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Stoppering Techniques for Prefilled Syringes
Prefilled syringes have gained popularity among patients and healthcare providers because of the convenience they offer. The dosage form has advantages for manufacturers, too. Packaging a drug in a prefilled syringe may help extend a product’s patent and distinguish it from competing products. In addition, prefilled syringes require much less overfill than vials (5–8% for prefilled syringes versus 10–20% for vials), according to Jörg Zimmermann, head of production at Vetter Pharma-Fertigung’s (Ravensburg, Germany) Langenargen facility. Reducing overfill spares the drug and decreases cost.
Two major stoppering techniques are used with prefilled syringes after filling is complete. The traditional, proven stoppering method is vented placement. In this method, a stopper is placed inside a tube that is then inserted into a syringe. A pin holds the stopper in place as the tube is removed from the syringe. The stopper then expands to fill the syringe diameter. This technique is widely accepted, repeatable, and locates the plunger precisely, according to Jeff Jackson, director of pharmaceutical-product management at Bosch Packaging Technology (Minneapolis, MN).
Vented placement sometimes smears the Teflon coating of newer stoppers, however. During inspection, “it can appear as though the drug may have gone up into the ridges of the plungers,” which would compromise the syringe’s sterility and cause a false reject, says Jackson. The problem also occurs with stoppers that incorporate Daikyo Seiko’s (Tokyo) “Flurotec” coating, which contains Teflon. Flurotec coating is sensitive, and if an operator touches it once, it might result in a little fold. The fold does not indicate that the Flurotec cover is damaged, but it might appear that the stopper has been compromised. Slight faults in the coating can be mistaken for particles and lead to false rejects. If stoppering equipment is maintained properly and operated carefully, this problem can be avoided. But vented placement might cause problems for rigid plungers, too. When a plunger is forced through a tube, it becomes deformed. The process could damage the ribs of the plunger and possibly compromise container integrity.
An alternative stoppering technique is vacuum placement. In this method, a vacuum is pulled in each syringe, and the vacuum draws the stopper into the syringe. Vacuum placement does not compress stoppers as much as vented placement does, says Jackson. This method creates a syringe without leaving an air bubble and eliminates the potential for oxygen to interact with a protein drug, says Patrick Begley, manager of technical services at BD Medical–Pharmaceutical (Franklin Lakes, NJ). Removing the air bubble also is preferred in the administration of highly viscous ophthalmic medicines, he adds.
On the other hand, vacuum-placement entails potential inconveniences. The process contains more variables than vented placement, so it is less repeatable, according to Jackson. Vacuum placement also places stoppers less precisely than vented placement, he adds.
Even though vacuum placement can require more time and decrease the syringe-filler line speed, says Begley, new, high-speed equipment can perform vacuum stopper insertion at rates of more than 300 syringes per minute. This equipment provides an alternative to slower, manually loaded vacuum-stoppering units.
Vacuum placement is gaining wider acceptance among manufacturers. “We’re seeing more requests for vacuum-stoppering machinery,” Jackson says. “I believe it’s due to the increased focus on the Teflon-coated stoppers.” Yet many drugmakers still choose vented placement. These companies want to be able to shake up their solution to check for particles, and this criterion requires the small air bubble that vented placement leaves in the syringe.
All plungers can be inserted by vented or vacuum placement, regardless of the material they’re made of, says Begley. Several equipment vendors offer lines that perform both techniques. Switching from one technique to the other requires a set of change parts and several programming steps. Some units that perform vented placement can be retrofitted with a vacuum module.
Today, prefilled syringes are manufactured with both techniques, and neither technique has serious drawbacks. Rather, vacuum stoppering offers specific benefits, and manufacturers decide between the two methods based on whether their small- or large-molecule drug needs those benefits, explains Begley.
The choice of stoppering method depends on the needs of the drug, the syringe, and the pharmaceutical company. A company must decide how important the air bubble, stopper position, stopper coating, and line speed are, says Jackson.