Closed-vial manufacturing process description

The major innovation of the closed-vial technology is the production of the vial components in an ISO5 clean room. As a result, the components are ready-to-use and do not require the complex cleaning process that is mandatory for glass vials and rubber stoppers.

Ensuring cleanliness. To ensure the cleanliness of the vial components, various conditions have been imposed on the process. First, the molds should not contain lubricating additives that are sometimes used to ease removal of the part from the mold. Second, once the room is qualified for operation, the operators cannot enter. Vial conveying must be fully automatic and should not create particles above the specified level. Vial transportation is performed by robots as shown in the first step of Figure 1. Such robots are already widely used in the ISO4 or ISO3 cleanrooms in the electronic industry as well as in the pharmaceutical industry for applications such as syringe filling.

Ring assembly. After assembly of the two components, top and bottom rings are added. Each step is checked by visual sensor control or mechanical challenge before moving to the next operation. This complete PAT ensures that the vial is fully and properly assembled.

Sterilization. Because the TPE used for the stopper is sensitive to heat, the only classical sterilization procedure suitable for the closed vial is irradiation. Gamma irradiation is preferred to beta irradiation because it is available worldwide and can process a complete pallet at once.

Filling methods. Closed vials are provided ready-to-fill. The five most frequently used methods for loading are:

• Wrapped vials are loaded into the filling area before sanitizing so the external part of the bag is sanitized along with the equipment. This method is used for very small batches (i.e., maximum of a few hundred vials).
• Beta-bags are connected to rapid transfer ports. This method is used for small batches (i.e., a few thousand vials) with robot filling lines using closed vials in racks.
• Vials enter through vaporized hydrogen peroxide airlock with sanitization of the last bag. This method has a limited capacity, due to either the small size of the airlock or the long cycle time, and is therefore efficient for low-capacity filling equipment.
• Vials entry through airlock cascades from an ISO8 to ISO5 environment, using robots to perform automatic debagging and box opening. This is used for mid to large scale batches (e.g., 25–200 vials/min.).
• Vials are removed from bags and boxes, followed by e-beam sterilization of the stopper top surface. This method is used for very large batches (i.e., up to 600 vials/min.).

Using ready-to-fill vials eliminates component preparation and thus has a huge impact on the entire facility. Equipment for vial washing, a hot-air tunnel, and equipment for stopper washing/sterilization is not needed, and clean room space is reduced. WFI for formulation and equipment cleaning can be sourced from a much smaller WFI loop, or containers may be purchased from external sources.

Another change to the filling process is that a needle must pierce the vial stopper before filling, and the hole must be reclosed after filling. The vial must be held in a fixed position during piercing, filling, and removal of the needle. The vial must also be held in position under the laser head to be resealed, and the laser must ensure complete coverage of the piercing trace, so the laser has a uniform energy beam on a 6 mm diameter surface. After resealing, a snap-fit cap is pressed in place.