1072

DISINFECTANTS AND ANTISEPTICS

INTRODUCTION A sound cleaning and sanitization !og!a" is needed #o! cont!olled en$i!on"ents used in t%e "anu#actu!e o# P%a!"aco eial a!ticles to !e$ent t%e "ic!o&ial conta"ination o# t%ese a!ticles' Ste!ile d!ug !oducts "a( &e conta"inated $ia t%ei! %a!"aceutical ing!edients) !ocess *ate!) ac+aging co" onents) "anu#actu!ing en$i!on"ent) !ocessing e,ui "ent) and "anu#actu!ing o e!ato!s' Cu!!ent -ood .anu#actu!ing P!actices /c-.Ps0 e" %asize t%e size) design) const!uction) and location o# &uildings and const!uction "ate!ials) and t%e a !o !iate "ate!ial #lo* to #acilitate cleaning) "aintenance) and !o e! o e!ations #o! t%e "anu#actu!e o# d!ug !oducts' 1%en disin#ectants a!e used in a "anu#actu!ing en$i!on"ent) ca!e s%ould &e ta+en to !e$ent t%e d!ug !oduct #!o" &eco"ing conta"inated *it% c%e"ical disin#ectants as a !esult o# t%e in%e!ent to2icit( o# t%e disin#ectants' T%e !e,ui!e"ents #o! ase tic !ocessing include !eadil( cleana&le #loo!s) *alls) and ceilings t%at %a$e s"oot% and non o!ous su!#aces3 a!ticulate) te" e!atu!e) and %u"idit( cont!ols3 and cleaning and disin#ecting !ocedu!es to !oduce and "aintain ase tic conditions' T%e cleaning and sanitization !og!a" s%ould ac%ie$e s eci#ied cleanliness standa!ds) cont!ol "ic!o&ial conta"ination o# !oducts) and &e designed to !e$ent t%e c%e"ical conta"ination o# %a!"aceutical ing!edients) !oduct4 contact su!#aces and5o! e,ui "ent) ac+aging "ate!ials) and ulti"atel( t%e d!ug !oducts' T%ese !inci les also a l( to nonste!ile dosage #o!"s *%e!e t%e !o !iate "ic!o&ial conta"ination is cont!olled &( t%e selection o# a

%a!"aceutical ing!edients) utilities) "anu#actu!ing en$i!on"ents) sound e,ui "ent cleaning !ocedu!es) !oducts es eciall( #o!"ulated to cont!ol *ate! acti$it() inclusion o# suita&le !ese!$ati$es) and !oduct ac+aging design' In addition to disin#ectants) antise tics a!e used to deconta"inate %u"an s+in and e2 osed tissue and "a( &e used &( e!sonnel !io! to ente!ing t%e "anu#actu!ing a!ea' C%e"ical ste!ilants "a( &e used to deconta"inate su!#aces

in "anu#actu!ing and ste!ilit( testing a!eas' Fu!t%e!"o!e) ste!ilants "a( &e used #o! t%e ste!ilization o# P%a!"aco eial a!ticles) and U6 i!!adiation "a( &e used as a su!#ace sanitize!' T%is gene!al in#o!"ation c%a te! *ill discuss t%e selection o# suita&le c%e"ical disin#ectants and antise tics3 t%e de"onst!ation o# t%ei! &acte!icidal) #ungicidal) and s o!icidal e##icac(3 t%e a lication o# disin#ectants in t%e ste!ile %a!"aceutical "anu#actu!ing a!ea3 and !egulation and sa#et( conside!ations' 7io#il" #o!"ation and its !elations%i to disin#ectants a!e outside t%e sco e o# t%is c%a te!' Additional in#o!"ation not co$e!ed in t%e c%a te! "a( &e o&tained #!o" standa!d te2ts on disin#ectants and antise tics'
1

DEFINITIONS Antise tic8An agent t%at in%i&its o! dest!o(s "ic!oo!ganis"s on li$ing tissue including s+in) o!al ca$ities) and o en *ounds' C%e"ical Disin#ectant8A c%e"ical agent used on inani"ate su!#aces and o&9ects to dest!o( in#ectious #ungi) $i!uses) and &acte!ia) &ut not necessa!il( t%ei! s o!es' S o!icidal and anti$i!al agents "a( &e conside!ed a s ecial class o# disin#ectants' Disin#ectants a!e o#ten catego!ized as %ig%4le$el) inte!"ediate4 le$el) and lo*4le$el &( "edicall( o!iented g!ou s &ased u on t%ei! e##icac( against $a!ious "ic!oo!ganis"s' Cleaning Agent8An agent #o! t%e !e"o$al #!o" #acilit( and e,ui "ent su!#aces o# !oduct !esidues t%at "a( inacti$ate sanitizing agents o! %a!&o! "ic!oo!ganis"s' Deconta"ination8T%e !e"o$al o# "ic!oo!ganis"s &( disin#ection o! ste!ilization' Disin#ectant8A c%e"ical o! %(sical agent t%at dest!o(s o! !e"o$es $egetati$e #o!"s o# %a!"#ul "ic!oo!ganis"s *%en a lied to a su!#ace'

Sanitizing Agent8An agent #o! !educing) on inani"ate su!#aces) t%e nu"&e! o# all #o!"s o# "ic!o&ial li#e including #ungi) $i!uses) and &acte!ia'

S o!icidal Agent8An agent t%at dest!o(s &acte!ial and #ungal s o!es *%en used in su##icient concent!ation #o! a s eci#ied contact ti"e' It is e2 ected to +ill all $egetati$e "ic!oo!ganis"s' Ste!ilant8An agent t%at dest!o(s all #o!"s o# "ic!o&ial li#e including #ungi) $i!uses) and all #o!"s o# &acte!ia and t%ei! s o!es' Ste!ilants a!e li,uid o! $a o!4 %ase agents' .ic!oo!ganis"s di##e! g!eatl( in t%ei! !esistance to disin#ection agents' T%e o!de! o# !esistance o# clinicall( signi#icant "ic!oo!ganis"s to c%e"ical disin#ectants #!o" "ost to least !esistant is listed in Ta&le 1' Ta&le 1' T%e Resistance o# So"e Clinicall( I" o!tant .ic!oo!ganis"s to C%e"ical Disin#ectants /:isted in O!de! o# Dec!easing Resistance0 Type of Microorganisms Bacterial spores Mycobacteria Nonlipid-coated viruses Fungal spores and vegetative molds and yeast "egetative bacteria $ipid-coated viruses

Examples Bacillus subtilis and Clostridium sporogenes Mycobacterium tuberculosis Poliovirus and rhinovirus Trichophyton Cryptococcus and Candida spp! Pseudomonas aeruginosa #taphylococcus aureus and #almonella spp! %erpes simplex virus hepatitis B virus and human immunodeficiency virus

C:ASSIFICATION OF DISINFECTANTS C%e"ical disin#ectants a!e classi#ied &( t%ei! c%e"ical t( e' T%is includes alde%(des) alco%ols) %alogens) e!o2ides) ,uate!na!( a""oniu" co" ounds) and %enolic co" ounds /see Ta&le 20' Ta&le 2' -ene!al Classi#ication o# Antise tics) Disin#ectants) and S o!icidal Agents

Chemical Entity &ldehydes &lcohols Chlorine and sodium hypochlorite Phenolics /0one %ydrogen peroxide

Classification #poricidal agent )eneral purpose disinfectant antiseptic antiviral agent #poricidal agent )eneral purpose disinfectant #poricidal agent "apor phase sterilant li3uid sporicidal agent antiseptic $i3uid sterilant vapor phase sterilant "apor-phase sterilant

Example '( )lutaraldehyde *+( ,sopropyl alcohol *+( alcohol +!-( #odium hypochlorite -++ .g per g Chlorocresol -++ .g per g chloroxylenol 1( )as by 2eight 4 .g per g %'/' vapor 5+(6 '-( solution 7( solution +!-( Chlorhexidine gluconate +!'( Peracetic acid 5 .g per g peracetic acid 8++ .g per g Ethylene oxide '++ .g per g Ben0al:onium chloride 5++ .g per g -Propiolactone

#ubstituted diguanides &ntiseptic agent Peracetic acid Ethylene oxide

9uaternary ammonium )eneral purpose disinfectant compounds antiseptic -Propiolactone #poricidal agent

T%e e##ecti$eness o# a disin#ectant de ends on its int!insic &iocidal acti$it() t%e concent!ation o# t%e disin#ectant) t%e contact ti"e) t%e natu!e o# t%e su!#ace disin#ected) t%e %a!dness o# *ate! used to dilute t%e disin#ectant) t%e a"ount o# o!ganic "ate!ials !esent on t%e su!#ace) and t%e t( e and t%e nu"&e! o# "ic!oo!ganis"s !esent' Unde! t%e Fede!al Insecticide) Fungicide) and Rodenticide Act /FIFRA0) t%e En$i!on"ental P!otection Agenc( /EPA0 !egiste!s c%e"ical disin#ectants "a!+eted in t%e United States and !e,ui!es "anu#actu!e!s to su l( !oduct in#o!"ation on t%e use dilution) t( e o# "ic!oo!ganis"s +illed) and t%e necessa!( contact ti"e' Ce!tain li,uid c%e"ical ste!ilize!s intended #o! use on c!itical o! se"ic!itical "edical de$ices a!e de#ined and !egulated &( t%e U'S' Food and D!ug Ad"inist!ation /FDA0'

SE:ECTION OF AN ANTISEPTIC FOR ;AND AND SUR-ICA: SITE DISINFECTION

;ands and su!gical sites a!e disin#ected in a %os ital setting to !educe t%e !esident #lo!a and to !e"o$e t!ansient #lo!a /e'g') St!e tococcus (ogenes0 and "et%icillin4!esistant S' au!eus and P' ae!uginosa t%at %a$e &een i" licated in %os ital4associated in#ection' Use o# antise tics to disin#ect %ands %as &een s%o*n to &e "o!e e##ecti$e t%an soa and *ate! in !educing t%e counts o# &acte!ia on t%e s+in3 !e eated antise tic use #u!t%e! !educes t%ese counts' T%ese !inci les "a( &e a indust!(' Co""on antise tics include <= c%lo!%e2idine) 10= o$idone>iodine) ?= %e2ac%lo!o %ene) 70= iso !o (l alco%ol) and 0'@= c%lo!%e2idine in A@= alco%ol' lied to clean4!oo" o e!ato!s in t%e %a!"aceutical

SE:ECTION OF A DISINFECTANT FOR USE IN A P;AR.ACEUTICA: .ANUFACTURIN- EN6IRON.ENT 1%en selecting a disin#ectant #o! use in a %a!"aceutical "anu#actu!ing a!ea) t%e #ollo*ing oints s%ould &e conside!edB t%e nu"&e! and t( es o# "ic!oo!ganis"s to &e cont!olled3 t%e s ect!u" o# acti$it( o# co""e!ciall( a$aila&le disin#ectants3 t%e !e utation o# t%e disin#ectant su ste!ilant3 t%e disin#ectant o! sanitize! su concent!ation) a lie!3 t%e clai"s as a o!ted &( t%e EPA !egist!ations3 t%e

lication "et%od) and contact ti"e o# t%e disin#ectant3 t%e

natu!e o# t%e su!#ace "ate!ial &eing disin#ected and its co" ati&ilit( *it% t%e disin#ectant3 t%e a"ount o# o!ganic co" ounds on t%e su!#ace t%at "a( inacti$ate a disin#ectant3 t%e ossi&le need to "aintain a !esidual &acte!icidal acti$it( o# t%e disin#ectant on t%e su!#ace3 t%e co!!osi$eness o# t%e disin#ectant to e,ui "ent *it% !e eated a lication3 t%e sa#et( conside!ations #o! o e!ato!s a l(ing t%e disin#ectant3 t%e co" ati&ilit( o# t%e disin#ectant *it% cleaning agents and ot%e! disin#ectants3 t%e lanned disin#ectant !otation3 and t%e ste s t%at need to &e ta+en to a$oid t%e conta"ination o# %a!"aceutical !oducts &( a disin#ectant'
2

T;EORETICA: DISCUSSION OF DISINFECTANT ACTI6ITC

Plots o# t%e log o# t%e nu"&e! o# "ic!oo!ganis"s e! ": su!$i$ing in a disin#ectant solution indicate t%at #i!st4o!de! +inetics can &e a a lied as a g!oss !o2i"ation to t%e !eduction in "ic!o&ial count *it% !es ect to ti"e' In !actice)

t%e lots s%o* a "o!e sig"oid cu!$e *it% a slo*e! initial !eduction in nu"&e!s #ollo*ed &( an inc!easing !ate *it% !es ect to ti"e' T%e !ate constant) D) #o! t%e disin#ection !ocess can &e calculated &( t%e #o!"ulaB /1 5 t0/ log NO 5 N0 in *%ic% t is t%e ti"e) in "inutes) #o! t%e "ic!o&ial count to &e !educed #!o" NO to N3 NO is t%e initial nu"&e! o# o!ganis"s) in c#u e! ":3 and N is t%e #inal nu"&e!) in c#u e! ":) o# o!ganis"s' As *it% a #i!st4o!de! c%e"ical !eaction) t%e sa"e concent!ation o# disin#ectant !educes t%e nu"&e! o# o!ganis"s "o!e !a idl( at ele$ated te" e!atu!es' T%is can &e e2 !essed as a te" e!atu!e) T) coe##icient e! 10 !ise in te" e!atu!e) E10) calculated &( t%e #o!"ulaB Ti"e to deconta"ination at T 5 Ti"e to deconta"ination at T in *%ic% T is T > 10' Fu!t%e! e$idence t%at a #i!st4o!de! !eaction is an inade,uate desc!i tion o# disin#ection is t%at t%e E10 $alues #o! c%e"ical and enz("e !eactions a!e 2 to ?) *%ile t%e co""on disin#ectants %enol and alco%ol %a$e a E10 o# < and <@) !es ecti$el(' C!itical to t%e success#ul e" lo("ent o# disin#ectants is an unde!standing o# t%e e##ect o# disin#ectant concent!ation on "ic!o&ial !eduction' A lot o# t%e log o# t%e ti"e to !educe t%e "ic!o&ial o ulation in a standa!d inoculu" to ze!o against t%e log o# t%e disin#ectant concent!ation is a st!aig%t line *it% t%e slo e o# t%e line te!"ed t%e concent!ation e2 onent) n' T%e !elations%i can &e e2 !essed as #ollo*sB

n F /log o# t%e +ill ti"e at concent!ation C20 > /log o# t%e +ill ti"e at concent!ation C10 5 /log C1 > log C20 in *%ic% C1 and C2 a!e t%e %ig%e! and lo*e! disin#ectant concent!ations) !es ecti$el(' T%e *ide di##e!ences in concent!ation e2 onents) n) %a$e !actical conse,uences in ic+ing t%e use dilution o# di##e!ent disin#ectants and in using dilution to neut!alize a disin#ectant in disin#ectant4e##ecti$eness testing and !outine "ic!o&ial "onito!ing o# t%e "anu#actu!ing en$i!on"ent' Fo! e2a" le) "e!cu!ic c%lo!ide %as a concent!ation e2 onent o# 1) so a ?4#old dilution *ill !educe t%e disin#ectant acti$it( &( ?1 /o! &( one4t%i!d0) *%ile %enol *it% a concent!ation e2 onent o# G *ill %a$e a ?G /o! a 72A4#old0 !eduction in disin#ectant acti$it(' Disin#ectants *it% a la!ge! concent!ation e2 onent o! dilution coe##icient !a idl( lose acti$it( *%en diluted' T%e concent!ation e2 onents #o! so"e disin#ectants a!e listed in Ta&le ?' Ta&le ?' Concent!ation E2 onents o# Co""on Antise tics) Disin#ectants) and Ste!ilants ;isinfectant %ydrogen peroxide #odium hypochlorite Mercuric chloride Chlorhexidine Formaldehyde &lcohol Phenol 9uaternary ammonium compounds &liphatic alcohols Phenolic compounds Concentration Exponents +!+!5 ' 5 < 8 +!1 to '!8!+ to 5'!* 4 to <!<

Anot%e! i" o!tant conside!ation "a( &e t%e ; o# t%e disin#ectant' .an( disin#ectants a!e "o!e acti$e in t%e ionized #o!") *%ile ot%e!s a!e "o!e acti$e in t%e nonionized #o!"' T%e deg!ee o# ionization *ill de end on t%e Da o# t%e

agent and t%e ; o# t%e disin#ection en$i!on"ent' Fo! e2a" le) %enol) *it% a Da o# 10) *ill &e "o!e e##ecti$e at a ; &elo* 7 *%e!e it is nonionized) *%ile acetic acid *ill &e "o!e e##ecti$e at a ; &elo* < *%e!e it is ionized'

.EC;ANIS. OF DISINFECTANT ACTI6ITC Ta&le < lists t%e sites and "odes o# action o# so"e !e !esentati$e disin#ectants' Ta&le <' .ec%anis" o# Disin#ectant Acti$it( Against .ic!o&ial Cells Target Cell 2all ;isinfectant Formaldehyde hypochlorite and mercurials

Cytoplasmic membrane action on &nilides and hexachlorophene membrane potential Membrane en0ymes action on electron-transport chain &ction on &TP &ction on en0ymes 2ith 6#% groups &ction on general membrane permeability %exachlorophene Chlorhexidine and ethylene oxide Ethylene oxide glutaraldehyde hydrogen peroxide hypochlorite iodine and mercurials &lcohols chlorhexidine and 3uaternary ammonium compounds

Cell contents general coagulation Chlorhexidine aldehydes hexachlorophene and 3uaternary ammonium compounds =ibosomes Nucleic acids Thiol groups &mino groups )eneral oxidation %ydrogen peroxide and mercurials %ypochlorites Ethylene oxide glutaraldehyde hydrogen peroxide hypochlorite mercurials Ethylene oxide glutaraldehyde and hypochlorite Ethylene oxide glutaraldehyde and hypochlorite

.ICRO7IA: RESISTANCE TO DISINFECTANTS T%e de$elo "ent o# "ic!o&ial !esistance to anti&iotics is a *ell4desc!i&ed %eno"enon' T%e de$elo "ent o# "ic!o&ial !esistance to disin#ectants is less li+el() as disin#ectants a!e "o!e o*e!#ul &iocidal agents t%an anti&iotics and a!e

lied in %ig% concent!ations against lo* o ulations o# "ic!oo!ganis"s usuall(

not g!o*ing acti$el() so t%e selecti$e !essu!e #o! t%e de$elo "ent o# !esistance is less !o#ound' ;o*e$e!) t%e "ost #!e,uentl( isolated "ic!oo!ganis"s #!o" an en$i!on"ental "onito!ing !og!a" "a( &e e!iodicall( su&9ected to use dilution testing *it% t%e agents used in t%e disin#ection !og!a" to con#i!" t%ei! susce ti&ilit('

DISINFECTANT C;A::EN-E TESTINUnde! FIFRA) t%e EPA !e,ui!es co" anies t%at !egiste! u&lic %ealt% anti"ic!o&ial esticide !oducts including disin#ectants) sanitization agents) s o!icidal agents) and ste!ilants to ensu!e t%e sa#et( and e##ecti$eness o# t%ei! !oducts &e#o!e t%e( a!e sold o! dist!i&uted' Co" anies !egiste!ing t%ese !oducts "ust add!ess t%e c%e"ical co" osition o# t%ei! !oduct) include to2icolog( data to docu"ent t%at t%ei! !oduct is sa#e i# used as di!ected on t%e la&el) include e##icac( data to docu"ent t%ei! clai"s o# e##ecti$eness against s eci#ic o!ganis"s and to su o!t t%e di!ections #o! use !o$ided in t%e la&eling) and !o$ide la&eling t%at !e#lects t%e !e,ui!ed ele"ents #o! sa#e and e##ecti$e use' 1%ile t%ese di!ections !o$ide $alua&le in#o!"ation) t%e( "a( not &e %el #ul in te!"s o# t%e !oductsH use as disin#ectants in a "anu#actu!ing en$i!on"ent' In t%e United States) t%e o##icial disin#ectant testing "et%ods a!e u&lis%ed &( AOAC Inte!national and include t%e P%enol4Coe##icient Test) Use4Dilution
3

.et%od Test) ;a!d Su!#ace Ca!!ie! .et%od) and S o!icidal Ca!!ie! Test' A scienti#ic stud( su&"itted #o! EPA !e$ie* in su o!t o# disin#ectant !egist!ation "ust &e conducted at a la&o!ato!( #acilit( t%at #ollo*s t%e -ood :a&o!ato!( P!actices /-:P0 !egulations /21 CFR @I0' To de"onst!ate t%e e##icac( o# a disin#ectant *it%in a %a!"aceutical "anu#actu!ing en$i!on"ent) it "a( &e dee"ed necessa!( to conduct t%e #ollo*ing testsB /10 use4dilution tests /sc!eening disin#ectants #o! t%ei! e##icac( at $a!ious concent!ations and contact ti"es against a *ide !ange o# standa!d test o!ganis"s and en$i!on"ental isolates03 /20 su!#ace c%allenge tests /using standa!d test "ic!oo!ganis"s and

"ic!oo!ganis"s t%at a!e t( ical en$i!on"ental isolates) a

l(ing disin#ectants to

su!#aces at t%e selected use concent!ation *it% a s eci#ied contact ti"e) and dete!"ining t%e log !eduction o# t%e c%allenge "ic!oo!ganis"s03 and /?0 a statistical co" a!ison o# t%e #!e,uenc( o# isolation and nu"&e!s o# "ic!oo!ganis"s isolated !io! to and a#te! t%e i" le"entation o# a ne* disin#ectant' T%is is conside!ed necessa!( &ecause c!itical !ocess ste s li+e disin#ection o# ase tic !ocessing a!eas) as !e,ui!ed &( -.P !egulations) need to &e $alidated) and t%e EPA !egist!ation !e,ui!e"ents do not add!ess %o* disin#ectants a!e used in t%e %a!"aceutical) &iotec%nolog() and "edical de$ice indust!ies' Fo! t%e su!#ace c%allenge tests) t%e test o!ganis"s a!e enu"e!ated using s*a&s) su!#ace !inse) o! contact late "et%ods' Neut!alize!s t%at inacti$ate t%e disin#ectants s%ould &e included in eit%e! t%e diluent o! "ic!o&iological "edia used #o! "ic!o&ial enu"e!ation o! &ot% /see Ta&le @0' Additional in#o!"ation on disin#ectant neut!alization "a( &e #ound in 6alidation o# .ic!o&ial Reco$e!( #!o" P%a!"aco eial A!ticles 1227 '

Ta&le @' Neut!alizing Agents #o! Co""on Disin#ectants ;isinfectant &lcohols )lutaraldehyde #odium hypochlorite Chlorhexidine 9uaternary ammonium compounds Phenolic compounds Neutrali0ing &gent ;ilution or polysorbate 1+ )lycine and sodium bisulfite #odium thiosulfate Polysorbate 1+ and lecithin Polysorbate 1+ and lecithin ;ilution or polysorbate 1+ and lecithin

Mercuric chloride and other mercurials Thioglycolic acid

Uni$e!sal neut!alize! &!ot%s "a( &e #o!"ulated to contain a !ange o# neut!alizing agents' Fo! e2a" le) De(5Engle( /D5E0 &!ot% contains 0'@= ol(so!&ate I0) 0'7= lecit%in) 0'1= sodiu" t%iogl(colate) 0'G= sodiu" t%iosul#ate) 0'2@= sodiu" &isul#ite) 0'@= t!( tone) 0'2@= (east e2t!act) and 1'0= de2t!ose3 let%een &!ot% contains 0'@= ol(so!&ate I0) 0'07= lecit%in) 1'0= e ta"in) 0'@= &ee# e2t!act)

and 0'@= sodiu" c%lo!ide3 and T!( tone>Azolectin>T*een /TAT0 &!ot% &ase J t*een 20 contains <'0= /$5$0 ol(so!&ate 20) 0'@= lecit%in) and 2'0= t!( tone' In !actice) su##icient o!ganis"s need to &e inoculated on a 24inc% K 24inc% s,ua!e o# t%e su!#ace &eing deconta"inated) i'e') a cou on) to de"onst!ate at least a 2 /#o! &acte!ial s o!es0 to ? /#o! $egetati$e &acte!ia0 log !eduction du!ing a !edete!"ined contact ti"e /i'e') 10 "inutes o$e! and a&o$e t%e !eco$e!( o&se!$ed *it% a cont!ol disin#ectant a lication0' T%e e##icac( o# t%e neut!alize!s and t%ei! a&ilit( to !eco$e! inoculated "ic!oo!ganis"s #!o" t%e "ate!ial s%ould &e de"onst!ated du!ing t%e use4dilution o! su!#ace4c%allenge studies' Points to !e"e"&e! a!e t%at disin#ectants a!e less e##ecti$e against t%e %ig%e! nu"&e!s o# "ic!oo!ganis"s used in la&o!ato!( c%allenge tests t%an t%e( a!e against t%e nu"&e!s t%at a!e #ound in clean !oo"s /see .ic!o&iological E$aluation o# Clean Roo"s and Ot%e! Cont!olled En$i!on"ents 111G 03 t%at inocula #!o" t%e log

g!o*t% %ase t%at a!e t( icall( e" lo(ed in la&o!ato!( tests a!e "o!e !esistant) *it% t%e e2ce tion o# s o!es #o!"ed du!ing t%e static %ase) t%an t%ose #!o" a static o! d(ing cultu!e o! st!essed o!ganis"s in t%e en$i!on"ent3 and t%at "ic!oo!ganis"s "a( &e %(sicall( !e"o$ed du!ing actual disin#ectant a in t%e "anu#actu!ing a!ea' Alt%oug% not all inclusi$e) t( ical c%allenge o!ganis"s t%at "a( &e e" lo(ed a!e listed in Ta&le G' Ta&le G' T( ical C%allenge O!ganis"s &/&C Challenge /rganisms Bactericide> Escherichia coli &TCC 55''<? #! aureus &TCC 8-71? P! aeruginosa &TCC 5-44' Fungicide> C! albicans &TCC 5+'75 or '+<5? Penicillium chrysogenum &TCC 55*+<? &spergillus niger &TCC 584+4 #poricide> B! subtilis &TCC 5<8-< Typical Environmental ,solates Bactericide> Micrococcus luteus #! epidermdis Coynebacterium @ei:eium P! vesiclaris Fungicide> P! chrysogenum &! niger lication

#poricide> B! sphaericus B! thuringiensis

7ecause a *ide !ange o# di##e!ent "ate!ials o# const!uction a!e used in clean !oo"s and ot%e! cont!olled a!eas) eac% "ate!ial needs to &e e$aluated se a!atel( to $alidate t%e e##icac( o# a gi$en disin#ectant' Ta&le 7 contains a list o# co""on "ate!ials used in clean !oo" const!uction' Ta&le 7' T( ical Su!#aces to &e Deconta"inated &( Disin#ectants in a P%a!"aceutical .anu#actu!ing A!ea Material )lass Plastic vinyl Plastic polycarbonate $exanB CplexiglassD Epoxyl-coated gypsum Fiberglass-reinforced plastic Tyve:B Terra00o tiles &pplication Aindo2s and vessels Curtains ,nsulation coating #hields Aalls and ceilings Aall paneling E3uipment 2raps Floors

#tainless steel 7+4$ and 758$ grades Aor: surfaces filling e3uipment and tan:s

DISINFECTANTS IN A C:EANIN- AND SANITILATION PRO-RA. T%e selection o# suita&le disin#ectants and t%e $e!i#ication o# t%ei! e##ecti$eness in su!#ace c%allenge testing is c!itical in t%e de$elo "ent o# a cleaning and sanitization !og!a"' Issues associated *it% t%e success#ul i" le"entation o# suc% a !og!a" a!e t%e de$elo "ent o# *!itten !ocedu!es) sta## t!aining) decisions on disin#ectant !otation) institution o# a lication "et%ods and contact ti"es) en$i!on"ental "onito!ing to de"onst!ate e##icac() and e!sonnel sa#et(' T%e c-.P 21 CFR 211'G7) E,ui "ent Cleaning and .aintenance) details t%e !e,ui!e"ents #o! *!itten !ocedu!es #o! cleaning) "aintenance) and sanitization o# %a!"aceutical "anu#actu!ing e,ui "ent' T%ese !ocedu!es s%ould add!ess t%e assign"ent o# !es onsi&ilit() esta&lis%"ent o# sc%edules) details o# cleaning

o e!ations) !otection o# clean e,ui "ent !io! to use) ins ection #o! cleanliness i""ediatel( !io! to use) and "aintenance o# cleaning and sanitization !eco!ds' Sta## in$ol$ed in disin#ection !e,ui!e t!aining in "ic!o&iolog() indust!( !actices #o! cleaning and sanitization) sa#e %andling o# concent!ated disin#ectants) t%e !e a!ation and dis osal o# disin#ectants) and a !o !iate a lication "et%ods' It s%ould &e e" %asized t%at t%e !e a!ation o# t%e co!!ect dilutions is c!itical &ecause "an( disin#ectant #ailu!es can &e att!i&uted to use o# disin#ectant solutions t%at a!e too dilute' T( icall( disin#ectants used in ase tic !ocessing and #illing a!eas a!e diluted *it% Ste!ile Pu!i#ied 1ate!) and a!e !e a!ed ase ticall(' Alte!natel() t%e disin#ectant "a( &e diluted *it% Pu!i#ied 1ate!) and t%en ste!ile #ilte!ed to eli"inate "ic!oo!ganis"s t%at "a( otentiall( e!sist in a disin#ectant' Diluted disin#ectants "ust %a$e an assigned e2 i!ation dating 9usti#ied &( e##ecti$eness studies' 7ecause it is t%eo!eticall( ossi&le t%at t%e selecti$e !essu!e o# t%e continuous use o# a single disin#ectant could !esult in t%e !esence o# disin#ectant4!esistant "ic!oo!ganis"s in a "anu#actu!ing a!ea) in so"e ,ua!te!s t%e !otation o# disin#ectants %as &een ad$ocated' ;o*e$e!) t%e lite!atu!e su o!ts t%e &elie# t%at t%e e2 osu!e o# lo* nu"&e!s o# "ic!oo!ganis"s on #acilit( and e,ui "ent su!#aces *it%in a clean !oo" *%e!e t%e( a!e not acti$el( !oli#e!ating *ill not !esult in t%e selecti$e !essu!e t%at "a( &e seen *it% t%e anti&iotics' It is !udent to aug"ent t%e dail( use o# a &acte!icidal disin#ectant *it% *ee+l( /o! "ont%l(0 use o# a s o!icidal agent' T%e dail( a lication o# s o!icidal agents is not gene!all( #a$o!ed &ecause o# t%ei! tendenc( to co!!ode e,ui "ent and &ecause o# t%e otential sa#et( issues *it% c%!onic o e!ato! e2 osu!e' Ot%e! disin#ection !otation sc%e"es "a( &e su o!ted on t%e &asis o# a !e$ie* o# t%e %isto!ical lied on otential !oduct contact en$i!on"ental "onito!ing data' Disin#ectants a

su!#aces a!e t( icall( !e"o$ed *it% 70= alco%ol *i es' T%e !e"o$al o# !esidual disin#ectants s%ould &e "onito!ed #o! e##ecti$eness as a !ecaution against t%e ossi&ilit( o# !oduct conta"ination'

T%e g!eatest sa#et( conce!ns a!e in t%e %andling o# concent!ated disin#ectants and t%e "i2ing o# inco" ati&le disin#ectants' Fo! e2a" le) concent!ated sodiu" %( oc%lo!ite solutions /at a concent!ation o# "o!e t%an @=0 a!e st!ong o2idants and *ill deco" ose on %eating) on contact *it% acids) and unde! t%e in#luence o# lig%t) !oducing to2ic and co!!osi$e gases including c%lo!ine' In cont!ast) dilute solutions /at a concent!ation o# less t%an 0'@=0 a!e not conside!ed as %aza!dous' Unde! no ci!cu"stances s%ould disin#ectants o# di##e!ent concent!ations &e "i2ed' .ate!ial Sa#et( Data S%eets #o! all t%e disin#ectants used in a "anu#actu!ing a!ea s%ould &e a$aila&le to e!sonnel %andling t%ese agents' A !o !iate sa#et( e,ui "ent suc% as #ace s%ields) sa#et( glasses) glo$es) and uni#o!"s "ust &e issued to e!sonnel %andling t%e disin#ectant !e a!ation) and e!sonnel "ust &e t!ained in t%e !o e! use o# t%is e,ui "ent' Sa#et( s%o*e!s and e(e *as% stations "ust &e situated in t%e *o!+ a!ea *%e!e disin#ectant solutions a!e !e a!ed' 1 Ascenzi) M'.') Ed' ;and&oo+ o# Disin#ectants and Antise tics) @t% ed'3 .a!cel De++e!B Ne* Co!+) 1AA@3 7loc+) S'S') Ed' Disin#ection) Ste!ilization) and P!ese!$ation) @t% ed'3 :i incott 1illia"s N 1il+ins Pu&lis%e!sB P%iladel %ia) 2000' Russell) A'D'3 ;ugo) 1'7'3 A(li##e) -'A'M') Eds' P!inci les and P!actices o# Disin#ection) P!ese!$ation and Ste!ilization) ?!d ed'3 7lac+*ell Science Inc'B :ondon) 1AAA' 2 Denn() 6'F'3 .a!si+) F'M' Cu!!ent P!actices in t%e Use o# Disin#ectants *it%in t%e P%a!"aceutical Indust!(' PDA M' o# P%a!"aceutical Sci' and Tec%') 1AA7) @1) /G0) 227>22I' ? AOAC Inte!national O##icial .et%ods o# Anal(sis) 1@) 1G) and 17t% editions' A!lington) 6A' Au2ilia!( In#o!"ation8 Please c%ec+ #o! (ou! ,uestion in t%e FAEs &e#o!e contacting USP' TopicE9uestion Contact )eneral Chapter =adha:rishna # Tirumalai Expert Committee CM#&+-D Microbiology and #terility

TopicE9uestion Contact Ph!;! #enior #cientist 5-7+5-158-177< USP?2>NF27 Page @17

Expert Committee &ssurance

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