Pharmaceutical companies are realizing the benefits of prefilled syringes and are exploring their use for a variety of drug products.
by Jenevieve Blair Polin, Contributing Editor
|Image demonstrating the one-handed operation needed for the Ultrasafe Passive Delivery System courtesy Safety Syringes Inc.|
Within months, the number-one-selling low-molecular-weight heparin in the world, Lovenox (enoxaparin sodium injection), will be available in prefilled syringes equipped with a needle-safety device and a sharper needle. Gerhard Mayer, PhD, is director of marketing and business development for Becton Dickinson Pharmaceutical Systems (BD; Franklin Lakes, NJ), which supplies the prefillable BD Hypak syringes and the safety device to the drug's manufacturer, Aventis (Bridgewater, NJ), and manufactures most of the prefillable syringes used worldwide. He says this launch is just the tip of the iceberg for prefilled syringes. He and the other experts interviewed for this article agree that the U.S. market for prefilled syringes has been growing at a rate of about 20% a year for at least 5 years.
PRODUCTS IN PREFILLED SYRINGES
Prefilled syringes accommodate volumes that typically range from 0.25 to 5.0 ml. They are therefore best suited to products administered by subcutaneous or intramuscular injection. Three categories account for the bulk of prefilled syringes: antithrombotics, vaccines, and biotech drugs.
Antithrombotics. Lovenox belongs to the class of drugs known as antithrombotics, which account for about 40% of all prefilled syringes available globally, estimates Erik Miller, director of marketing for Safety Syringes Inc. (SSI; Carlsbad, CA). This class also includes Arixtra (Organon Sanofi-Synthelabo, West Orange, NJ), and Fragmin (Pharmacia Corp., Kalamazoo, MI). Vetter Pharma-Fertigung (Ravensburg, Germany) fills the Fragmin prefilled syringes, which are supplied integrated with the UltraSafe Passive Delivery System manufactured by SSI.
Vaccines. Vaccines are also increasingly marketed in prefilled syringes. While elimination of overfill is one factor driving the switch to the prefilled syringe, another is the removal of preservative thimerosol from vaccine formulations. With the removal of the preservative, says BD’s Mayer, “a move from a 10- or 15-dose vial to a single-dose prefilled syringe makes a lot of sense.”
Home-use products. Home use is also contributing to the growth in this market sector. “I would say home use is growing faster just because there are some terrific new therapies,” says Mayer. Many drugs for long-term treatment of chronic disorders, including treatments for rheumatoid arthritis and growth hormones, are good candidates for self-injection. Ease of use is paramount for products designed for patient administration.
One such drug is Copaxone, a treatment for multiple sclerosis marketed by Teva Pharmaceutical Industries Ltd. Teva originally marketed Copaxone as a lyophilized powder that patients had to reconstitute before administration. Then in spring 2002, Teva launched a liquid form (20 mg glatiramer acetate and 40 mg mannitol) in a prefilled BD Hypak syringe. The company previously supplied 32 vials of the powdered product as a 30-day supply to allow for reconstitution problems. With the prefilled syringes, the possibility of error is dramatically reduced, so this waste is unnecessary. Teva now need only supply 30 prefilled syringes as a 30-day supply, and the cost to the patient is unchanged.
DRUG COMPATIBILITY OF COMPONENTS
|Prefilled syringes, such as these from |
Baxter Pharmaceutical Solutions, help ensure accurate dosing.
Switching to a prefilled syringe presents some challenges for packaging engineers. In a prefilled syringe, a drug comes into contact with materials it does not encounter in a vial.
Silicone. Lubricity is of limited importance in a stopper for a vial. Just enough lubricity is needed to allow high-speed automated filling and closing equipment to position the stoppers in the vials, explains Don McMillan, vice president of marketing for the Americas region for West Pharmaceutical Services Inc. (Lionville, PA). The company manufactures elastomeric components for vials and syringes. In syringes, however, lubricity is essential for the proper functioning of the device when it is eventually used. “Whether used a few days or years after its manufacture, the plunger must move smoothly and easily,” McMillan emphasizes. Silicone is often the agent used to ensure lubricity.
“A vial has no silicone in it, and a vial stopper generally has no silicone on it,” explains Jeffrey Turns, senior vice president of Vetter Pharma Turm. “But when you go into a prefilled syringe, the drug is going to see some silicone. You have to ask, how much can the drug stand? How long does the drug stay stable? Does the drug aggregate? Does the drug change?”
Vetter, he adds, can vary the amount and type of silicone in a custom syringe for a client. To do so, the company uses a proprietary striping system. This system applies thin stripes of silicone onto the glass, which reduces the overall amount of silicone in the system.
“Silicone levels have been drastically reduced in syringes. As pharmaceutical companies look to minimize contact of silicone with their drug, you see a lot less particulate and cleaner systems,” BD’s Mayer says. BD manufactures a nonreusable prefilled injection device, the BD Uniject, with an elastomer- and silicone-free drug reservoir, which Mayer says reduces levels of particulate in the drug.
Elastomers. When it comes to elastomers, the most desirable option, says West’s McMillan, is to use the same formulation for the components in a prefilled syringe as was used for the vial stopper in the drug’s previous packaging. If that’s not possible, he says, West analyzes the drug product and suggests a possible formulation or develops a custom solution.
Proteins may potentially interact with elastomeric components over a drug’s long shelf life. It’s a challenge to combat this possibility, says McMillan. For a lot of the protein and peptide products, West laminates FluroTec, a conformable fluoropolymer film, onto the surface of the elastomeric components. This coating reduces protein adsorption and minimizes interaction between the drug and the closure.
Synthetics are replacing natural rubber, particularly latex, in elastomeric components, but McMillan warns that not all synthetics are suitable. The moisture vapor transmission and oxygen transmission rates of thermoplastic elastomers (TPEs), he says, exceed the rates needed for packaging of drug products. Lyophilized drugs are of course sensitive to moisture, and many drugs in liquid formulations are sensitive to oxygen. Therefore, for a vial stopper or a prefilled syringe plunger, currently available TPE formulations are not suitable, McMillan says. West is developing custom formulations of TPEs in which these properties are improved. “We’re very close to going to commercialization with a couple of products for a couple of pilot customers. It might be widely available in the next two to four years,” McMillan predicts.
Metals. “Some proteins may be averse to needles,” says Mayer. “In rare circumstances, they may not like the amount of steel or carbon that is in the needle itself. Although that’s not a lot of contact surface, it could set some of these things off.”
Manufacturers have therefore developed sophisticated closure systems employing a barrier between a preattached needle and the prefilled drug. Many prefilled syringes have no preattached needle and instead have a luer-lock closure.
OPTIONS FOR LYOPHILIZED DRUGS AND POWDERS
Making the transition from a lyophilized drug that requires reconstitution to a ready-to-use liquid formulation is the fondest wish of many pharmaceutical manufacturers, says Turns. This goal, however, is often hard to attain. “I talked to people in 1990 who thought they would have a liquid formulation in a year or two, and they still don’t,” he says.
Dual-chambered syringe. To extend the advantages of a prefilled syringe to manufacturers of lyophi-lized drugs, Vetter Pharma-Fertigung offers the Vetter Lyo-Ject dual-chambered syringe.
This system is a glass-barreled syringe with a stopper in the middle to serve as a barrier between the two chambers. Vetter lyophilizes the drug in the syringe itself and seals that chamber while the syringe is still in the lyophilizer. Filling equipment then dispenses the diluent into the remaining volume of the syringe and adds another stopper. On the distal portion is a screw-taper plunger rod that goes through the finger rest. As the user advances the plunger, it puts pressure on the diluent. The diluent then moves the center stopper into a bypass in the side of the glass. That movement allows the diluent to escape to the front chamber and reconstitute the lyophilized product.
“Some of these drugs may be administered in the emergency setting to patients who have had myocardial infarction,” says Turns, “so time is of the essence.” The prefilled syringe allows faster administration.
Two manufacturers of leuprolide acetate for depot suspension (Lupron, Eligard) employ variants of the dual-chambered syringe. This drug inhibits growth in certain hormone-dependent tumors. The new formulations, given once every four months, replace daily subcutaneous injections.
TAP Pharmaceutical Products Inc. (Lake Forest, IL) offers Lupron Depot– four month 30 mg (leuprolide acetate for depot suspension) in a prefilled dual-chamber syringe. One chamber contains lyophilized microspheres that, when reconstituted with diluent, become a suspension for intramuscular injection once every four months.
|The combination of West’s Clip’n’Ject connector mechanism, a vial, and the prefilled diluent syringe helps patients reconstitute drugs easily and accurately.|
For Eligard, Sanofi-Synthelabo Inc., the U.S. subsidiary of Sanofi-Synthelabo (Paris), uses the Atrigel drug-delivery system developed by Atrix Laboratories Inc. (Fort Collins, CO). Atrigel consists of biodegradable polymers that are mixed with the active drug and injected subcutaneously, then solidify. Sanofi-Synthelabo supplies this product in two syringes. One contains leuprolide acetate powder; the other is prefilled with the Atrigel polymer matrix. Before use, the user mates the two syringes, dispenses the polymer into the powder, and depresses the plungers sequentially for 45 seconds to obtain a uniform suspension. The user then draws all the suspension into one syringe and administers it subcutaneously.
Mike Duncan, vice president of technical operations for Atrix, describes the engineering challenges of this unique design. The male syringe, he says, is a stock BD Sterifill plastic prefill system with a male luer lock. “We needed to custom manufacture a female luer lock that would mate perfectly and not leak in the mixing process,” he says. The two syringes had to be made of the same resins.
“Furthermore,” he adds, “the polymer delivery system is terminally sterilized by gamma irradiation, so it also had to be gamma resistant. The mixing cycle involves 30 to 60 sequential plunger actuations, so we had to ensure that the product couldn’t leak back behind the plunger tips. It had to be a very tight feel on both the coupling and the back side.”
Prefilled diluent syringes. While dual-chambered syringe or dual-syringe delivery systems are elegant, they are not compatible with many lyophilized drugs. Alisa Wright is vice president of business affairs for Baxter Pharmaceutical Solutions (Bloomington, IN), the largest contract manufacturer of prefilled syringes in North America. “There are limitations on what you can do with most lyophilized product, “she says. “Most of the products that we freeze-dry must be put in a vial due to the volume of liquid filled and the corresponding lyophilized plug size but also to get the best freeze-drying characteristics, which in turn yields longer stability.” For these products, another option—the prefilled diluent syringe—offers some of the advantages of a prefilled syringe. Baxter and Vetter both offer prefilled diluent syringes.
West currently offers Clip’n’Ject, a reconstitution system consisting of a prefilled diluent syringe packaged with the drug vial, containing the lyophilized or dry powder drug.
Prefilled diluent syringes reduce the possibility that the customer will inadvertently use the wrong diluent or the wrong volume of diluent. “This cuts down on a lot of the handling errors that could occur,” Wright says. “Such handling errors may result in the loss of an entire vial or the patient getting the wrong dose or, the worst case, getting way more than they should have received. It’s not about manufacturing costs. It’s about safety.”
Many prefilled syringes just coming to market are sporting the latest accessory: a needle-safety device. The OSHA Needle Stick Safety and Prevention Act, enacted in 2000, gave an initial boost to sales of needle-safety devices, but home use of prefilled syringes is another impetus.
The idea is false that needle safety is not an issue for patients that self-administer injections using prefilled syringes. As Baxter’s Wright points out, patients who self-administer treatments for chronic conditions may carry syringes with them to use when they are away from home—at work, at restaurants, at hotels, in the mall—locations where there are no sharps containers and where the trash is handled by others. Even at home, patients are concerned about possible risk to children in the household. Therefore, the demand is growing for needle-safety devices not only on products destined for administration in OSHA-regulated hospitals or clinics but also on those marketed for home use.
SSI, which introduced the manually activated UltraSafe Needle Guard in 1999, now offers a passively activated design, the UltraSafe Passive Delivery System, which is integrated with Pharmacia’s Fragmin. (The integrated UltraSafe/Fragmin product has been on the U.S. market since August 2002). SSI offers the UltraSafe Passive Delivery System to other users and can accommodate a broad range of syringe sizes and staked or luer lock/slip needle configurations.
“We believe that the UltraSafe Passive Delivery System offers the highest level of compliance,” SSI’s Miller says, “because as long as the clinician administers the full dose of product, he or she can be assured of safety guard activation with no thought or further action required. When the plunger bottoms out, the syringe slides back into the body of the device, and the needle is covered by the guard portion of the device. Our market research supports the belief that clinicians want needle safety and ease of use. The UltraSafe Passive Delivery System maintains current technique, thus it is familiar and requires little or no training.” SSI’s current customer base includes Abbott, Amgen, Bayer, Pharmacia, and Ortho. The UltraSafe Passive Delivery System will be integrated with a European pharmaceutical prefilled syringe and launched in 2003.”
BD supplies the BD Preventis safety device that Aventis is using on Lovenox prefilled syringes, the largest-selling prefill therapy in the United States. The company offers BD Preventis as a stock item for use with BD Hypak prefilled syringes. BD designed and manufactured both the syringe and safety device, ensuring that they work together optimally as a system, both for the pharmaceutical company’s processing needs and for end-user safety and ease of use.
West offers a captured-needle version of its Clip’n’Ject prefilled diluent syringe. In this design, a safety device that contains the syringe mates to the vial. When the user withdraws the syringe after reconstituting the drug and drawing it back into the syringe, the needle remains shrouded within the safety device. The user may then attach a new needle for drug administration.
|Increased demand for the BD Hypak syringe drove BD to open a new facility.|
In January of this year, TAP announced the availability of Lupron Depot packaged with an integrated needle-safety device, the LuproLoc. Specialized Health Products International (SHPI; Bountiful, UT), a manufacturer of needle-safety devices, custom engineered this device for TAP. Mark Ferguson, SHPI’s director of product development, says the device is a modification of SHPI’s FlexLoc design, a manually activated folding plastic needle-safety shield that is advanced over the needle by the user following the use of the syringe. The company’s safety needle devices for prefilled syringes are suitable for virtually any syringe, particularly custom syringes with or without stakes needles.
Dennis Kim, TAP’s manager of packaging development, says the syringes are manufactured, sterilized, and filled in Japan. Secondary packaging and primary labeling, however, occur in the United States. It is during this secondary operation that the LuproLoc is integrated with the syringe. Ensuring that the devices could be attached without compromising product sterility was essential, as was developing a design that would work with the existing syringe.
“We were unable to use a snap fit, because that would have required us to change the syringe,” Ferguson relates, “so we opted for a spin welding process.” TAP added a rotary table that incorporates a spin welder (Branson Ultrasonic Corp., Applied Technologies Group, Danbury, CT) into the packaging line.
Choosing a material for the safety device was not easy, either. “We needed to find a resin that had a low melt index and good injection-molding properties and was compatible with the resin of the syringe hub,” Kim says. “Fortunately, Branson and SHPI had experience in this area.”
Many suppliers are adding capacity to accommodate market growth.
Wright says Baxter currently has about 120 to 130 million units of capacity and is expanding that significantly. By the end of the year, she says, Baxter will have three high-speed syringe fillers in operation.
Turns says Vetter, which is an FDA-approved site for prefilling syringes in Ravensburg, Germany, commissioned its latest two filling suites just this year, which added approximately 75 to 80 million units. “With what we have in place, we can make around 300
million pieces a year. Just last month we began construction in a third facility to be completed and making FDA-approvable product in 2007,” he adds.
BD just built a new BD Hypak facility, located in Columbus, NE. “We have two other large plants: one in France, one in Mexico,” Mayer says. “These plants, using the same manufacturing technologies, can operate virtually independent of one another and are designed to meet world demand from multiple locations.”