HOLD TIME VALIDATION

INTRODUCTION With all of the work and focus on cleaning validation, (1 !" one facet of the #rocess often overlooked or not understood is the as#ect of $old Ti%e &tudies' &o, what e(actl) are $old Ti%e &tudies* There are two as#ects of +hold ti%es+ generall) evaluated for validated cleaning #rocesses in #har%aceutical %anufacturing, - Clean Ti%es, The ti%e ela#sed fro% the end of the cleaning #rocess until the .eginning of the use of the cleaned e/ui#%ent for %anufacture of the ne(t #roduct - Dirt) $old Ti%es, The ti%e ela#sed fro% the end of %anufacturing until the .eginning of the cleaning #rocess 0ither of these two ti%e #eriods can have a significant i%#act u#on the cleaning #rocess' 1ee# in %ind that a cleaning validation stud) is a reflection of the #rocess(es" used for cleaning and %aintaining ite%s in a cleaned state' 2n investigator %a) note two different t)#es of situations during an audit' One is that e/ui#%ent is stored with a status of +Clean Read) for Use+ for #er#etuit)' That is, no ti%e li%it has .een #laced on when the ite% is to .e recleaned' 3uestions that are asked include, - Is this e/ui#%ent reall) clean now* - Do &tandard O#erating 4rocedures (&O4s" indicate how long the cleaned e/ui#%ent can .e stored #rior to re cleaning* - Does ade/uate data e(ist to su##ort the storage of the cleaned e/ui#%ent* 2 second o.servation regards dirt) e/ui#%ent held over a #eriod of da)s so%eti%es longer #rior to cleaning' This can .e #ro.le%atic for cleaning es#eciall) if )ou deal with li/uids, which dr) and cr)stalli5e onto the surface, or if )ou handle #owder, which is h)grosco#ic and soon transfor%s into a #aste' 3uestions for these situations include, - What is the i%#act on the surface of the e/ui#%ent .eing held for that #eriod of ti%e* - $ow is the dirt) e/ui#%ent held so as to not conta%inate other ite%s* - Is there data to su##ort the cleaning of the dirt) e/ui#%ent after it has .een held for long #eriods of ti%e* (To illustrate, cleaning off a #owder or li/uid is handled %uch differentl) fro% cleaning off a #aste or a cr)stalli5ed su.stance'" This article is #resented as a guide to understanding the a##roach to conducting validation studies which co%#ile data in su##ort of t)#ical o#erational #ractices'

CLEANED EQUIPMENT HOLD TIME VALIDATION This section covers issues related to the +Cleaned 0/ui#%ent $old Ti%e+ (which will .e a..reviated C0$T"' C0$T is so%eti%es called the e(#iration or e(#ir) #eriod for the cleaned e/ui#%ent' Why CEHT Is Important for the Control of a Cleanin Pro!ess 0ssentiall), the .est reason to conduct such a stud) is that nothing sta)s clean forever, no %atter how well #rotected it is in storage' Re conta%ination of the e/ui#%ent %a) .e an event related #heno%enon' $eating, 6entilation, and 2ir Conditioning ($62C", #ersonnel, storage areas, etc', %a) all have an i%#act u#on the clean status of e/ui#%ent' In dealing with #ossi.le wa)s the e/ui#%ent could .e re conta%inated, one should consider .oth endogenous sources (such as the growth of %icroorganis%s alread) within the e/ui#%ent" and e(ogenous sources (such as the entr) of e(ternal conta%inants into the e/ui#%ent"' Three I%#ortant Issues for the C0$T Include, 1" The characteristics of the cleaned e/ui#%ent 7" The nature of #ossi.le re conta%inants 8" The storage conditions of the e/ui#%ent NOT0, These three factors are interrelated in ter%s of effects on re conta%ination of cleaned e/ui#%ent' E"#ipment $tora e Con!erns 2 %a9or issue related to the characteristics of the cleaned e/ui#%ent is whether the e/ui#%ent is stored wet or in a %anner such that %icro.ial #roliferation is a #ossi.ilit)' This is covered in the :ood and Drug 2d%inistration;s (:D2;s" Cleaning 6alidation <uidance (1"' If the e/ui#%ent is stored wet for a sufficient length of ti%e, there is reasona.le #ro.a.ilit) that %icro.es will grow to an unacce#ta.le level' 2nother issue related to the characteristics of the e/ui#%ent involves #ossi.le routes of entr) for e(ternal conta%inants' :or s%all #ieces of e/ui#%ent (scoo#s, for e(a%#le", this involves e(#osure of the ite% itself' :or larger #ieces of e/ui#%ent (such as tanks", this involves an) o#ening in the e/ui#%ent' :or #ossi.le re conta%ination, the two %a9or sources are as follows, - =icro.es that %a) alread) .e in the cleaned e/ui#%ent - 0(ternal +dust+ which is in the storage at%os#here

Residues, such as #roduct residue and cleaning agent residue, which are in the e/ui#%ent at trace levels, are generall) not e(#ected to change over ti%e' NOT0, The onl) e(ce#tion to this %a) involve an active, which is #resent in the cleaned e/ui#%ent at an acce#ta.le level at the end of the cleaning #rocess, .ut which, over ti%e, degrades to a #oint that would %ake the e/ui#%ent unacce#ta.le for use' &torage conditions include an) ste#s taken to #rotect the e/ui#%ent, such as, wra##ing e/ui#%ent in a #lastic fil% or covering o#enings in the e/ui#%ent with a .onnet of #lastic fil%' Consideration of storage conditions includes the roo% in which e/ui#%ent is stored' Conditions of the roo% include te%#erature, hu%idit), air /ualit) (i'e', via.le and non via.le #articles", and e(ternal access' Esta%lish the Hol&in Time for Clean E"#ipment $el#ful $int, It is reco%%ended that the 6alidation <rou# contact the =anufacturing (or &cheduling" <rou# to deter%ine, under nor%al conditions, the longest holding ti%e interval that %ight .e used for the e/ui#%ent after cleaning' O%'e!ti(e of CEHT The #ur#ose of the C0$T is to ade/uatel) #rotect the e/ui#%ent during the designated ti%e #eriod including a conservative safet) %argin' 2nother #ur#ose is to #rovide a%#le 9ustification that e/ui#%ent re%ains safe to use throughout that ti%e #eriod' 2nal)5e the &torage &ituation &tud) the storage situation closel) and consider factors such as, - Characteristics of the cleaned e/ui#%ent - The nature of #ossi.le re conta%inants - The storage conditions >e 4roactive While considering the situation and factors uni/ue to )our storage circu%stances, verif) what can .e done to ade/uatel) #rotect the e/ui#%ent fro% re conta%ination' ?ustif) the $olding Ti%e of Cleaned 0/ui#%ent 2 #rofessional 9udg%ent should .e %ade .ased on an anal)sis of the storage situation' If

e/ui#%ent is ade/uatel) cleaned and then stored dr), all e(ternal #orts or o#enings to the storage roo% environ%ent are closed or covered with a #lastic fil%, and the storage roo% is controlled, it is feasi.le to 9ustif) a C0$T of several weeks or %onths' It should .e noted that this a##roach has its li%its@ for e(a%#le, 9ustif)ing a C0$T of one )ear .) this %ethod would .e unreasona.le' )) De(elop Data This involves holding the cleaned e/ui#%ent for the %a(i%u% C0$T and then sa%#ling surfaces and anal)5ing those sa%#les for #ossi.le re conta%inating residues' The #ossi.le re conta%inating s#ecies or %aterial %ust .e deter%ined' 2s a general rule, these are li%ited to .io.urden and dust' Testing #rocedures for .io.urden are relativel) straightforward using acce#ted %icro.iological techni/ues' :or dust, consider either a #article counter, Total Organic Car.on (TOC", or #erha#s an enhanced visual ins#ection, such as a white or .lack wi#e cloth' :or sa%#ling sites, do not auto%aticall) sa%#le the sa%e sites that were sa%#led in the cleaning validation #rotocol' Consider which sites are %ost likel) to .e re conta%inated during storage' :or e(a%#le, for agitator .lades, the .otto% of the agitator .lade (a worst case cleaning location" %a) .e the a##ro#riate sa%#ling #oint as #art of the cleaning validation #rotocol@ however, for deter%ination of the C0$T, the to# of the agitator .lade %a) .e the a##ro#riate sa%#ling #oint for dust, since dust is %ore likel) to settle on the to# of the .lades' DI*T+ EQUIPMENT HOLD TIME VALIDATION This section covers issues related to the +Dirt) 0/ui#%ent $old Ti%e+ (which will .e a..reviated D0$T"' Wh) D0$T Is I%#ortant for the Control of a Cleaning 4rocess The nature of the +dirt+ on the e/ui#%ent surfaces %a) change over ti%e' This %a) include dr)ing of the dirt andAor %icro.ial #roliferation' &uch changes %a) %ake the dirt %ore difficult to re%ove .) the standard cleaning #rocess' The cleaning #rocess should .e designed to ade/uatel) clean the e/ui#%ent under the worst cases of nor%al o#erating conditions' 2 de%onstration of effectiveness under the worst case, usuall) the longest, D0$T should .e conducted' It should .e noted that there %a) .e so%e cases where the hold ti%e will have no effect on the ease or difficult) of cleaning' In such cases, esta.lishing a %a(i%u% D0$T, and de%onstrating effectiveness at that %a(i%u% ti%e is reco%%ended'

Esta%lish a Dirty E"#ipment Hol& Time Limit The %ost i%#ortant considerations are that holding ti%es .e achieva.le and #ractical for the %anufacturing environ%ent and its ca#a.ilities' :or the %a(i%u% D0$T, ask the o#erations de#art%ents a.out the longest ti%e the e/ui#%ent would .e dirt) .efore the cleaning #rocess would .e started' >e conservative and add so%e e(tra ti%e to what the =anufacturing and 4roduction De#art%ent s#ecified' :or the %ini%u% D0$T, a si%ilar a##roach is used' O#erations should .e asked for the shortest ti%e #ractical .etween the end of %anufacturing and the .eginning of cleaning' Do!#mentation If a D0$T is s#ecified for a cleaning #rocess, and that D0$T is critical for control, then it is i%#ortant to docu%ent that ti%e' The ter%, docu%enting, %eans that the ti%e of the end of the %anufacturing #rocedures and the ti%e of the .eginning of the cleaning #rocedures are to .e recorded' The .eginning of cleaning ti%e should .e defined .ased on the cleaning #rocess' It should not .e .ased on a 3ualit) Control (3C" release ti%e' The end of the %anufacturing ti%e is defined .ased on the %anufacturing #rocess' NOT0, If it is i%#ortant to control the D0$T, then it needs to .e %easured in so%e wa), and it should .e defined' CONCLU$ION Once the data is co%#iled and anal)5ed, two new #ara%eters will e%erge with regard to cleaning, - 2 ti%e li%it for holding clean e/ui#%ent - 2 ti%e li%it for holding dirt) e/ui#%ent 4rocedures should .e a%ended to reflect this new #aradig%' It is highl) reco%%ended that stickers or tags used on e/ui#%ent .e altered to indicate an +e(#iration+ date that reflects these hold ti%es' *E,E*ENCE$ 1' :D2, +<uide to Ins#ections of 6alidation of Cleaning 4rocesses, +Office of Regulator) 2ffairs, ?ul) 1BB8, ?ul) 7CCD' 7' $ealth Canada, +<=4s Cleaning 6alidation <uidelines,+ $ealth 4roducts and :ood >ranch Ins#ectorate, &#ring 7CCC' 8' <il >is%uth and &hosh Neu%ann, +Cleaning 6alidation, 2 4ractical 2##roach,+ Inter#har% 4ress, 7CCC' D' >ill $all, ;The 0ssentials of Cleaning 6alidations,+ in 4har%aceutical 4rocess

6alidation .) Ro.ert 2' Nash E 2lfred Wachter, =arcel Dekker, Inc' New Fork Third 0dition 7CC8' G' ?ose 2' =orales &anche5, +Road =a# for 0/ui#%ent Cleaning 6alidation within a =ulti 4roducts =anufacturing :acilit),+ ?ournal of 6alidation Technolog), 6ol'11, No'8, =a) 7CCG' H' =owafak Nassani, +Cleaning 6alidation in the 4har%aceutical Industr),+ ?ournal of 6alidation Technolog), 6ol'11, No'D, 2ugust 7CCG' !' 4raful D' >haradia E ?ign)asha 2' >hatt, +2 Review of Current I%#le%entation &trategies for 6alidation of Cleaning 4rocesses in the 4har%aceutical Industr),+ ?ournal of 6alidation Technolog), 6ol'17, No'8, =a) 7CCH' A-OUT THE AUTHO* Tro) :ugate, 6ice 4resident for Co%#liance Insight, Inc, located near Cincinnati, Ohio, is a worldwide co%#liance consultant in the areas of #har%aceutical /ualit), o#erations, #ackaging, la.orator), and construction activities' Tro) has worked around the glo.e on a variet) of #ro9ects and s#eciali5es in /ualit) s)ste%s, audits, investigations, :D2 issue resolution and training' Tro) is an active, #artici#ating =e%.er of the 0ditorial 2dvisor) >oard for the ?ournal of <I4 Co%#liance and can .e reached through his #rofessional e%ail address, tro)Jco%#liance insight'co%' Arti!le A!ronym Listin C0$T Cleaned 0/ui#%ent $old Ti%e D0$T Dirt) 0/ui#%ent $old Ti%e :D2 :ood and Drug 2d%inistration <=4 <ood =anufacturing 4ractice $62C $eating, 6entilation, and 2ir Conditioning 3C 3ualit) Control &O4 &tandard O#erating 4rocedure TOC Total Organic Car.on NOT0, 2ll illustrations and #hotos have .een re%oved fro% this article' Loo.in for a&&itional arti!les/ &earch our data.ase of over 8 %illion articles' Loo.in for more in0&epth information on this in&#stry/ &earch our co%#lete data.ase of Industr) E =arket re#orts .) te(t, su.9ect, #u.lication na%e or #u.lication date' A%o#t 1oliath Whether )ou;re looking for sales #ros#ects, co%#etitive infor%ation, co%#an) anal)sis or .est #ractices in %anaging )our organi5ation, <oliath can hel# )ou %eet )our .usiness needs' Our e(tensive .usiness infor%ation data.ases e%#ower .usiness #rofessionals with .oth the .readth and de#th of credi.le, authoritative infor%ation the) need to su##ort

their .usiness goals' Whether it .e strategic #lanning, sales #ros#ecting, co%#an) research or defining %anage%ent .est #ractices <oliath is )our leading source for accurate infor%ation'