Vetter produces a dual-chamber syringe in which one chamber is filled with lyophilized product and the other is filled with
diluent. When the plunger is pressed, the diluent and lyo products mix and can then be injected. The dual-chamber syringe
can also be used with powder and liquid or two liquid products. The latter is, as Vetter's Zimmerman says, a niche market,
but it can be used for a multi-dose application that requires a preservative but might not be compatible with the protein
for storage.
Stoppers.
A necessary component of the prefilled syringes is the rubber stopper or plunger, which carries with it its own challenges.
Because stoppers are in prolonged contact with the drug, the primary concern is with leachables from the rubber interacting
with the drug.
One example is the case of the antianemic "Eprex." Produced by a subsidiary of Johnson & Johnson (New Brunswick, NJ), Eprex
was reformulated to eliminate human serum albumin for the European market and then packaged in a prefilled syringe that replaced
the uncoated stopper that had been used before with a coated one. The new formulation of the drug interacted with leachables
from the stopper and was later linked to pure red cell aphasia (PRCA) in certain patients, leading to severe anemia.
To combat the problems that may arise from interactions between drugs and rubber stoppers, Stelmi has developed high-purity
formulations with a low level of extractables for their rubber components. In the late 1990s, Stelmi launched its "UltraPure
6901" formulation adapted to prolonged contact with water for injection. In 2004, as prefilled syringes continued to gain
in popularity, the company began producing elastomer-based formulations 6955 from a new elastomer known as BIMS, which is
exempt from oligomers and, thus, less prone to leaching into the drug.
Meanwhile, West Pharmaceutical Services (Lionville, PA) is taking a different tack. Rather than retooling the rubber formulation,
the company has begun molding a laminate known as "FluroTec" film onto its stoppers. The film acts as a barrier between the
stopper and the drug, reducing the amount of leachables going from the rubber stopper to the drug in the syringe.
Protecting product quality
Concern over extractables and leachables is growing. At a recent AAPS conference, extractables and leachables came third in
a list of the Ten Hot Topics of 2007, whereas a mere seven years ago, they didn't even make the list. Whether made of glass
or plastic, prefilled syringes deserve special attention when it comes to controlling extractables and leachables.
When it began moving one of its protein drugs to a prefilled syringe, Amgen, Inc. (Thousand Oaks, CA) was surprised to notice
that the protein was aggregating. After much investigation (and cooperation between Amgen and BD, the manufacturer and supplier
of the syringes), the culprit was found to be tungsten, which is used to hold open the fluid channel at the base of the syringe
during the manufacture of the glass. The heat used during the molding process vaporized some of the tungsten, which then settled
in the glass at the base of the needle. Prolonged exposure of the drug to the tungsten resulted in visible particles in the
solution. BD now has the ability to produce a tungsten-free prefilled syringe.
Some drug makers are concerned that plastics pose a greater risk of extractables and leachables. Plastics and resins are composed
of many different components and the formulations can easily change, so there is more uncertainty and potential for extractables.
When working with plastics, "you have to take more chemicals into consideration, and therefore there are more unknowns because
the plastic vendors will not tell you ... the exact formulation because it is proprietary," says Eakins. The uncertainty means
that more testing is often necessary when packaging in plastics, and, according to Eakins, "the last thing you want to do
is a lot of research on your packaging, it makes the risks even higher."
One method of cutting down on the amount of testing is to improve communication between pharmaceutical manufacturers and the
companies supplying them with prefilled syringe components. Most components manufacturers will provide their clients with
lists of possible extractables and leachables, thus allowing the pharmaceutical manufacturers to narrow the field when testing
their drugs. Robert Swift, principal engineer of Amgen, hopes that the increased communication between suppliers and the biopharmaceutical
industry will "allow [pharma] companies to identify and mitigate formulation-container interactions very early in development."
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