿½s revised draft aseptic processing guidance as an example of this open-minded philosophy (see sidebar, page 68). ï¿½There 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.ï¿½
FDA, Friedman says, encourages pharmaceutical manufacturers to investigate ï¿½how 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.ï¿½
|Hypak syringes from BD Medical-Pharmaceutical Systems can be prefilled for self injection.|
Transferring sterile components that cannot withstand extreme heat into aseptic processing suites or barrier isolators is not a new problem. West Pharmaceutical has offered prewashed stoppers for years through a process called Westar RS. Soon, however, the company will launch Westar RU stoppers, which will be not only prewashed but also presterilized. Thorpe says BD sees the same need. BD offers the TSCF package for safe transport of BD Hypak plunger stoppers into barrier isolators or RABS systems.
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.
ï¿½A lot of our customers are anxious to get out of silicone,ï¿½ says Westï¿½s Paproski. Daikyo Seiko combines CZ resin with FluroTec-coated stoppers to produce a silicone-free syringe. ï¿½To our knowledge, itï¿½s the only silicone-free syringe system that meets the needs of the injectable market,ï¿½ 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.
ï¿½The customers that Iï¿½ve worked with have been more concerned with knowing consistency of silicone content than with eliminating silicone,ï¿½ says Guazzo. ï¿½They 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.ï¿½
|West Pharmaceutical Servicesï¿½ 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.|
West also manufactures a FluroTec-coated plunger in Europe that offers some reduction in silicone levels. ï¿½It is configured in such a way that it evacuates the bottom of the concave end of the syringe barrel,ï¿½ Paproski explains. ï¿½The plunger tip has a FluroTec coating, and the elastomer ribs seal against the glass. Because the sealing characteristics are similar to what our customers are used to now, itï¿½s an easy adaptation for those who are already familiar with glass prefilled syringes and want improved performance. Customers get very good results with respect to extractables because of the characteristics of FluroTec.ï¿½ West has manufactured and sold this FluroTec plunger exclusively in Europe for almost two years, ï¿½but we believe a lot of it is working its way back to the States,ï¿½ Paproski says. He adds that when demand in the United States warrants it, West will no doubt transfer that technology here.
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.
BDï¿½s 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, ï¿½simplifies the filling process and the regulatory process, and its economics are based on a large volume of existing capacity.ï¿½
ï¿½We like to call them sprayers because those who are afraid of syringes may like the term sprayer more than syringe,ï¿½ says Edward Smith, PhD, manager, package testing, for Wyeth.
A further modification is the dose divider. ï¿½This is an add-on component to the plunger rod,ï¿½ Thorpe explains. ï¿½It 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.ï¿½
When customizing a syringe, Smith advises companies to start early. Wyeth Global Packaging Services started testing the FluMist package design two-and-a-half to three years before product launch.