General Requirements / (1) Injections
`
`2455
`
`l.
`2.
`
`3.
`
`4.
`5.
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`es or solutions thereof.
`
`[DRUG] Injection—Liquid preparations that are drug substanc-
`[DRUG]for 1njection—~Dry solids that, upon the addition of
`suitable vehicles, yield solutions conforming in all respects to
`the requirements for Injections.
`[DRUG] Injectable Emulsion—Liquid preparations of drug
`substances dissolved or dispersed in a suitable emulsion
`medium.
`[DRUG] Injectable Suspensz'on—Liquid preparations of solids
`suspended in a suitable liquid medium.
`_ [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
`APharmacybulkpackage isacontainerofa sterilepreparation 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 ofempty 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 ofthe contents. The Pharmacy bulkpackage 1S
`to beused only in a suitable work area such as a laminarflowhood (or
`an equivalent clean air compounding area).
`fiom Nomenclature categories l, 2, or 3 as defined above. Pharmacy
`Designation as a Pharmacy bulkpackage is’ limited to preparations
`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 ofmicroorganisms.
`Where a container is offered as aPharmacy bulkpackage, the label
`shall (a) state prominently “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
`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 SMALDVOLUME INJECTIONS
`_
`_
`_
`_
`_
`Where used in this Phaimacopeia, 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 33 °°m3i“i“g 100 “IL °‘ 1355-
`
`FRESENIUS KABI 1035-0001
`
`Ge
`Te and AS
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`(1) INJECTIONS
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`
`
`INTRODUCTION
`Parenteral articles are preparations intended for injection through
`the skin or other external boundary tissue, rather than through the
`flllmfirrtary canal, so that theflactive substances they contain are
`inistered, usinggravity or force, directly into a blood vessel,
`A
`“E3
`n, tissue, or lesion. Parenteral articles are prepared scrupulously
`by
`rriethods designed to ensure that
`they meet Pharrnacopeial
`cmgzlifritlltlents for sterility, pyrogens, particulate matter, and other
`inant
`#0 h
`§, and, where appropriate,‘ contain inhibitors of the
`“rm Ofmicroorganisms. An I11_]€CtlOl’l
`is apreparation intended for
`me teral a'IIl1I11S-tratlon and/or for constituting or diluting a
`“ efal article prior to administration.
`NOMENCLATURE AND DEFINITIONS
`Nomenclature:
`e f
`_
`types of
`memmtizgowing nomenclature pertains to five general
`Idmmistr t_S, all ofwhich are suitable for, and intended for, parenteral
`med Su[:1 ion. They may Contain buffers, preservatives, or other
`stances.
`
`ms
`g:'mmlt"‘;>g1iei;cIamre has been adopted by the USP Drug Nomenciamre
`:3. °""entiy o11%“P1em
`'
`ye
`C
`entation by supplemental revisions of USP 23-NF 18.
`’¢,.m;cl;
`,1 reviS1;1iTT1tiJ]nograph titles in the form Sterile [DRUG] that have
`I mm
`:
`(1
`s
`I? following nomenclature continues in use in this
`“Ii
`c “On, bear-i) medicaments or solutions or emulsions thereof suitable
`Fmeentratesng t“1_es_ ofthe form [DRUG] Injection; (2) dry solids or
`Upon thee(;?;§,‘‘.11Y1g 110 buffers, diluentsi or other added SUbStat1C_eS,
`to th
`ition of suitable solvents, yield solutions conforming
`ere ui
`_
`_
`_
`_
`_
`_
`the fo
`§vte:l?;e"e‘g;§3rGI‘}l°§t'°“5a and ,‘”h1°hh.ar° dlstmgulihed
`sub )exceptthat[they cghtgizl glfipfirrigglgguffeigrrifilflznisogi
`,j:““};e§, and which are distinguished by titles hr the rohh
`harel’
`(4) solids which are suspended in a suitable fluid
`S
`be injected intravenously or into the spinal canal,
`on th
`the _f£_)mi Sterile [DRUG] Suspension; and (5) dry
`5 ad tion of. suitable vehicles, yield preparations
`7
`the requirements for Sterile Suspensions, and
`es of the form Sterile [DRUG]for Suspension.
`
`Y
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`

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`
`
`2456
`
`{1} Injections / General Rt?cgatre:nent.s*
`
`BIOLOGICS
`
`the Pharniacopcial. definitions for sterile preparations for paren-
`teral use generally do not apply in the case ofthe hiologies because of
`their special nature and licensing requircrnents (see Biologists
`{ I 04 I )).
`t
`t
`
`INGREDIENTS
`
`Vehicles and Added Substances
`
`A.s:s’umnce (gf'Coo2pena’tcl /lrifcfes’ {I21 l)). The air in the C
`may be evacuated or be displaced by a chemically inert gaqontaim
`specified in a monograph, information regarding Séllsitivjh
`hsé
`article to oxygen is to he provided in the labeling.
`iy 0
`
`AA
`
`US}; 2:}
`
`Change to read:
`
`LABELS AND LABELING
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`»
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`pyréitllt’
`
`.
`
`‘Aluminum in Lal'g€~—V(}ll!.!llC Ifllecg I,
`Small~V’olume Injections (SVISl» 51”] Pa
`Bulk Packages (PBPs) Used in T0”
`_
`8}
`Nutrition (TPN) Therapy
`.
`{mitt}
`(4%) The aluniinuin content of LVIS used in TPN t {M
`25 pg per l. ,
`>
`V
`0
`,
`_
`zit” 5'
`"s
`(h)
`packagelinscrt ofLVls used in FPN2l;?‘;:;poyt‘2il“§:::;:iW
`the drug product contains no more than 1 ‘in
`,3 “W ,
`L. This inlhrniation mustbe contamei
`one
`section of the labeling of all l.Vls used lflvrg».
`it the maxiinurn amount of aluininuffl ll‘. ‘
`per L or less instead of stating the <3?<‘¢!*‘r;h
`that each may contain,
`in pzii‘21gI;3llm thpprsl
`container label for SVIS and Plslfs use at
`the administratioti of TPN injectionb‘ {fig 8; “
`hclowjvand injectablc emulsions iris;/V3 01.198? ’”
`than 2:3 pg,/L ot“alu»minum”. If the 5’
`1 ma
`powder, the immediate container lithed81.
`c
`ifthe SV-I or l’l:3P is a lyophilizcd ?_W':mgilsit1
`of TPN injections and irIjGGl3l3’l‘3 “
`FRESENIUS KABI 1035-0002
`
`{C}
`
`Labeling—-[NQTt?~i»Sec definitions of “label” and «e .
`under Lczlieling in the section Preservation, Pazzlcagtags
`lictiieiing of the General Notices and Requfreinerstsj
`The label states the name ofthe preparation; in the case 01“
`preparation, the percentage content of drug or amount ofd a
`
`specified volume; in the case of a dry preparation, the 31
`
`active ingredient; the route of administration; a statement of st
`conditions and an expiration date; the name and place of basin
`the manufacturer, packer, or distributor; and an ideiltifyine
`number. The lot number is capable of yielding the comg 118-?
`manufacturing history of the specific package,
`includin pf?
`manufacturing, filling, sterilizing, and labeling operations.
`g M
`Where the iiiclividual monograph permits Varying (ggncentmtie E
`ofactive ingrcdients in the large-volume parenteral, the C()21C€Iilmll{?;’:
`of each ingredient named in the official title is stated as ifparr Qffigfi
`official
`title, e.g., Dextrose Injection 5%, or Dextrose (5%) mg
`
`Sodium Chloride (0.2%) Injection.
`The labeling includes the following int‘orrnation if the conipfea;
`formula is not specified in the individual monograph: (l) In the cue:
`
`iquid preparation the percentage content of each ingredient in
`'
`'
`’
`specified volume, except that
`
`just to agivcn pH or to make the solution
`isotonic may be declared by name and a statement oftheir effect; and
`(2) in the case of a dry pzreparation or other preparation to which is
`diluent is intended to be added before use,
`the amount of
`
`
`ingredient, the composition of recommended i:lilue.nt{s) {the namtiti
`alone,_il‘ the formula is specified in the individual l1l(ll10g.r3Ph,l>
`amount
`to he used to attain a specific concenuatioii of anti}:
`ingredient and the final Volumeof ‘solution so obtained, ‘E! {flit
`description of the physical appearance of the constitiited s<ili§1flfi-
`dir ctions for proper storage of the _constitutfeti solution, eifmgfl
`expiration date limiting the period during which the COIl$sfl’i§x%
`solution may beicxpectcd to have the required or labeled l30“3”‘33’
`has been stored as directed.
`‘
`diafyggfifl
`Containers for Injections that are intended for use 35 iumfifg
`heinofiltratioiig or irrigation solutions and that contain a XEIEW
`more than 1 L are labeled to indicate that the contents an? 130
`for use b
`intravenous infusion.
`an
`Injectigins intended for Veterinary use are labeled to $118? ‘if
`»
`The container is so labeled that a sutlicient ariiif 0f ‘e
`remains uncovered‘ for its full
`length or circumtcrcnc
`inspection of the contents.
`
`.
`
`
`
`Aqueous Vehicles--5i“he vehicles for aqueous Injections meet the
`requirements of the Pyrogen Test
`15 I} or the Bacterial iizztiotcixinsi
`Test (85), whichever is specified. Waterjr';2‘ {njewirm geiierally is used
`as the vehicle, unless otherwise specified in the individual
`monograph. Sodium chloride may he added in amounts sufficiciit
`to render the resulting solution isotonic; and Sodium C1ii<)rz'(>'e
`[lt_j8(?fi()It, or Rz'ngerfs' Injection, may he used in whole or in part
`instead of Waterfozc Injecn'r)n, unless otherwise specified in the
`individual monograph. For conditions applying to other adjuvants,
`see Added Szzbszances in this chapter.
`Other Vehicles--—Fixed oils used as Vehicles for nonaqucous
`lnjcctionsarc ofvegetable origin, are odorless or nearly so, and have
`no odor suggesting ranoidity. They meetthe requirements of the test
`for Solid paretgfiiiiz under Mineral Oil,
`the cooling bath being
`niaintained at 10°, have a Saprmg'ficr:tz'()n I/Ziziue between l85 and
`200 (sec Fats oI1dl":Lreo’ Oils (40.l })‘, have an Iodine‘ Value between 79
`and léii (see Fats and fired Oils {40l )), and meet the requirements
`of the following tests.
`a
`j
`‘
`Uizsaporzgfialiie Matter'—»»-Reflttx on a steam bath 10 mL of the oil
`with 15 mL of sodiurn 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 at
`steambath, and mix the residue with I00 mid of water: a clear
`solution results.
`Free Fatty Aci'a's~———The free fatty acids in 10 g of oil require for
`neutralization not more than 2.0 ml, of (}.O2ON sodium hydroxide
`(see Fats and Iiixea’ Oils (401)). ‘
`Synthetic mono or diglyceridcs of fatty acids may he used as
`vehicles, provided they are liquid and remain clear when cooled to
`ll)” andhavc an [od_r‘ne kéilzte of not more than ‘l40 {see Fats‘ mm’
`Fixed Oils (401)).
`‘
`'
`7
`These and other nonaqueous vehicles may he used, provided they
`are safe, in tliewkoltime of Injection administered, and also provided
`they do not interfere with the therapeutic efficacy ofthe preparation or
`with its response to prescribed assays and tests.
`t
`‘
`Added Substances“-§Suitahle 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 aclministered and do not interfere with the
`therapeutic eflicacy: or with the responses to the specified assays and
`tests No coloring agent may be added, solely for the purpose of
`coloring the iiiiishcd prepatatioii, to a solution intended for parenteral
`administration (see also Added StzI2szouce.s under Gerzerasl Notices‘
`and A:::tin;u'croZ>iaZ r':_‘[?e<:tivenets:s* Testfizg {S l }).
`’
`Observe special care in the choice and use of added substances in
`preparations for injection that are adttninistercd in 21,volume exceeding
`5 ml. The following maximum limits prevail unless othocrwise
`directed: for agents containing mercury: and the cationic, st1rt’ace~
`active compounds. 0.01%;
`for chlorohutanol, eresol, phenol, and
`similar types of substances, 0.5%; and for sulfur dioxide, or an
`equivalent amount oi’
`the sulfite, hisulfite? or mctahisulfitc oi“
`potassium or sodiuin, 0.2%.
`the
`A suitable substance or mixture of substances to prevent
`growth ofmicroorganisms must he added to preparations intended for
`injection, that are packaged in n1ultiplc~dose containers, regardless of
`the method of stcrihzation employed, unless one of the following
`conditions prevails: (l) there are dilicrcnt directions in the individuttl
`monograph; (2) the substance’ contains a radionuclide with a physical
`half-life of less than 24 hours; and {3} the active ingredients are
`themselves antiinicioriial. Such substances are used in concentrations
`that will prevent
`the growth oi’ or kill rnicroorganisins in the
`preparations for injection, Such substances also meet the require-
`ments ofAnzi2nic:rcf)r?of Ejfecrtiveness Te.s‘?.ing <51} and Antirnicrootui
`Agents——~»~~C0nte.ct (3/ll). Sterilization processes are employed even
`though such substances are used (see also Stert‘Z2'2-oriria care’ Snarz'Zz‘zy
`
`

`
`j
`USP 29
`General Requirements / (1) Injections
`2457
`
`(d)
`
`I
`'
`2
`3'
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`container label muststate the f:0l_l0Wing: “When reconstituted in
`accordance with the package insert_instructions, the concentra—
`tion of aluminum will be no more than _25 ng/L”. .
`.
`Themaximum level ofaluminum, at expiry must be stated on the
`immediate‘ container label of all SVls and PBPs used in the
`preparation. or. _the administration of TPN injections and
`mjectable emulsions. The aluminum content must be stated as
`follows: “Contains no more than W ng/L of,aluminum”. This
`maximum amount of aluminum may be stated, as the highest one
`of the following three levels:
`-
`.
`.
`»
`s
`.
`The highest level for the batches produced during the last three
`ears
`.
`.
`'
`The highest level for the latest five batches
`_
`'
`_
`.
`_
`The maximum level in terms of historical levels, but only ‘until
`_
`.
`comp16t1011 01 Pr0d11C11011 Q1 the 1115‘ hVe hetehes ehe1 the
`.effeG._tiVe date 01July 26v120.04
`.
`_
`The package lf1Seff_f0T _311 LVIS, SVISI and PBPS 118661 ,1n_ the
`preparation , or administration of TPN products must contain a
`,
`_
`_
`_
`‘mg statement. . This warning .must - be ._COI1lZalI16d
`in the
`Warm
`_
`.
`_
`uwamings” SeCh011 Ofihe 1aheh11g=311d- 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 lafge_3111°“htS Of, °h19,1u,1h ahd Ph0SPhe1e 50111110115 Whleh
`contain aluminum. Research indicates that patients with impaired
`_
`.
`_
`_
`kidney 11111011011» ,1heh1‘_h11g P1emeh11‘e heehatesa. Whe 1‘e0e1Ve
`parenteral 1eVe1S 01 311111111111111 31 81e31e1 than 4 1_0 5 Hg Pe_1 kg P01
`day accumulate aluininiim at levels associated with central nervous
`system and b<_>n_6 t0X_1C1tY- TISSUE? 1030111}; may 000111 31 eVeh 10“/e1
`rates Of ad1111111$11eh.011 0f_ _TPN,.P10d“0t5 3110 0f the 10°k'fl“5h
`solutions used in their administration.”‘(/Spgg
`
`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
`ofa black band or series ofbands above the constriction on an ampul
`is prohibited, except for Potassium Chloridefor Injection Concen-
`trate.
`.
`
`t
`‘ii A
`dP 1
`cki
`scula
`Neuo
`ng an
`0
`gen S
`ara yzl g
`i r
`.r mu
`All injectablepreparations 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
`(whicheverprovides=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
`an
`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 0fhand1’ing.,_ 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
`Assaypreparation, in which the total withdrawable contents are to be
`withdrawn from a single-dose container with a hypodennic 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 or VOLUME OFINJECTION IN CONTAINERS
`.
`Select one -or more containers ifthe volume ofthe container is 10
`ml; or more,~three or-more ifthe volume is more than 3 mL and less
`than l0'mL, orfive ormore if‘thevolume is 3 m_Lorless. Individually
`take up the contents ofeach container selected into a dry hypodermic
`syringe ofa rated capacity not exceeding three times the volume to be
`measured and fitted with a l—gauge needle not less than 2.5 cm (1
`inch) in length. Expel any air bubbles from the syringe and needle,
`and then discharge thecontents ofthe syringe, without emptying the
`needle, into a standardized, dry cylinder (graduated to contain rather
`than to deliver the designated volumes) ofsuch size that the volume
`to be measured occupies at least 40%.ofthe cylinder_’s i'ated‘vo_lume.
`Alternatively the contents of the syringe may be discharged into a
`.
`2
`$113’, tared beaker, the volume, in
`being calculated as the weight,
`in g, of Injection taken _divided by its density. The contents ofup to
`five 1- or 2—mL containers may be pooled for the measurement,
`provided that a separate dry syringe assembly is used 'for each
`container. The content ofcontainers holding 10 mL or more may be
`determined by means of opening them and emptying the contents
`directlyvinto 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-mL
`containers, is not less than the sum of the labeled volumes of the
`containers taken collectively.
`‘
`
`FRESENIUS KABI 1035-0003
`
`
`
`,
`
`_
`PACKAGING ‘
`Containers for Injections
`.
`,
`_
`_
`, Containers, including the closures. for preparations for injections
`‘not interact physicallyor chemically with the preparations in any
`finiler to alter the strength, quality, of purity beyond the oflicial
`_ _uirements under the ordinary or customary conditions ofhandling,
`,1Pment,.storage, sale, and use. The container is made of riiaterial
`"‘Pe1mits inspection of the contents.
`'n°“°h
`Ofltainers (661)).
`‘e £?’.defini_tions 10f single-dose and multiple-.dose containers, see
`M et“tfi’e1'S In the General Notices and Requirements. Containers
`‘ C0 erequirements under Containers (661).
`samfiifigfffre l°1°Sed 01 Sealed "1 Sueh *1 manner €15
`‘°.P1eVe111
`.
`st demo
`01‘ oss of contents. Validation of contairie_r integrity
`F V. mical 0 nstrate. no r,Pehe.1_1e11011 . 01 1111e_10h1.a1 i.°0h13m1hat1°h 01
`fhthicle musrt physmil
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`"hint cum
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`contents ,w(i:[1i1h.111l1:1tIl]f::)Il:;)(;l](;Sleg)r0I1d1I:;It1reuI':t£)E;H1Efhttllrleevséilt(hSdur:eWa_h(l>ef
`units penetration b 5 héédle and u on Withdrawal éfthe
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`and
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`I
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`

`
`
`2458
`(11) USP Reference Standards / General Requirements
`U333 29
`
`
`
`place when inspecting for other critical defects, such as era
`defective containers or seals, or when characterizing tl
`of a lyophilized product.
`~
`Where the nature of the contents or the ctititainer~c1ogm.e
`permits only limited capability for the inspection ofthe tom} ,3 Syilem
`the 100% inspection of a lot shall be supplemented W9
`elltg
`inspection of constituted (egg dried) or withdrawn
`darklr
`containerlcontcnts of a sample of containers from the lot.
`All
`large-yolurne Injections for singledose infusion and ‘
`volume Injections are subject to the light obscuration Q? mm small.
`procedures and l,irn.its for suhvisible particulate matte]; W futcopic
`Particulate Matterln Iitjecrions (788}, unless otherwise a e ‘O
`I
`the individual monograph. An article packaged as bath glfiedm
`volume and a small-volume Injection meets the requirements 3
`a
`for small-volume Injections where the container is
`label
`containing 100 ml; or less, if the individual monograph state 6
`for Parricu1atctMatier (788); it meets the requirements set {S a his
`large-‘volume l1’l_l8CilOI’lS for singledosc infusion where the co mifgl
`is labeled as containing more than 100 inl... Injections aclminmamel
`exclusively by the intramuscular or subcutaneous route o1~paé:lered
`and labeled for use as ‘irrigating solutions are excrn t gig“
`requirementsfor Particulate Matter <?88>.AL.§(p;9
`p mil‘
`
`STERILITY
`
`.
`1-
`Sterility Tests-—P1‘eparatioins for injection meet the re '11‘
`under Sterility Tests (71).
`q memml’
`
`CONSTITUTED iSOLU'I‘I()NS
`
`injections in multiple-dose containers labeled to yield a
`For
`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 yolurnc is such that each syringe
`delivers not less than the stated dose.
`l-‘or injections containing oily Warm the containers, if necessary,
`and thoroughly shake them inunediately before removing the
`contents. Cool to 2.‘i"’ before 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 slmyly 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.
`l container, and
`For large-volume intravenous solutions, select
`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 Overscals
`
`Only cautionary statements are to be printed on the ferrules and cap
`cverscals ofyials containing an injectable drug product. A cautionary
`statement is one intended to prevent an imminent life-threatening
`situation if the injectablc drug is used inappropriately, Examples of
`such statements are the following: “Warning”, “Dilute Before
`Using", ‘Taralyzing Agent”, “l.l\/I. 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 ovcrseal is constructed so as to
`allow the cautionary statement below to be readily legible.
`
`Packaging and Storage
`
`The volume of injection in singledose containers provides the
`amount specified for parenteral administration at one time and in no
`is more than suflicient
`to permit
`the withdrawal and
`administration of l L.
`Preparations intended for intraspinal, intracistcrnal, or peridural
`administration are packaged only in single~»dosc containers.
`Unless otlfterwise specified in the individual monograph, a
`multiple-dose container contains a volume of lnjection sufficient to
`permit the withdrawal of not more than 30 mL.
`‘lrriections «packaged for use as irrigation solutions, for hemofiltra~
`tion or dialysis; or for parenteral nutrition are exempt iron) the l~l..
`restriction 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 1 L.
`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.
`
`Change to read:
`
`‘FOREl(}N AND PARTICULATE MATTER
`
`All articles intended for parenteral administration shall be prepared
`in a manner designed to exclude particulate matter as defined in
`Perztczltare Matter in Ia;‘eerz‘oas (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 1'(:‘»iN(r>l”x3l’lC<;?rt(3 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 particu~
`lates shall be rejected. The inspection for visible particulates may take
`
`
`Dry solids from which constituted solutions are prepared for
`
`injection bear titles of the form [DR UG] 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
`constituted for administration are not
`included in the lndlfitllial
`monographs on sterile dry solids or liquid concentrates. However. in
`the interest of assuring the quality ofinjection preparations as they at
`actually administered, the following nondestructive tests are pI‘t2i‘~’Jfi1l$?¥§
`for demonstrating the suitability of constituted solutions WWI lliilft
`are prepared just prior to use.
`‘
`_
`Completeness and Clarity of Solution-~Constitutc‘the solutlsfi
`as directed in the labeling supplied by the manufacturer for the sitti
`dry dosage form.
`.
`.-
`.
`"
`1
`t
`1 w
`pd dt
`A. Th
`no Visible ressdfd
`.
`e so 1
`isso yes comp etely, leaving
`as undissolved matter.
`‘
`_
`Y My
`a
`B: The constituted solution is not significantllt 1833‘ hlgffié £5 3
`an equal volume of the diluent or of Purified Water contai
`similar vessel and examined similarly.
`_
`d E3 3;}:
`Particulate Matter—-Constitute the 'solution_ as
`{nan
`labeling supplied by the manufacturer for the sterilt; dI'Y 3 .
`the solution is essentially free from pa1‘iiCl'€S of foreign Y?’
`be observed“ on Visual inspection.
`
`
`
`.
`
`
`
`<11) USP REFERENCE
`STANDARDS
`
`as i
`
`USE’ Reference Standards are cstahlishad andééiiinril ii
`up0‘>:3’lllCil
`ilasfi.
`authority of the USPC Board of ”l‘rus1€?5
`the USP Reference Standards C()IXlI“I11llZ{'7e~_.tiC9_lCll€!Y5l"€’
`selection and suitability of each lot. The {glare ustiall
`each lot of specimen selected for the stander St
`B: Lin
`indellendelitly in three or more lab0f&l0’§€t’he
`FD3
`
`
`Standards Laboratory {see i’refa::e} 332,65 an
`
`participate in testing almost all new éstan fl
`1-anally
`Standards. In additiori, labcfalwes grey
`existing
`“"15" $1.’
`both academic and industrial. paITi01P“i‘ifI:}-
`Reference Standards are specifi'ca1lY""i::l Y
`peial assays and tests and are proyltiffll 50 88:5
`for other no,noffi.cial. application{_S)
`iwsays 0
`Originally introduced for the lf)l()l0giCa
`
`
`
`"
`
`
`
`FRESENIUS KABI 1035-0004