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
APharmacy bulk packageis 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 packageis 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 packageis limited to preparations from Nomenclaturecategories 1,2,or 3as defined above.Pharmacy bulk packages,although containing more than one single dose,are exempt from the multiple-dose container volume limit of 30mLand 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 solutionapplies to a single-dose injection that is intended for intravenous use and is packaged in containers labeled as containing more than 100mL.The designation Small-volume Injectionapplies to an Injection that is packaged in containers labeled as containing 100mLor 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 á1041ñ).
Vehicles and Added Substances
Aqueous Vehicles The vehicles for aqueous Injections meet the requirements of the Pyrogen Test á151ñor the Bacterial Endotoxins Test á85ñ,whichever is specified.Water for Injectiongenerally 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 Substancesin 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 paraffinunder Mineral Oil,the cooling bath being maintained at 10,have a Saponification Valuebetween 185and 200(see Fats and Fixed Oils á401ñ),have an Iodine Valuebetween 79and 141(see Fats and Fixed Oils á401ñ),and meet the requirements of the following tests.
Unsaponifiable Matter Reflux on a steam bath 10mLof the oil with 15mLof sodium hydroxide solution (1in 6)and 30mLof 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 100mLof water:a clear solution results.
Free Fatty Acids The free fatty acids in 10g of oil require for neutralization not more than 2.0mLof 0.020Nsodium hydroxide (see Fats and Fixed Oils á401ñ).
Synthetic mono-or diglycerides of fatty acids may be used as vehicles,provided they are liquid and remain clear when cooled to 10and have an Iodine Valueof not more than 140(see Fats and Fixed Oils á401ñ).
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 Substancesunder General Noticesand Antimicrobial Effectiveness Testing á51ñ).
Observe special care in the choice and use of added substances in preparations for injection that are administered in a volume exceeding 5mL.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%.
Asuitable 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 24hours;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 á51ñand Antimicrobial AgentsContent á341ñ.Sterilization processes are employed even though such substances are used (see also Sterilization and Sterility Assurance of Compendial Articles á1211ñ).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
Labeling [NOTESee definitions of labeland labelingunder Labelingin 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 activeingredient;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 pHor 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 1Lare 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.
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 Containers á661ñ).
For definitions of single-dose and multiple-dose containers,see Containers in theGeneral Notices and Requirements.Containers meet the requirements under Containers á661ñ.
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 forPotassium 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 Agentor 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.
(Official October 1,2005)
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.
Acontainer 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 theAssay in a monograph provides a procedure for theAssay 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 2.5cm (1inch)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 sizeor that volume which is to be withdrawn.See Injections underPharmaceutical Dosage Forms á1151ñ.
DETERMINATION OF VOLUME OF INJECTION IN CONTAINERS
Select one or more containers if the volume of the container is 10mLor more,three or more if the volume is more than 3mLand less than 10mL,or five or more if the volume is 3mLor less.Individually take up the contents of each container selected into a dry hypodermic syringe of a rated capacity not exceeding three times the volume to be measured and fitted with a 21-gauge needle not less than 2.5cm (1inch)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 the cylinder's rated volume.Alternatively,the contents of the syringe may be discharged into a dry,tared beaker,the volume,in mL,being calculated as the weight,in g,of Injection taken divided by its density.The contents of up to five 1-or 2-mLcontainers may be pooled for the measurement,provided that a separate dry syringe assembly is used for each container.The content of containers holding 10mLor 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 labeled volume in the case of containers examined individually or,in the case of 1-and 2-mLcontainers,is not less than the sum of the labeled volumes of the containers taken collectively.
For Injections in multiple-dose containers labeled to yield a specific number of doses of a stated volume,proceed as directed in the foregoing,using the same number of separate syringes as the number of doses specified.The volume is such that each syringe delivers not less than the stated dose.
For Injections containing oil,warm the containers,if necessary,and thoroughly shake them immediately before removing the contents.Cool to 25before measuring the volume.
For Injections in cartridges or prefilled syringes,assemble the container with any required accessories such as a needle or plunger.Following the same procedure as above,and without emptying the needle,transfer the entire contents of each container to a dry,tared beaker by slowly and constantly depressing the plunger.Weigh,and calculate the volume as described above.The volume of each container is not less than the labeled volume.
For large-volume intravenous solutions,select 1container,and transfer the contents into a dry measuring cylinder of such size that the volume to be measured occupies at least 40%of its rated volume.The volume is not less than the labeled volume.
Printing on Ferrules and Cap Overseals
Only cautionary statements are to be printed on the ferrules and cap overseals of vials containing an injectable drug product.Acautionary statement is one intended to prevent an imminent life-threatening situation if the injectable drug is used inappropriately.Examples of such statements are the following:Warning,Dilute Before Using,Paralyzing Agent,I.M.Use Only,Chemotherapy,etc.
The printing must be in contrasting color and conspicuous under ordinary conditions of use.The cautionary statement may be printed solely on the ferrule,provided the cap overseal is constructed so as to allow the cautionary statement below to be readily legible.
(Official October 1,2005)
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 1L.
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 30mL.
Injections packaged for use as irrigation solutions,for hemofiltration or dialysis,or for parenteral nutrition are exempt from the 1-Lrestriction of the foregoing requirements relating to packaging.
Containers for Injections packaged for use as hemofiltration or irrigation solutions may be designed to empty rapidly and may contain a volume of more than 1L.
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 MATTER AND PARTICLES
Every care should be exercised in the preparation of all products intended for injection to prevent contamination with microorganisms and foreign material.Good pharmaceutical practice requires also that each final container of Injection be subjected individually to a physical inspection,whenever the nature of the container permits,and that every container whose contents shows evidence of contamination with visible foreign material be rejected.
All large-volume Injections for single-dose infusion,and those small-volume Injections for which the monographs specify such requirements,are subject to the particulate matter limits set forth underParticulate Matter in Injections á788ñ.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 100ml or less if the individual monograph includes a test forParticulate Matter;it meets the requirements set forth for large-volume Injections for single-dose infusion where the container is labeled as containing more than 100mL.Injections packaged and labeled for use as irrigating solutions are exempt from requirements for Particulate Matter.
Sterility Tests Preparations for injection meet the requirements under Sterility Tests á71ñ.
Dry solids from which constituted solutions are prepared for injection bear titles of the form[DRUG]for Injection.Since 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 USP23-NF18.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.