Validation of
`Pharmaceutical
`Processes
`Third Edition
`
`BRI fl H LI BRARY
`DOCUMEN SU PPL V CENTRE
`
`2 1 JUL 2009
`
`- m09/.
`28978
`-
`
`Ed ited by
`James Agalloco
`Agalloco & Associates
`Belle Mead. New Jersey, USA
`Frederick J. Carleton
`Carleton Tech nologies Incorporated
`Boynton Beach, Florida, USA
`
`informa
`
`healthca re
`
`ew Yori< London
`
`Regeneron Exhibit 1052.001
`
`

`

`lnh1rm,1 I k.:ilth·.,re L::-..\, Inc
`:; ~ \ ·;inderb11t \ ullll'
`\. ·1\ 'll1rk
`,
`ll.)017
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`' 2001:l b\ lnform,1 Hl•.:ilthc.:irc U 'J\, In ·
`lnfnrma HL•,1ltlw.1rl' 1,; H1 lninrm.i bu-,111 ·,~
`
`'\1> dJ1m t., ,,ri~in ii L
`t.o"ernmt.>nt worJ..~
`l'nnteJ m the Lnikd Stat•. of m,•nc;i on ;iud-tree paper
`i I -
`111 </
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`
`International tanJJrd B()11
`lntt•rn.1tipn,1I · t.1n i,,ri Hoo
`
`urnbl•r-10: 0-H4Q1-i05"-
`(Hard CO\ er)
`'.\umber-11 Q7R-0-MCJ1-705--7 (HarJCO\L'r)
`
`£hi· book cont,un" mtormation obtamc•d tr m authentic ,md high!, regarded -;ource ReprintL'Ci 111.iterial 1" 1untL•d with
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`C .. 1 .in it-for-prl1fit l1rg,m1zation that pnl\ Ilk-. lic'l'n'>t."i ,md reg1str.1til111 tor a, a.rid~ lit u •r, h1r orga111z,1bon th.it ha, c bt.'<'11
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`Library of ongres Cataloging-in-Publication Data
`\.'alid,1l1on nf ph.:irrnac 'uhc,,I proces es ' ei.l1led by ),,mt", r . \ ,,,lloco, Frederick. J
`- 1rd ed
`p.; Lill
`In ·lud ·~ bibliographical rl'icrences ,md mdc•
`~Bt\-l l 1r~O-S-191-705'>-7 (hard((wer
`,,I . paper)
`LB, ·-10: 0- 41-70-;. (hardco,er : alk. p,1pc•r)
`I.
`tcrihzation.
`2. Ph,1rm,,reuhc,1I technolog) Qualil) Llllltrol
`3 Pharmaceutical technolngv-Standards.
`I. A •.:illoco James r., IIJ.\8- ti. Carleton. rrcdcrid. J., 19'.!S-
`[D L \I I
`ll' hnolng\ Ph,1rm,iceuh ·;ii 2 Quality Control 1 ~tenlizahon-methnd,
`
`.irleton
`
`1 'l
`!:>73\ 1..1:; 2t11r
`/;J",',14-do.:2'.!
`
`Visit the lnforma Web ~ite at
`wi w.informa.com
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`and the lnforma I leallhcare \ eb site at
`ww,....informahealthcare.com
`
`\
`
`I
`
`\ ' [72 '.!007]
`
`2l'l0701R22'i
`
`Regeneron Exhibit 1052.002
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`16
`Validation of Ethylene Oxide Sterilization Processes
`
`,ii/is
`/0/111 R.
`SGM Btotech. Inc Bozeman, Montana. US.A.
`
`Gregg 1\,fosley
`810/est Laboratories Inc., Minneapolis Minnesota. US A
`
`;
`
`, ...
`
`••
`
`'1
`
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`
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`:_~~-!,r;:~:·~'" )it/~~
`
`INTR ODUCTION
`fhe recent h1stnn ot EC) -.tl•nh,atmn h.is bet.'n dnminal •J
`b\' .iJ, ,m(l'" in ·n~1I1l't'T111g technoltiby I h ''>e t1lh·,mce ...
`indud•• nl,t unh the crnnpuh•ri,l•d rontr,1).., tnr the
`,,perallnn ,,f ·t•·nlv,•r,;, but ilbo lhL phv ·tcal l'l1\ iron(cid:173)
`ment,11 c,mtrnls th,1t pL•rmit s,1fe use of I [)(1' ,, F gas.
`\Ill tot tht''>l' imprml'l11 ·nts ~hH'l' b •n drl\l'n by ·con-
`I"' i...tt·r. che.:ir •r F wee.., t'!'> Jr•' indt•ed 1, orthv
`1m1ic..,
`nb11xh, es I hn, e, er.
`llmelum.: 1! -.eem.., ,, e ha, e lo t
`the k "lL ,in 1, h,H we Mt: TL',tlh ,llk•mpting to ,1u·omph'>h
`in thL· sl •ril11.ition pn es',t's. ,\m ·tenl17,1tion proce<;,;
`mu'>t dt•lh er t1 ldh,1lit~ th,1t J...ill:-. lhl' naturally tKcurring
`l->1oburdl'n mi rol:'>l'~ th,1t ..:nnt,1m111 1t' the I rnduch ,1nd
`ni.11t:ri.1k It the proc •. -., Jrx.>s not rl·nJ •r the rwduct or
`m.:iteri,1b frL'L' from Ii\ mg mkworg.ini,;m,;, tlwn ,;(L•rilin(cid:173)
`hon h,b m•t been ,1ch1e\ed.
`Tlw 1111 ruhinlogical Jinwnslllll pf tlw l·O rnX'L'S:-.
`lH en, helmed b~
`h,1. bi.:en
`the recent -;trides m
`en~meenn, ,ind th,• ph~·..,, ,ll pnicl•..,.., cc,ntrnl'>. The
`1nu·l•,1 111~
`-umpk-'<1t\ nl ml'J1c.:d products would
`be much nwre difficult
`to ,tcrili,e with,>ut these
`·nginl' •nng pron•-.., 1mpro\'t•ments.
`correspondm,
`f-ll)\\',:\l·r. t,1 ilure h prnperh addn.>,;s m1crob1.1I lethality
`rl•ndt:rs .111 ul tht:::,,• •nginL'eri11g .1d\ ,111 l·rn,·nh mean(cid:173)
`ingl,:s., d thl' rL'sulting prnJud is rn,t stcrik•.
`Pnxt'"" \'Jlid,1111,11 me.iii... establishing by nbjecti've
`,,nsi. lt.>nth f n1du ·t·., ,l re ... ult or
`<'\ idence that ,l pnx . .,..,
`produd m 'L'llng it... prl'dl•k·rmm1·d ~pl'cific,1tion ... ( l).
`1 lw EO ,;tenhzat1lltl proce~s I e,pectcd to deliver
`'>lt•ri ll' prnducls thc1l p, >,Se!:>s ,111 olllt'r "P<'Citi,•d lJuality
`,1ttnbuk.,. \,1liJ.ition must Jou1men l all criti ·al proce s
`contmk The prndu..:h to be ,tenli.ted nw~t bt' ch.illengcd
`with .m 1ppn1pn,1!1· miuobi,d ..,, . ..,tl'rn lnc,1ted in the
`.. ,,ur ... t l,,.,1•' nr " le.isl letha l" pwducl ll, ,1tion. In
`
`,\ \\II \,~ou,1lmn lnr lht• \ lhance
`\li/•r.· •r,rf,,111
`11 ,,/ i11 tlr:stfor1'/,·
`mt.'nl ,,1 \kd1 .11 ln,l ru11wn1.1tu,n, Bl. b,"lnJ.:KJI indicllor· BIER,
`hi<1k,µ_1l,1l indh.:.,h.n
`'\ .1lu41t11r rt•,1,tnnwit'r ( t \ ~. \~ubtH1 t.110'\ldL",
`, h n,,mK enqrunmc•nt,11
`·u11d1tion1ng. DLT d,•\ 1,,, under
`IJ~C
`te~I FO. Ill 1, ,•lhj !en,• ,,x1d1-; l'D,\. fuod .md Drug ,\dnu11i,1r.1t1lm,
`t ,l , g.,,, hn,m.1t11gr.1pll\ II' montlatt t pr<>durt . m ,ninr · I; ii.I
`.
`m11l<'u1l.ir '"'' t-;ht. ,tl )SI I, ,Jti.1n.1l Jn,-11tute tit l Lllp,11li>n,,l S.,f ... 1~
`,.., r , .,1t,1n,1l ln ,lilut • nt S..11·11et.' -tnd 1, ... h11nlni-;v PFl,
`,m d I k ,1 hh . ,
`perrnis,,bl ... '''I"'""' hmib, RI I. rel.1t1\,· hum1d1t\ , R 11) re..,1,t,mce
`1emper.1111r d ·tt~·lnr, 'i \l , ,t,111, atnw,phl'ric co11d1111111111)1; S.t1l
`,tcriht\ ,h,tir 111n· il·n•I. '>I R. ,p,,rt' lt>I_\ rc·Ju, lio n : 1 \I{ , lt...,l ,1ccur.in
`fl R. t, ... t 11n-,•rt.11nt, r.11 ><•. 11\' ·\
`th,•rm,icnupl,
`t>me·
`l l
`rill<>.
`\\ l~t~hlt.>d .n l'r,1~t·
`
`,1dditll n th, 1111cwh1.1l ch,11lengl' product mu::.! b · posi(cid:173)
`!Luned in tl1l' wor.,t l<l"l', lea ·t lethal location( ) m the
`produlliun 1,,.iJ. II tlw mi.-rubi.11 ch,11lenge~ are not
`ll
`.ilL•J m the, ' L1:,l k•thal locatinns, then the re ulting
`documented e, iden.:e may be b1a!>cd and n:.-sul! in false
`t.:l>nclu,;111n., .1bout th,• 1d .. quac; ot the sterilization , ·ali(cid:173)
`datinn pwgr,1m.
`Th · , ,1liJ,1tion of lhl' EO gas sterilization proces i ·
`one of the mnr • comrlc, progr.ims fa ing process eno-in(cid:173)
`eers ilnJ rn ii:mbinlogi'>h bl'caw,e s11me criti al proce -(cid:173)
`terilization ha ·
`paramell.'r-. are interadi\ e EO gaseou
`been shm, n IL b • .in L·,tremt'ly df !Cti, e prl css that can
`be perfnrmeJ \\'1th ,11\ infm1te number of combmations
`of par.imeter. Ke\ p.ir,1melt'r'-i that ,1fiect slL•rili,.ation
`J) Lllll(l' ll!ralion .. r EO gas, (ii) RI!,
`dfo:il,') MC
`(iii) temper,1ture ot th• pron: ::., (r.•)
`cce
`ibility of
`the produ..:t ,ind p,1d, .. 1ging fnr th,·-.l' parameter_, and
`(,·) time
`A I alid..ititm program mu. I demon,;trate that the
`selected combm.:il1,,n of these 111teracti,·e prnce s p,1r(cid:173)
`,1rn •kn, rl":>ult in .in l'ffocti,·e ph~·sical and biological
`process. The> cffocti, t•nt>-.:-, of th1 pn -c
`i · mea ured by
`c,,libratl'd F lw.,i.;al 111..~trumen
`and a calibrated micro(cid:173)
`b1.il h,1llenge TI1c,;, proc
`p.ir,1mell.'r mu · t then be
`·orrl'l.1tc-d In .:i cakul,1tcd AL for the product. AL i the
`prob,1bilil) ot .i -.inglt· 1 i.1blt· micnx1rg,111i m nccurring on
`,1 product. TIP rl'quired as,;urance level may varv
`Jcpendin); on the produd it:,elf l'r the end u e oi the
`product, but i. typi ·.illv le,- than one chance in a million
`of a non-st.crilt' unit Llr Al of lll "
`th e ta ·k of a ·suring that
`/\nother chc1ll0nge i.
`the E( g.i~ uset! dues not creat' .:i health hazard
`for the cmplo\ ees in the working , r •,1 nr lea\C
`un.icceptabll· r ... iduilb in the prudud dcl.i,ered to the
`..:on umcr Ad · orbed EO !!:as is r •mm cd l.itrly rapid l)
`from pron· . et! rn,1tl'l'i,1I , while absorbed EO ga., is
`rel •ascd much more ~lowly. This ,1b orplinn rate i
`highl~ d 'pendent on the pe 1fic process conditions,
`mat •ri,11 bemg pniccsscd, a well as the geometry of the
`prudlll t, which affrch material surfc1nHo-n1lumc ratios.
`Apprnpri.1te measure., mu t c1lsn be taken tn .issure th,11
`EO g, ... tN'U in ti , ',ll rilizing en\'irt1nment i~ cont'.ollcd
`.ind contained so tb,1!
`·m·imnmental insult in attectcd
`work elf•,,-. i', within acceptablt.> n:gulated limits
`During tht' F() g.:is
`teril11c1tion pmCl",,;, the gas
`intnacts with the matcri.ib prncessed by reaction,
`,1b ·orptit111 t1r ad ... ,,rption. The F ) ga
`i al
`t~apped_ in
`the air ... paces \\ ith1n !he product or material being
`
`Regeneron Exhibit 1052.003
`
`

`

`242
`
`II STERILIZATION SAWTIZATION MJO STERILl r < ASSURANCE
`
`i!> r<1pidl~ rt?rllmed
`-;tl'rill/l'J. Lnreactcd re~idu,1! g,1.
`thrnugli <'\ ,,~u.111011, h ',lied mtrngen 11r air c,thiln •c·.
`l'ruduct th,1t is rem(i,·e,l from ,1
`:,ll.•ril1/.t'r mu ... t bt>
`in,,ult to the
`nintmlll'd
`to pre\tmt Cl1\· ininmental
`worl..t'J'', . Till' be l pnlCL'dUrL' i" IP rl,1n• th' ... icrilLted
`m.1t<·ri,1I..; in an en, ironment th,1t .iids tlw (k..,orption of
`the g,,._ ,ind 1~ en\'ironmenlJJI\ contn,Jh~d to mimmih~
`W<1rkpl,1 · l' contJminahon.
`·
`
`CHARACTERISTICS OF EO
`Chem ica l Properties.
`ro I .
`,1J,.,o referred to J,, FtO, 1. 2-epo, \'t'lh,1n . and
`~11 1 The
`iiml'lh\ I ·ne o, iJe (2). It h,h ,1 formul,1 of
`tt1lln1nng
`tructure i,, 1llu trJll•d
`
`H2C,--;CH2
`0
`It is ii colorless g<1!>, with J molecul.u weight of
`-1-Ul'i. It h.i:; ,1 ·harc1cteri. tic ,ther-lil..e odor .it to.· i le\'el .
`FD h,,., ,1 boiling pomt of I0.7C (51.3cF) at 7ti0 mmHg
`pre-.,ur ·, a mt'lting pt1int ot - 112.b C ( 170 7 F), a
`,;pecith. grJ, itv of 0. '~11 Jpparenl Jt :?.O C. (t,(1 ~). or a
`"P<'C1tic •r.i, it) of 0., Q7 at .J C. E ha: a , Jpor densit} of
`1.-. ,,ith dr~ air bein<> equal t 1.0, and J ,apl1r pre" ure
`,1t W of I()()<; mm Hg. It i complete!) mi ·cible in water,
`alcohol. ,teetone, benzene, ether, carbon tclr.ichloridc,
`H r s, ,111d 111 ~t organit solvL•nb, and i
`J F'Llwerful
`·oln:-nt for fat , oiL, greases, w.1,es, :ome rubbt>r formu(cid:173)
`lations, and pamts It is highly ex< thermi and potl·ntiillly
`xplusivc ,,·hen heated or mi,L•J with (i) .ilkJli mctJl
`h~·dro ides (1i) high Iv active catalyti • surfa es ,uch
`,,., .1nhydrn hlorides nf iron, tin, or aluminum, and
`(111) tlw n id s of iron and aluminum. Th1 1 t•xrlos1,·e
`limit!:< , re 3°,, to 97",., b} volume in air. It has a flash
`(20°F). It i., relatively non ·orro_ i\"e f r
`point oi -6
`materit1b. EO i~ relah\ely t.t,1ble in neutral aqueou
`solutitins and \, hen diluted with liquid or ga eou
`carbon d1n\1de or h<ilncarbons -;uch as HCF ~. EO 1
`rclati, Iv un~table in
`ither acidic or alkJline aquL·ous
`solut11111" ,md may rapid I~ fr,rm cth\ lene gh .:ol.
`
`Biological Activity
`E rca ·t · 1m:n~r ibly with numcmu chemic.ii moietie
`on cellular molecul1:. bv .in alkvlation reJctwn where the
`[ H_OH H~-1 all..:} I ·,roup i~ co,·alently bonded \\ ith
`the a, ailable mrnetv via an addition reaction. Reactions
`OH, .:ind Cl-1 2 )H group~ ML'
`\\ ith - H~, - H, -
`common ,ind illu tratt;d in Figure I (3J.
`RL·action rate · ,dr) ,rnd dl•pend 1111 th,.: <;pc ·1tic pk,
`fM each moiety and the c>.istcnt pH . For a more comprc(cid:173)
`f po,,~ible re,1 ·tions wt• reter th rl'.ldt>r to
`hcn ... iYP re\'lt'\\
`Rus:,,ell (-1). First-order lethal it\ kinetics require that onh
`·ritical targd C 7). l{e,1dic n
`on• mole ult' rer cell i<; th
`Jther th,111 the critical reaction le;iding to m1cr1)bial
`mac ti\ ;it ion mu.:;t be cono;idered c Jl],itt•r,ll Jam,lge
`rl·,1di11m,
`c,t all micn,bial in,1cti\.iti11n obe,., first
`I l<l\\'l'Yer, e\ 1m wh,m" multiple sit•, or
`order 1-.mehcs
`mnle ·ulL'" m,1,· ht· r quired tor inacti\ation, the concept
`rcgardm~ .:r1ti..::,1I re,Ktion
`,ind c.:oll.1tcral rc.:icl1ons is the
`~c1m • ~\ h •re ina..:ti, ation I
`the re:ult of cumulati, e
`d ,1m.igc, I\ hr.:h is not fir ·t-ordcr 1..incttc~. then ,omt!
`d.im<1g111g re,1ction~ must be c1111 1dered more tmport,mt
`tt1 the L'\'Cnt ... lt'.ldlll?; tn m i.:robi.il in,1cti\ ,1tion i.:nt1cal)
`
`EO Alkylation Action
`
`SH
`
`CH --CH2
`
`NH2
`\
`I
`~
`I
`
`COOH
`
`OH
`
`0
`EO
`
`NH-CH2CH20H
`S-CH2CH20H
`I
`~
`
`/
`
`/ "
`OCH2CH20H
`COO-CH2CH20H
`
`Figure 1
`lllustra 10n of the alkylallon reaction of ethylene oxide
`with chemically active moieties in the bacterial cell
`
`th,111 other re,Ktiuns (collatcr,11). Winaro .:ind Stumbl1 (8)
`1dentifa!d E ) rL1,1cli11n with LJNA as the critical rc,1ction ·
`resulting 111 micrnb1,1 I i11o.1cti\ r1tion . Law le_ and Bruoke
`(9) ddi1Pd peofic re,1ct1011.., nf 1~ with th • nucleic acid
`tcrti.1ry hden yclic nilrogi·n
`ites ( = i\. -) in numerou~
`e,periment n•5tiltmg rn m0re than IO publirntion:.
`bctwc'n l'-l'i7(1ll)and 1%3whcretht>~ ... tatc(9):
`it's 111 the nucil'IC ,1 ids r actl\P towards alk)'latin~
`I.
`agent · are sho1. n tll bt> . in order of dccrea ing
`r aLti, it} : for R. A, 1 -7 of uanin , ,\!-1 of adenme,
`-1 ot Cy to,ine .ind ,.1 of adenint? for D
`..\,
`-7 of
`u,rnine , N-3 of
`,1Jenint' and , -1 ol .:vto ine
`LA:n,ltured L) A bl'hJ\ e in thi,, re peel like R. A .
`2. The observed diffcr'nces between D A nnd
`A arc
`a. crit ed to lhl' involvem 'nt nf 1 - 1 of ,1denin and of
`cytosine in hydrngt·n bond format10n in D A.
`In all ·a e alkylation r'sult in d 'Stabili7ation of the
`nucleosidc~ or the corre ponding moietie
`in the
`nucleic acid '. Al neutral pH. with DNA, 7-all-.yl(cid:173)
`t>ruanine., and 3-alk: l.~denine. are ·lowh liberated
`b, h~ droh· · is, the latter at the greater r,l!e, wherca '
`with RN
`slow re.irr,ingement~ o cur, 1-alkyla(cid:173)
`denine moieties vie! ling 6-methlaminopmine
`moieties and 1-.:ill..ylcyto.;ine gi, ing the corre(cid:173)
`.::_.pondin h1lkvlura.:ib.
`~Ion: recent studie::. suggc · t thJt di ruption of the
`DNt\ molecule m,w Kcur different!~, depend in, on
`, ariou~ repair mechani.m , ( 11). In the ca e of certain
`repair me.:hanism.,, th, rl'Klion~ with ytosinc may bt
`the injury which ultimat l) leads lL1 the in,1ctivatiL n of
`the microbl'
`
`1.
`
`VALIDATION OF EO STERILIZATION PROCESSES
`
`Validation of the EO prncc_, i divided into two pha ·cs
`Engineering Qu,1'1ftcatmn and Proce,,s Qu.ilific.:ition.
`When thP-.e activities arc ·ompleted ucces,;fully and all
`,1sp ·cts of the pmces,; are dlKUmcnted, the proceo;.; can b
`certified for routine u e for m,mufactunng goods.
`
`Engineering Qualification
`Engmcenne; Qu,1lifi .ition i ·1b \\ ith th ' ~tcrill7er ,111J
`.,.,~nci,11l•d etjuipment u,,t:J 111 the proce;,s. Thi · phase i!>
`divided intll three "l'~mt:-nts: Installation Qualification,
`C alibrdlllln . dnd Oper,1tion.:il Qualifit.:,1ti1m.
`
`Regeneron Exhibit 1052.004
`
`

`

`Installation Oual//1cat1on
`[n.,t,il!Jtio11 QuJlifi.:,1ti,•n r,·quirt''- an audit of the ·qu1p(cid:173)
`1t h.i hn•n 1n"t,1lkd 111 tlw fa cilitv. Thi" .iuJit
`n1L'nl ,1
`indudL'" clwd,ing ,111 util1L1,•!> anJ up1 liL·-. to the equ1p(cid:173)
`nlL nt tn make -,urL' that the\ me •t thl• manufa · turer '.,
`recnmmcndcd :,.pcciti,·ahnn~. l·.ng in •cring dr.iwmgs mu;;t
`be L'\ alu<11L•d tn .1~~urL' that (1
`the •quipmcnt is as~L'mhll'd
`accordmg t<i th n1,mufoct11rer\ prints, (ir) the et1u1pment
`i~ 1n-,t,11ied ,1,cording to the in:t,1ll,1tion chem.itks, .ind
`/iii) all as~sects of the equipm •nt are do umenkd with
`a~,pn,priate engineering dr,1wi"ngs or ·ketches. rhc~e
`dr,11, ings ML' ess •ntia l l,1r tutu rt• reference to compare
`th,• h,1rdw,1re \ .ilidated t,1 Jm· future configurations Thi-.
`cgment nt Ll1c• \ ,1hd,1tiLm pr,,gr,1rn is probably the mo;;t
`,ibus,·d with stcril1.1cr,, u:,ing nonL·~pk1:,i,l' con t,1incrs ot
`EO. S\.,tem,, usin~ 100' ., .ire L tremeh well documented.
`\,·hith i · dm L'!l b, the atL'l~ !'i,ut•. O~cc tht• equ1pm nt 1.
`h,1of..1.>Cl up .ind 1t "rut!>.'' lttlll' nlllrl' h ,:n:r Ul ·umented .
`\\ ith the prL•-.sur tut; ·I thmg-. \ ·11 rk1m;. little attention 1-.
`paid tu tlw dou,m ·ntah m I r tuture retcrencc. lnc1,k(cid:173)
`<llliltely trc.:1ted 1IL•ms t~ p1calh in.:ludc ,focument,,tion ot
`Utilitie,,, -.p,lrt.' rart-. [i-.t-. ,111d prL'\Clltl\·e nliltnten,:tn(e
`pm,L•dure.,. 1\1.rny ,.ilid,1t10n, h,1\1' be,·n pcrfnrml'd
`with .ill thc nco.:,-..ir, test;, tin llw h,1rdw.ire rcl.iling to
`pn1<.luct load-., hut with no re.:ord ,b to the e,act confi~u(cid:173)
`r,1t1t1n of the equipment when the , ,1lid,1ti,,11 was
`c,,·cute I. !:,1ncc am mech,1nic,1l device will routm,·I\
`m.iltunction, ,,r 1, t·.ir out .ind rcquirl' rq l,icemL'nt, it 1s
`ab ... ulutel\ , . .,..,,.nti,11 that ,1 well-p repared lnst,1Uation
`Qualificati,m document be J!> embled tor each piecc ,,t
`eqwpmenl to be\ .ilid,ltcd. If this i, not done, ~uhs qul·nt
`, alid.ition d,llil m.1 prm·t• rn •amnglt'""
`
`Calibration
`The ~ecund .,,•gml'nt t>f the Em;mecring Qualitication is
`the calibrat11,n oi ,111 prc>,:e !'> :>en,ing, contnilling, indic,1t(cid:173)
`ing,
`and
`rt'cord1ng device!> on
`the
`sterilizer
`,,r indepentlcnl ,p,tcms a,;,1,ci.1tPd \dth it. Rl>cordin •
`instrum •nt-. that .ippct1r on th • control p,111el are t,·p1c.i lh·
`c,1librated, but man} of the control instrument:, arc
`ften
`i.~calt!d out o t ,ight ,md -.houlJ not bf! it-,'l1ored ~ince lht'~
`m,1 · hit\T .i trl·rrwndmb impact 1111 the cycle fun tion. For
`e,ilmple 1, ith the DEC ph.ise of an E
`·terilizing proce. "·
`1l is e,tremeh· important to calibrall' th· st.ill point ot tht•
`v,1cuum pump hl'forl' the ,1ch1,1l pressure o r temp ratun
`~et pl1int" .ire calihrated. TI1i · measurement is critical ll'
`b.il,mce the
`ll•.1111 input into the ,hMnlwr in relat11in t0 lht•
`c.ip,icity uf tlw v.1 ·u um pump to remo\ c the stc.1m from
`the chamber. All cnt1cal pnx:ess control instruments that
`,1re recorded ,ind di,plaved bv the nmtrol ·y ·tern must I e
`calibrated . lhi 1:, l'\en more rnmphcated when miLro
`prlx.e~-.or t:ontrnl un1l:, Ml' L'mploved. b •cause not t nh
`.ire there 5pcc1hc oper,1ting ,;et point· for tho ·e ~ystem~.
`therl' are also high- and low-limit ,1larm and other default
`'>V'>tem:, thilt mu,t be d,11:umentcd anti -:alibratL-d. ThL
`.:,1libr,1tion progr,1111 wi ll ,1!:,11 \ ar\ depl'nding ,,n the t\ pt'
`<'t CL mputeriLed ,;y:,tem
`Tlw ,·,11ibr.it1nn pr 1gr,1m '>hm1ld be performed 1 1th
`in~trumcnh rcfl•n•rKed ,is senmdan -,t,1ndard~. The
`"L'(11ndan t1r lran,,fL·r ·t.mdard 1." a :,l1n i,1rd th.;it can l'll
`tr,m-.pprtt•d to and lrum the a-:tual slenhzahcm equ1p(cid:173)
`mt•nt l'lt>,,111.,,· mo t mstr11nwnh .is..,ouated with the
`h'rih,,•r mu-.t bt• 1.ihbr 1tcd at he -.ll'ril iter , t, .... ,1tmn.
`
`16 VALIDA 10 OF ET•WLENE OXIDE STCRILIZ,\TIOrJ P<;QCESSES
`
`243
`
`:x•cnnd,1r\ :t.111d,1rJ,,. mu-.t b ' tr<1 ·c<1ble tu a ren,gnitctl
`t,md.ird su, h ,,., tho,t• mamtamed b, tJ1e l\ J<;T
`me,1 ·ur,•rnent or cahbrat1un omp.ir •-. .1 DL ·1 to ,1
`t.mdard or rderence rh1. -.t,1nd.ird should nutperf<irm
`lhl' DUl b, a "pcdfiL r.itio. c,1lkd the "TUR" ab1, knn\\n
`,1. th,· L\[{ .h ,1 rule ,,t thumb, the TLR hould be ),lreater
`nr eyual to 4:1 (12).
`l'nm,ir\ -.t.md.1rds should ha\ , an enm gn·,1tl'r
`-,,•nsitl\ it,. It 1s recommended that tht·se prnn,1ry ~t.111-
`d,trd · b • submitted to the NI r for calibration and
`rcccrt1f1c,1t1011 on a pL:riodic b.1s1 .. l'rirnarv st,rnd.irds
`,1rl' ll!>ll,1lly recertified annually. [t is Pxtr •m •I) 1mport.111t
`that det.iiletl pro(ctlure · be stablish ti indudrng limits
`,rnd ,Kn•pt,1bk correction \ aria nee
`,11lowl'l.i and r,1h(cid:173)
`for all the in ·trumcnt · on the
`br.1 tion freq111:11cy
`t •ril11,.•r. ,.\ klJUatt' records mu t b m,11ntamc :l. A
`i t metrology, d · unng
`lr,i.:kin~ -.1 slt•m 1s e. ,ential to a
`th<1t required ,alibratillll:,. occur al their de:,ig11,1tctl
`tile hould be m,tintained tor
`lrc,1ucn ·ic . ,\ hi:,tC1n
`l'ach mstrumenl. and the records reviewed to a ·su re
`•,ta bhsht'd c,1libratmn frequencic ar c1ppropriatc.
`
`Operational Qualification
`Tiw third segment of En~ineering (_)u,1lification is Op1:r(cid:173)
`<1tional Quatific,Hion that deal with th, operating
`p,irameter, of the sterilizer: their funtlion. , dju ·tment,
`and control. rhc<;e tl·sts arl' performl•d with an empty
`t.h.:irnber. I he , .irinus pa rameters for the cycle are eval(cid:173)
`u.;itetl to determmc tf they perfo rm a. pccified b,· the
`t and e, al(cid:173)
`m,mufacturer. lcmpcnturc ontroill'T'- <1rl'
`u<1ted
`tn dl'lnminl' pertonnan e The temperature
`distribution ,, ithin the sterilizer i · documented. !he
`u111t 1s -,equenced through its operatmg st •p, 10 as ... ure
`that the sequencing is appropriate. EH:r: opl•rJtmg
`p<1rametl'r mu. l be do, umentcd to dcl<•rmine its cumpli(cid:173)
`,111 ·1: \\1th tho: m,rnutc1ct1.1rer· · operating ·pec1fic.:ihon The
`Dpt!rallonal ualifirnhon protncnl will serve .is the basi:
`tandartl Operating Proccd urc for
`fnr de\ doping the
`rliutint· op •ration 11t the ·terili.tcr. Th!! Oper.it11mi1l Qi1,1li(cid:173)
`ficatil1n tei;ting -,pecifics m detai l h n, the equipment
`npcrat' .
`
`Process (Performance) Qua I ification
`I he final phase of validation ea!· with l'mces-. Qualif1ca(cid:173)
`t1on. b ,·n though th' unit tunctions ,1ppropri,1tl'ly \\ 1th
`,m emptv rh,1mbcr, it mu. t mm be Jemon!'>tr.ited th.ti it
`~tcrilizes produd Thi· phase ma\' require repehhon \,·ith
`d1Jtcrenl products and loads.
`
`Load Configuration
`Tlll'r • ilrt' -,e, cr.11 kc\ a, peels of l'rocess Qualificatinn.
`hr ... t the speoti · product and all its pack.iging mu I be
`detmed. fhe next step ,.., to defin
`the way mastt>r L,irtoru,
`ar • arranged into pallets Palll•t arrangl'mcnt within the
`stl'nli,,•r i . .i[-,o part ol the lo.;id configurahlm dctinitmn.
`\l,mv m,mu tacturers ha,·e numerous produ ts that must
`be mi
`•d togl'lhl r in nrder tn achieve effocti, l' ~tcrilil'er
`throughput.
`Catcgonting product tor th• Stl'nhz1ng lo<1d is an
`l' tr,•mt:I\ import.in element. It is import.mt that the
`r,1rtirul.ir product m1, i · nmiigurctl ,, ilh
`rationale
`th.it p.i,kaging i..,
`imilar and products should be ot
`CllllSa...tent m.i;, and ma eriab ,rnd actual product
`
`Regeneron Exhibit 1052.005
`
`

`

`244
`
`Ill
`
`STERILIZATIOIJ SA JlTIZATIO ANO STERILITY ASSURANCE
`
`cnnfi~uration. It 1 · pu!-stblc that ,1 m,mufa turl'f m,l\'
`h,Hc in Lb catalog hunJrcd nl Jilfl'rL'rll prndlllb. It
`th •,t• ,111 h,l\' C the ,,1mt' -haracll'nstil' ... ,rnJ packaging,
`it 1:-. pl•'--.1blc th,1t the~ uiulJ be ,tt·ril1/t•d \\'ith111 11w 11r
`\\\, d111ercnl -;rerili,atwn c\"dc.;; It b also po-. ... 1blc th.ti
`a m.inuta.::turer mil~ pwduce onl\ a tt•11 pnxlm t.,, l',h h
`b ·m~ -;p d1tfcrt•nt twm the nrhcr pwdu · t-, ni,rnutJdurcd
`that e,ll..h product stt•rihzation ~,nxcss I\ ill h.i1 l' lo h·
`, .ilid,1lcd 111 different cvdc,
`Onn• product c.1lcgone: h,nc bCl'n 1denllht•d 11 i,,
`,il-,n pos,1hll' to , ,lr\' the ll1,1d et1nfigur.1tions. Lo.id:- mu-.t
`bee h< md~ -.pccii1c' in the\\ 11 lhc1 .ir• defined . ~111.11!
`t,1k•r,111t:es arc permi.,sible \\'ith()ut d1ilngin)'\ th,• o, t·r.111
`imp,it tun the bioh,gic,11 eftcctivencss of th ~terili1,1tion.
`I lowt•1·pr, ,hanges 111 th• qu.iliti,->d ln,1d mu..,t bl' ·1·.i lu(cid:173)
`<1 t_Pd
`,1ml propt·rl~ d,11..umentcJ
`tn Jctcrmmc the
`potcnt1<1l 1mpa.:t nn the biol,lgt.:.il ctkcti\ en~·s;. ,1t
`th> rroce,<;
`onJ!linns \, hii.:h 111tluenn• U1e lethalih Jdi1 l'reu
`by the pro,css arc ma:,;., density, packaging, pnid ud
`design ,ind matcri,11',. External preconditioning of
`product lnJds is common and ,11lows eas\ prnCl'"
`nw.i-;urt•nwnt,. PrtYond1honing time may \ ·,in \\'tth
`gas and
`different lo,1J . Dctl'rmining ml,isture, E
`tcntpL'r,1turc penetration into the palletized load is
`mu h more difficult in tht:" · terilizer. If time t achieve
`l'ptabl1• le\ el.., of these parameters is similar to the
`,1
`originally Jcfined lo~d, then loads can be considered
`equh alcnt. Measured lethality . hould be · imilM with
`·imilar Ill.ids. It should be noted that configur,1 tion
`chan~c<; may intluenc · the loc;ition of "wor t case-(cid:173)
`cinfirmation will h,wc to be
`least IPth.il" position.
`perform1..·d ,md appmpri,1te a !ju ·tmcnts may hal'c to
`be made t1, as urc U1.1t
`ii proper m,,nitnring l
`,1ti m
`is d >Cum •nteJ .
`nn• thl· product and load h,n e bt•t'n defined , then
`the wor'>t cc1se---lem,t lethal l,JCatinns 111 thl' produ ·t, 1, ithin
`each pallet and within the \ ' l' ~el must be determined.
`fhc~c kxallons will ha\ e 111 l::>e mo111ti1rl·d phy..,i..:.1lh ,md
`biol gicJlh to pro\ 1dl' d.ita ,,n ,111 crittc,11 pro · l•,; _
`p<1r,1m•te~
`
`Pallet Configurations
`Palld onstru tion m.11 deptmd in p,1rt ,111 h,m mu h
`hipping \,·ill t.1kc pl,KC bctween the lime ot con:,lruction
`until stl•ril11,ltion . Wbt•n pr ces 111g was performed
`in-house, 1t w.i. easy Ill ..:onstruct pallets with "ch1mn,•v..,"
`i.:ont1gurpd bl'twe •n columns of ma'>ler cartons. Tlll'sl'
`d1imnc ,.., ilssurcJ th.it more surfd 't' 1r •,1 ut thl' m,1..,ll'r
`c.irtnns \\'ii, dire th ,1u·e..,qble for thl'rm,11 tr.111. fl•r ,md
`type of conftguratwn prov1dcs tlw
`ga e,ch,111ge Thi
`greatest h11mogene1t') ol sterili7.11t,1n ,onditlllns Jcrn ·,,
`thl• rrodud lnad .
`(onlr<1ct EO ... terilit,Hion 1s c,trl'nll'h p<•pular
`toda) and pro,·ides user:. with "s t.ite-L•l·thc-.irt "
`~~ stem
`,1t rea nnable t.'\P •nse. I he problem Cllnw.., fll•l
`from tht•
`tenli7er, but from the l11g1st1CS llln,h cd 111
`lr.im,p,,rtu,g the product off-site to the contr,1 lur
`.u • n,ns tructcJ .it I.he pmJuct manuf,ll luring
`l',ill,•l!
`,,itc with tr.in. port.ilion in mind, nut kril1t.1l1on
`l',111 .,.., Mt' dcn.;;cl\ packed becaus~· thl') sun I\ c the
`n •nr of ,11 erl,mJ ,hipping rnm:h bl:lkr th<1n p,1 llt•t,
`\'Oid space~ (chimn y--)
`cnnh~ured 1, ith
`tor g,,,.
`
`Figure 2 An example of a banded pallet of product prov1d1ng
`maximum sur1ace exposure to sterilization vapors Note: Corner
`protectors on pallet protecting the master ca ons
`
`pt·rnwation . Strt•t ·h wr,1p 1~ comm,,nl: U"L'd tti hold
`!ht• p,1lll't1;,ed bti,es together. "itrL'l, h \1 r,1p i:, e,ceptional
`for milint,1in111g p,tlll't
`int<•gnll Jurin!{
`,h1pp111g,
`but If m<1) cre.ik· ,1 trcm<'nlh,u, b,irrwr t,1 ~tl'nhzmg
`1 ,1 p11r p netrdtlllfl. · 1retlh 1, rap m.1nut.1ctttrl'I' ,ire n '"
`Lllfrring a '' net " type ut 1, rappinl! 111.11 ·rid] 1, hi ~1i ,igni(cid:173)
`lic,1nti\
`in..:rca es the 11rf,Kl' 111
`the m.:tstcr cartons
`dirl'Lll)· exposed to the
`terili1ing , apur .... The bl'sl tech-
`1 ll!Ul' from .:I ~teri lihlhllll F'l'l',r' tiH· i-. tn lJ',l' ,tr,1r Plllf!
`the use of
`t,1 b.mJ the p,1llt•1 ... tn~l'ther. fhis rl'<luire
`corni:r protectors ·,, .i .. 1wt to Lntsh llw ouhidl' i:ornt'r
`of the master carton, (Fig.:!) An t'\,1111pll· t,t 11111ft,rmly
`constt·ucted pallets loaded into ,l .;;tl•rili,cr vcss,•I appPar~
`in fil{ure 3. \lore pall •t coniigur.:1111111.'> cc1n b' stL·rihzed
`,u.:cl's .. fully of n1ur ... ,•, hut pnK<"" hrnc-, ma~ b1• longer
`
`Figure 3 An example of a uniform load conflgurat1on Two
`1dent1cal pallets s,de by side All pallets are exactly the same 111
`construction and product
`
`Regeneron Exhibit 1052.006
`
`

`

`anJ v,1n,111l,n'> of m1cmbial lt!lh,1lit\' anJ 1.:0 rc,1dual-.
`aero.,., thL' ln,1d m.i,· be gn:ater.
`
`g,1., "urply lme allo\\ in~ mJkeup ch,1rgl'" tu rnamt,1 111 the
`t..1rgl'l gJ conccntrah,m .
`
`6 VALI DATION OF E1HYW E O IOE STER ILIZAT ON PROCESSES
`
`245
`
`CRITICAL STERILIZATION PROCESS PARAMETERS
`There ,lre ,e,·er.il m,1jor con-.idL·r.1tit,n: to be ,11\',Hl' t1l m
`order I(> ... 1ructu1e a ,alid.1t1un program th.,t ,,111 ,1 ,un•
`th.it thl' skrili.r<1t11111 prnn·~s d(lCS wh,1t 1t i, mtL•ndcJ
`tn do.
`The. e cons1dl'r.1hons include: (iJ controlled pn•re,
`pc1ra11wkr-. and their mter.ichon; (ii) .ir1 inkgration t f the
`·nnd1tions; (Iii) the seb:(itm Of ,1rpro(cid:173)
`phV',ll,il rW<L'S!>
`priatc rnxt•.,.., condition'-; 1,• ) the prlidud de~ign; (,•) hn"
`the pwducl h prctn.>ated pnor to c,po ·urc; (i'i ) h,m thL'
`product I handled followmg "tL·rili7alil,n· (,·ri l hti,, the
`,tnJ
`pron• s ,., rnonit,>rl·d , induJing phvs1c,1l, hem1l',1l
`biulogi, ,ii nwthod ·, ,ind (!1111) the cffc t nt' l'<''>iJ ual ·o .111d
`ii!> re,Kti1m prtx"l ucb on thL• material bem~ stcriliLt.'d
`lh,11
`TI1L'rc ,ire tour criti~al mter,,cti, e p.ir,1ml'IL'r
`must bl' controlled for EO '>lt•rili.r.1tion proces~ 11) EO gJ'(cid:173)
`conccntrati 1n; (11) moisture; (iii ) lemperahtre; ,md (11•)
`hmc .\II the'>L' parameters inter,1ct to ,1ff •ct the ldhJltt\
`d •li,·erl'd h
`the proc~~~.
`
`EO Gas Concentration
`General Use Range of EO Gas Concentration
`EO ga-. n,ncentr,1l11 ns bdlH 100 m • L and ,,b,1\,
`J _oo mg L .ire m,t commonly LI . l'J in the mdu .. ·tr. FO
`ga ctmLentr.ition., k·.,~ than .100 mg , L .1re not di..: ·t1\ ,, in
`pr.ictiL,,I prot.es-. times. Cllnccntrati,m · abo\'e 9ll0 tu
`1_[1() mg / I Jo not !:ihortcn the procc ... s times sulfiLiently
`to wMr,mt tiw additional co::.l of g,15 Stenlilalit,n dfrc·
`ti, ent· "1:, dL'pcndent on thl• mnlenilar colli:,ion of the F )
`molernle ,md the bwlogical L'nht\' that i:, being tcrilt1t'ti
`Therett,rl', mt r' FO molet:ule~ bid tt, more rapid m1Crn(cid:173)
`bial lcth,1ht\'. A ... t,•nli.ring pmce:, · u:<ing 00 m~ l ,ii F()
`dcli,er-. approx1m,1tl'l) lw1,t• lhe leth.1lity a · a pnx: •-.
`u ·mg ~llll mg / I 1n the
`,1n1e time. Howt•, l'r, ·on:,idL•ring
`.ire gen,•rally desi •ncJ tL)w.ird
`th' cost 11f 1::.0. processe
`the k ,,·er cm •ntraht,n,; of FO. onc.entrJtion. ot .Jllll tL,
`,1ppear t11 be th • mtm: popul.:ir condtht>n-.
`oOll mg I
`tod,1, ttir oper,1tHHh to b,11.:inLl' thL· cn"t of r·o. equ1pnwnt
`and throu •hpul lime.
`
`EO Gas Concentration Controllers
`TI1l' ro ~as Ll)l11;l•f1lrati,m l', umlrollL·d In one l I (\\ ,,
`~,a, .... The mo ... t common method of control is th· indirect
`metht d throu •h thL' u;;e of a pre-. ·ure L·ontrul svstem [he
`tht.>
`co n ·entr.1hlln de,,ircd 1:, caku l,1teJ ,1-. 111
`EO ~·
`,:orre-.ptinding 1n, rl'ase in pre:,-.ur • Th,:, :II.' ired pn• ... url'
`setting.., Ml' then m,1intainl•d b\ con, enhonc1l pre-.. ure
`cnntroll •r<,. Th, Jin:ct control method use:, c1n,1lyt11 .. ,1l
`m. trument-. that a.:tualh det ~ct th1• EO g.i-. uincentrat1on
`111 thl' em irnnml•nt m ide the., enlitl'r.
`Th' ,11\al\ t1cal systl'n,,, arc either gas chrom(cid:173)
`Tlw e
`or micro\, a, e dclectors
`I I~
`.1tograph1 -
`mstrun t.'nt" ,1re m,talleJ Jirecth 11, the ... tenli,er. Pt•ri1 >,h.
`ga ... ,ample" ,u · ~, 1thdrawn trL>m thl' ,;tenluer or ga .
`cirl'ulc1tmn ltnc:, and pa,; .. ·cJ through the J ·ledm 1,rn'
`IR or microwil\'l' 1.h·tectors m.i~· bt• mnu 11ted on th,• ... , terinr
`ch,1mbcr \\ all u::;mg ,lll acces~ pl1rt or 111 lh1: gas ornilc1l1on
`·nt to control ,·al\ e, m the
`y:,tern [ lectro1111 ..,,~nab .ir"
`
`/11rlire t
`fr tfiods
`Tht!rl' Ml' l\ ·o appro<1 hes tor the ind 1rect method
`ot n l',i...unng EO ga concentration in thL'
`tt•nlizer(cid:173)
`the\ .ire w1.cight .ind prl'S. ure. The ind ired method arc
`depl·ndent nn using g<1!:i ylinder~ rnnt.,ining ·L·rt1fiL•d
`\'Vlwn the chamber is pressur11l'd, it i
`mi,ture, ot E
`a ... urned th.it thL' mixture contains the gi\'l'll percentage of
`E() rd,1th,e to the ch.:ingc in pres ure. I h •refore. thi.
`chJnge 111 pn,•ssurt• can be equated to ,in as urned ga
`(tl11Cl'ntration. Thi · y-.tem 1. ve ry ea y to m n1tor u.,ing
`F ressun.' tran ... duc •r.. and rL'Corders.
`The :,e ·l,nd ind 1rt'rt m ·thod rnea. ure the weight of
`the g,,., cvhndL'r contt•nts dispensed into the ve ·sel [his
`mt.'lh 1d ,1:,-.umL~ th,1t a unifnrm mixture of the E and
`diluent ga wa:. dispcr,L•d into th vess I, yieldmg an
`,1 ·.,um •d .:onccntration of g,1.., in the terili,ing chamber.
`In munitl•r usin, acceptably
`I" e<1,,
`Thi, s,· ·tern
`"('nsill\'C ,;cale ..
`The-.P indirect methods are re,hrm,1bly good esti-
`i\.cither method
`for most g,h mi lure
`mate .
`compen,,,1tc,. il r absorption of EO hy the packagin
`itfcrent maten,11 · ab .. 1)rb EO
`m,1ten,1l,; or the pnx:lud.
`JI different r,1les than the, do diluent gri,L'.., (1