Freeze-Drying with Closed Vials - Pharmaceutical Technology

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Freeze-Drying with Closed Vials
The authors present an aseptic-filling process for freeze-dried liquids using the closed-vial technology.

Pharmaceutical Technology

Thilly and coauthors introduced closed-vial filling systems, called "Crystal" technology, for aseptic filling of liquid products in Pharmaceutical Technology's 2005 Aseptic Processing supplement (1). Aseptic Technologies (Gembloux, Belgium) has now taken closed-vial technology a step further by developing a process using the closed vial for lyophilization. The technology consists of using ready-to-fill, gamma-sterilized, closed vials and filling them using a needle passing through the stoppper, followed by a laser resealing to restore the closure integrity. The vial body, made of cyclo-olefin copolymer (COC), rather than glass, and the stopper, made of thermoplastic elastomer (TPE), are injection molded and assembled by robots in an ISO 5 (Class 100/Grade A) environment.

The process involves securing the closure integrity with a top ring, and then gamma-irradiating the vial to ensure sterility. The closed vial is then determined to be clean on the inside and sterile and therefore ready for filling. Plastic molding of vial elements allows the vial to have specific functionalities such as an optimized stopper shape and fully secured closure integrity (2).

In the filling line, the TPE stopper is pierced by a special filling needle. Immediate self-reclosing takes place at the needle withdrawal and the piercing trace is resealed with a noncontact laser beam, restoring a continuous upper surface of the stopper. Overpressure inside the vial during filling is eliminated by venting grooves in the outer surface of the needle shaft. A sterile plastic cap is then snapfitted on top of the stopper, which is still inside the barrier. The special cap design protects the piercing target until use by a healthcare professional (1, 2).

Figure 1: Closed vial process: Vial bodies and stopper are molded in ISO 5 (Class 100/Grade A) environment and immediately assembled by robot before the top and bottom rings are added; after packaging, the vials are gamma-irradiated; at the pharmaceutical site, vials are filled with a needle passing through the stopper, which is then laser resealed; and finally, capping is completed. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Because the container is permanently closed, the entire process from vial manufacturing to liquid filling benefits patients by optimizing sterility assurance (see Figure 1). Pharmaceutical manufacturers also benefit from the simplicity of the filling operation compared with the classical but complex glass-vial filling process. This article describes the concept and process of closed-vial, freeze-drying technology in more detail.

The closed-vial, freeze-drying concept

To maintain optimal sterility assurance, an opening in the vial is required but has been limited in this particular process. The vial actually remains closed most of time, especially between the filling station and the freeze dryer's shelf. The opening and closing of the vial is generated by rearranging the movements of the freeze-dryer shelves. When the cycle is finished, the vial closes again before the freeze dryer's door is opened and stays closed until the vial is resealed with a laser and capped. This process has several advantages over traditional glass-vial processing:

  • The closed vial content is not exposed during its movement from the sterilization tunnel to the freeze dryer (no half-seated stopper).
  • There is no risk of product spillage on the vial track to the freeze dryer or on the shelves themselves. Moreover, the plastic vials are shock resistant and nearly unbreakable.
  • The stoppers do not stick to the upper shelf.
  • There is no risk of incomplete reseating of the stopper or stopper pop-up after the stoppering step; closure integrity is maintained throughout the process.
  • When required, this process has the capability of inspecting for particles of the liquid before freeze-drying, provided that the inspection machine is compliant with a Class 100 environment. The vial's bottom ring enables it to be held from the bottom only for the rotation, without an upper spindle above the vial. Its slightly elevated bottom allows for a perfect view on the critical bottom part of the content.


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