Packaging/Container Issues: Unit-dose, Pre-filled Syringes, Pre-packs, Etc.
The proper packaging of pharmaceuticals is essential for drug stability. Different specifications are required for parenteral, nonparenteral, and bulk containers and for those made of glass, plastic, and metal. Depending on the intended use and type of container, among the qualities to be considered include: (1) physicochemical properties, (2) light-transmission for glass or plastic, (3) drug compatibility, (4) leaching and/or migration, (5) vapor transmission for plastics, (6) moisture barrier, (7) toxicity for plastics, (8) sterility and permeation for parenteral containers, and (9) drug stability for all packaging. In selecting a container or package for a finished compounded preparation, it is important to realize that although a drug may be stable when stored in one type of container (glass), it may not be stable in a plastic (polyvinylchloride) container or an infusion device made of an elastomer. Glass is generally considered to be the most inert and stable container material, but plastic has gained wide acceptability and usefulness.
"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 immediate container is in direct contact with the article at all times. The container, including the closure, should be clean and dry before it is filled with the drug. The container must not interact physically or chemically with the drug so as to alter its strength, quality, or purity. An interaction example would be the sorption of lipophilic drugs, such as diazepam, to low density plastics resulting in a loss of drug that is available for administration. The problem can be avoided with the use of glass containers.
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
Dosage forms, such as tablets, capsules, and oral liquids, may be packaged in single-unit or multiple-unit containers. A single-unit container is designed to hold a quantity of drug intended for administration as a single dose promptly after the container is opened. Multiple-unit containers contain more than a single unit or dose of the medication. A single-unit package is termed a unit-dose package. The single-unit packaging of drugs may be performed on a large scale by a manufacturer or distributor or on a smaller scale by the pharmacy dispensing the medication. In either instance, the single-unit package must be appropriately labeled with the product identity, quality and/or strength, name of manufacturer, and lot number to ensure positive identification of the medication.
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.
Many hospitals with unit-dose systems strip-package oral solids. The equipment can be adjusted to produce individual single-cut packages, perforated strips, or rolls of doses. The packaging materials may be combinations of paper, foil, plastic, or cellophane. Some drugs must be packaged in foil-to-foil wrappings to prevent the deteriorating effects of light or permeation of moisture. The packaging of solid dosage forms in clear plastic or aluminum blister wells is perhaps the most popular method of single-unit packaging.
Unit-dose Oral Liquids
Oral liquids may be dispensed in single units in paper, plastic, or foil cups or prepackaged and dispensed in glass containers having threaded caps or crimped aluminum caps. A number of hospital pharmacies package oral liquids for children's use in disposable plastic oral syringes with rubber or plastic tips on the orifice for closure. In these instances, the nursing staff must be fully aware of the novel packaging and special labeling used to indicate that they are not for injection. These oral syringes are designed so they will not accept a needle. Other dosage forms, such as suppositories, powders, ointments, creams, and ophthalmic solutions, are also commonly found in single-unit packages provided by their manufacturers. However, the relatively infrequent use of these dosage forms in a given hospital, extended-care facility, or community pharmacy does not generally justify the expense of purchasing the specialized packaging machinery necessary for the small-scale repackaging of these forms.
Some pharmaceutical manufacturers use unit-of-use packaging; that is, the quantity of drug product prescribed is packaged in a container. For example, if certain antibiotic capsules are usually prescribed to be taken 4 times a day for 10 days, unit-of-use packaging would contain 40 capsules. Other products may be packaged to contain a month's supply.
Many pharmaceutical products require light-resistant containers. In most instances, a container made of a good quality of amber glass or a light-resistant opaque plastic will reduce light transmission sufficiently to protect a light-sensitive pharmaceutical. Agents termed ultraviolet (UV) absorbers may be added to plastic to decrease the transmission of short UV rays. A recent innovation in plastic packaging is the coextruded two-layer, high-density polyethylene bottle, which has an inner layer of black polyethylene coextruded with an outer layer of white polyethylene. The container provides light resistance (exceeding amber glass) and moisture protection. It is increasingly being used in the packaging of tablets and capsules.
The glass used in packaging pharmaceuticals falls into four categories, depending on the chemical constitution of the glass and its ability to resist deterioration. Types I, II, and III glass are intended for parenteral products, and type NP is intended for other products. Each type is tested according to its resistance to water attack. The degree of attack is determined by the amount of alkali released from the glass in the specified test conditions. Obviously, leaching of alkali from the glass into a pharmaceutical solution or preparation could alter the pH and thus the stability of the product.
Today, most pharmaceuticals are packaged in plastic. Plastic bags for intravenous fluids, plastic ointment tubes, plastic film-protected suppositories, and plastic tablet and capsule vials are other examples of plastics used in pharmaceutical packaging. The term plastic does not apply to a single type of material but rather to a vast number of materials, each developed to have desired features. Plastics have become the most popular material for packaging pharmaceuticals. It is strong, lightweight, reasonably inert, chemical resistant, and can be made from various polymers for select applications.
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.
Among the problems encountered in the use of plastics in packaging are (a) permeability of the containers to atmospheric oxygen and to moisture vapor, (b) leaching of the constituents of the container to the internal contents, (c) absorption of drugs from the contents to the container, (d) transmission of light through the container, and (e) alteration of the container upon storage. Agents frequently added to alter the properties of plastic include plasticizers, stabilizers, antioxidants, antistatic agents, antifungal agents, colorants, and others.
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
Numerous factors can affect the stability of a drug and dosage form, including pH, temperature, solvent, light, air (oxygen), carbon dioxide, moisture or humidity, and particle size. pH is one of the most important factors affecting the stability of a product. Glass may change the pH of some solutions. A solvent affects the stability of a product if the preparation is a liquid. Some plastics allow solvent to escape. Light may provide the activation energy required for a degradation reaction to occur. Many light-activated reactions are zero-order, or constant, reactions. The effects of light can be minimized by packaging products in light-resistant containers; products that are light sensitive can be covered during administration with aluminum foil or an amber plastic overwrap. Air (oxygen) can induce degradation via oxidation. Degradation can be minimized by filling the container as full as possible, thereby decreasing the headspace, or by replacing the headspace with nitrogen. Another option is to add an antioxidant to the formulation. Carbon dioxide can cause insoluble carbonates to form in the solid dosage form, which decreases the disintegration and dissolution properties of the product. Packaging in tight containers and filling the containers as full as possible minimize this condition.
Are compounding pharmacists involved in all these types of containers? Yes, they may be; consequently, it is important to understand their function, design, and use. Prior to being used, a container must be "clean." Sometimes, special precautions and cleaning procedures may be necessary, as in the case of sterile products and others. Another important consideration is that the container must not interact physically or chemically with the preparation it contains and alter the strength, quality, or purity of the article beyond the official requirements. These requirements apply not only to manufacturers of drug products but also to dispensing pharmacists of drug products and to compounding pharmacists for drug preparations.
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
<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.