Silicone, however, is one ingredient that's proving very difficult to eliminate. Silicone is used to coat the inside of syringe
barrels. Although silicone poses no threat to some drugs, others have exhibited adverse reactions caused by prolonged exposure
to it. West Pharmaceutical Services will soon be introducing its resin CZ system, which eliminates the need for silicone.
The plunger is coated with FluroTec, which protects the drug from leachables from the rubber and provides the lubrication
needed to allow the plunger to move. Other companies are baking on the silicone, and still others are working to reduce the
amount of silicone in the barrels to the least amount possible to still allow the plunger to move.
Besides testing for leachables, pharma companies also must test for break-loose and gliding forces for drugs of various viscosities.
For those forces to remain low, there must be some sort of lubricant present. Thus, eliminating or reducing the amount of
silicone is challenging.
Figure 1: Glass syringes are currently preferred, and innovations in automation and robotics have increased the efficiency
and consistency of handling glass prefilled syringes on the processing line. The photo shows automated heat-tunnel unloading
of prefilled syringes (courtesy of Vetter Pharma-Fertigung GmbH & Co. KG).
Increasing interest in prefilled syringes has lead to innovative solutions in filling and stoppering technologies, barrier
designs, automated processing and transfer systems, and robotic handling.
Filling and stoppering.
Filling and stoppering syringes present a unique set of challenges than those encountered when processing vials.
"The method you choose to fill and stopper a syringe can influence the stability of the drug product, the movement of the
product inside the syringe during shipping, and, in some cases, the sterility assurance of the product," says Shawn Kinney,
president at Hyaluron Contract Manufacturing (HCM, Burlington, MA).
Vacuum stoppering technology has been available for several years, but vacuum filling is relatively new. Vacuum stoppering
has, until recently, only been performed offline, away from the fill line in a vacuum box. Recently, syringe manufacturers
have developed vacuum filling and stoppering capabilities online, primarily for viscous products.
Pulling a vacuum through very thin solutions such as water for injection or buffered solutions causes the liquid to boil and
splatter. If splattering occurs during the stoppering process, the liquid product may be entrapped in the ribs of the stopper,
posing a potential sterility issue.
Successfully removing air from thin solutions does have several advantages, including increased product stability, lack of
stopper movement during shipment and post-sterilization processing, and even potentially enhanced sterility assurance of the
solution. Hyaluron has patented a bubble-free filling process that eliminates the air inside the syringe. Bubble-free filling
is especially beneficial for oxygen-sensitive pharmaceuticals and proteins that are sensitive to a gas-liquid interphase that
appears on small gas bubbles inside the syringe.
"Some proteins tend to rearrange themselves such that the hydrophobic groups point up into the gas phase and the hydrophilic
amino acids point down into the liquid phase, which causes more rapid degradation, says Kinney. "The presence of a gas bubble,
in conjunction with the silicone coating, will further exacerbate protein aggregation."
Other companies are reportedly working on closed-filling systems similar to those used for vials (1).
The challenges in handling the shape and composition of syringes also are leading to new barrier system designs, specifically
isolators and restricted access barrier systems (RABS).
"Traditional cleanrooms are being phased out in exchange for operations within RABS or isolators," says Eric A. Isberg, product
manager, Pharmaceutical Operations, Robert Bosch Packaging Technology (Brooklyn Park, MN).