Medications, and in particular injectable medications, need to be stored sterile in aseptic commercial packages until the time of use. Some medications are stored in pre-filled single dose dispensing devices such as pre-filled syringes, for example, the pre-filled syringes from Vetter (Ravensburg, Germany). Yet most of injectable medication are stored in aseptic packages and are transferred to a dispensing device (i.e., drug delivery device) shortly before use. The term dispensing device include without limitation hypodermic syringes, micro needle syringes, micropumps, autoinjectors, jet injectors, topical dispensers, intradermal delivery devices, patch pumps, auricular dispensers, oral dispensers, eye droppers, autoinjectors, infusers, prefillable syringes, pre-filled syringes, cartridges for pen injectors, cartridges for auto-injectors, or any other type of drug delivery device.
Several aseptic packages for storing injectable medications are commercially available. Perhaps the most common aseptic package for injectable products is glass vials. Some medications are stored in separate vials and are mixed just prior to use. Often this is done to improve the medication's stability or to extend the medication's shelf life. In one example, the medication is a vaccine that is kept dry in one vial to extend the vaccine thermo stability, and a companion vial stores a diluent that is dispensed to the vaccine vial via a syringe and needle prior to injection. In another example, the medication is a vaccine where one vial stores the formulated antigen and the second vial stores an adjuvant.
Several existing products include a flexible package made from film or foils in which a product can be stored in an aseptic manner until the time of use. Some of these products further include a dispensing port communicating with the product in the dispensing package. In some cases, a rupturable barrier is presented between the port and the product to enhance the integrity of the package until the time of use. These flexible packages may comprise at least two product compartments that are mergeable prior to use to allow the substances from the different compartments to mix and form the dispensable product. In some cases, these packages are made from a film or a foil (together referred to as webs or web walls) where a first web wall is sealed to a second web wall to define the boundaries of a product compartment. These packages are sometimes referred to as bags, blisters, pouches or sachets.
Packages for drugs, pharmaceutical agents or other beneficial agents are sometimes referred to as containers, primary containers, and container-closure systems. Packages are typically filled using a filling system. In the broader sense, fillings systems are configured to receive a package empty, fill the package, seal the package, and in some instances further arrange the package in a secondary package. At the filling step, the package is filled with one or more materials that are typically measured to receive a precise dose in the package. For liquids and other flowable substances, metering pumps are used to measure a precise dose into the package. Weighing the package is another common method of measuring a dose into a package. For powders, solids, and non-fluidic substances, filling systems may incorporate a volumetric transfer instrument or an acoustic measuring system to facilitate filling a precisely measured dose into a package.
In most cases, the package is received at the filling system open, or it is open during the filling step such that the interior of the package is exposed to the surrounding environment. For pharmaceutical products, and particularly for sterile products that are administered parenteral such as by intravenous (IV) infusion and injection, rigorous measures are taken to prevent contamination, foreign biologic matter, and foreign particulates from entering into the container. In several cases, the pharmaceutical ingredient cannot be sterilized after filling, hence the filling process is executed using pre-sterilized packages in a controlled clean environment. Several types of filling systems incorporate the steps of receiving open packages, washing, drying, sterilizing, and inspecting the packages prior to filling. After filling, the packages are sealed, still in the controlled environment, by joining the walls of the package or by introducing a closure to the package.
The filling process described above requires a sophisticated filling system that involves very high capital equipment expenditures and operation costs to the pharmaceutical filling company. These systems typically occupy significant and expensive clean-room space at the filling site while having a limited production throughput.
Some of the foregoing shortfalls have been partially addressed by several packaging suppliers. The Stevanato Group, Nuovo Ompi division (Padua, Italy) provides pre-fillable containers that have been pre-washed, sterilized and inspected, in sterile nesting trays, hence avoiding some of the upstream steps of preparation steps prior to filling.
Aseptic Technologies S.A. (Les Isnes, Belgium), and Medinstill (New Milford, Conn.) provide a pre-sterilized, sealed containers, particularly vials, and filling systems for accessing the container by piercing a rubber stopper with a piercing member, in a form of a needle, by which the package is filled; and resealing the access region after the package has been filled and the piercing member has been removed. Using such methods, these containers and filling systems avoid a number of upstream preparations typically required as filling steps at the filling site. Accessing the package for filling in a fluid-tight fashion, while the package is otherwise closed, reduces the risk of exposure of the interior of the package to contaminants, and can potentially reduce the controlled environment requirements during filling. The foregoing technologies have the potential of reducing capital equipment and filling operation complexities and costs while reducing contamination risks. However, such filling systems would benefit from further simplification and minimization of downstream operations after filling.
One limitation that is common to the foregoing filling systems is the challenge to scale up production on a single line because of the filling metering systems. Whether the filled dose requires weighing or metering with a pump, manufacturing scale up require more measuring systems installed and operated on a single line, thereby resulting in more expensive, larger, and less reliable filling systems. Therefore, filling metering systems that allow manufacturing scale up without compromising reliability or increasing the system size and costs would be an important advance in this field.
In some package applications, another limitation is the presence of air bubbles in the package after filling (i.e., sometimes referred to as headspace). Head space, and particularly inconsistency of head space, in a package may affect the accuracy of the dose received by a patient. This is particularly true with cartridges for pen injectors and auto injectors with limited options for removing air bubbles prior to injection, and where air may be injected to the patient in place of the actual drug. Another problem with headspace in the package is that some pharmaceutical products are sensitive to interaction with air, hence the presence of air bubbles may adversely affect the drug stability and efficacy.
The packages and packaging limitation listed above are valid in other industries beside the pharmaceutical industry, including, for example, medical device packaging, food packaging, cosmetic packaging, and nutraceuticals packaging.