Procedures and acceptance criteria for testing parenteral drug products are divided into two categories: (1) those that assess product quality attributes, e.g., identification, sterility, and particulate matter, and are contained in this chapter and (2) those that assess product performance, e.g., in vitro release of the drug substance from the drug product. Whereas quality tests assess the integrity of the dosage form, the performance tests assess performance (bioavailability) after the product has been administered to the patient. A product performance test, i.e., drug release test for suspensions, emulsions, powder for suspension (including microparticles and liposomes), and drug-eluting stents, should be carried out using appropriate test procedures.

A solution is a clear, homogeneous liquid dosage form that contains one or more chemical substances (e.g., drug substances or excipients) dissolved in a solvent (aqueous or nonaqueous) or a mixture of mutually miscible solvents. Solutions intended for parenteral administration (e.g., by injection or for irrigation) must be sterile and biocompatible with the intended administration site. This includes consideration of factors such as tonicity, pH, pyrogenicity, extraneous particulate matter, and physicochemical compatibility, among others.

Unless otherwise justified, the following tests are required for solutions for injection:

Sterile powders for solutions (also referred to as sterile powders for injection) consist of drug substances and other components as dry-formulation ingredients to ensure the chemical and physical stability of the presentation within a final-use container. Companion sterile diluent or diluent compartments may be provided to facilitate constitution to the desired final volume.

The sterile article for injection may be presented in several forms: lyophilized powder intended for final solution, powdered solids intended for final solution, or dry solids that form viscous liquids upon constitution.

The description should include a section that deals with ease of dispersion and reconstitution. The dosage form is a homogeneous solid that is readily constituted to the final form with the specified diluent, and dispersion is completed with gentle agitation.

Unless otherwise justified, the following tests apply to sterile powders for injection:

The following applies to constituted solutions:

Parenteral suspensions are liquid dosage forms that contain solid particles in a state of uniform dispersion. Suspensions for parenteral administration must be sterile and compatible with the administration site. Consideration should be given to pH and pyrogenicity, and appropriate limits should be identified. Physical stability evaluations of parenteral suspension preparations should include evaluations to confirm that the particle size range of suspended matter does not change with time and to confirm that the solids in the preparation can be readily resuspended to yield a uniform preparation.

In addition to the tests for injectable solutions, the following tests are required for suspensions for injection unless otherwise justified:

Liposomes are unique drug products with unique properties that can be either solutions or suspensions. Liposomes are aqueous dispersions of amphiphilic lipids and have low water solubility. They are organized as a bilayer sheet that encloses an internal aqueous compartment and are known as lipid bilayer vesicles. Liposomes can have a single lipid bilayer (unilamellar vesicle) or can have an onion-like multilayered structure (multilamellar vesicle). The amphiphilic lipids comprise a hydrated head group at the water interface of the bilayer attached to a hydrophobic group that forms the interior of the bilayer by association with the hydrophobic group of lipids from the opposite leaflet of the bilayer. The physical properties of the liposome and its bilayer can vary widely and depend on lipid composition, aqueous composition, and temperature relative to the acyl components' phase transition points. Because of the central aqueous compartment, a simple test for the presence of liposomes in a lipid dispersion is to determine the presence of an entrapped aqueous phase.

A liposome drug product consists of the drug substance, liposome components, and other inactive but critical ingredients such as an aqueous dispersion unless the contents are a lyophilized product.

Unless otherwise justified, the following tests are required for liposomes:

Sterile powders for suspensions consist of drug substances and other components as dry-formulation ingredients to ensure the chemical and physical stability of the presentation within a final-use container. Companion sterile diluent or diluent compartments may be provided to facilitate constitution to the desired final volume.

The sterile article for injection may be presented in several forms: lyophilized powder intended for final suspension, powdered solids intended for final suspension, and microparticles that retain their integrity and are delivered as a sterile suspension. The description should include a section that deals with ease of dispersion and reconstitution. The dosage form is a homogeneous solid that is readily constituted to the final form with the specified diluent, and dispersion is completed with gentle agitation.

Unless otherwise justified, the following tests apply to sterile powders for injection:

The following applies to constituted suspensions:

Emulsions for parenteral dosage forms are liquid preparations of drug substances dissolved or dispersed in a suitable emulsion medium. Oil-in-water or water-in-oil emulsions typically entrap the drug substance.

Emulsions typically are white, turbid, homogeneous liquid dosage forms that contain one or more chemical substances (e.g., drug substances and excipients) dissolved in a solvent (aqueous or nonaqueous) or mixture of mutually miscible solvents. Emulsions intended for intravenous administration must be sterile and must be compatible with the intended administration site.

Unless otherwise justified, the following tests are required for emulsions for injection:

Implants for extended release consist of a matrix of drug substance and polymeric excipient that may or may not have an outer rate-controlling membrane. The polymeric excipient must be biocompatible but may or may not be bioresorbable. Some implants are made from medical-grade metal with an osmotic pump inside that effects the extended release of the drug substance. Implants must be sterile and usually are formed in the shape of a cylinder, although other shapes are used. Solvents used to dissolve the formulation can lead to sterilization, and thus the internal sterility test method should demonstrate that the sample preparation does not lead to sterilization of the test sample.

Cylindrically shaped implants for systemic delivery usually are provided in an inserter for subcutaneous or local administration such as local ocular delivery. Implants also can be surgically implanted for local delivery, e.g., ocular delivery.

Unless otherwise justified, the following tests are required for implants:

Depending on the drug product, the following tests may be required:

Unless otherwise justified, the following tests are required for in situ gels:

Just before intramuscular or subcutaneous administration, the microparticle powder should be suspended in an aqueous injection vehicle (diluent). The injection vehicle usually consists of Water for Injection, surfactant, and a viscosity enhancer, and the vehicle may contain a compound that adjusts osmolality, e.g., a sugar with or without a compound that controls pH, e.g., an acid. The injection vehicle must be sterile and must be tested according to requirements for solutions that are intended for parenteral administration.

Unless otherwise justified, the following tests are required for microparticles for injection:

Depending on the drug product, the following tests may be required:

Drug-eluting stents are stents, tiny metal, or polymer scaffolds used to keep arteries open following a medical intervention, in which a drug substance is incorporated into or onto the stent platform. Drug-eluting stents typically have two components of testing: (1) functional tests that generally are American Society for Testing and Materials (ASTM) International methods that fall outside the scope of this chapter and (2) analytical tests.

Unless otherwise justified, the following tests are required for drug-eluting stents: