This chapter provides guidance for the packaging and repackaging of single-unit containers, and for the use and application of unit-of-use packaging. Although the chapter is intended for use by drug manufacturers, repackagers, and pharmacists, the information in the chapter may also be useful for suppliers of packages and packaging components. For the definition of specific types of packaging, see Packaging and Storage Requirements 659.

Single-unit containers that package a prescription drug to be dispensed directly to the patient are required to be child-resistant. Single-unit packaging intended for institutional or hospital use may or may not be required to be child-resistant. Single-unit containers that are child-resistant include supported blisters, such as separate, peel, push, and tear notch, and enclosed or in-card blisters, such as pull tabs and slide packs.

Materials used to manufacture single-unit packaging containers include glass and plastic. Glass used as a primary packaging component should meet the requirements of Containers—Glass 660. Plastic materials as a primary packaging component should meet the requirements of Containers—Plastics 661. The test for moisture permeability may be carried out as described in general test chapter Containers—Performance Testing 671.

Reclosables and nonreclosables may be used for solid, semisolid, and liquid dosage forms. Both must be packaged in compliance with the 16 CFR 1700.15 standards. The Poison Prevention Packaging Act (PPPA) of 1970 requires in certain cases the use of special packaging—child-resistant and senior-friendly. Child-resistant packaging protects children from serious injury or illness resulting from ingesting or handling hazardous products including drugs.

Because drugs packaged in unit-of-use packaging are intended to be dispensed to the consumer without repackaging by the pharmacist, the manufacturer or repackager is responsible for the special packaging of PPPA-regulated substances in unit-of-use containers (16 CFR 1701.1).

Unit-of-use packaging, when provided by the manufacturer, offers some of the following attractive advantages. (1) A dosage form can be dispensed to a patient in the manufacturer’s original container, a practice that recognizes that the suitability of the container has been established on the basis of the manufacturer's stability studies. (2) The counting and repackaging of dosage units in the pharmacy is eliminated, thereby reducing the possibility of human error. (3) The pharmacist is able to affix the label for the patient onto the unit-of-use package and is free to use the manufacturer's expiration date as the beyond-use date. (4) The number of dosage units in a single unit-of-use package may be determined on a case-by-case basis. (5) Patient compliance is improved. (6) The unit-of use package can protect against counterfeiting because traceability of product is ensured through bar coding techniques and National Drug Code (NDC) numbers.

Unit-of-use packaging, when provided by repackagers, offers the same attractive advantages as those offered by the manufacturer. However, unit-of-use repackagers should conform to all requirements as presented in Good Repackaging Practices 1178. There are a number of reasons why repackagers produce unit-of-use packaging, for example, (1) requests from institutions, (2) better inventory control, (3) reduced dispensing times, and (4) variations in some drug therapies.

The packaging of a unit-of-use system may be a multiple-unit or single-unit container. A unit-of-use system may contain a drug product in a liquid, semisolid, or solid dosage form (see also FDA Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics). [Note—The terms “unit-of-use package” and “unit-of-use container” may be used interchangeably. ]

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. The following section contains minimum standards to be used as a guideline for repackaging practices.

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, and the second concerns commercial pharmaceutical repackaging firms.

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 properties of the finished container are defined by the materials used in constructing the unit-dose container, and by the process used to form and seal the 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 until 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.

The following guidance is intended for those engaged in pharmaceutical dispensing, and does not apply to commercial dispensing. An official dosage form is required to bear on its label an expiration date assigned for the particular formulation and package of the article. This date limits the time during which the product may be dispensed or used. Because the expiration date stated on the original manufacturer’s container–closure system has been determined for the drug in that particular system and is not intended to apply to a product that has been repackaged in a different container, repackaged drugs dispensed pursuant to a prescription are exempt from using the expiration date from the original manufacturer’s package. However, under no circumstance should the repackaged pharmaceutical preparation’s expiration date exceed the original manufacturer’s expiration date. It is necessary, therefore, that other precautions be taken by the dispenser to preserve the strength, quality, and purity of drugs that are repackaged for ultimate distribution or sale to patients.

The following guidelines and requirements are applicable where official dosage forms are repackaged into single-unit or unit-dose containers or mnemonic packs for dispensing pursuant to prescription.

In lieu of dispensing two or more prescribed drug products in separate containers, a pharmacist may, with the consent of the patient, the patient’s caregiver, or a prescriber, provide a customized patient medication package (patient med pak).3

A patient med pak, i.e., a package prepared by a pharmacist for a specific patient, comprises a series of containers and contains two or more prescribed solid oral dosage forms. The patient med pak is so designed, or each container is so labeled, as to indicate the day and time, or period of time, that the container contents are to be taken.

It is the responsibility of the dispenser to instruct the patient or caregiver on the use of the patient med pak.