Promoting Dosing Accuracy with Prefilled Syringes
The mechanical toughness of COP from Zeon Chemicals allows intricate molding of large syringes.
Prefilled syringes have experienced increased adoption as their advantages are embraced for home use and in clinical settings. Wyeth Pharmaceuticals Inc. markets Enbrel (etanercept) in a prefilled syringe for home treatment of adult rheumatoid arthritis. (Enbrel is made by Immunex Corp, a division of Amgen.) The 50-mg/ml syringe system eliminates the need to mix the drug prior to injection and allows weekly injection by most patients, replacing two injections from 25-ml vials.
Besides being easier and faster to use, prefilled syringes support the delivery of accurate premeasured dosing, so medication errors are less likely than they are with vial-and-needle systems.
“The prefillable syringe is the ideal container for single-dose administration. The format has taken hold primarily in vaccines and in bio-tech drugs used by self-injectors, where companies are looking for ways to differentiate themselves in the market,” says Eric Borin, director of sales and marketing, BD Medical—Pharmaceutical Systems (Franklin Lakes, NJ).
Regulations and concerns about the preservative thimerosal have made the prefill a preferred container for vaccines. “Immunization schedules are starting to come close to the allowable limits of thimerosal in infant administration. Many vaccines have moved to preservative-free products that require the single-dose format,” Borin says.
“We see a strong movement to prefilled syringes from vials and ampules on new and existing products, with sustainable growth rate between 10 to 15%. In certain applications, companies are targeting development of liquid-fill formulations to reduce the additional time required to freeze-dry products,” says Patrick Grueninger, business development manager, North America, Schott Forma Vitrum (Lebanon, PA).
When doses are delivered premeasured in prefilled formats, overfill requirements are greatly minimized, representing a major cost savings to the pharmaceutical customer.
“Vials [are] sometimes [overfilled] by 20–30% to account for the difficulty of accessing the drug. With prefilled syringes, you can fill close to the exact amount and be assured the patient will have access to the full dose,” says Scott Young, director for CZ (Crystal Zenith) technology, West Pharmaceutical Services (Lionville, PA).
“Worldwide, 1.8 billion prefilled syringe units were sold in 2005, with a forecasted 15% compound annual growth rate,” says Young.
Prefilled syringes are designed as container-closure systems that maintain the integrity of drugs or diluents for a sustained period of time. Tip-end systems and plunger stoppers must be configured to prevent microbe ingress. Materials need to ensure that plunger stopper breakout and sustaining forces—forces that move the plunger down the barrel of the syringe—are sustained over the product’s shelf life, says BD’s Borin.
Enbrel is packaged in the BD Hypak SCF PRTC syringe, an option in the BD Hypak line of non-needle-based, prefillable glass syringes. GlaxoSmithKline (GSK; Research Triangle Park, NC) is also using the system for its recently approved prefilled Fluarix flu vaccine. GSK’s Tip-Lok product using the BD syringe is the first prefilled flu vaccine for people ages 18 to 64 offered exclusively in a prefilled syringe. It follows GSK’s adoption of the BD Hypak PRTC for delivery of hepatitis A and B vaccines.
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In the BD Hypak PRTC (plastic rigid tip cap) system, a plastic rigid cap houses a rubber rib-tip cap for sealing the syringe tip aperture. The rigid cap fits into a luer-lock adapter, ensuring proper tip-cap positioning onto the syringe tip. The plastic cap’s large surface area promotes safe, easy, and aseptic cap removal. In a research study commissioned by BD, 60 healthcare professionals rated the BD Hypak PRTC highest among competing products in attributes including closure stability, intuitive design, and ease of opening.
“BD Hypak PRTC minimizes the potential for contact of the user’s fingers with the syringe tip, when compared with rubber or elastomeric tip caps. The system is becoming the standard for luer-based syringes, and we expect the U.S. market to convert to that system almost 100% in the next two or three years,” Borin says.
Baxter BioPharma Solutions (Bloomington, IL) is the leading contract filler of the BD Hypak syringe, which BD provides in sterile, clean, and ready-to-fill (SCF) format for filling and finishing at Baxter’s Bloomington facility. “BD’s new micro- needle syringes will be in ready-to-use 100-count tub format, allowing us to use the same filling equipment used for the standard SCF syringes,” says Tom Polen, senior director of marketing, Baxter BioPharma Solutions.
In most cases, pharmaceutical companies send Baxter their active ingredient, for filling and finishing, in configurations such as in blister packaging with inserts. In some cases, drug companies handling filling internally have packaging constraints and will send their already-filled syringes for packaging,” says Polen.
“Customers with vial and prefilled syringe diluents increasingly are looking to kit their systems. We kit 80 packages per minute with our fully automated robotic kitting assembly line,” he says.
Polen says that needlestick-safety devices are among the systems that Baxter offers for safety in home use. For use with BD Hypak, it adds the BD Preventis needlestick prevention device to the syringe at a second campus facility, after inspection and quality control of the filled units. Baxter’s proprietary Bio-Set injection delivery system features a luer adapter on the vial replacing the standard metal vial crimp, for providing a needleless easy-to-use method for home- or clinical-setting drug reconstitution.
Schott Forma Vitrum offers ready-to-fill syringes for prefill applications. Syringes are fabricated, washed in a sterile environment, depyrogenated, siliconized, packaged in 100-unit and 160-unit tubs, and delivered in a sterile package to the customer. Glass syringes require EtO sterilization. Schott’s ready-to-fill TopPac COC (cyclic olefin copolymer) syringes are gamma sterilized. Stored by the customer, the syringes are guaranteed sterile, normally for two years, says Grueninger.
“Companies typically can achieve a cost advantage with ready-to-fill if they are doing fewer than 30 million pieces per year,” says Grueninger.
BD provides the BD Hypak SCF sterile, clean, and ready for filling in 100-count tubs.
Polymer-based prefillable syringes have to meet barrier requirements for product susceptible to water vapor and oxygen, feature suitable leachable and extractable profiles, and ensure overall sterility.
Cyclic olefins as alternatives to glass for prefilled formats are gaining attention because of the increasing prevalence of protein- and peptide-based drugs, which can adsorb or bind to the surface of glass syringes. These drugs are also more likely to be sensitive to leached components from glass and to chemicals derived from polysorbate surfactants.
Olefins such as COC and COP (cyclic olefin polymer) are relatively inert materials that minimize leaching of container components. In packaging of nonbuffered water diluents, they eliminate the pH shift caused by alkali leaching from glass. COC and COP provide glasslike transparency for assisting users in checking drug levels, quality, and particulate concentrations.
Glass’s fragility is an issue with high-viscosity drugs where there is an increased risk of breakage and contamination, says Brian Cail, business manager for new business development, Zeon Chemicals (Louisville, KY). Zeon Chemicals markets Zeonex, a COP material manufactured by Zeon Corp. (Tokyo).
“COP is an exceptionally clean polymer with excellent compatibility with protein- and peptide-based drugs. COP addresses the issues of glass leachables, and diluent pH shifts. Water permeation is extremely low, leading to the ability to store the drugs for long periods of time,” says Cail.
Cail says that COP is mechanically tougher than COC, minimizing breakage in the integrated molding of high-volume syringes used for contrast media. “The cyclic olefins have been talked about as alternatives in syringes, but COP is also appropriate for vials. We are studying applications in which COP is used to replace vials made of glass and other plastic materials,” he says.
BD’s Sterifill SCF prefillable plastic syringe is made of a proprietary crystal clear polymer. “The use of plastics in the marketplace is evolving. The stability and compatibility of our customers’ products will be the deciding factor as to what material is used,” says Borin.
Borin notes that prefilled plastic syringes have gained wide use in nondrug applications such as contrast media and imaging and viscoelastics. BD offers prefilled Flush syringes—the first syringes specifically designed for flushing applications for cleaning out catheters and IV lines. The BD PosiFlush saline syringe comes in four different volume sizes, with the same 10-ml barrel diameter, to comply with manufacturers’ recommendations for flushing with a 10-ml syringe. And they provide consistent tactile feedback to users.
“The market interest in COC syringes has been promising over the last several years, and with recent FDA submissions, we expect to experience continued growth in the future.
Schott has been working with a pharma company that plans to launch a line of products that will include prefilled TopPac COC syringes, says Grueninger. One of the products will be a reconstitution system with freezed-dried product in a vial and a prefilled COC syringe with water-for-injection. COC is used to prevent the pH shift that occurs when alkali ions leach from glass into a non-buffered water diluent.
“It has been demonstrated that there is no pH shift in the water diluent with COC,” he says. “We continue to make investments into our COC operation in Switzerland, which includes additional product offerings as well as expansions.”
Grueninger says that COC is an alternative to glass for drugs that extract and are degraded by leachables from glass such as sodium, potassium, calcium, and aluminum.
“With COC, you eliminate all known glass interactions. Bio-tech drugs are often constituted as high-potential proteins in low concentrations. The active ingredient concentrations are many times less, but you get the same effect, because the active proteins are so specific and powerful. With these drugs, you tend to see heavier interaction with glass,” says Grueninger.
Prefilled syringe vendors have focused on minimizing silicone used to facilitate plunger action in glass and plastic vials. Protein drugs have been found to be more susceptible than small-molecule drugs are to degradation from silicone oils.
Schott’s Type I Plus silicone-dioxide coating improves the stability of glass and polymaterials, inhibiting chemical interaction between product and package.
Type 1 Plus is a pure silicone oxide layer applied to the syringe or vial surface to generate low interaction and almost no extractables, Grueninger says.
“Some protein-based products will immediately coagulate in the presence of silicone. The Schott polymer coating and application process reduces the potential for product degradation by reducing the free silicone that interacts with the ingredients. The ability to coat the inside surface of the barrel will increase the oxygen barrier of COC,” he says.
“Many of the new bio-pharma drugs will aggregate at the silicone over time, reducing the stability of the drug and increasing supply-chain risk,” says Young.
The CZ Syringe System from West Pharmaceutical is a silicone-free syringe system. The syringe barrel is made of CZ, a proprietary COP formulation (Daikyo Resin CZ). With Daikyo’s FluroTec laminate on the patented syringe elastomer components, the syringe functions without silicone oil.
“The fluoropolymer laminate on the plunger and on the nozzle cap combined with the good dimensional characteristics of the CZ barrel [yields] gliding forces that are very comparable to syringes employing silicone,” says Young.
Companies are also beginning to use laminated pistons in glass and plastic syringe systems. “We have found that FluroTec lamination dramatically reduces leachables from elastomeric components. “By completely covering surfaces that touch the drug, the fluoropolymer coating reduces possible interaction of extractables from the rubber and the accumulation of leachables that can get into the drug formulation,” he says.
Young says the CZ Syringe is used in Japan for many prefilled applications, most notably with a major peptide product in a 1-ml syringe. “In this specific application, the customer is washing and sterilizing the syringe. U.S. companies want to receive the product ready to fill. We are currently sampling customers with a ready-to-use tub format we plan to launch this year. Syringes will be delivered sterile in 100-syringe formats that will work with customer’s aseptic-filling processes.”
The CZ resin has been adopted in the United States for a number of vial applications. Several cytotoxic drugs are also filled in the CZ vial. CZ Syringes are in stability trials with U.S. manufacturers and are being tested in conjunction with customers’ real-time aging studies without a drug product to test functionality and extractables,” says Young.
NEEDLE AND PIN RESIDUALS
Product can be degraded by tungsten residuals derived from glassforming processes that use heat-resistant tungsten pins to form the glass syringe’s luer cone. Plastic syringes injection molded without forming pins avoid the issue of crosscontamination from tooling materials.
Some “bio pharma customers are finding that tungsten extractables will cause aggregation of their protein formulations. They can’t use stakedneedle glass syringes where tungsten tools are used in the fabrication of the glass and leave a small amount of tungsten that reacts with the drug product,” Young says.
Tungsten contaminants derived from needles are also an issue. In prefill syringes where the stainless-steel needle is attached and always in contact with the product, tungsten residuals may initiate catalytic reactions with the drug product. Schott is developing a needle system that guards product from the element. The system physically separates the needle from the glass barrel during filling and storage. Before injection, the user mechanically links the needle to the barrel. Since the needle tip is stored dry, the system obviates the need for a rubber needle shield for closing off the tip.
“The rubber cap can reduce needle sharpness. Schott uses a polymer cap that minimizes or eliminates the conact between the rubber cap and needle. With this preassembled syringe-and-needle system, you can go right to injection and know that both the needle and syringe are sterile. Prototypes for industrial testing will be available this year,” Grueninger says.
Baxter is awaiting approval of the first drug packaged in its Clearshot copolymer syringe, having submitted a drug master file for the 3-ml container last summer and a Prior-Approval Supplement for Ondansetron injection USP in December.
“Ondansetron is a small-molecule drug that we currently offer terminally sterilized in a vial and a premixed bag. We have confirmed compatibility of the drug with both the Clearshot container and aseptic filling process, and are awaiting an FDA decision in the very near future,” says Polen.
Baxter’s integrated manufacturing process for the Clearshot syringe “completely changes the supply-chain paradigm for syringe manufacture and supply.” Glass syringes require three manufacturing lines for syringe manufacture, filling, and inspecting and packaging. In the Clearshot process, copolymer pellets enter the line where syringe barrels are molded, components sterilized, and syringes are aseptically filled under a barrier isolator, inspected, and finished. “With this integrated process, there are no lead times for ordering syringe components and you can provide just-in-time inventory,” Polen says.