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`§
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`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C'.,
`March 8-10, 1990. Prepared by the Committee of
`Revision a-nd published by the Board of Trustees
`
`Official from January 1, I 995
`
`
`
`SlNCE1820
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`I
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`-
`
`NPS EX. 2062
`
`CFADV.NPS
`IPR2015—01093
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Page 1
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`Page 1
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`NPS EX. 2062
`CFAD v. NPS
`IPR2015-01093
`
`

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`
`
`General Chapters
`
`
`
`General Tests and Assays
`
`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 dispe:nsing 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 buIk_ package 15 limited to prep-
`arations from Nomenlqlature categories 1, 2, or 3 as defined above.
`Pharmacy bulk pac ages, 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 mi-
`croorganisms.
`Where a container is offered as a Pharmacy bulk package, the
`label shall (a) state pr:ominently “Pharmacy Bulk.Package—Not
`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 t e time frame in which the container may
`be used once it has been entered, provided it is held under the
`labeled storage conditions.
`
` .-2.
`
`LARGE- AND SMALL-VOLUME INJECTIONS
`
`Where used in this Pharmacopeia, the designation Large-vol-
`ume intravenous solifition applies to a single-dose injection that
`is intended for intra enous 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 con-
`tainers labeled as containing 100 mL or less.
`
`BIOLOGICS
`
`The Pharmacopeial definitions for sterile preparations for par-
`enteral use generally do not apply in the case of the biologics
`because of their special nature and licensing requirements (see
`Biologics (1041)).
`
`INGREDIENTS
`
`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 Injec-
`tion generally is usedl‘ 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 Waterfor Injection unless otherwise
`specified in the individual monograph. For conditions applying
`to other adjuvants, se'e Added Substances in this charpter. 2
`age
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`
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`General Requirements
`for Tests and Assays
`
`
`
`(1 )
`
`INJECTIONS
`
`INTRODUCTION
`
`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 pre-
`pared 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 administra-
`tion.
`
`NOMENCLATURE AND DEFINITIONS
`
`Nomenclature
`
`The following nomenclature pertains to five general types of
`preparations, all of which are suitable for, and intended for, par-
`enteral administration. They may contain buffers, preservatives,
`or other added substances.
`1.
`[DRUG] Injection—Liquid preparations that are drug sub-
`stances or solutions thereof.
`.
`.
`2.
`[DRUG] for Injection—Dry solids that, upon the addition
`of suitable vehicles, yield solutions conforming in all respects to
`the requirements for Injections.
`3.
`[DRUG] Injectable Emulsion—Liquid preparations of drug
`substances dissolved or dispersed in a suitable emulsion medium.
`4.
`[DRUG] Injectable Suspension—Liquid preparations of
`solids suspended in a suitable liquid medium.
`5.
`[DRUG] for Injectable Suspension—Dry solids that, upon
`the addition of suitable vehicles, yield preparations conforming
`in all respects to the requirements for Injectable Suspensions.
`
`Definitions
`
`PHARMACY BULK PACKAGE
`
`A Pharmacy bulk package is a container of a sterile prepa-
`ration for parenteral use that contains many single doses. The
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`1650
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`USP 23
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`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 Sapomfication value of between
`185 and 200 (see Fats and Fixed Oils (401)), have an Iodine
`value of between 79 and 128 (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 al-
`cohol 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 hy-
`droxide (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 prep-
`arations 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 in-
`tended for parenteral administration (see also Added Substances
`under General Notices and Antimicrobial Preservat.ives—Effec—
`tiveness (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 cat-
`ionic, surface-active compounds, 0.01%; for those of the types of
`chlorobutanol, cresol, and phenol, 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 in-
`tended for injection that are packaged in multiple-dose con-
`tainers, regardless of the method of sterilization employed, unless
`otherwise directed in the individual monograph, or unless 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 sub-
`stances also meet the requirements of Antimicrobial Preserva-
`tives—Ej_"fectiveness (51) and Antimicrobial Agents—Content
`(341). Sterilization processes are employed even though such
`substances are used (see also Parenteral and Topical Prepara-
`tions in the section Added Substances under General Notices and
`Sterilization and Sterility Assurance of Compendial Articles
`(1211)). The air in the container may be evacuated or be dis-
`placed by a chemically inert gas. Where specified in a mono-
`graph, information regarding sensitivity of the article to oxygen
`Is to be provided in the labeling.
`
`General Reduirements / Injections
`
`(1)
`
`1651
`
`concentration of each ingredient named in the official title is
`statedias 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.spe|cified in the individual monograph: (1) In the
`case_of a liquid preparation, the percentage conteiit_of each in-
`gredient or the aniount 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 w ich a diluent is intended to be added before
`use, the amount of each ingredient, the composition of recom-
`mended 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_descr_iptio_n of the physical ap-
`pearance 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
`gave tlzie required or labeled potency if it has been stored as
`irecte .
`Containers for njections that are intended for use as dialysis,
`hemofiltration, or [irrigation solutions and that contain a volume
`of more tclliaéifl liter age labeled to indifate that the contents are
`not inten e
`or use y intravenous in usion.
`Injections intended for veterinary use are labeled to that effect.
`Thelcontainer is so labeled that a sufficient area of the con-
`tainer ‘remains uncl:overed for its full length or circumference to
`permit inspection of the contents.
`
`PACKAGING
`
`‘
`~ (Containers for Injections
`Containers, incllliding the closures, for preparations for injec-
`tions do not interact physically or chemically with the prepara-
`tions in any manner to alter the strength, quality, or purity beyond
`the official requirbments under the ordinary or customary con-
`ditions, of handling, shipment, storage, sale, and use. The con-
`tainer is made of material that permits inspection of the contents.
`The type of glasslpreferable for each parenteral preparation is
`usually stated in the individual monograph.
`.
`For definitions of single-dose and multiple-dose containers, see
`Containers under General Notices. Containers meet the require-
`ments under Contbiners (661)..
`_
`_
`_
`Containers are closed by fusion, or by application of suitable
`closures, in such manner as to prevent contamination or loss of
`contents. Closures for multiple-dose containers permit the with-
`drawal of the coritents without removal or destruction of the
`closure. The closu'-re permits penetration by a needle, and, upon
`withdrawal of the needle, at once recloses the container against
`contamination.
`
`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 lampul,
`is p:rohibited except for Potassium Chloride for
`Injection Concentrate.
`
`Containers for Sterile Solids
`
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`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,_a_nd use.
`A container for a sterile solid permits the addition of a suitable
`solvent and withdirawal of portions of theresulting solution or
`suspenjsiond in such manner that the sterility of the product is
`maintaine .
`Where the Assay in a monograph provides a procedure for
`Assay preparatio in which the total withdrawable contents are
`to be withdrawn frlom a single-do_se container with a hypodermic
`needle and syringe, the contents are to be withdrawn as com-
`pletely as possible[into a dry hypodermic syringe of a rated ca-
`pacity not exceeding threetimes the volume to be withdrawn and
`fitted with a 21-gauge needle not less than 2.5 cm (1_ inch) in
`length, care being iaken to expel any air bubbles, and discharged
`into a container folr dilution and assay.
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`LABELS AND LABELING
`
`Labeling—[NOTE—See definitions of “label” and “labeling”
`under Labeling in the section Preservation, Packaging, Storage,
`and Labeling of the General Notices.]
`_ 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 state-
`ment of storage conditions and an expiration date; the name of
`the manufacturer and distributor; and an identifying lot number.
`The lot number is capable of yielding the complete manufacturing
`history of the specific package,-including all manufacturing, fill-
`"18. sterilizing, and labeling operations.
`_ Where the individual monograph permits varying concentra-
`t10ns of active ingredients in the large-volume parenteral, the
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