The Ins and Outs of Prefilled Syringes

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The Ins and Outs of Prefilled Syringes
May 2003
by Jenevieve Blair Polin, Contributing Editor
Pharmaceutical & Medical Packaging
Pharmaceutical companies are realizing the benefits of prefilled syringes and are exploring their use for a variety of drug products.
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.
PREFILLED SYRINGES VERSUS VIALS
Prefilled syringes offer several advantages over traditional packaging in vials.
Ease of use. Use of a prefilled syringe eliminates several steps that are required before use of a drug in a vial. If the drug is lyophilized, one of these steps is reconstitution.
Elimination of dosing errors. Prefilled syringes contain the exact deliverable dose desired. Pharmaceutical manufacturers overfill vials by up to 25%, especially if the desired dose is very small, to ensure that the user may withdraw the desired dose. This overfill of vials allows the possibility of dosing errors that are eliminated with prefilled syringes.
Increased drug supply and reduced waste. Elimination of the need to overfill reduces waste of product. This is a godsend for manufacturers of product that is in short supply, such as some vaccines. This is also true for product that is extremely costly to manufacture, such as biotech drugs.
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
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 (Lup