Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. Parenteral articles are prepared scrupulously by methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of the growth of microorganisms. An Injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration.
NOMENCLATURE AND DEFINITIONS
The following nomenclature pertains to five general types of preparations, all of which are suitable for, and intended for, parenteral administration. They may contain buffers, preservatives, or other added substances.
pharmacy bulk package
A Pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes.
The closure shall be penetrated only one time after constitution with a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents. The Pharmacy bulk package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area).
Designation as a Pharmacy bulk package is limited to preparations from Nomenclature categories 1, 2, or 3 as defined above. Pharmacy bulk packages, although containing more than one single dose, are exempt from the multiple-dose container volume limit of 30 mL and the requirement that they contain a substance or suitable mixture of substances to prevent the growth of microorganisms.
Where a container is offered as a Pharmacy bulk package, the label shall (a) state prominently Pharmacy Bulk PackageNot for direct infusion, (b) contain or refer to information on proper techniques to help assure safe use of the product, and (c) bear a statement limiting the time frame in which the container may be used once it has been entered, provided it is held under the labeled storage conditions.
large- and small-volume injections
Where used in this Pharmacopeia, the designation Large-volume intravenous solution applies to a single-dose injection that is intended for intravenous use and is packaged in containers labeled as containing more than 100 mL. The designation Small-volume Injection applies to an Injection that is packaged in containers labeled as containing 100 mL or less.
The Pharmacopeial definitions for sterile preparations for parenteral use generally do not apply in the case of the biologics because of their special nature and licensing requirements (see Biologics 1041).
Vehicles and Added Substances
Aqueous Vehicles The vehicles for aqueous Injections meet the requirements of the Pyrogen Test 151 or the Bacterial Endotoxins Test 85, whichever is specified. Water for Injection generally is used as the vehicle, unless otherwise specified in the individual monograph. Sodium chloride may be added in amounts sufficient to render the resulting solution isotonic; and Sodium Chloride Injection, or Ringer's Injection, may be used in whole or in part instead of Water for Injection, unless otherwise specified in the individual monograph. For conditions applying to other adjuvants, see Added Substances in this chapter.
Other Vehicles Fixed oils used as vehicles for nonaqueous Injections are of vegetable origin, are odorless or nearly so, and have no odor suggesting rancidity. They meet the requirements of the test for Solid paraffin under Mineral Oil, the cooling bath being maintained at 10, have a Saponification Value between 185 and 200 (see Fats and Fixed Oils 401), have an Iodine Value between 79 and 141 (see Fats and Fixed Oils 401), and meet the requirements of the following tests.
Unsaponifiable Matter Reflux on a steam bath 10 mL of the oil with 15 mL of sodium hydroxide solution (1 in 6) and 30 mL of alcohol, with occasional shaking until the mixture becomes clear. Transfer the solution to a shallow dish, evaporate the alcohol on a steam bath, and mix the residue with 100 mL of water: a clear solution results.
Free Fatty Acids The free fatty acids in 10 g of oil require for neutralization not more than 2.0 mL of 0.020 N sodium hydroxide (see Fats and Fixed Oils 401).
Synthetic mono- or diglycerides of fatty acids may be used as vehicles, provided they are liquid and remain clear when cooled to 10 and have an Iodine Value of not more than 140 (see Fats and Fixed Oils 401).
These and other nonaqueous vehicles may be used, provided they are safe, in the volume of Injection administered, and also provided they do not interfere with the therapeutic efficacy of the preparation or with its response to prescribed assays and tests.
Added Substances Suitable substances may be added to preparations intended for injection to increase stability or usefulness, unless proscribed in the individual monograph, provided they are harmless in the amounts administered and do not interfere with the therapeutic efficacy or with the responses to the specified assays and tests. No coloring agent may be added, solely for the purpose of coloring the finished preparation, to a solution intended for parenteral administration (see also Added Substances under General Notices and Antimicrobial Effectiveness Testing 51).
Observe special care in the choice and use of added substances in preparations for injection that are administered in a volume exceeding 5 mL. The following maximum limits prevail unless otherwise directed: for agents containing mercury and the cationic, surface-active compounds, 0.01%; for chlorobutanol, cresol, phenol, and similar types of substances, 0.5%; and for sulfur dioxide, or an equivalent amount of the sulfite, bisulfite, or metabisulfite of potassium or sodium, 0.2%.
A suitable substance or mixture of substances to prevent the growth of microorganisms must be added to preparations intended for injection that are packaged in multiple-dose containers, regardless of the method of sterilization employed, 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 hours; and (3) the active ingredients are themselves antimicrobial. Such substances are used in concentrations that will prevent the growth of or kill microorganisms in the preparations for injection. Such substances also meet the requirements of Antimicrobial Effectiveness Testing 51 and Antimicrobial AgentsContent 341. Sterilization processes are employed even though such substances are used (see also Sterilization and Sterility Assurance of Compendial Articles 1211). The air in the container may be evacuated or be displaced by a chemically inert gas. Where specified in a monograph, information regarding sensitivity of the article to oxygen is to be provided in the labeling.
LABELS AND LABELING
noteSee definitions of label and labeling in Labeling in the section Preservation, Packaging, Storage, and Labeling of the General Notices and Requirements.
The label states the name of the preparation; in the case of a liquid preparation, the percentage content of drug or amount of drug in a specified volume; in the case of a dry preparation, the amount of active ingredient; the route of administration; a statement of storage conditions and an expiration date; the name and place of business of the manufacturer, packer, or distributor; and an identifying lot number. The lot number is capable of yielding the complete manufacturing history of the specific package, including all manufacturing, filling, sterilizing, and labeling operations.
Where the individual monograph permits varying concentrations of active ingredients in the large-volume parenteral, the concentration of each ingredient named in the official title is stated as if part of the official title, e.g., Dextrose Injection 5%, or Dextrose (5%) and Sodium Chloride (0.2%) Injection.
The labeling includes the following information if the complete formula is not specified in the individual monograph: (1) In the case of a liquid preparation, the percentage content of each ingredient or the amount of each ingredient in a specified volume, except that ingredients added to adjust to a given pH or to make the solution isotonic may be declared by name and a statement of their effect; and (2) in the case of a dry preparation or other preparation to which a diluent is intended to be added before use, the amount of each ingredient, the composition of recommended diluent(s) [the name(s) alone, if the formula is specified in the individual monograph], the amount to be used to attain a specific concentration of active ingredient and the final volume of solution so obtained, a brief description of the physical appearance of the constituted solution, directions for proper storage of the constituted solution, and an expiration date limiting the period during which the constituted solution may be expected to have the required or labeled potency if it has been stored as directed.
Containers for Injections that are intended for use as dialysis, hemofiltration, or irrigation solutions and that contain a volume of more than 1 L are labeled to indicate that the contents are not intended for use by intravenous infusion.
Injections intended for veterinary use are labeled to that effect.
The container is so labeled that a sufficient area of the container remains uncovered for its full length or circumference to permit inspection of the contents.
strength and total volume for single- and multiple-dose injectable drug products
For single-dose and multiple-dose injectable drug products, the strength per total volume should be the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per mL enclosed by parentheses. For containers holding a volume of less than 1 mL, the strength per fraction of a mL should be the only expression of strength. Strength per single mL should be expressed as mg/mL, not mg/1 mL.
The following formats are acceptable for contents of greater than 1 mL:
Total strength/total volume: 500 mg/10 mL
Strength/mL: 50 mg/mL
Total strength/total volume: 25,000 Units/5 mL
Strength/mL: 5,000 Units/mL
The following format is acceptable for contents of less than 1 mL: 12.5 mg/0.625 mL
There are, however, some exceptions to expressing strength per total volume. In certain cases, the primary and prominent expression of the total drug content per container would not be effective in preventing medication errors (e.g., insulin). An example is the use of lidocaine or other similar drugs used as a local anesthetic where the product is ordered and administered by percentage (e.g., 1%, 2%) or a local anesthetic in combination with epinephrine that is expressed as a ratio (e.g., 1:100,000). In such cases, the total strength should be expressed: for example, 1% (100 mg/10 mL). Dry solids, which need to be reconstituted, should follow the same format, with the exception that only the total strength of the drug should be listed, not the strength/total volume or strength/mL.
(Official February 1, 2009)
Aluminum in Large-Volume Parenterals (LVPs), Small-Volume Parenterals (SVPs), and Pharmacy Bulk Packages (PBPs) Used in Total Parenteral Nutrition (TPN) Therapy
The package insert for all LVPs, SVPs, and PBPs used in the preparation of TPN products must contain a warning statement. This warning must be contained in the Warning section of the labeling and must state the following: WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions that contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg per kg per day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of TPN products.
Containers for Injections
Containers, including the closures, for preparations for injections do not interact physically or chemically with the preparations in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling, shipment, storage, sale, and use. The container is made of material that permits inspection of the contents. The type of glass preferable for each parenteral preparation is usually stated in the individual monograph. Unless otherwise specified in the individual monograph, plastic containers may be used for packaging injections (see ContainersPlastics 661).
Containers are 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 chemical or physical impurities. In addition, the solutes and the vehicle must maintain their specified total and relative quantities or concentrations when exposed to anticipated extreme conditions of manufacturing and processing, and storage, shipment, and distribution. Closures for multiple-dose containers permit the withdrawal of the contents without removal or destruction of the closure. The closure permits penetration by a needle and, upon withdrawal of the needle, closes at once, protecting the container against contamination. Validation of the multiple-dose container integrity must include verification that such a package prevents microbial contamination or loss of product contents under anticipated conditions of multiple entry and use.
Piggyback containers are usually intravenous infusion containers used to administer a second infusion through a connector of some type or an injection port on the administration set of the first fluid, thereby avoiding the need for another injection site on the patient's body. Piggyback containers are also known as secondary infusion containers.
Potassium Chloride for Injection Concentrate
The use of a black closure system on a vial (e.g., a black flip-off button and a black ferrule to hold the elastomeric closure) or the use of a black band or series of bands above the constriction on an ampul is prohibited, except for Potassium Chloride for Injection Concentrate.
Neuromuscular Blocking and Paralyzing Agents
All injectable preparations of neuromuscular blocking agents and paralyzing agents must be packaged in vials with a cautionary statement printed on the ferrules or cap overseals. Both the container cap ferrule and the cap overseal must bear in black or white print (whichever provides the greatest color contrast with the ferrule or cap color) the words: Warning: Paralyzing Agent or Paralyzing Agent (depending on the size of the closure system). Alternatively, the overseal may be transparent and without words, allowing for visualization of the warning labeling on the closure ferrule.
Containers for Sterile Solids
Containers, including the closures, for dry solids intended for parenteral use do not interact physically or chemically with the preparation in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling, shipment, storage, sale, and use.
A container for a sterile solid permits the addition of a suitable solvent and withdrawal of portions of the resulting solution or suspension in such manner that the sterility of the product is maintained.
Where the Assay in a monograph provides a procedure for the Assay preparation, in which the total withdrawable contents are to be withdrawn from a single-dose container with a hypodermic needle and syringe, the contents are to be withdrawn as completely as possible into a dry hypodermic syringe of a rated capacity not exceeding three times the volume to be withdrawn and fitted with a 21-gauge needle not less than 2.5 cm (1 inch) in length, with care being taken to expel any air bubbles, and discharged into a container for dilution and assay.
Volume in Container
Each container of an injection is filled with sufficient excess of the labeled size or that volume which is to be withdrawn. See Injections under Pharmaceutical Dosage Forms 1151.
determination of volume of injection in containers
Suspensions and emulsions must be shaken before withdrawal of the contents and before the determination of the density. Oily and viscous preparations may be warmed according to the instructions on the label, if necessary, and thoroughly shaken immediately before removing the contents. The contents are then cooled to 2025C before measuring the volume.
Single-Dose Containers Select 1 container if the volume of the container is 10 mL or more, 3 containers if the nominal volume is more than 3 mL and less than 10 mL, or 5 containers if the nominal volume is 3 mL or less. Take up individually the total contents of each container selected into a dry syringe of a capacity not exceeding three times the volume to be measured and fitted with a 21-gauge needle not less than 2.5 cm (1 inch) in length. Expel any air bubbles from the syringe and needle, and then discharge the contents of the syringe, without emptying the needle, into a standardized, dry cylinder (graduated to contain rather than to deliver the designated volumes) of such size that the volume to be measured occupies at least 40% of its graduated volume. Alternatively, the volume of the contents in mL may be calculated as the mass, in g, divided by the density. For containers with a nominal volume of 2 mL or less, the contents of a sufficient number of containers may be pooled to obtain the volume required for the measurement, provided that a separate, dry syringe assembly is used for each container. The contents of containers holding 10 mL or more may be determined by means of opening them and emptying the contents directly into the graduated cylinder or tared beaker.
The volume is not less than the nominal volume in the case of containers examined individually or, in the case of containers with a nominal volume of 2 mL or less, is not less than the sum of the nominal volumes of the containers taken collectively.
Multi-Dose Containers For Injections in multiple-dose containers labeled to yield a specific number of doses of a stated volume, select 1 container, and proceed as directed for single-dose containers, using the same number of separate syringe assemblies as the number of doses specified. The volume is such that each syringe delivers not less than the stated dose.
Injections in Cartridges or Prefilled Syringes Select 1 container if the volume is 10 mL or more, 3 containers if the nominal volume is more than 3 mL and less than 10 mL, or 5 containers if the nominal volume is 3 mL or less. If necessary, fit the containers with the accessories required for their use (needle, piston, syringe) and transfer the entire contents of each container without emptying the needle into a dry tared beaker by slowly and constantly depressing the piston. Determine the volume in mL, calculated as the mass, in g, divided by the density.
The volume measured for each of the containers is not less than the nominal volume.
Large-Volume Intravenous Solutions For intravenous solutions, select 1 container. Transfer the contents into a dry measuring cylinder of such a capacity that the volume to be determined occupies at least 40% of the nominal volume of the cylinder. Measure the volume transferred.
The volume is not less than the nominal volume.
Labeling on Ferrules and Cap Overseals
Only cautionary statements are to appear on the top (circle) surface of the ferrule or cap overseal of a vial containing an injectable product. A cautionary statement is one intended to prevent an imminent life-threatening situation if the injectable drug is used inappropriately. Examples of such statements include but are not limited to the following: Warning, Dilute Before Using, Paralyzing Agent, I.M. Use Only, and Chemotherapy.
The text must be in contrasting color and conspicuous under ordinary conditions of use. The cautionary statement may appear solely on the ferrule, provided the cap overseal is constructed so as to allow the cautionary statement beneath the cap to be readily legible.
Identifying numbers or letters, such as code numbers, lot numbers, etc., may appear on the side (skirt) surface of the ferrule on vials containing injectable products. The appearance of such identifying data on the skirt surface of the ferrule, placed where it does not detract from, or interfere with, the cautionary statement on the top surface, should be considered to be a beneficial attribute of the in-process quality control of a product throughout the manufacturing process. Any anticounterfeiting scheme must not detract from or interfere with the cautionary statements.
Under no circumstances would advertising such as company names, logos, or product names be permitted to appear on the top (circle) surface of any ferrule or cap overseal.
(Official February 1, 2009)
Packaging and Storage
The volume of injection in single-dose containers provides the amount specified for parenteral administration at one time and in no case is more than sufficient to permit the withdrawal and administration of 1 L.
Preparations intended for intraspinal, intracisternal, or peridural administration are packaged only in single-dose containers.
Unless otherwise specified in the individual monograph, a multiple-dose container contains a volume of Injection sufficient to permit the withdrawal of not more than 30 mL.
The following injections are exempt from the 1-L restriction of the foregoing requirements relating to packaging:
Injections packaged for intravascular use that may be used for intermittent, continuous, or bolus replacement fluid administration during hemodialysis or other procedures, unless excepted above, must conform to the 1-L restriction.
Injections labeled for veterinary use are exempt from packaging and storage requirements concerning the limitation to single-dose containers and the limitation on the volume of multiple-dose containers.
FOREIGN AND PARTICULATE MATTER
All articles intended for parenteral administration shall be prepared in a manner designed to exclude particulate matter as defined in Particulate Matter in Injections 788 and other foreign matter. Each final container of all parenteral preparations shall 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 shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates. Qualification of the inspection process shall be performed with reference to particulates in the visible range of a type that might emanate from the manufacturing or filling process. Every container whose contents shows evidence of visible particulates shall be rejected. The inspection for visible particulates may take place when inspecting for other critical defects, such as cracked or defective containers or seals, or when characterizing the appearance of a lyophilized product.
Where the nature of the contents or the container-closure system permits only limited capability for the inspection of the total contents, the 100% inspection of a lot shall be supplemented with the inspection of constituted (e.g., dried) or withdrawn (e.g., dark amber container) contents of a sample of containers from the lot.
All large-volume Injections for single-dose infusion and small-volume Injections are subject to the light obscuration or microscopic procedures and limits for subvisible particulate matter set forth in Particulate Matter In Injections 788, unless otherwise specified 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, if the individual monograph states a test for Particulate Matter 788; 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. Injections administered exclusively by the intramuscular or subcutaneous route or packaged and labeled for use as irrigating solutions are exempt from requirements for Particulate Matter 788.
Sterility Tests Preparations for injection meet the requirements under Sterility Tests 71.
Dry solids from which constituted solutions are prepared for injection bear titles of the form [DRUG] for Injection. Because these dosage forms are constituted at the time of use by the health care practitioner, tests and standards pertaining to the solution as constituted for administration are not included in the individual monographs on sterile dry solids or liquid concentrates. However, in the interest of assuring the quality of injection preparations as they are actually administered, the following nondestructive tests are provided for demonstrating the suitability of constituted solutions when they are prepared just prior to use.
Completeness and Clarity of Solution Constitute the solution as directed in the labeling supplied by the manufacturer for the sterile dry dosage form.
A: The solid dissolves completely, leaving no visible residue as undissolved matter.
B: 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.
Particulate Matter Constitute the solution as directed in the labeling supplied by the manufacturer for the sterile dry dosage form: the solution is essentially free from particles of foreign matter that can be observed on visual inspection.
* This nomenclature has been adopted by the USP Drug Nomenclature Committee for implementation by supplemental revisions of USP 23-NF 18. For currently official monograph titles in the form Sterile [DRUG] that have not yet been revised, the following nomenclature continues in use in this Pharmacopeia: (1) medicaments or solutions or emulsions thereof suitable for injection, bearing titles of the form [DRUG] Injection; (2) dry solids or liquid concentrates containing no buffers, diluents, or other added substances, and which, upon the addition of suitable solvents, yield solutions conforming in all respects to the requirements for Injections, and which are distinguished by titles of the form Sterile [DRUG]; (3) preparations the same as those described under (2) except that they contain one or more buffers, diluents, or other added substances, and which are distinguished by titles of the form [DRUG] for Injection; (4) solids which are suspended in a suitable fluid medium and which are not to be injected intravenously or into the spinal canal, distinguished by titles of the form Sterile [DRUG] Suspension; and (5) dry solids which, upon the addition of suitable vehicles, yield preparations conforming in all respects to the requirements for Sterile Suspensions, and which are distinguished by titles of the form Sterile [DRUG] for Suspension.
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