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.

Dispenser—A dispenser is a licensed or registered practitioner who is legally responsible for providing a preparation for patient use, with a specific patient label, pursuant to a prescription or a medication order. In addition, dispensers may prepare limited quantities in anticipation of a prescription or medication order from a physician. Dispensers are governed by the board of pharmacy of the individual state.

Package—The term “package” is synonymous with the term “container.” See Containers under Preservation, Packaging, Storage, and Labeling in the General Notices and Requirements.

Pharmacy—A pharmacy is an establishment that is legally responsible for providing the drug preparation for patient use, with a specific patient label, pursuant to a prescription or a medication order. The terms dispenser and pharmacy are used interchangeably.

Repackaging—Repackaging is the act of removing a preparation from its original primary container and placing it into another primary container, usually of smaller size.

Repackager—A repackager is an establishment that repackages drugs and sends them to a second location in anticipation of a need. Repackaging firms repackage preparations for distribution (e.g., for resale to distributors, hospitals, or other pharmacies), a function that is beyond the regular practice of a pharmacy. Distribution is not patient specific in that there are no prescriptions. Unlike dispensers, repackaging firms are required to register with the FDA and to comply with the Current Good Manufacturing Practice regulations in 21 CFR 210 and 211.

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.

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.

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—Performance Testing 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—Performance Testing 671. 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.