Packaging/Container Issues: Unit-dose, Pre-filled Syringes, Pre-packs, Etc. Introduction "Manufactured products" must be exhaustively tested for compatibility and stability in the packaging materials because the materials will be in contact with the product for an extended period of time (2 to 3 years) and may be exposed to extremes of storage conditions during transportation. "Compounded preparations," on the other hand, are designed for short-term storage and minimal shipping exposure. Pharmacists packaging compounded preparations, however, are required to properly package their preparations in accordance with the United States Pharmacopeia (USP) compounding standards. United States Pharmacopeia Container Types/Definitions The USP classifies containers according to their ability to protect their contents from external conditions. The minimally acceptable container is a well-closed container; it protects the contents from extraneous solids and from loss under ordinary conditions of handling, shipment, storage, and distribution. A tight container protects the contents from contamination by extraneous liquids, solids, or vapors, from loss of the article, and from efflorescence, deliquescence, or evaporation under the ordinary or customary conditions of handling, shipment, storage, and distribution and is capable of tight re-closure. A hermetic container is impervious to air or any other gas under the ordinary or customary conditions of handling, shipment, storage, and distribution. Sterile hermetic containers generally hold preparations intended for injection or parenteral administration. A light-resistant container is intended to provide protection from light. A single-dose container is one that holds a quantity of drug intended as a single dose and when opened cannot be resealed with assurance that sterility has been maintained. These containers include fusion-sealed ampules and prefilled syringes and cartridges. A multiple-dose container is a hermetic container that permits withdrawal of successive portions of the contents without changing the strength or endangering the quality or purity of the remaining portion (vials). Containers
and Dosage Forms Although single-unit packaging has particular usefulness in institutional settings, e.g., hospitals, extended-care facilities, it is not limited to them. Many outpatients find single-unit packages a convenient and sanitary means of maintaining and using their medication. Among the advantages cited for single-unit packaging and unit-dose dispensing are positive identification of each dosage unit and reduction of medication errors, reduced contamination of the drug because of its protective wrapping, reduced dispensing time, greater ease of inventory control in the pharmacy or nursing station, and elimination of waste through better medication management with less discarded medication. Unit-dose Strip-Packaging Unit-dose Oral Liquids Unit-of-use Packaging Light-resistance Glass Containers Plastic Containers Most commonly used plastics include polyethylene (Low Density-LDPE; High Density-HDPE), polystyrene, polypropylene, polycarbonate, and polyvinylchloride. Plastics are a mixture of homologous compounds with a range of molecular weights and each type of plastic has different characteristics. These plastics also contain other substances, such as residues from the polymerization process, plasticizers, stabilizers, antioxidants, pigments, and lubricants. Plastic Problems Drug substances that are subject to oxidative degradation may undergo a greater degree of degradation when packaged in plastic than in glass. In glass, the container's void space is confined and presents only a limited amount of oxygen to the drug contents, whereas a drug packaged in a gas-permeable plastic container may be constantly exposed to oxygen because of the replenished air supply entering through the container. Liquid pharmaceuticals packaged in permeable plastic may lose drug molecules or solvent to the container, altering the concentration of the drug in the product and affecting its potency. An example of solvent loss involves large volume parenterals that are packaged in one-liter plastic bags that are packaged with an "overwrap" that is removed to yield the container of fluid that is actually used. The inside bag may feel slightly damp due to the loss of fluid from the primary container that is entrapped between the primary container and the overwrap. Sorption, a term used to indicate the binding of molecules to polymer materials, includes both adsorption and absorption. Sorption occurs through chemical or physical means due to the chemical structure of the solute molecules and the physical and chemical properties of the polymer. Generally, the un-ionized species of a solute has a greater tendency to be bound than the ionized species. Because the degree of ionization of a solute may be affected by the pH of a solution, the pH may influence the sorption tendency of a particular solute. Furthermore, the pH of a solution may affect the chemical nature of a plastic container so as to increase or decrease the active bonding sites available to the solute molecules. Plastic materials with polar groups are particularly prone to sorption. Because sorption depends on the penetration or diffusion of a solute into the plastic, the pharmaceutical vehicle or solvent used can also play a role by altering the integrity of the plastic. Sorption may occur with active pharmacologic agents or with pharmaceutical excipients. Thus, each ingredient must be examined in the proposed plastic packaging to determine its tendency. Sorption may be initiated by the adsorption of a solute to the inner surface of a plastic container. After saturation of the surface, the solute may diffuse into the container and be bound within the plastic. The sorption of an active pharmacologic agent from a pharmaceutical solution would reduce its effective concentration and render the product's potency unreliable. The sorption of pharmaceutical excipients such as colorants, preservatives, or stabilizers would likewise alter the quality of the product. Methylparaben may be sorbed to some types of plastics, resulting in a decrease in the available concentration of the preservative; this may be reflected in a lowering of its preservative effectiveness. Deformations, softening, hardening, and other physical changes in plastic containers can be caused by the action of the container's contents or external factors, including changes in temperature and the physical stress placed upon the container in handling and shipping. Stability Issues Related to Packaging Pharmacists
Involvement USP General Chapters Resource Material on Packaging/Repackaging Pharmacy Practices <681> Repackaging into Single-Unit Containers and Unit-Dose Containers for Nonsterile Solid and Liquid Dosage Forms <1136> Packaging---Unit-of-Use <1146> Packaging Practice---Repackaging a Single Solid Oral Drug Product into a Unit-Dose Container <1178> Good Repackaging Practices Resource Material-International Journal of Pharmaceutical Compounding (IJPC) IJPC 14(1) Jan/Feb 2010, 32-37: Unit-Dose Packaging and Repackaging IJPC 7(1) Jan/Feb 2003, 37-41: Packaging Choices for Compounded Materials IJPC 12(4) Jul/Aug 2008, 316-320: Beyond-Use Dating, Labeling, Delivery and Storage of Compounded and Repackaged Medications in a Hospital or Institutional Setting IJPC 1(3) May/Jun 1997, 150-151: Drug Products and Drug Packaging for the Elderly IJPC 6(2) Mar/Apr 2002, 120-122: A Review of Parenteral Admixtures Requiring Select Containers and Administration Sets IJPC 7(3) 124, 124-125: Accuracy of Small-Volume Containers IJPC 13(3) 162-165: Drug Compatibility with a New Generation of VISIV Polyolefin Infusion Solution Containers Loyd V. Allen, Jr., Ph.D., R.Ph. |