Repackaging of solid oral drug products, such as tablets and capsules, into unit-dose configurations is common practice both for the pharmacy that is dispensing drugs pursuant to a prescription and for the pharmaceutical repackaging firm. This general chapter contains minimum standards to be used as a guideline for repackaging practices. This guideline is not intended to replace or supplant the requirements of regulatory agencies.

Repackaging preparations into unit-dose configurations is an important aspect of pharmaceutical care and of optimization of patient compliance. For purposes of this chapter, there are two types of repackaging: the first involves pharmacies that dispense prescription drugs; the second concerns commercial pharmaceutical repackaging firms.

Blister packages offer a wide array of designs both in functionality and in appearance. Various packaging materials are used to create blisters that are tailored to provide optimum performance. The blister container consists of two components: the blister, which is the formed cavity that holds the product, and the lid stock, which is the material that seals to the blister, as shown below.

Because of the variety of blister films available, film selection should be based upon the degree of protection required. The choice of lid stock depends on how the blister is to be used, but generally the lid stock is made of aluminum foil. The material used to form the cavity is typically a plastic, which can be designed to protect the dosage form from moisture. There are widely varying degrees of moisture protection now available. For purposes of this general chapter, they are referred to as nominal, medium, high, and extreme moisture barrier properties.

PVC/PCTFE Laminations— Polychlorotrifluoroethylene (PCTFE) film1 is a thermoplastic film made from polychlorotrifluoroethylene fluoropolymer. The PCTFE film is laminated to the PVC by an adhesive layer between the PVC and the PCTFE film (duplex structure) or by a layer of polyethylene (PE) between the PVC-adhesive and the PCTFE-adhesive layers (triplex structure). By using various gauges of the PCTFE film, medium to extreme moisture barriers can be obtained.

PVC/PVdC Laminations— PVC/PVdC is a film in which the PVC is coated with an emulsion of polyvinylidene chloride (PVdC). The PVdC layer is specified in g per m2 and can be constructed to provide medium to high barrier protection. The coating weights commonly used in the pharmaceutical industry are 40, 60, and 90 g per m2, and the film is offered with or without a middle layer of polyethylene (PE). The polyethylene is used with heavier coating weights, such as 60 and 90 g per m2, to improve the thermoforming characteristics of the blister cavity.

Polypropylene— Because of its morphology, polypropylene (PP) serves as a good moisture barrier, its spherulitic structure creating an arduous path for water molecules to traverse. Although not commonly used as a pharmaceutical blister film in the U.S., PP provides an economical alternative to medium barrier materials and is used in Europe as an alternative to PVC.

Cold Form Foil— This material is used for products that are extremely hygroscopic or light sensitive. It is an extreme moisture barrier and consists of three layers: PVC, aluminum foil, and nylon.

Peelable— Peelable foil, commonly used in an institutional setting, consists of several layers, as shown below, and can be peeled away from the blister. [NOTE—For child-resistant peelable foil, a layer of polyester with the appropriate adhesives would be added.] With the peelable foil lid stock, which is used in conjunction with blister tooling, a three-step process is required to open the blister.

Push-Through— There are two commonly used types of push-through foil: one with a paper outer layer separated from the aluminum by a layer of adhesive and one without paper. The paper outer layer serves as an aesthetic and makes it possible to print on the back of the blister.

Unit-dose packages can be formed and sealed in a variety of ways. Larger scale repackagers may use thermoformers that accomplish these functions in-line, while smaller repackagers may purchase preformed blister material. This section begins with an overview of the process involved in thermoforming a blister, the fundamental process that also applies to other unit-dose package types such as pouches. The overview is not intended to be all-encompassing, but it highlights the major operations along with their critical parameters.

Forming Station— Prior to entering the forming station, the blister material passes through a heating unit where the blister material is heated uniformly in stages to ensure proper formation. Because different plastics have different softening points, careful attention must be paid to determining the proper temperature of the heating station, which often has multiple temperature zones. The temperature, based on the blister material used and on the speed at which that material travels through the heating station, is a critical parameter for optimal performance. At the forming station the blister material is heated to the point where the plastic softens sufficiently to allow the cavity to be formed. The blister material is drawn from a reel-mounted roll (referred to as the web) and pulled through the machine. A splicing table is located at the reel unwind to provide room for a second roll of blister material to be readily available for splicing and resumption of the packaging process. An unwind device may be installed to aid in moving the blister material from the roll as adjusted for a specific index.

Filling Station— The product is loaded into the blister cavity at this station. An automated filling device may be used, or the cavities may be hand filled. The critical parameter at this station is proper filling of the formed blisters.

Sealing Station— At this station, the lid stock is sealed to the filled blister cavity, using heat and pressure for a defined dwell time. The critical parameters to be considered at this station are temperature, pressure, and dwell time.

Finishing Station— The finishing station encompasses all other steps in the packaging process, including embossing, perforation, and cutting. Embossing involves application of a lot number and expiration date to the package. Steel type is used to emboss information on the edges of the blister package. One of the critical parameters at this station is package integrity. It is important that the embossing, perforation, and cutting processes do not compromise the blister, lid, or seal. The quality of the embossing is another critical parameter in the process. The embossing must be legible, and correct and must include all required information.

Installation Qualification— Equipment should be installed and found to be in proper working condition prior to use.

Operation Qualificational— Operational qualification should be performed to establish that the equipment operates within the manufacturer's specified ranges. Incoming utilities for the equipment, such as air, electricity, etc., should be monitored and checked periodically.

Performance Qualification— Performance qualification should be done to ensure that the equipment is performing properly with the required materials to produce a container that functions as intended. The critical parameters include forming temperature and pressure, sealing temperature and pressure, and dwell time at the seal station. Qualified ranges should be readily available in a reference source for the setup of equipment. Re-evaluation may be necessary with changes to equipment, materials, or the process.

The primary purpose of the unit-dose package used in the packaging of a drug preparation is to ensure that until its intended expiration date there is adequate protection from the environment as the dosage form is distributed and stored. It is also essential that the materials used do not interact with the dosage form.

When determining what type of package to use in the repackaging operation, consideration must be given to the dosage form's sensitivities (if any) to the storage and distribution environments (e.g., temperature, light, and moisture).

The materials used in constructing the unit-dose container as well as the process of forming and sealing the container all together define the properties of the finished container. As discussed in Materials, there is a wide variety of commercially available film structures that provide unit-dose containers with a range of moisture and light protection. Suppliers of these materials typically provide quantitative data, obtained from well-established test methods, to highlight the protective properties of their material. These data are based on flat sheets of the film, not on the formed container.

It is critical to understand that once the film is formed, protective properties change because the overall thickness of the film decreases as the blister cavity is formed. Usually the change is a decrease, especially in the case of barrier properties. However, the extent of change will vary with the type of film structure used and is also highly dependent on the container-forming process used (see Process). Further, a suboptimal seal on the formed container will decrease the protective properties of the container. Insufficient temperature, time, or pressure during a heat-seal operation may enable the passage of moisture or oxygen through the seal area over time, which may have an effect on the dosage form. In addition, if the seal area is designed with insufficient surface area, the same problem may occur. To ensure a good seal, a minimum sealing distance of 3 mm from the edge of the blister cavity to the nearest edge or perforation is recommended. Therefore, it is important to measure the performance of the formed and sealed container rather than the performance of the flat sheet.

Moisture is a critical factor in preparation integrity. Containers—Permeation 671 describes how to determine and classify moisture permeation rates. If the manufacturer's labeling includes “Protect From Moisture,” the repackager shall utilize a high barrier film.

If light protection is required for a drug preparation, the repackager should follow the requirements for light transmission established under Containers 661. Again, this testing should be conducted on the formed container, because the light protective properties of the film are compromised once the film is thinned during the forming process. It is recommended that these tests, in conjunction with any guidance provided by the manufacturer, be considered appropriate for any container–closure system used in repackaging a drug preparation.

In the absence of stability data for the drug product in the repackaged container, the beyond-use dating period is one year or the time remaining of the expiration date, whichever is shorter. If current stability data are available for the drug product in the repackaged container, the length of time established by the stability study may be used to establish the beyond-use date but must not exceed the manufacturer's expiration date.

As stated in the General Notices and Requirements, the dispenser must maintain the facility where the dosage forms are packaged and stored at a temperature such that the mean kinetic temperature is not greater than 25. The plastic material used in packaging the dosage forms must afford better protection than polyvinyl chloride, which does not provide adequate protection against moisture permeation. Records must be kept of the temperature of the facility where the dosage forms are stored, and of the plastic materials used in packaging.

The previous sections serve as a general introduction to repackaging by providing a basic understanding of materials selection, the form-fill-seal process, and the importance of performance of the sealed container. In this section, certain minimum requirements for repackaging, which must be met, are described in more detail.