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DATA AND REVIEW

Managing Aseptic Interventions



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andR9ft~i~tiorg,~$tabJjshing effective pr6t~$ simo'iJtion~;:arid ... .

determining which vials to incubate.

erforming an aseptic process almost aJways requires operators to manipulate sten1e or sterilized products and components. These activities are uniYersaDr considered to offer the greatest potential fur introducing miL"tObial

;pii1!amj"~ iati"( m (J-4). That potential has been recognized by and Drug .I\.dministmtion inspectors and has led

:~~.'~~iJltial concerns raised in vo1lmingletfers issued in :.·lCl.:(S:~); The measures taken to respond to these concerns cQJUPluU4e5 involved have implications fur other firms :~~mjlig aseptic p~ng. The PDA held a conference caD jfl!~eiitlber 1001 widJ representatives of the Office of CAlm-

VHilHJq~.in FDKs Center for Drug Evaluation and Research tvlJLJiJo.J to address reJa"3nl issues and establish some ground

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F4mnuldFrf;~ !'.t+n,.m~~~~grepresented ..., .. ~,.,.,q" .. essen~:pf tbi. cogVer53ticm "''* sU~uentfy .Te-

nnrt ....... ;.in. ~,r:gA~m<. iC' ';

This artideoudines a romprehensil-'e approach for organizing,finn'sa~opmrtio~ ~wit4~e ~ofthat distussion ahiblign&t withlecerIliyddindlttguJatOt}, especmUMs. The apprnocb was initiaJly dn'elopnJ .in the spring of 2000 to mit the speri:fic ~ of a major manufactum-of aseplicpmdum and su~uendywas refined through application in a mriety of ~ at other firms .

James AgaIIoco is the president of AgaI!oco & Associates, PO Box 899, Belle Mead, NJ C8502, tel. 908.874.7558, jagaIIacoOaof .. oomc

.............. iila5IfIk".,.,

It is appropriate to focus on human interventioos performed during aseptic procemng ~ no other factor has the same Pc!t1mtJa1 fOr in~cing contamination. Sterilization pnxnses. ~talsaoitization, room design, aDd heating and ven:tilation systems are all Substantially less significant as sources Of COnlamiJl3jjori. Personnel continuously shed miCroorgaR~ i;ms and particles to-jjje;r surroundings and gtlWJlingm~~caniiOi oontain the mI11ions of organisms present on h1JDl3Jl s!iJb'11ii proninity of personnel and thus substantial numbers of potentiaRy contaminating microorganisms to sterile materials, components, and surfaces during the performance of interventions is largely unavoidable in stafkd deanrooms.

........ _IWIine .... MIIf1IIS.Jnten-ention~ in.asepti~ procemng operatitJns f.ill info two mairi artegories:: routine and

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DATA AND REVIEW

nonroutine. Routine interwntinns are activities that are inherent parts of the'aseptic process and integral parts of every batch 'I}-pical routine interventions include:

• aseptic assembly ofthe equipment before U5e;

• initial product connection OJ" introduction;

• start-up component supp]}' or introduction;

• initial fill weight or volume adjustment;

• periodic component replenishment;

• periodic fill weight or volume checking and verification,

• fiJI ~'right or YOJume adjus!meJIJt;

• enrironmmtaJ monitoring;

• ~or bmtb and meals;

• operator shift cbanges;;

• product 5iIDlIpting;

• filter infegritr resting;

• produrt rootainer repJaammt;

• component change (different mes};

• liD-volumecbange;

• 3Il}' ether intern~lItional actit;tywhich is an integral part of tbrproass.

Notmnlfine intermrtions are adirities tJm arepredlJ~IIm1Jy. coiin-tiYe ~ mar not be a part of nny iheOii;nonloUiiJre .inteiventions may not be n('(:eSS~~dijiidR the ~ ~ in practice sum inten'ftltiooS :Ii"I"::iiiIi'i'iIM*: ~ requilai to cmred sonr mornaJy. Smne connnc.n rouline iotrnmtions inm:hr.

• stopper mi'ikeds or dmnping;

• f.aJJm.l1mken. or jammed containers;

• def«tiwe ~ on container'S)

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• fiJl-pjlnp repJ~.

• rtopper bowl changes;

• ~~ts; ::: i: .:: ...

• ~oiguiderail~tmd5;::

• ilDf' other line malfunction ~ mammd correction.

tablishing tighter acceptable qualitr b-ek for containers, seals, and other parts that must be assembled; and ensuring better control over component preparation to provide greater operational consislmq.

P'nass .......... Huma. n mten'mtion also call be reduced by automating processes. Examples include robotic sampling for fiU weights, servo-adjustable fijI volumes, automated remov ... I of downed containers, and automated stopper seal integntr testing.

Another~iJftomJocet.lJeJ)umberofintnventionsjstoencourage operators to esamme the necessity of an intervention bemre perfOrming it. for 1f'DIDJJIe, a flat that has fallen over on 3 turntable should be )eft 00 irs side until it presents a problem feeding other rontainns. If no problem OCC'Ul'S, the fallen vial ""ill still be on the turntable at the completion of the fill, !hereby eliminating theintenmtion mtireJr.

... tif,iagiabl ___

looling at the list of interventions provided above, it might ''ilin-..r that a firm need only address those items. That ap=-~"··"'''_be inruffici~ however. The preferred approach

'~~iilltbe operaIingpenonneJ and bare each operator

:~ of routine and noruoutine interventions. For

::m_'Wi11b ~lIIltJlpIe ascptic opaations. intenmtiOns lDlI}'vary line to another. ('Y('O if both are filling similar

::m!~~~;anld rontaine1s. Variations inpmdurt t)'pe: may add

. . are specific to indiriduaJ situations. The initial

goal .. ,. .. actMty ism oompi1e a Jist of aD inknention." for

each cin::urnstal.lCe.

•••.•••.•.... The k~t~ti)~rt'l'i i~~¥mti~S~~!he operat-

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preseOt,an~!W~fPl¢lminatioJititL Thdij~h interYmtion should be disrossed .in detail and a preferred means for

~~~~+ouJdlJf'~~two or ~ operitors nJar~ ideritifitd the.·~ intdVention, thq maynot. perform it in an identicaJ or even full), acceptable manner. A competentmicmbio1ogi5f familiar with 3!CpIic tech-

nique should participate in this process. Once agreed upon, each intenmtion (~mutine and oonrouline) should be established within a single standard operating procedure for each fill line, process, or product type. This SOP Should be app1iaI to both process simWatioos and routine operations.

The procedures must indude sufficient detail to eliminate ambiguity. For eum.,Ie, became many interventions require the mnoval of rontainers or components &om the line, the extmt of mJ'IImII must be euct. For instance. an SOP might indicate that when dearing a stopper jam, the operator sbould re!J'JOt-etbJ're'rontaincn on either side of tbe container under the trnd:where the jamoa:mml ~possib1e,lbenumhen of oomponenl$ to be U'IDOtw'i during tach intervention shouJd be identified and that number should be ronsistent fOr simuJation and production.

In some instances, it may be preferable to define the extent of removal by location rather than number. The procedure might state, "remove all open containers between the last fill

1111 perfedintel NRIien

~_~ proces.siog. the perfertintenmtion i'S the one that is, ~.~ TIte_~~ inf~~tiorJs, the ~ ~ likeJi:boodof contaminatioo.~dJenumber ofintrnmtions &m1d be the goal in eftIT aseptic process, Opmttors should ~&- this goal throughout 1be operationaJ Jifr of !he proce!5. futenmtions can be eliminated by at least three major means:: procns and proadumJ design, wtpnwq oomponent quality. md procei5 automation.

......... pracallnlIlsi!Jt.Process and procedural design elmsmtslhat can .reduce j~ indOOr eJiminaling mrervmIiom brperfmmingdean.,in-pba and sb!rWlr-in-pIaaproadores b Ihr filling 3S1JtIDIJIy; mooring samph afirr ~ materiaJs ~ hem tran:skrttd; diminating ~ry $lID-ping steps; and using the pressure-hoJd.method for filter inkgrity verification to obviate the need for a downstream connection.

........ iif~ ... Ity. Interventions also can be eliminated h}' improving component quality.. Examples inchtde es-

_ 1I1111_ ••• UlrlldIIIIJ1 WIIICH 2IJI'J6

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Pnusssim ..... ofrouliReald

----------------------------------~------------------" ... NUtiIeHdM~

Because routine interventions are integral and necessary parts of e\"ery aseptic process, their execution during process sirnuJation should occur at the same frequency asin an ordinary-aseptic produc-

tion process. Fortunately, this is relafu.d)' ~ to accomplish. The setup of the line for the proceu simulation should follow essmtiaJly identical procedures to those used for production. The only tifferences

I might be using air instead of nitrogen for ! bJmIret.ing or pmging (to enhance recov! err of potential mi.crobial contaminants) ! and adapting in-line polishing filters to ! maintain flow rain. The remaining rou-

I line intenmlions are eilher presc:beduJed i\bJ.;P~~ (e.g.. ~(;hecb or adi jllfimmts),. OCC11~~t r~r intervals i (~i, ~t ~ltiient). BY'rei q*in~~~ iD"~on to follow

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. I. be ~o~at the. same frequency in

:b0tb4.us~~~~nis

r a valid rePresentation of the routine I procas..

lNfomoutioe iImw:otions wrysubstmliaDr from routine inIaw:ntions.lNonrouIt1nt intnwntiom occurrmdomly during the proass in response to faults.. The frequmcywith which they occur may~'lI.l}' subsIantiaDy as a result of factors outside our ~OI'abilityto controL 10 enSIltr Ihcir correct el«Ulioo. during routineopentiom. tbcsein~must be included in process simula:1ioos at a reaIisric tia]ueru:y Ierel.

INonmutine inlerYmtion s should not be optional in simulations. If operators do DOt practice nooroutine interventions during simllbtious, the operators wiD be 1UJ.3ble to perform those intereentions dmingadual aseptic production.

The suggested means for integrating noorouti.ne inten'£Dtions into a process

DATA AND REVIEW

head and the stopper machine,"" rather than, "remose the six open containers between the stopper machine and the last fill head." If the ronveyor happens not to befull between those locations, requiring the reJ11O\'a1 of six ¥ials may cause confusion and lead to inconsistent execution of the task,

Training personnel to execute the interventions is of paramount importance. Earn perron who is expected to pnform

an intervention in routine operation must become proficient in its execution. The preparation of a video depicting the proper methods for each intervention is higblyrecommended because it can beestremeJy difficu1t to convey in words the proper method for performing an intervention. If the intervention methods are identical for all operators, questions regarding operatOl' participation WJlJ be re-

duced, Thus, the Intervention procedure becomes qualified regardless of whidl operator performs it. If a firm has manr operators, this alignment of procedures can help simplify the process simuJationprogram. When new operators are introduced into the operation. the aPJlll»'m intersenlion procedures become a major focus of their task-specific training.

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something may occur during an aseptic process that requires an inten'ention that was never considered or that was considered to ~ a onaa:eptabJe Jem of risk.

The proress should beterminated at that point. urnJess an intervention bas been \ \ fully integrated into both the plOCeSlS siJn-. tiJation and routine operati0rutl srtti~, 'no assurance exists that it can be perfOOned without introducing rootanliD~ .¥ion, ~o inter'ventionsi!()uld J:re. permjt-

-------------------------___" ted unless it hasbeensatisfactoriJyac:coD!-

plisbed in at least one media fill If the Dmt to periorin an UlllIppl'O¥ed infenu... !ion occurs with increasing frequmq..lbe finn should take corrective measures 10 alleviate or eliminate the situation. If ap-

propriate, the firm can add interventions to its approml ~ prorided those interftDtions are incorporated into the process cimnlatioo program.

It is important to document in the 1 ' baJdll'coords all nonroutine intermJt:ions i that are perfonned during both process simulation and routine filling. The docu- i , mmIation should indudetbetime tbeia~ was per:fOl1D£d and its identification (using a number- syYem can

\.\~~~.ing)~~rou-

i~:=tr~~~~

! e.lIli~\iS~part~P- the prodac-

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, ations and ddennine wbethera '-

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quimI. Thrlingthe nonmutine interventOt fRquencyallc:m1s the firm to develop its JJIOCf'SS simulationprognm 10 support !he more-mmmon nonroutine intersenhom in every ~ simulation and relepk 1ho5e that are less frequent to a louger intenal bdwem simuJatiom .

DATA AND REVIEW

simulation is to schedule them as ifther nonroutine interventions are executed were integral to the process, at approai- correctly.

mately the same frequency mth which

they ocrnT during normal operatioes, ...Iiw __ iMIIIi6e

The operators should perform the non- ..... eaIiaws ........... atiaII routine intervention foJlowing the ap- I Interventions that occur during routine proved procedure as closely as possible. operations should be performed lL'.ing the

, The media fill observer (whose presence methods that have been established as IS strongly recommended during every . ~&';md practiced during process simupYOCn5 simuJation} must ensare that ,i Jation studies_ OccasionaD". however,

........... 1Iel

All proa:!5 mnuJalioos includetbree p0pulations (see Figure 1). Population 1 rep!!aenu marketable product and coesists of fully acceptable llIlils with integral cootaiocr-chwre and units with C05IJX'Iic. defects that ordinarily would be removed during post-611 insp«tiOIL Popu1ation 2 consists of intmrmtion units teIl10Ved by prourlure or practice during the course of the fiIlAoy uni".s that are automatically :sorted out of the batch by the equipment

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resentative of marketable product should be incubated.

This means that onl)' Population 1 should be incubated. Units removed from the filling process, either as part of an intervention during the media fill (ie., Population 2) or aikr the fiJI is completed ti.e; Population 3) should be discarded. The majority of these units will be unfilled, unsealed, or uncrimped. Manually sealing ;

and crimping these units is not a part of routine operations because it is likel)' to introduce contamination. Little benefit will be gained from testing such vials, Detecting contamination in the removed units does not impll' contamination of the overall aseptic process; the presump-

tion of contamination that prompted their removal in the first place suggests that an)'

contamination detected in those units would not be represen.•.•.. tam-e of the the remaining units.

during processing l't'OuId also be incIudro in AJpulation ..... .... ·.containers in Population I must be included in the statisuJalion 3 oonsists of my unit with OOI1lJpJomRcI conlamel!iiid!oi': ::Jiic:aJ.~.~. ~Ition of the media fijI. No rontainers can be disre-

sore intt'grity that ,roo]d be cuBed &om the fiJI have been incubated. This population repre-

inrubation inspection. produrt and vials with cosmetic defects that

Attertbecompldion of a process.:simulation, in post-fillinginspe::tion. The cosmetic de-

be cardUJJy inspected before iDmhltioo in.~.l because theirmnoval during

m:witb mmpmmisedjnlf!gljt!.~onJyunits batdt issubjecttolhevagariesoflhecosmeticin-

DATA AND REVIEW

Population 1

Represents marketable product plus cosmetic defects from post-fiB inspection operations.

t

GIas&" Sterilizing" SoIUliion .. Stopper .. CappIng .. SOOing

runnel filing insertion i

Popu~on2--------~ Examples:

• IntelVention units

• Change in filling needle

• Change in filling equipment

• Stopper jam

• Dose adjustments/samples

• Automaticany rejected units

Population 3 Examples:

• Cracked or broken units

• Missing stopper

• Raised stopper

• Leaking units

• Any units on fIocx

..... 1: The 111188 pap......".1IJaI occur In all process sIndaIirJns.

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ner for both process simulation and routine operation. the adequaq.< of the aseptic process can be demonstrated b)< suecessful media 611s. Aligning the mtervention procedures diminates the uncertainties associated with varying prsctiers and supports the successful esecubon. Incubating the units removed during processing provides no additional ~lJJ)its are aM'lIfS rejects during either production or process sim----------------------------. ulation. Incubatingnonintegralcootain-

ers is an exercise in foil) .... Process simula- r tions are assessments of aseptic processing . capability and are not definitive determinations of sterility assurance, Inferences that not-incubated units evidencing con-

tamination are indic:atM: of aseptic process failure represent a biased viewpoint •

DATA AND REVIEW

spection process, and thus they are potentially repre;eotative of marketed product.

Incubating any remaining media that was not filled into containers may be useful, but certainly is not required If that media is heavily contaminated, it might invalidate the entire fill However, if the residual media is contaminated but the filled units are free of growth. then the remits of the fiJI must stand. In dfed, the

presence of growth in the residual media has little relevance to the media 611, en-ept in those instances where it results in the failure oftbe media fill. which ordinarily is considered a non-lest, requiringtbat the test be repeated

CcmdasioIt

\'\rtten intervention practices are detailed in procedares used in an identicaJ man-

........

I, J. ApJlooo and B.. GonIon. "Cmrmt Puclias in Iho: UK. iii ~kdia Filk in the YaIida-· tion oLL\sq1tic Processing. ~ J. Plm:nteml Sci. Tedrtwl. 4. ('I), 123-141 (l9S7).

1. J. ~ <!lid J .• <\hn., "Ommt Practices in the V.idubtion of .MeptK. Processing-1992: f. ~Sci Tdml41 (2), ,~.(1993)..

3. J. Agldloco and J .• U:ers •• Current Practices i:ttJ"'ffie ~lida.tio~'Aof~tic Process:;:iDt-I~!DA t;~~ 24, IDA

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m}in:j.he VaJjd.if'~}of .~ic Processmg-2(Xn;PVA Tromi<:al Report 24. PDA f,.J'lHirm •. S4 Tedtwl. ~ (3),li4JIPPkmnlt

S. ~!J~.~atm.~~ld-

te:rtoAlwnlabor.mnes,.l1 NOIo~ 1t!tlJ. ~""w.fda.gtwIt1{lif"'"aming-Ieum,fm4877n..pdf ~~J8~2005).

6.. l1ood..II>rug.~ ....... '\~Ld-ur to Eli lilly & Co, loc •• l March 201n. _w.ila.pifCli/wamiog_ldtasim.>2S7n. ,\pdf{~ 18 H:1!mwy 2005J.

7. }PQA,J>n4 Newslf:lkr.&~ 200.?

S. LlS FOOd and Drug Administrntion, Dmft c:-qt ltrper dIIJJ.5urie DnIiK Pmtlracts Pm- 1kItad",. J\sqltic~ (FDA. Rocbile. l4D" 5cptmJha 2001}_ PT

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