Chapter 84
`Preparations
`
`l(e,....ch E. Avlt, DSe Pro!t~Uor and CIWI, Oiv~ ol Paron:G<al ModicatJOM.
`College of Ph~~tmacy. University ot Tenne.- Cente1lor the Heahh Sciences,
`Men'lllhiS. TN 38183
`
`history
`adminl•tr.!llon
`component•
`pr~tlon
`quality control
`packttglng
`l~linQ
`
`be;ude the in(cid:173)
`Tht terlll parenteral (Gk, para enteron
`rtl'ers w the route of ndminis~rat.ion of drugs by in(cid:173)
`or through one or more layers of ijkin or mu<'oul!
`Since thi11 route circumvents the nij!hly efficient
`•-·'"'''"cbarrie1'11 of the human budy, the l!kin snd mUCUU•
`Jlrlllbrnt1CII. eJ<ccptionnl purity of the do~a11e form mulll 00
`~Vf(l The proce~~es utilized in prcpnring the dosage form
`:..n •mb~>•h good manufacturing practices lhal will ~roduce
`.-1 . int.Jn the required quahty of the produc:L New de
`~~pnwnl in procea technology end quality control shwld
`J,coarlCJJII{'(I a~ soon n~ their valut~ and reliability have been
`~oiabllllhlod as a meang for furtl1er improving tnt~ quality of t.he
`,..IIIII
`
`HISiory 1
`
`On• u! Lho most BiHilificanl c'Vl•nts in Lhe bcJ!inninl(~< uf
`~meral lherapy wn.• lhc fir~l recllrded ID fl cUon of clru~
`•till ~Ci f\' oflivin.t animal.., 10 n1M141I lhf' ~r·1r 16i)'i,bv clw
`MII(!Ct t:iir Chrilitophcr \\'rl'n
`l•'rom >rtwh 11 \"Cry n11dt
`'-&innint:. tlw tcl'lmique for 111lrnn•nm1J\ injection und
`O...WI&tiJI' or the itnJ)It(,ll iunh tlwr!'uf cl€'veluJX'fl Hluwly durll\1,1
`dte!lfl•l 11 nl.ury ancl n half. Ourin&~lhefin<l h11lfof lhe> l!llh
`llr.'urv, l.bl! subcutan«lu- rout I' r1f adroinistmtton _, IN·crq:
`lfntlorti!l. In IAA:i Or Alt>x.1ncler Wood uf Rdinburgn dP..
`rcrill.. what was probably the first subcuhtneous injecl1on
`ol rlrlllt& for therap10utic purpolll'll using a true hypodermic
`mill
`T'ht latter half of the 19th century hrnught increa.-ing
`._.,,n lor safety in the administration of parenteral solu
`~, lftrttolv becou-.1• of the work of Rober1 I<nch and Louis
`~leur While Charle~ Chamberland waR developing hot.h
`t ·rctmnint: filt4!r (made of ungll!Zed porcelain). H.
`r a.nd steam atenliution te<"hniqoes and the fint hac·
`lit ~~~lly~r Was developing II filter made or kieselguhr (the
`illlir Clttltl filler) , and Stanislaus Umousin WAS developing o
`~--~le container, the aU·g1ass ampul Shortly after the
`?nu,, or the 20th century, att.cntion focu ed on the dis-
`;t" ~ thilb and fever which often followed the intravenous
`~·1111 of drug~. In 1 he middle 1920s l}r lllurcncc Sllihrrl
`kl.l clrd flroof t hnt l11is rencl in11 wAll cnu~ed hy JIHt;•nl
`~t tb1 of microhinl growth, J>)rogetl.\1, whil'h could he
`l.t.j llol(!() from W,IIN bydi>lillnlillrl J'Jnd fnWI !IIIlSCW.!lrt IJy
`~"'I at eluvotc:d tt•m,wrntul'f'll. The$€' dM<o• lt!fllllcrtl" '"'"'e
`trt.,.lnent amunr: th•~rt·lhal provi;lt•d tht> folliiHial itm fc1r in
`'f1."K Use ot' pnrenlt'ral roult.'!l for the ll.clminiHtrntintt of
`~lnlstration
`.
`.
`. .
`hli·tn
`Cltlt; rnay be classified m five general culcgottcs: ll)
`'-ltttl
`"'" 11"~ rendv for injection, {2) d ry. ooluble products ready
`'l:lnlh ned wit.b • sol,·enl,JUSt prior to use, (3) auspen"'l>nS
`for InJection, (•I) dry. inaoluble products ready lo be
`· with a vehicle Just prior to use, nnd (5) emulsions.
`
`The~ tnJCCticru. rutty be odmtnllitcJ'l'(l h} auch rout~" u, 10
`1 mvr tarous, subcul"nPuus, iut rAdrrmnl, inl rnm u,;culnr, intra·
`' l'hC' naturl' uf lhP
`SJ)inul, intnwi~LOrnnl, ond inlrulhcc·nl.
`produ<l will det~rmtnl' the JlUrticular rnnh· uf ndmini •lrntlun
`thnl moy be emJ>IuyC!d. Convt r..el~·. th" di" ired roul.£' of nd(cid:173)
`mini,l.rrtlion wiiiJ>Itll't" f'e(JI ir• mcnL' on In<· f•1rmuL lion
`l•'ur
`r:tnm plc, ~U&t>en.~iun~ would notlw nchmniHH,rt'll <lirNtlv 1nf<•
`tltl' hltll>d !I ream II()CI.IUS<' nl tho clongPr of in~nlublc Jlllrf id~"'
`hh>t ki IIJi ntpill~~rh '1. S.·lltitntK tu he MlnuniMII'n-d '1111\ utu·
`oeuu Jy \WIUiril'f<tUitc wit lllllt•nltun In t .. mnlynclj<L~lm nl,
`,,Lhuwi~e irritnl1m1 nr the pi nliful SUfJill~ uf nervp tndings
`in lhiH n llok•mit·~ l nrcn wr1ulcl ~iw ri~e lu pwnmm•·c•tl p.1ill.
`lnjcl(•lltml! iuteulit'l! fur inlf110C'Uinr, inlnt~Jiill•l, i•ll nl~'lsfNMI,
`nnd in lrntht.'Clll admlllistrul ir••l rt.oquiJ'I' the hi,c!:heqt purity
`~IJIOtlatJ'tl, IIC"'Q lh(' uf lhe1- ll iii\ it\ tlf IWTVI tj,,tJ(' l•t imlnnl
`and f fiiCICSUI)f;hlnri'S.
`•
`Wlwn <loruporNI witJl nthl'r lltll!.CIIle fomt11, ittjcdimlH plltlHCl!S
`If lmmf'clinlt· tlhvruulu~rlc:d ACI iun ill
`s<'lt•cl
`lltlvanl"f\1'~
`nccdt-.cl from 11 dr~~~o. 1t UI'Uillly wn be pro\ id1'tl l1J int m\t'nclt.ll'
`injection nf on nquc<JUS soluttnn. Mudificuuoo of tile lor
`mulnt io•n or anullt4.:r ruuLo ufiujrt•liun ennlu· m~d tu ~~~~~~ lhe
`onlit'ltlnd prulunu I h~ uctim1 ul ll1t1 drliJ(. The l hornpoutit·
`rC!IJIIonM> nr 11 drur. jj;, more r1 ntlily conln>llcri hy tJM<'nh•raJ
`ndminuttraticln u.n:- tl~t irret:Uiurilie!l ttf iut,.,.tinalllh.,.,rpti 111
`nr,. ri Tl'Unweoted. Ab41, ~im·t·lhr dru&: nurm111ly i:outl~tunio;­
`lN«I by n profet.'111unnlly trninrd IJCI'l!Otl, ilmny IX' etmJitlcmtly
`ex pede·d rhnt U1e du.o;e wa~ lll'lwdly nod nec~urnlcly ttdluinis(cid:173)
`!A-rfd. Orugs rJtn he adminilt(,-ed J)lll'f lllt•rrtll} wlwn l~y
`c:mn"t Le ~i~<l'n or11.Uy becau>(' c•f the uncc>tll.duu~ nr 11nro
`opcmtive ~lliU' uf thP pauenl, ur lx>olu..cuf lflocli'~•li• •ll ur lnck
`of llh'<mpl inn iu the inteslinnl l rtiCI.. A mung I h~ di-.mlvnn·
`lfii:!'S o[ this doi llllt' fo1m art\ the requi r(·mcnl. or .wet~•ia Ill
`11dmi n•qtroLion, Lht> ri.-k ufu~"" tout it) fromi1'Clll irr1tntwn.
`tht> rt•lll or psychllll>~:ical J).llll f.'\ctur, 1111•1 Ill(> dlffk 1ltY in
`rorrt>lltn~ on rrrur, 'lhould on\' he mndc•
`In the loltt•r All uo·
`t im1, unless o dJrecl pllllrmnc~llugical ru1tuno•\i:;t i$ lmmrdi
`IJtl'ly avuilnblP, c'url't'; t ion HI rtn c•rrnr mny l10 itnJ>OSllihlt>. One
`olhc r dtsodYIUli(\J:l' 111 lh11l doily nT (JI!(JliC'III odmllliolnalinn
`pu.w .. ditliculti~ mlhcr for lhft pal rent In vir\! L 11 prof e... 1cll'llilly
`t rnin,·({ JH'n;<>n 11r tulenrn tu inj
`l onf'~rlr.
`
`Parenteral Combinations
`S tttt'f' there i. n deter!!(· .. r cl1-wmnfurl f11r lhr JIIH H•nt with
`ooch h1jcction, n ph}'Nici:m will frequl'n ii;Y lll'f'k lo redutt• th1s
`di'l4."<om ltu·l h} cmnhining mnm lhJJn nne drul( in 01\l' in jc•cl inn.
`'fhi, i; mt"il commonly encuunlc-rt;d whrn thf III I'ICUtit• Ujt·nL•
`arc ndt.led to lnrJlf'·Volume ~olullcm~ or eledr<•lst•"' ur nutri-
`1'11~ (~ lmmt•nl y c•nllP<I ''IV adllilives,'' durinlt intrnv4•nous
`adm0im~trotion. Sinte I hetll·Jifi'JIM:lliun~ wunltl bvnqucous
`snlultcmr Lhrrc i~ n lugh [l(>lentjul f11r dw111lclll :~mlpll y~lc-,fll
`inl•'f IC'hl;n,; (II IN ~ur 'l'hc 11horrn.aciJt ~<· lho• tm>ft>-<iunnl bo<t
`lJIHtltli;<ll•l Ct>Jll! with these lflet•mflllhhiliti '!1.
`IJowf'\t'r, in
`tlw 11 .,~1 . t b~ lu1~>c> hl't'n hnndl~d ltJ!'j;I'IV 111 Ott• Jlllllt!l•l's
`
`1483
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals L.L.C- Exhibit 1029- Page 1463
`
`

`

`14fl.4
`
`CHAPTER 84
`
`hcd•id .. by the nuNe and pb)"'ir~ul Only rrot.>nlly h.J.' it bc<'n
`ret~ll!ni7.ed tl- .L this pru(essional ure~ Ill th•· proper functinn
`of o pharmMH and ~~ been .,., 6talf'n by tJl~ .Jnint C<1m·
`mi~~ion on AC'crcditaucm of Ho"pltalll.?
`A" ,,han nm·ist"' have a<tSumecl in<"rrasing re.(XIn.•1hilitv in
`th111 artoa. aware~- hn !!Tlldually den•l~oped of tht' v.ide·
`~>Pr.,.Kf tiCC'llrrt-nee uf \ l.ible, "' -.ell a~ lnvi .. ihlt', physiNil,
`cbonurol, and Lheropeulic incompati bilities whrn cerlnin
`dru~> are cmnhined or added lo inLntvpnooL' fluid .•.
`l~·t:lopmt·nt of a prt'Cipit.ate or a 1'<11 •r cban.:e v.hcn
`prrp:u-at.ion,. are combined i.~ 1111 immooinLC' warrunJ: that an
`olHrnhon ho• c><oeunetl Sud• tocmnbin lltlt>n ~hm.Jid noL he•
`a<lminister(!() to the patient lx-cause the 11.wd particles mny
`'"'d<1de Lht' hlood vr:<.•t'l r~ thfrapeulic . .gent mft)' not h~
`avnilab!e fur nbsorpliun, or the drug mtty have been dt"gTadcd
`inltt tHxic suh.tances. Mort>owr. in of ht r instani'P~ I'Mllg('<
`oot vtSuaUy apparent may bavt' occurred .... h,lh could hi!
`equallv or more dangc>mus to th~ welfare f•l the p:1tienL
`1'h~ almrn;t innurncrnble pull'ntial combination~ pret-<'nl
`a cumplex ~oiluntion even for thl! pharmodsL In un aW'-mpt
`w orpmUe the- infonnatlvn available and to !lid tho pharmn·
`ci~l in making r:rpid decJShm~ roncemint: po~ntiul probll!ml',
`a mlmht-r o f rharb hove ocen cum piled hi\Sed ml the ~ibl~
`clungl'!' that rnn\ he oll!'en:ed whcon rwo or moce prrpan!tion~
`an t·nmbirwcl. T'h4o volu .. u( -u~h chart-11 ii limitl'd by l>Urh
`fiu:tun as frc<tu~nt chnn~ in commt'rciol prnducts, varu.tionll
`in nrdtr of mixing or lht> pmvurtie>n~ in thr mixture, difffr
`enct. m conr;ontrauun of rnch injlred.ienl, or variati"ns in lhr
`pt-riud .. r 1 irne thai the romh:mtli<•D i- htld beforr use.
`A11 st~ ha\'e been undertaken and more infonnulion ho&
`lwc11 t:ained. it bas twcon shoY.n that knowledge of vnriohl~
`factor• ruch ft!l pH and the KJntc c:haradl'r ot the tJ("Iivc ron·
`.. l1f Ul'nt..o; aid~ ~uh;ctanl iltll~· in undentandin,: and prP<iic:tinJI!
`pot('ntiol inmmr>atihilitu.•s. J.,Jnclic studlc>~ of rcortlon ralt'll
`mt1y be utili7ed to dt'!lrrihe or pl't'dict the enent of detrrodll
`twn L'lurnately. a thurou.;h 11fudy «houlrl be wtdPrt.aken uC
`each lhvnpcutica;;cnt in romhmntion w1lh other d~ IIJld
`inuavenuus fluids-, nnt unly of generic b\ll of t•ommercilll
`preparation!!, from thf' phy-.ical. chemical, and therapeultc
`a.~JJ«t..-.. !'uC"h "l Jd1e~ llff' bttn~e u~rtakt'n aoo 'lome M\'41
`hePn rPJlnrt!'rl
`Tdo•nlly, " ' ' p:tremLerol combination ~;hould be administ.t,red
`unl~ it ha,. llftn lbun>t&ghly ,tudic-d to drt.;rmine t.he eff(!('t
`of I hi! cnmbination bn rhf. rhHap('Utic ~alue and the Mfd}' of
`each t<urlt mmhination Howev('r, ouch 1\ll ideal siluntion dot>!~
`not nnd mn)' nc\·er exiRt. Th<'reforc, 11 18 the re11ponsihilily
`oflhl' pharmn• ... ~ tu l~e"" famihr.ira.~ pc>-·iblewith the phy~­
`JCIIl, chem1cal, and thcrapeuuc ll~<l>ed.s of parmteTIII ccmbi
`nAt inns and tu exerrill<' the ht.lll P<• ... ~ihll' judgnu>nt 8!1 Lu
`whether o.r not the ~1-Ml('irlc combinat•on ex:lt<mf>Oraneou..ly
`prf'•cribed" "titable fo>r ll~ in 11 patient. A ~en ice w phl!r
`muc1t-.ll> bu been prov1drd through rcvitl"" or this suhjcrt.
`IITCLI.:t
`General Requirements
`An inhen:ut rrQUirC:Omrnt for pnremerol Jlrcpamt inns is thnt
`lhev he of thc> vel) bt·~l <1.mlitv oud prnvide lbt maximum
`~frty for l}\(- pati~nl. Therelnrt:, t.ht- phtlrmacJ.-t, ~ing re·
`
`spon!ilhlc for their prt-pnration, mu:.t ullhre sktll\ a-.,:
`$<lUff r ulne-.." ~I th~ highl'f.l!ew) Ol rfficiel')(')' lo II( h~
`t-nd Among thf' an-a .. rcquirin~ d...-di('IIIC·olatlentirm \t
`following:
`i<wl.a
`l'no.~ • n •n<l applonl..., vi h~o h .,.. ~ ••"' prot:
`I
`P.•-nolh~ I "'llihl ,.( W41 m(, r• ,.. ~h· ique,. w llll:~lo ;11
`t n<•l 1,. '"""''' ~u!m,:i.-d hy thr pbor11u,.~ IIOt
`(•luruoc 11••><• ·• m
`PNI~•rniLilu.L• .. fl lot-r'f,_,, .. ,,, .,.Jhll'f,..th. I'"'P.orai.IJ..,of tfl, ~
`;,. It• 101116t, ,, ,J tll~r.Ji-11 1
`Pr.,.
`rt-n'lwd ....a lw-utsl-.1 IIIli\.
`'l'li pt. 111'1W• ll
`l!.
`l,.,n
`..,..,. .. ,,... The d .. !lena:cw 111 !hi• •nu•~lp t~ ... ~ "ill 1.., 11\Jt
`, .... d.
`"' illoo!
`:t SJW'Iall2lNi tL-chniquo. ... n be ,...,uiroo r., lllelonan~, rt
`lftt>a111l--. -Jiio)mrt llwtn tril.h OllHII-and ""'nd ~L q,..
`~""1',.. m.ut be -..bj•dultooc41tinJ- uillut1 r~-ftor ~
`""'"'IC>no. and omptuVen< nl•
`ln~ndwnlli <If !.he ltijlhCJitcl'l'llil)' nbtainabl" nt.-tb, ulilo 1<1.
`4.
`limo il11rwd.ttlli MaY IN(IIi,_ opwoaJ JKOrilicllJJ4lft ~d ~I( ~
`I'JIIY. Tbi& wdl n....ny Nq':lin U..t <•..t fnt.,... be Q,
`.....unncial
`-..nd ~ m imtJ01\.<IIftl.
`El'-
`'•· Tbe t.tbolityomdefiO<'h...,_,u( l heprod~t m.,.Lt..,u 1r_.1J:.L ,
`,.;m ~toh•t-tiatnll d8to!. r1tllllf from< ri•inal « fl~tl ~•.ttfd...,.111ea ~
`t t.t.. at..• """"""' P~ ftt'..U•"• _. <lirr .. _
`•n 'IIC
`'lJkoilionrt.._ (rum plu& to pbuL
`6. A-t~ hrvd ....tn•nlrollledprwrllllt DU'.t~~ ttJ
`U... 'I'"' hi) ot th~ ttroduct und tb., rep~ I hk>n cof vohd prodJO<llcm ""
`d ~re
`'l"baimulvcsrrahu.ltlonol'alllnlredieaw,v~e•"'lruioit~
`Utpolln thrpmdur•~ .. r.--lva.and r relw ~·~ rlth. 11
`,
`r00U("l
`l nj(-djoru; <~ruther~~ orile prDducl.l! are rnrely poopar<!(J 11
`the comTP~tlllil) p.harmnty bee-all"!! of lhf 13clt uf dt t~.~a•
`fanlit•c:. ne«~l\ary t•• 1/fC:J)o.rt-11 n•llable and -afe protlu..1.
`In aome h011pu.al phar ma cies injl'rtiaru or 1rrigatinf( n111d,
`~~~ munufactu1cd, but in nn il'trt>n;ingnumber IISf'plu.·Jl~
`cewing IS ot.il 1~rd primllrily in tlu• additit•n olvari<.w dr
`lO illii'O\~ 1t0luLi.,n,. fnr t.be md ividual fllltJeDL The~
`m:1jnri ty ol m jectable products wu'Ci chnicolly srn preplllfd
`bv the pharm (<'u lirol•ndunf)·.
`
`General Process
`
`Tb.> p repanj t ion oln IXtrrnla'al produM may be ~·D-llcieled
`to Cn<'Ompall four generaJureaso~ rolJow;
`( I) proc:ur>!*lll
`and ~ele<'ti<m <•r t he cx•miX>nenta, (2) produt'tJ<Ml fo< chti~.~> a:
`proced ures, (JJ control or qUDlity, nnd (4) packag~ug and 11-
`'I'll<' wmponen ll' of lh.- p n>dUt't l<> be prorur" i
`belinl(.
`awie VC!hicl.. NJlutea., ronl.alnera, and cla~Juret.. The .teJ._
`<"ollllo litu ti~ IJroduclJOn indo<!(• th!; mainl 4 nnnee orroctlrtP~
`and t'(tuipment, !Heptlrlu~t and conlrolltnr: the envir<HIPM!II
`cledning the coolainen: and eq wpmcnt, pl'4.'pan:D1t lhro prod
`filterihg the loolulion, fillin( cont•inen wi tJl the pro.itl(
`lll!Ollllft the rontoinrn, nnd st.crilhi~ the product Con!rt'l
`
`of Quality inclurles lhe t"olu.tl i.m oi the tomptmt. nts. \t
`
`d.ltiun of equipment and p~. determination lvtt
`pnKJuction halt hoon e><C!('\1~ "'ithin pre.cn'hcd r eqtDTI'meo
`a.nd tX'rforuw nce of ne<:flfiJitlry C\ ~luoth e ko~tt- on thll finis !des
`product. The final "1'4.'11 of packaJCiag and lnhelirut utr h
`all.tc_118 oeccatry to ide-ntify c.lK (mtsbed rmxluct .nJ 1111-d r:
`il in • ut h m.loll<'r thall i 1 :.afelv s nd pr()!~rlr p111Vi'"' ~
`rolotmd delivery to th 11~er.
`In tJu~ folwwing~u~~··' dt(cid:173)
`foor llfC'M 11ntl ~pproprillle subtupic!> .,..m be dit;cus;•C'<' Jn
`tail
`
`I?AtablisJung Fperifklllions lU in~ure tho reuali~y of earh of
`lhc m mp<Jne nta (}fan injection i~ uf vilal impclfl.ttll't'. ~
`.. p~ificatiunM will be coordil\dled with the reqmremu t , ,f
`th e ~JM'Cific formulation and w.ll n•ll n - n1} be· idf'flti~:al
`for n p11rticulnr OOtnJJOnmt if u~:C'd in toevcral d ifferent for
`mululiun ...
`fhe mo:A ~trin«ent rt'Quiremtonta normally v.-.11 be en·
`countA:ored with &qW!O\Ill soluuonh. pa.rtic·uiAPI) ill h.- producL
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LL.C- Exhibit 1029- Page 1464
`
`

`

`, "'' '!i and dc""Urrs ••wlwrfin ,,,~~>idrred ("lfllomwniJ.
`,cJuct I>OC3~' l hf>) are-m pn•~llj;oo, mtimRI{' t'fllliMl
`~ prxluct IIJ'd mny relrast sui">IJon~ or n'mf>\"1' m
`rrocn tht' prndnct. Who I~ II< t U&UIIIlv con...,dentd 8
`, ad mim~t.mtiun ~in•• lite 11 p;~rt c>t a
`~~em and lhl'ir e(JC't't upoo the prudud miL•t bt
`even thnu~th th.., <<miMI PCtk..d h \l$lllllly !mel.
`
`It' .;t ljq.Url injcdio11s Me c1uiv dilut.-, the.- c·romponenl
`.. an the holht<~LI•mroortlun is he vc hide•. 1\ vchicl!'
`J~u "" thernJ'IC'utic a. I ivity mel i~ h<·ntl\i• Hco"
`i$ol grrot illlJ)C'rt'\OC'e in tloe l'e>rmulution ~inC'C' ot p re(cid:173)
`leo \)c.d) tis!IUI'l' lhP form ur thl' ll<'l iW C'IIU•hhiC'Ill rur
`1 ~jM.. AhliNploton nMTI\llllv cwcur• m(t'l rapid!_, 11ml
`-"'' lillY when ll d rUJ,: as prl::'lellted as un nqu('ouJ; •ulultl1ll
`Jlilli!" 1tion of lhl' V('hide wilh WUit'r·m•.ciblt' liquid, or
`'-=' rl.i..-J with water mun>M>-ihl., lic;UJ( normally dettei&SC!Il
`t 1 II' of tJ hJ!orplion. A hsorpticm from II I>USJM'IlSiOD IDliV
`j_~ by ~uch Joclunr aJI tJw Vi>COIIII)' of the \ehidt, i
`~· ~~ (<II ~ellrD!: the )l'l lid pa~lldl!ll, lhl' 'ltlluhili1y l"IIUi
`~rhUD produced by the vclucl~. tmd th di lribulion c·uf{tl.
`. ~n tht Ydlicle and . .quct us body IV" It rlllf.
`11le vehicle ol ,nmti'S.l importlloct for panm!Btli1Jruclutu
`,.,, r. Water uf ~uHable quality lutJIIIrenternl Mlmini<.
`lflllk , must be JlleJI3rt'd C'ithtr h~ rlistillntion or~ rc~cn<l'
`..-m ~ i~ Only b)llhlllle m('lll'l• i_ it llO"-"bll! lt ""f\41'· 11~ dr•
`~ !.1.\ \"llli.OU> liquid Jell~ "nd .;olid l'ltnlllminolm~ ~b.lnn•W
`"' \\lkr
`
`f>rriHJ-ro l run f Watr r
`In g~_rlt•ral, a fflll\'t!nl.l"""' -.till co""' l .... r"' hmlf'T II!T'JP"
`'f I >lltaiatillf, r aW Wlll.ilr (d i,lrl HOd). II !.OIIIl't• l•f !11 RL I"
`I •ri'l.e the wattor in the t'\"llf.IC>nt't•r,ll h!'.tdiipat'f Rho~(' I hi'
`1 d dl•tilland with rondr•lt-111& ,,.rf:\Ceot fnr .,.nu,in:. Lh~
`>t nr>el thc:rehy rc>turnint r>nnl"ola·•le imr>unlit!-1 lc1 lh(
`'
`diulUand, & mruns for ehmintltin-,:vtthti.le imrmnlte I fore
`h..t "' l N VIIJ>'If ,,.. Modrn-.(>d. and 11 cundt'flill'l fur rc(cid:173)
`oum~ the heal of vopori41tmn, thtrob) «!flVtrting the walor
`IA)r l<l rt li(IUid daat illate.
`lt liv-uld be &I)IJOI't'Dt lML tht IPf(atr CotlStl'\lC'tmn fealuri"'
`tl a ~1111 11nrl Uw prorc:ss •pecilit'Uiwn ,..,u mnkedly 11rfect
`I Quilty l>( cbJtiJJniAa obUJurcd (IJm II ~till 111111!;4' ft'q\lli'Ull
`~s'P•nducm~r b~h·purat) wnter,atcb, Wat<•r rur lttjl.'<'tion
`P, mlllot be ronsidcrnbty more lltringenl than thi..e requinJ
`P trift.,d WatPr IJSP Amoor tlon fac:tor• lMt mu•l !)('
`l >ldt n·d 11 re:
`
`•' 1
`c,nt..a.raw..-.:n•Uaff«tll o (JIJI!Il,a,<IU...d .. un..u.
`l
`.,,.l'lt,.....,,ry lhallll~ ..,.......,.,., , .. rmr~ d"""' •<'ti. &n .. ••d ''x.......,...
`z.' 1111 "'••en di.UU...I!i.<olllAitu ri ..J <'l•t ll.tJ.IIt>f~ '*k' q.t~f<ly
`, ._IIC ibe .. liP'lftlo•r..rJJ "'""" UwtlrlC~. 1,..r~.or
`boJ..ro;~e"' O"" IOprvvld;- a Jvw o'SI"f>l "4 .. 11Y, thiJIIrc<l ... lllgt ll
`IPII
`<&:t;~ml ,.r dbilillauol ell.t•r '"' 1 Ci. uo "'"~"" t..._Ltoit;. "' "'kpamlt
`It~ I~ '•Illes -
`d•rrr.U.,. ...,.{,,.-..j .lf'l.trm: o' the t l! , l <'<'tlt~-.. .. 1
`11 u, '1i They oto.,uk) bo d&lcned •~ elf'~t ••nU< ru~>• •• e.toluoliJe<nl
`liP! baa!.-.. .,.. \dotity, mlecll1111 • •d notumi"'l lhr "'"'it' •In pl<!b
`1 Ma.d will dL.t.IJa, d
`1~ ,"fili""Cllvmc<>r"""\l,.lml"'" ' -mth• .l .. aan ll!n..Ju "''~"II' ·
`·~~ .. ,,. ""· 111<1 liD I '"'""' .& ... ld ...... p...-.w.d . mdrr \Jy ln "' ,t .. "'~
`Ill:,-=~ autl t~.a~ .... ...J bY Mf"'Alml w II• dm1 , •• lenun:: '" "'~
`r.
`~
`I ~Ol1lA1'1ltulhun •• r IN- YWT"•' :u•l ri• II !lot.., frum ,,. mollll<>rl> ui
`~ ~ . . , •:>tnlr , ) ........... •toriard. r w h,.h I'.Uily ti•IIU uP that •II
`''•ltod~lo<:-r...t h:rthe•ap<oto~dlttilbl<> I• •l<l l"' ""lfil r K:LM ul mel.l l
`tl. to "'llbllu"'lll\,ctl!lOtor~l aiA..,__ !otiPI.,,CJ(tbo..o ntllu.,..•'-"'>t
`
`~r~~•gn fcnlur~ of o MJIJ nl-.Q tnfluenre 1ls effin(>lley (d UJI-(cid:173)
`~,· ll<•h, rel.:>lti\'CJ rleedom Crom 11111-int.rnanC'C probltom.,, tor the
`\~ 1"llt of aulc•rnall< oper~tu.n. StiJJB m.ny llf' Ctlru.l rue I~ ol
`fytng ~ize. m t.ed acrotdinl( 1.0 lhl> \'Oiuml' or d~tiJiaw thal
`
`PARENTERAL PPEPARA TfOIIIS
`
`1415
`
`Fig $.4-1
`
`V8f>Ot QIT'C)I'P."'•JOn Sl•ll
`
`can he pruducod per hour ol opcmtion under or>timllm Ctttl·
`ci,Lioru.. Only mils desJj;T)OO to product birch vurity water
`moy be etlo"d!'red for v..e in the nrld ucuon uf\\ a~r ''"In
`ji'CU/111 l S I'.
`C 111vtniwoal Wlllll'leJ1
`lt.Ul' ,dtoOi<.ned ,,.. thee f'" l Jc.1dl
`ur bigb·J>UriLy Woler tlr& ovnrlnhlf' from !I('V!'ral ill pj)hl'l'!!l.
`Cotapr HS.ion Dl.nlllalioo- Th• \.tl)<•r e<•mJ•I'f>V;jun qtill.
`primaril\ dl!lll~ Cur Lh producti,., ufL•-'1:• w.ur,.,.. .t/1\Jj:h
`pur it v disUUnt.c wit.h low e~onsumr1~i"" ur enei'J:Y nnd waiE>r,
`.. iJJwtrut.OO dil(I'Mim..Lcall~· i .. r.,. IU-1
`·ro Ul.rt. th-. f<'efl
`woU'r is beat.ed ;,, lhe e\'apumu1r lf. huilinj;. The \iJJ)IIr I'"'
`duN>d in llw• Lui~ i« .,.,,Jaraw.J fN.ml!nlrai ned di~l illnnd in
`l~ ""'J)J'rakrT nd t.On\'e)'ed t.J a CUn:.f r •• ,.,...,. wtuc h 01111p
`lhc vapor 11nd rai~es h t> I ~mpcrnl.tort' tu apprnxrmately 22·l•F.
`11 thNl flo\W 14 ltlt! Fteam ~·ht< l vhc-re it c:on<Jt n•...,; Oil l.hr
`11\UN IStu f"~"" orlh.e lu ..... ~ Mnlain·nl! di ltnnnd, lhen-bythf(cid:173)
`\'llpor i n111den:wtl tllld d rttwn uffa~tli•lillalfo whihq.,'IVIOII 1111
`i ,. n. at let lnit 1 lh<' di:-til 1.'llYI ir tht tub~-. 1 •he boilirq:
`point.
`Vapur et•mJire<. ... ion '\HIIs,.re 8\'lulahle in capa< ille~ I ron~ .'>0
`1.&1 2bOf gc~l/buw (At c..a-C1 ""' Born..:fflrl M· "'I In aHa
`linn lo tb!'!r ut.e by t lw pbarmat'\lutical iudu~try. I hey aro
`diliRd t>.lfnavdv by mil.itAIT)' md g.~rntntfltallll tallatirnc
`fe1r th(l J1rodurhl'lf1 n1J»I.nblt!11o<ltet tromteattnd hracnh "'1.:11
`watt.r.
`Rc•crM Qsmosi,-~ c ~ t... renottth ~
`ndded by the USI' tu 11 mollwd Juitnbln [nr prepum-Lion uf
`\\' at .. r for in }"("Lon. As the namr "''~til. Uw natUTD1 1tro
`('CM of ~~elocme ilerrnealioo or m11lerul~ lhl'\.cWl a ..cnipn.
`meabll' membrane l!epaTotiolf two aqut'OUll qolutium of dif
`tercmt conomtrauons ~ n!'\-..rd. ,,,_,11!. U&UIIUv 1 .. ~en
`:ZOO !IIld <tOO p~jg, is npphct:l to overcome cJ6mot,.. prcsaUN nml
`forcr pun QlJter lo permMll' t.hrool(b the membrane.
`:\tembnmes. U5lla!Jl compoa._..t o1 u J'ul,_ rslen:.., p.>l} .. m
`ides, Me selec.l.cd to vruvide an efficient rejrcti<lu ,,r •·t.nlllm·
`hsnt mol·~ in ... '~' "'"-Uir The rnolerule rru •I difficult
`to remove ar!l ~1'1\AU innr~tanic mulect.~lf, Stll h a.. -JOdtt.m
`dtk•ridf'. Pa~t:"e lhJOOUI(h l11.n nwmhrane<~ in llllrie,; ;_,
`__,metin>ell utifW!d to IOcn!:be- he ~rfi, ~I)(:) uf N:mt"' 11 < f
`I hcse sm11ll molecule;. anct l.o det;rea~~ thl' ri~k uf :.lruclurul
`C..il""' .,[ • ,..,.n1l•rane j;, rtmv\.'tt•l.h..r et•otamin.mt., l!U•·h 1
`IJflcteriu aud pyn>gOJn-. Uur eddit otlllll tnlnrrllllllon ~"""'"""~:
`revrr!lt• {, ;,_m,,,JLq loCI!' under lhl• •it!<' in (.'hn plc•r 77, IHtd Pl~:.
`7"i 21. in ci).~L charMer, 11! o bt ri ' u- ;., ond~r w,tc-r in
`Chat}IN 8.1).
`C'ur111ntlv. UL(-n> ive valid11ion i-. l'f'ing tu~<knurn t" dr(cid:173)
`aenninto wht-tll('r, in lat"',thia method 1~ tnptNe .. r ·-i.t.t. olly
`ptt..duc·int: hilth·purlty WPII•r ,,r a qunliLy equul or ~upt~ri ur t.o
`that pruduol Jto l;y di«tillawn.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC- Exhibit 1029- Page 1465
`
`

`

`1466
`
`CHAPTER 8_.
`
`Water [11r 111)1'< ti1111 l iSP
`Thi~ it; a high-puri~y wnter inl.<•nclt-d lu oo u~pcl nA a vehicle
`lor inj(•rL.1ble preparationK. Sleril~ Wolf'r f?r lnj~clion t!S!'
`is described inn separal~ llli)IH>I(roph nne! d 1flers m that. 1L1s
`inlt>llded ns a pncktl.J:cd nnd sterlll~l'd JmKiud ..
`Htortll{e- Waler for ln.ic<'tiOn ~hnuld ho ~d immediately.
`'l'his is u!lunlly not tJOtu,ibl!' ~ince the quantity rcqt1ired. in
`production or a product mu•t lw·''~·•·umuloted owr n P_o~md
`of time. Whl'll ~lorn~e or wnlur ~~ nOCCIII&4tY. the cond 1tmn
`ft1r sH>ra~;:e 110d -.ub$toquent deltver)• to the pomt of use must
`meet strict standar&. Otherwioe, rcccmt.amination may
`occur. 1'o prf'vent ~uch rf'('unl.llminlltion. 't\-ater for lnjecti~n
`should oo collected in a >!(:Npulnu.~ly clt•a11, clu.,ed S)'ftem; ul
`it>. ~imple..t form, tlu• uullt!l from the rondenser should be
`connected directly to a d OI'ed 8h>r&l(l' tlnk. Such a s:,,;:t~m
`1. 'ht~Wn in Fig.IW-2. T() nllc.w for chango~~ tn pressure du.nng
`fi lling ond emptying of the tonk, nn nir wmt shoul~ be pro(cid:173)
`vided through 11 tiller 1t0 um~tructcd thnt mic.rooTgantSm& aud
`C'llcmicnl vapors will be prevented frtlm e11 l.crinj! t~c t~nk.
`'!'he malarial of oooatrurlion fur the IJ!nk And ronnecung h ne~
`should be of chemicplly resh.t.Mll r,lftM~, uf met~! part.~ wilh a
`henvy inlemnl coating of purt- tin, nr of :104 or 316 stainles~
`steel.
`Althou!(h wat.er VllJ)clT ~hould he ~lcrile w!1en condensed.
`runlamination of diqtillatll can occur even wtth a closed col(cid:173)
`lection so,.'51.em. Thrrrfure, Jf ~turtlt!· i~ to be at room I em·
`pcralur~. ll 5huuld nnt t-'ICI't>t-d 2 1 hou~. f'M lung~r per10ds.
`the watPr must be kept undu condltloM th11t w1ll ptewnt
`growth or mic:roorgani>'llh and inJ(fC>..~ Of other COOUIDIJ·
`nants.
`If bmall q\.Uintiti4..,. of \Ynter for Injection are.oo be ooll_oc:ted
`and stored. clean. altrili: l»tllt marlC' of cftem•cally resu,Ulnl
`gla"" may be used. Aft<.>r fillHI~, th bottll!llaruealcd, st:eri(cid:173)
`liwd by autoclavin~t ond ke1>l until nl.'t'dcd. lnte~medun.e
`quantities may be ooUectod 10 dOI't>d tank~. In 110me mstont'CII
`
`t rull!'d l1y u~ of nn immel'!lion utt.raviolel lamp nq 'h:'
`slorol{l' i~ nl mum H•nll)frPlllr!' with miccolual Kro
`Pig.IH-2. Most frrqul'nlly, ht,wever, lhe wotor'i~ 1' I .-q ill
`tMvnl.()fl tMmporntu re of about 80~C hy maJan~t ~r "•t"'
`jaakctcd l.Atnk~. 11 t~mpcroL~•rolon h1gb for mic:rolll I"-..
`11 «~~
`to IJ<'t~ur. WhllrO lar~e quantities of wnter llr!l 0
`multiple lo('ation'l in thll lllant. for exllmJ)le, h1 u10 P ~ed 1!1
`of lorl(l! volume poronwml!!, very 110phistlcat4ld 11~0l ilru._
`distribution s;'illem-; h11vr hN:n developed. Such 1'1Jt •-d
`encomprll»l lfii'J(o jnclcel.f>d rutinless steelstoralle ~nk 'Y'I~
`and Ullulot.ed alliin It: . ~lffl pipes to circulate lhft ~d.d
`tr
`remote JlOllll!l u( 11&1', p1pm~ 6ystems de!!!ig114>d \l.ith 11
`l l<l\18 t,>Op hark lclthe tank vorith no ''dead lqn, ~ "~•nl "-111..
`c:irculalml{ pumJ:I", o.nd oontroh w be ~r~ that ~~~lllel
`()C'mhii'Cla>f all "'1\tl'r 1n the system rernam wtlhi11 e-tllbl'~
`limJlJ.
`-
`Wht'n tht• Wfih•r ('llllllUL be u..ted nl aooc. h at cxch
`muat be iostallcd w redure the temperature lll lhr ~~~~::­
`U'IC. Rortr>rinl rotcnlivc filt.e!'!l 8bouW not be hltilallecl in..:
`ll)"ilemil because oflhe risk OfiUICll'fiaJ hiJiJd up Olllh• ru
`and th1• c·"n;w•turnl iol roloaso of pyro~enie suhntnnct•• '-
`Pu rit.y The USP monographs prov1do slanda\'dq 1)1'11~
`for Wolor for lnjooLion ond for StoTilc Water ftlr lnj&ctlna. A
`few of I hcNc ~t.unclurdK require cocnment.
`Sterile Wulcr f'ur l njcCI.ion must meeL the requirl!mtntul
`the liSP StcrilityTrsl, but Water for lnjcctiun nero 11ota1~
`it Lq lu bo u~ed m ll prod uct wbicb will be KU'nliletl ~
`mUllt meet thl' rettuiremcnt.~ uf the USP Prrf!etn'l'• t fPI&t
`.').10).
`'l'he hmlts ft•r leota! ~<llids varies in the t,.o mOQOIJIJib4:
`The la'llfr the Jurface acea of the ~tlas! conl.8mer ~ ~ UAit
`\'oluoa· of Wlllt'r, thr !V'elller the amount of gla~c.c,m,uwer.ta
`lhlll mov be learhed mto the water, parl.lcular.; durtr.r tht
`clt>vat.-d 1.11mr.orat un• of steam sterilization.
`1'1w Woter ror lojection monograph •llp\ll{ltel n m111._
`'J'hiA is g~mnrolly c011ddt•r•al ....
`ofl 0 f)Jilll uf tul111 w l icl .
`much tuo hi)1h l tiiU\IIUTt' 11 quaUty of w11t.~r \hill wtmld pelllll
`Ahthlr fnrmulntion of mrmydrugs. A relutivolyfewmetallr
`ion~ 1,rlloon l rnn nftnn render a rormuhtL1ol1 ontuhlt.
`Therefore lt i~ common prMlice to set ullmlt of 0 l J11*•
`i('!!M uf 11111;,. C"U11llllllinnllt8 expressed II.S 81l<fiun'l chl«>f'!dt' ...
`tonic contllminnnl leveJ is uol the Mme 81 t<~tnl "''lid~
`forrn(IT helll¥, n m(IMUrt>m!'llt of only Lhe iooicwnt rnl
`tha lotwr ia ~ merumrement of UlldiJ;Soci•t.ed ron~htu~
`v•fll 1~ tonicmnlenLofWlltercan be _ml!a"'urcd '':''
`by mean~ o( n conductivi ty meter. ond IS frequ.nt ~ill
`an indiCA I ion uf tb<' puritv The results nrt oxpl'liA liCill'
`Oft"- Lemu· namel" ll!l sodium cblorid<> 1011..• liS"'
`m'"'
`'
`·
`k
`tnhOI
`~'
`in t~lunw ur IIIC,:t>hllu., M &R cood~a~ U1 m h"'""''·,_
`ond mh011 have a r«iprot'al relut.ion~htp toea< ~ .. tw!IMI..., ...
`ore relntl'l-1 In Jlpm 11odium chlo~dc bY_0
`11,,,nr·t•••n,
`d~~ermined r urvr
`01 meie<llll•.~
`'l'o gh•e one JX>!Dlof
`!!Odium chlurido i.q enunl t.o npprOJnmaLCIV l.
`L' od thllt
`'
`.,
`r
`0.9U mJcrond1oo. li sho~ld b~ m~n '~11
`roJC•'"
`meo~urcmcnl11 givl' no dtrect md1~l 1011• 0le~y 011111nlo
`of wut.t•r ~i nco pyrogenti ore uod1ssoctn
`.
`11 addtd Atlb-5
`pound~.
`w a ~.tor rllr I ojl•('licm Ill flY nol collt8.'" llh•••ttrioli~!':!
`Stl'rile Wotcr f'or lnjecliun may ~'On~tn 11
`~t.lll·'ller
`whrn in ~·nntniner~ of !lO-m l capac~t1 °t1L~tratinn
`stnctmn ;,. de.ail{ncd t.o prcveo~ the 11'11~11 __ ,1_~-,llv ~-ou~ '""'
`ll<UIII\Ily of n hltcteriostatic ~~~:enl ibaL voluntt' -' ... n•-·~
`iuthe 81.'\:Umulated amount of a Lllrge
`lhoul(h the oonc:Pntration was Jow.
`
`,M
`
`Fig. 84-2. H~p~o~rlty sti ll and sooled·Wd!Ell :otorage system. A
`E~etor: 8: h~urlty b:l!lle unlt: C: eondenser; D: storage tank
`with ultraviOlet lamp; E: control p3nct (cotxtesy. Clba-Geigy).
`
`T> P"5 of Wfuc/1!<
`·
`queNifo
`C
`er1~1!' 11 I'd Ufll
`Aqu eou!i Vehicles
`1 ott~~lk
`uiled oCfidnlly hccau~e of th~~ va.
`rnulntion~. Ofl en they nro use<-• 811 111
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC- Exhibit 1029- Page 1466
`
`

`

`11dded 11t the h mt> of admini~<lmt.iuu. '!'he oo
`,.ffecl ol the drug muy ru.~ I~ cnnugh lt1
`when admillliltered ThrJ>e v~hicle10
`Cbloridl' lnjrcLmtl, RinJ~er't~ lnJc<:lion,
`()ell rot;(' and Sudium Cltl.aritl ln.i«ttivn
`lnjectiun ..
`A num hi!J' of .ulvcm1.!! t hl\l llf O
`'::. •. ~iKIIUIC Vebid
`havo heeu used as u fl<>ttinn ur Uw ""''irle
`r..rliDIJ"""'''" uf !)4\renl<'ntlli. Thrse ""lvcuiM are Ull('tl
`effe-1"1 10oluhilit.y of c:ert~~in dn tjl'I! Bnd Lo r{!dUCC!
`1'be must importnnt '>(liven" 111 thi11 ~:r•>Up an•
`polwlhylt:nt' l~ fycol of t lt<t ltquid ~CTII'lt, and
`Ethyl alroholas u"'!d partic:uiMly in Uw
`_.,.. ... ···
`or iolutionll o( carclinc gl.yet.)llidi•H nnd the gtycull\
`Clf bsrhitu mt.es. CCJ't.aio ttlkaloid.:>, 11nd C1'rtaio
`. Sucl1 preporol ioa~q 11rc u.tunlly trivon in I rrtmu~·
`
`., lwuts, ru1 well Wlll<tuilltueoUJj v~l.idos, bnvt• becrl
`l)y SJ.nt!gtl ttod NON'worthv 1
`-.... aut!UUS Vehicl<'ll-'rhe musl im])ltrl.tlnl grnt1t> ur
`euull whicles art' the fixed uiiR. Thl" USV pnovid~
`~-t)(.n~ for BUrb \'l'hicil'll 1\ f'uw or tht'!IC rcrtuiramenl ~
`ill tu be dl><rt~At'<L Tl1e fitced nil~ rnu•l be of Vf1:t l411e
`_.,,1 ordt•r t.hnt I hey may he rnolu1Jollze<l,willl1o liquid ut
`N~~tltrnpern~urr, 11od wrU nol become mnnd raprdly Tht
`•r~tiriCIItion t•liminR le~ nilq of mlltcr·tll ori1•in fttHI tho
`rtM. thw" of 11nimnl ori~in. To IH•Iiquid nlru< rn l.cm
`tll't , a fixed oil m118t COIJlu.iiH'Nler>t n( Ull!Ull.urnt.ed foUy
`iMI lfowevor, tt~c:essh·e unMtlUratinn v. ill produ('.(! liRRut•
`itilllk•"' Thcrefurc, I hf' liSP ~I ipul<ll.ell UPJX'r 1111!1 h1w~ r
`1J1i16 to the UKhoc• vaht\ fflr U.r uil.
`'l'h" ,,.,...,,, pm.,nt u(
`•idlt> must be prevented by the inclusion t>f nntio:lidnntB
`. . hs Wt:oph~>rnl, A nnlural ecm~li lutnt of m11n}· ftXt'd oil •.
`"'I .'P olso pr~trilx•!~ All UJlper lunil for rrec folly Ill' Ida In
`It~ mimmho the degree of t1ssue imtotloo. Othfr
`•
`•fit~1ticmr ore included prim11rily lu fletN·lAdullru'nlLc)ll.
`1111 oil m0:.1t tonllll(•llb uwcl or .. oorn nil, wtt<~llS«ii uil
`,_.r ol~and IICiiii.ITieoiJ IL~<houkll* noted thnl Uw urf1cial
`~apl\5 for !loQme nr tht!5t' ail, prcwide for JtTI!•liA'r latitude
`tltlbihe~J)t(•ificatinns r(l(jUircd for the UJ;E' tlf lhl' uii R• a\'~
`'I'Iwlrefore, 1>arcnt.eral \-chide oils must
`ltir for a parentmDl
`bul'lec~oilllor o.p~y flurifincllo me(>l the mnrt!Slringonl
`'IIIIi tell)onts.
`l"ixt'fl ~til., ,lre u-<ed l':trtieulari.Y n., \•f.'hid
`ft~r
`Ill 13 hmmnnc pnparahor~~~. T ltcsc 1md other nonnttueouq
`~ 'uc.b 1111 eth,vl oiN~te, i~ropyl rnyri~taw end holl7) I
`~~le. may l.~e u~cd ruovidrd they ar~» 'ltlfo in ~he volume
`-ln1o~ered nud do not intcrferc WJth Ibn tbcrapcullr effi·
`::t •nd l e!\111, Th11 Ia !tel al1.0 mu~l c,l~1te the nnnu: nr lht
`~~q <If tJa, Ptel\ll.rtlllnll or with its respon.'IC t u prr~~Crihcd m.
`
`leiiU that tb(luser ml\)' bl·wore l.n c~c rJI' Iutown &cn~<l
`lh
`ty or othor reactions lo it.
`
`Solutes
`
`..!h~ tequiwrnentJJ for puntv of lh" mcdlciool '"~m))<lund
`~n nn injuctinn orum mnkc it neeCffllllry to undt•rtako
`11 ! JlUrification ul th11 usUill ch••mieol gro<le av••ilahlt~. In
`ilt.!l~llAn~ouK, a l;[)ecitll tm rr•nte.mlgrclde uf 3 CXHUP•IIInd i..t
`~ t .. far examt>lc.IWilrhic u<·id fn'+'d frt1m nil traces of
`Itt: \'er ronli.lmtnnl.iotl. 1\'11 n f(!'nerol rul••, tht· best ehrmic:t~l
`If.~ obt<~lru)ltlo• llhould be tc.'<Nl. II sh«luld be ohviou~ thnt
`~W PJlm of 1onic t'OnUJrmnii.Dt.s in Wal<'r lor ln.ifction moy
`... t.tabilit)• ,,mhlf.m., n ~>imil.ar l~vel af eo n l.:~minatinn in
`~ R~hrt...• it.r.cM moy, tikewl•c, CtlURC al.ability probll'mll.
`il.pq 1C C8U!Iysili of dll!m.icsl roact.ior\11 is one ol' tho m~t
`Ot rt..-n~ prnhlemq,
`~~~ her fth:l<l "' to he cun•id<rc.,-d with l"("lpt>ct w the quality
`t;a~llut~K include:
`lhc luvelol mrrrobinl and pymgeoit cvn
`'llst.iou, jofubiliL. cbamclerisllcs 118 dotlmnined hy the
`
`PARENTERAL PREP~TK>NS
`
`1467
`
`chemicsl or physico.l form CJf the compound, and frt>edom from
`grOSll dirt.
`Added S ubstanccs-1'he USP includes in this category
`ttl! sul~~otnn~ ltcldM to .1 prep.uamm to improve or safeauarcl