Change to read:
1 INJECTIONS
AND IMPLANTED DRUG PRODUCTS (PARENTERALS)PRODUCT QUALITY TESTS
(Chapter to become official May 1, 2016)
INTRODUCTION
Parenteral drug products include both injections and implanted drug products that are injected through the skin or other external boundary tissue, or implanted within the body to allow the direct administration of the active drug substance(s) into blood vessels, organs, tissues, or lesions. Injections may exist as either immediate- or extended-release dosage forms. Implanted parenteral drug products are long-acting dosage forms that provide continuous release of the active drug substance(s) often for periods of months to years. For systemic delivery, they may be placed subcutaneously; for local delivery, they may be placed in a specific region of the body. Routes of administration for parenteral drug products include intravenous, intraventricular, intra-arterial, intra-articular, subcutaneous, intramuscular, intrathecal, intracisternal, and intraocular.
Parenteral dosage forms include solutions, suspensions, emulsions, sterile powders for solutions and suspensions (including liposomes), implants (including microparticles), and products that consist of both a drug and a device such as drug-eluting stents. The reader is directed to Pharmaceutical Dosage Forms 1151 1 and to the later sections of this chapter for additional descriptions of dosage forms that fall into the general category of parenteral drug products. Nomenclature 1121 1 provides information on nomenclature used to establish USP names and monograph titles for parenteral drug products.
Chapter 1![](../../images/chars/rang.gif) provides a framework to support the revision and the development of individual monographs, and is not meant to replace individual monographs. Chapter 1![](../../images/chars/rang.gif) provides lists of common product quality test requirements in a concise and a coherent fashion. The chapter is divided into four main sections: (1) universal product quality tests that are applicable to parental dosage forms; (2) specific product quality tests, which are tests that should be considered in addition to Universal Tests; (3) product quality tests for specific dosage forms, which lists all the applicable tests (Universal and Specific) for the specific dosage form; and (4) product performance tests.
If a monograph exists, it will reference 1![](../../images/chars/rang.gif) or indicated chapter parts. If a specific drug product monograph is missing (not in existence), the general chapters provide the quality tests that can be used by manufacturers until the dosage form monograph is developed by USP.
The Pharmacopeial definitions for sterile preparations for parenteral use may not apply to some biologics because of their special nature and licensing requirements (see Biologics 1041 1). However, some biological finished drug products containing Injection in the monograph title must meet the requirements of 1![](../../images/chars/rang.gif) or indicated chapter subparts, where it is specified in the monograph.
Drug Product Quality and Drug Product Performance Tests
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.
PRODUCT QUALITY TESTS COMMON TO PARENTERAL DOSAGE FORMS
Universal Tests
Universal tests are listed below and are applicable to parenteral dosage forms.
Description:
A qualitative description of the dosage form should be provided. The acceptance criteria should include the final acceptable appearance. If color changes during storage, a quantitative or a semiquantitative procedure may be appropriate. This section specifies the content or the label claim of the article (see Labeling 7 ). Additional information about commonly used terms and definitions can be found in Nomenclature 1121 1.
Assay:
A specific and stability-indicating test should be used to determine the strength (content) of the drug product. In cases where the use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. A specific procedure should be used when there is evidence of excipient interference with the nonspecific assay.
Foreign and particulate matter:
Articles intended for parenteral administration should be prepared in a manner designed to exclude particulate matter as defined in Subvisible Particulate Matter in Therapeutic Protein Injections 787 , Particulate Matter in Injections 788 , and Particulate Matter in Ophthalmic Solutions 789 , as well as excluding other foreign matter as appropriate for the dosage form. Each final container of all parenteral preparations should be inspected to the extent possible for the presence of observable foreign and particulate matter (hereafter termed visible particulates) in its contents. The inspection process should be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates, as defined in Visible Particulates in Injections 790 . Qualification of the inspection process should be performed with reference to particulates in the visible range and those particulates that might emanate from the manufacturing or filling process. Every container in which the contents show evidence of visible particulates must be rejected. The inspection for visible particulates may take place during examination for other critical defects such as cracked or defective containers or seals or when characterizing the appearance of a lyophilized product.
When the nature of the contents or the containerclosure system permits only limited inspection of the total contents, the 100% inspection of a lot should be supplemented with the inspection of constituted (e.g., dried) or withdrawn (e.g., from a dark amber container) contents of a sample of containers from the lot.
Large-volume injections for single-dose infusion, small-volume injections, and pharmacy bulk packages (PBP) are subject to the light obscuration or microscopic procedures and limits for subvisible particulate matter set forth in 788![](../../images/chars/rang.gif) , unless otherwise specified in the chapter or in the individual monograph. An article packaged as both a large-volume and a small-volume injection meets the requirements set forth for small-volume injections where the container is labeled as containing 100 mL or less. It meets the requirements set forth for large-volume injections for single-dose infusion where the container is labeled as containing more than 100 mL.
Sterility:
The sterility of all drug products intended for parenteral administration should be confirmed by the use of methods described in Sterility Tests 71 or by an approved alternative method.
Container closure integrity:
The packaging system should be closed or sealed in such a manner as to prevent contamination or loss of contents. Validation of container integrity must demonstrate no penetration of microbial contamination or gain or loss of any chemical or physical parameter deemed necessary to protect the product (see Sterile Product PackagingIntegrity Evaluation 1207 ).
Labeling:
All articles intended for parenteral administration should meet the labeling requirements defined in Labeling 7 ).
Specific Tests
In addition to the universal tests listed above, the following specific tests may be considered on a case-by-case basis and, when appropriate, are referenced in the USPNF monograph.
Uniformity of dosage units:
This test is applicable for parenteral drug products and dosage forms packaged in single-unit containers. It includes both the mass of the dosage form and the content of the active substance in the dosage form (see Uniformity of Dosage Units 905 ).
-
Mercury and cationic surface-active agents: NMT 0.01%
-
Chlorobutanol, cresol, phenol, and similar substances: NMT 0.5%
-
Sulfur dioxide or an equivalent amount of sulfite, bisulfite, or metabisulfite of potassium or sodium: NMT 0.2%
Antimicrobial preservative:
Antimicrobial agents must be added to preparations intended for injection that are packaged in multiple-dose containers unless one of the following conditions prevails: (1) there are different directions in the individual monograph; (2) the substance contains a radionuclide with a physical half-life of less than 24 h; or (3) the active ingredients are themselves antimicrobial. Substances must meet the requirements of Antimicrobial Effectiveness Testing 51 and Antimicrobial AgentsContent 341 .
Water content:
The water content of freeze-dried (lyophilized) products should be determined when appropriate (see Water Determination 921 ).
Aluminum content:
Large-volume parenterals used to make total parenteral nutrition therapy (TPN) are limited to 25 µg/L. Small-volume parenterals and pharmacy bulk packages used to make TPN must state on the immediate container label the maximum level of aluminum at expiry if the maximum level exceeds 25 µg/L.
Completeness and clarity of solutions:
The following tests are performed to demonstrate suitability of constituted solutions prepared before administration. Constitute the solution as directed in the labeling supplied by the manufacturer:
-
The solid dissolves completely, leaving no undissolved matter.
-
The constituted solution is not significantly less clear than an equal volume of the diluent or of Purified Water contained in a similar vessel and examined similarly. Protein solutions may exhibit an inherent opalescence.
PRODUCT QUALITY TESTS FOR SPECIFIC PARENTERAL DOSAGE FORMS
Product quality tests for the specific dosage forms are listed below. Specific chapter(s) referenced for the test can be found in the Universal Tests and Specific Tests sections. When there is no compendial test available, a validated procedure with acceptance criteria should be used.
Solutions
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:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: Specific Gravity, Viscosity, pH, Osmolarity and Osmolality
Antimicrobial Preservatives
Sterile Powders for Solution
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:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: Specific Gravity, Viscosity, pH, Osmolarity and Osmolality
The following applies to constituted solutions:
Crystallinity:
The crystallinity of a material can be characterized to determine compliance with the crystallinity requirement where stated in the individual monograph of a drug substance.
-
Optical Microscopy
776 : Crystallinity can be characterized by polarized light microscopy for qualitative evaluation of the size, shape, and crystallinity of solids. Unless otherwise specified in the individual monograph, analysts should mount a solid specimen in mineral oil on a clean glass slide or cover slip and should examine the mixture using a polarizing microscope: The particles show birefringence (interference colors) and extinction positions when the microscope stage is revolved.
Vehicles and diluents:
Guidelines for constitution and suspension of dry powders are found in the specific monographs. If there is a specific packaged diluent for use with a particular product that is not included in a monograph, then the final article is prepared with that diluent.
Suspensions
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:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: pH
Uniformity of Dosage Units
Antimicrobial Preservatives
Liposomes
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:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: pH
Lipid and Fatty Acid Composition, including degree of unsaturation and positional specificity in acyl side chains and critical degradation products such as lysolipids2
Particle Size Distribution of Liposomal Vesicles2
Phospholipid Composition2
Percent Free vs. Percent Encapsulated Lipids2
Free Drug vs. Encapsulated Drug
Ionic Strength and Osmotic Strength2
Sterile Powders for Suspension
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:
-
Universal Tests
-
Specific Tests
-
Bacterial Endotoxins
Physicochemical Properties: pH, Osmolarity and Osmolality
The following applies to constituted suspensions:
Crystallinity:
The crystallinity of a material can be characterized to determine compliance with the crystallinity requirement where stated in the individual monograph of a drug substance.
-
Optical Microscopy
776 : Crystallinity can be characterized by polarized light microscopy for qualitative evaluation of the size, shape, and crystallinity of solids. Unless otherwise specified in the individual monograph, analysts should mount a solid specimen in mineral oil on a clean glass slide or cover slip and should examine the mixture using a polarizing microscope: The particles show birefringence (interference colors) and extinction positions when the microscope stage is revolved.
Vehicles and diluents:
Guidelines for constitution and suspension of dry powders are found in the specific monographs. If there is a specific packaged diluent for use with a particular product that is not included in a monograph, then the final article is prepared with that diluent.
Microparticles:
Some microparticles are provided as a sterile powder to be reconstituted as a suspension before injection. Major microparticle preparations are for reconstitution as a suspension for injection. For quality test requirements, please refer to Implants.
Emulsions
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:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: pH, Osmolarity and Osmolality
Globule Size Distribution
Amount of Fat Globules (lipids)2
Percent Free vs. Percent Encapsulated Lipids2
Free Drug vs. Encapsulated Drug
Implants
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:
-
Universal Tests
-
Specific Tests
Depending on the drug product, the following tests may be required:
In situ gels:
Sterile in situ gels are liquid preparations that are intended for injection into specific therapeutic targets. Typically they consist of polymers in organic solvents, and upon injection the solvents migrate away from the site, leaving a gelled mass. The preparations may be injected as-is, upon reconstitution, from in situ formation, or from chemically initiated catalysis that results in the final form.
Unless otherwise justified, the following tests are required for in situ gels:
-
Universal Tests
-
Specific Tests
Physicochemical Properties: Viscosity
Antimicrobial Preservatives
Catalyst Initiator Content and Activity2
Microparticles:
Injectable, resorbable microparticles for extended release generally range from 20 to 100 µm in diameter. They consist of drug substances embedded within a biocompatible, bioresorbable polymeric excipient, e.g., polyester excipients. Microparticles are provided as a sterile powder in a vial or syringe.
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:
-
Universal Tests
-
Specific Tests
Depending on the drug product, the following tests may be required:
-
Particle Size Distribution
-
Physicochemical Properties: pH, Osmolality and Osmolarity
Drug-Eluting Stents
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:
-
Universal Tests
-
Specific Tests
PRODUCT PERFORMANCE TEST
A performance test for injection and implanted products must have the ability to measure drug release from the manufactured pharmaceutical dosage forms. It must be reproducible and reliable, and although it is not a measure of bioavailability, the performance test must be capable of detecting changes in drug release characteristics from the finished product. These changes have the potential to alter the biological performance of the drug in the dosage form. They may be related to active or inactive/inert ingredients in the formulation, physical or chemical attributes of the finished formulation, manufacturing variables, shipping and storage effects, aging effects, and other formulation factors critical to the quality characteristics of the finished drug product.
Please refer to The Dissolution Procedure: Development and Validation 1092![](../../images/chars/rang.gif) while developing the drug release test, selecting the drug release medium, apparatus or procedure, and analytical method. Product performance tests can serve many useful purposes in product development and in post-approval drug product monitoring. They provide assurance of equivalent performance for products that have undergone post-approval raw material changes, relocation or change in manufacturing site, and other changes as detailed in the FDA SUPAC Guidances for Industry (SUPAC-IR, SUPAC-MR, and SUPAC-SS; available at www.fda.gov/cder/guidance). In this chapter, a USP performance test for injection and implanted products forms to support batch release is to be considered. USP38
1
All listed chapters above 1000 are for information purposes only; they may be helpful but are not mandatory.
2
No compendial test available; a validated procedure with acceptance criteria should be used.
|