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New Technology For Aseptic Filling of Injectable Drugs

The aseptic filling of injectable drugs has always been very challenging for the pharmaceutical industry. Contamination accidents, although rare, are still recorded among the 20 billion injections and infusions made every year in the world.  Authorities have taken a radical turn to strongly support the most advanced aseptic filling technologies, such as the use of isolators, whereas the use of classical processes in an Grade A/ISO 5  are increasingly challenged regarding risks due to the proximity of the operator to the open containers. The emphasis on the quality of aseptic filling has increased as well with the recent request from authorities to withdraw preservative agents whenever possible from injectables.

This article describes a new filling technology that has been initially developed to further increase the quality for the patient but also to simplify the filling process for the manufacturer compared to the classical glass vial. In addition, new features have been introduced to secure the supply chain, such as on-line coding by RFID or laser-coding.

THE CLOSED VIAL TECHNOLOGY

The closed vial technology is based on a vial that is provided clean and sterile with the stopper in place. Thanks to such container design, the most complex filling steps of classical open vials, such as vial washing, stopper washing, and hot air tunnel sterilization, are eliminated. The filling is done by means of a needle that pierces the stopper and dispenses the liquid. After needle withdrawal, the puncture trace is immediately resealed with a laser to restore closure integrity.

The Closed Vial

The closed vial is a container composed of 5 elements:

  • The vial body: Cyclo-olefin copolymer (COC) is used for this part of the container. COC was selected because of its excellent barrier and transparency properties, making it one of the most reknown plastics for containers in the pharmaceutical industry. The vial bodies are produced by injection molding for the smaller vials or by injection blow molding for vials that exceed a 3-mL volume.
  • The stopper: A thermoplastic elastomer with particular laser absorbance properties was selected to allow laser resealing. Under laser heating, melting is observed and the two sides of the puncture trace fuse to restore closure integrity.
  • The top ring: This ring secures the closure integrity of the assembly of the vial body and the stopper with non-return, right angle snap fits.
  • The bottom ring: This ring ensures very good stability of the vial and firm holding during piercing and needle withdrawal
  • The cap: The polyethylene cap protects the piercing area by maintaining it as Class 100 until use by the health professional. This last feature, obtained by a circular rib that presses on the stopper surface, avoids the appearance of contamination of the stopper surface during vial storage.

The manufacturing of vials is also completely innovative as they are molded and stoppered by robots in Grade A/ISO 5 cleanrooms. The manufacturing of the vials is comprised of the following steps:

  • The vial bodies and the stoppers are molded at the same time in two molds installed in Grade A/ISO 5 cleanrooms.
  • Immediately after mold opening, two robot arms pick up the vial body and the stopper and bring them in front of each other. The assembly is performed by the simple pressure of the two elements.
  • The vials, then closed, are transferred by one of the robot arms to an adjacent Grade C/ISO 8 cleanroom where the addition of both top and bottom rings are performed automatically.
  • The vials are packed in corrugated polyethylene boxes.
  • Six boxes are doubled wrapped in polyethylene foil.
  • Finally, the vials are gamma-irradiated at a minimum of 25 kGray.

This process provides vials with extremely high quality in terms of sterility and both particle and endotoxin contamination. Therefore, any additional steps, such as washing and depyrogenation, are not necessary and the vials are provided ready-to-fill to the pharmaceutical manufacturer.