Analyzing Cleaning Validation Samples What Method

8/18/2019 Analyzing Cleaning Validation Samples What Method

1/13

Analyzing Cleaning Validation Samples:What Method?

By Herbert J. Kaiser !h.".and

Maria Mino#itz M.$.S.Steris Corporation

Cleaning %alidations are %ery di&&i'(lt to per&orm. )hey 'an be made easier i& anappropriate method &or analyzing the samples is (sed. )he method (sed sho(ld be basedon the pre%io(sly established resid(e limits o& the a'ti%e and 'leaning agents. )here aremany 'hoi'es o& analyti'al te'hni*(es that 'an potentially be (sed. )his arti'le #illdes'ribe %ario(s analyti'al te'hnologies a%ailable &or (se parti'(larly &or 'leaning agentresid(es. +e&eren'es are pro%ided to g(ide the reader to more in,depth in&ormation.Cleaning %alidation in the pharma'e(ti'al ind(stry is o& 'riti'al importan'e.-/ )here aremany analyti'al te'hni*(es a%ailable that 'an be (sed in 'leaning %alidations.0 )he 'hoi'eo& the te'hni*(e (sed in analyzing a parti'(lar sample is %ery important in 'leaning

%alidation. )he te'hni*(e m(st be appropriate &or meas(ring the analyte at and belo# thea''eptan'e resid(e limit. )oday1s analyti'al 'hemist has a #ide %ariety o& te'hni*(esa%ailable &or (se. )hese 'hoi'es in'l(de spe'i&i' and nonspe'i&i' methods. Many methodsare 'omplementary to ea'h other. )he pros and 'ons o& ea'h te'hni*(e #ill be e2amined.Validating the methods #ill be dis'(ssed as #ell. )he re&eren'es in'l(ded #ith this paper'an be (sed to pro%ide more in,depth in&ormation to the reader and a't as g(ides to thea%ailable literat(re. Choosing the appropriate analyti'al tool depends on a %ariety o& &a'tors.34 )he mostimportant &a'tor is determining #hat spe'ies or parameter is being meas(red.5 6s it anorgani' 'ompo(nd or inorgani' 'ompo(nd? )he ne2t *(estion is meas(rement. Ho# is this'ompo(nd going to be meas(red? 6s it going to be s#abbed &rom a s(r&a'e or determined

&rom a rinse #ater sample? 6& it is going to be s#abbed &rom a s(r&a'e #here #ill thiss#abbing o''(r? Another important &a'tor in 'hoosing an analyti'al tool is establishing thelimits o& the resid(e. )he limit sho(ld al#ays be established prior to sele'ting the analyti'altool.78 )he limits sho(ld not be established solely based on dete'tion limits o& a parti'(larmethod. 9et another important &a'tor in 'hoosing an analyti'al tool is #hether or not themethod 'an be %alidated. 6& the method 'an1t be %alidated then another te'hni*(e needs tobe 'hosen.

Sampling )e'hni*(e

)he sampling te'hni*(e plays a large role in determining #hi'h analyti'al te'hni*(e to(se. Some te'hni*(es are more appli'able &or s#ab samples and other te'hni*(es aremore appli'able &or rinse #ater sampling. )he a''eptable sampling te'hni*(es in'l(dedire't s(r&a'e sampling s#ab; and rinse #ater samples.-


2/13

Another important &a'tor to 'onsider in 'hoosing an analyti'al method is the type o&resid(e being analyzed. +esid(es 'an be dr(g a'ti%es &orm(lation 'omponents 'leaningagents organi' inorgani' #ater sol(ble #ater insol(ble parti'(late mi'robial andorendoto2ins. 6& the resid(e being dete'ted is a dr(g a'ti%e and the method (sed &ordete'tion is the same method that is (sed &or *(ality 'ontrol p(rposes o& the &inal &orm(la

it m(st be established that the a'ti%e has not 'hanged its 'hemi'al nat(re d(ring the'leaning pro'ess. )hat is it m(st be established that the a'ti%e is still dete'table and*(anti&iable (sing the analyti'al method. )his 'an easily be established by per&orming&or'ed degradation st(dies. @2posing the a'ti%e to the 'leaning 'ompo(nd at an ele%atedtemperat(re and then analyzing that sample #ill help determine the 'ompatibility o& the'leaner #ith the a'ti%e. 6& the a'ti%e has indeed 'hanged its 'hemi'al nat(re d(ring the'leaning pro'ess a ne# te'hni*(e #ill need to be established &or its analysis.

Limit of Detection and Quantitation Be&ore 'hoosing a method some de&initions need to be established. )he $imit o&"ete'tion $"; is the lo#est amo(nt o& a 'ompo(nd that 'an be dete'ted. )he $imit o&

(antitation $; is de&ined as the lo#est amo(nt o& a 'ompo(nd that 'an be *(anti&ied.)he $" is (s(ally lo#er than the $ b(t is ne%er higher. )he $" sho(ld ne%er be(sed to establish resid(e a''eptan'e limits. )he resid(e a''eptan'e limit sho(ld be #ellabo%e the $ so that it 'an be a''(rately *(antitated.

Specific and Nonspecific Methods A spe'i&i' method is a method that dete'ts a (ni*(e 'ompo(nd in the presen'e o&potential 'ontaminants. Some e2amples o& spe'i&i' methods are High !er&orman'e $i*(idChromatography H!$C; ion 'hromatography atomi' absorption ind('ti%ely 'o(pledplasma 'apillary ele'trophoresis and other 'hromatographi' methods. 6t sho(ld be notedthat H!$C is not inherently spe'i&i'. What is meant is that the 'onditions in an H!$Cmeas(rement 'an (s(ally be ad=(sted to separate o(t >no#n potential 'ontaminants.

onspe'i&i' methods are those methods that dete't any 'ompo(nd that prod('es a'ertain response. Some e2amples o& nonspe'i&i' methods are )otal rgani' Carbon)C; pH titrations and 'ond('ti%ity. A %ery interesting and sensiti%e nonspe'i&i'te'hni*(e is dynami' 'onta't angle.-- )itrations may be spe'i&i' &or a'ids or bases b(t theyare not spe'i&i' &or parti'(lar a'ids or bases. )here are ho#e%er spe'i&i' titrations &or'lasses o& s(r&a'tants.-

Interferences A good nonspe'i&i' strategy that 'o(ld be &ollo#ed is to &irst identi&y possible

inter&eren'es. )hese inter&eren'es 'an be either positi%e or negati%e. )he nonspe'i&i'property is then meas(red and the resid(e is 'al'(lated as i& all o& the meas(red propertyis d(e to that resid(e. Dor e2ample i& the 'leaning agent #as the analyte and )C #as themethod (sed all o& the )C #o(ld be ass(med to ha%e 'ome &rom the 'leaning agent and'al'(lated as s('h. )his #o(ld then pro%ide a #orst,'ase (pper,limit %al(e. )here are many possible so(r'es o& inter&eren'es. Cleaning agents and 'ompo(nds 'anbe a so(r'e o& inter&eren'es &or e2ample. A'ti%e agents and their byprod('ts #atersystem 'omponents maintenan'e materials and the atmosphere 'an all be so(r'es as #ell as people i& samples are not handled properly. )he materials (sed to per&orm theanalyti'al method 'an also be a so(r'e o& inter&eren'e. Dor e2ample i& a s#ab that has ahigh )C %al(e is (sed to sample it 'o(ld in'rease the le%el o& )C dete'ted.

Dor spe'i&i' methods there sho(ld be no inter&eren'e i& the method is properly designed.Again it sho(ld be stressed that the method m(st be able to &ollo# the analyte a&tere2pos(re to the 'leaning en%ironment. 6t is ne'essary to establish that the 'leaning


3/13

en%ironment or the 'leaning pro'ess does not 'hange the analyte. Dor nonspe'i&i'methods #hi'h meas(re a nonspe'i&i' property; any 'ompo(nd #ith the property that isintrod('ed into the sample #ill inter&ere. Dor e2ample i& the method being (sed is )Catmospheri' 'arbon that may enter the sample 'o(ld 'a(se inter&eren'e. With allnonspe'i&i' methods there is a need to identi&y potential so(r'es o& inter&eren'e.

High !er&orman'e $i*(id Chromatography)he &irst te'hni*(e that #ill be dis'(ssed is H!$C. Almost e%ery pharma'e(ti'al 'ompanyhas an H!$C instr(ment. H!$Cs (tilize a %ariety o& dete'tors. )hese in'l(de (ltra%ioletEV; &l(ores'en'e ele'tro'hemi'al re&ra'ti%e inde2 'ond('ti%ity e%aporati%e lights'attering and many others. )he (ltra%iolet dete'tor is by &ar the most 'ommon. Ho#e%er@%aporati%e $ight S'attering "ete'tion @$S"; may be the most appropriate dete'tor &or'leaning agents. We #ill dis'(ss the (se o& both EV and @$S" dete'tors in depth.

Eltra%iolet "ete'tors)here are many ad%antages o& (sing EV dete'tors. Many 'ompo(nds ha%e 'hromophores

and there&ore they 'an be easily dete'ted by EV. Many instr(ments are e*(ipped #ithdiode array spe'tral 'apabilities. )his allo#s &or easy dete'tion o& imp(rities or potential'ontaminants #ithin pea>s. Eltra%iolet dete'tion (s(ally re*(ires no additional reagents orpost 'ol(mn or pre,'ol(mn rea'tions. EV dete'tors are not harm&(l to the sample i& that isimportant. )hey are generally ine2pensi%e and readily a%ailable. Also molar absorpti%itiesare generally not a&&e'ted by temperat(re and there&ore there is no need &or heating or'ooling the dete'tor.While there are many ad%antages o& EV dete'tors there are also some signi&i'antdisad%antages. EV dete'tors 'annot dete't all types o& 'ompo(nds and there&ore are not'onsidered to be (ni%ersal. All 'ompo(nds do not ha%e 'hromophores. )his is parti'(larlytr(e o& s(r&a'tants that are (sed in the pharma'e(ti'al ind(stry. "irty 'ells air b(bbles andthe (se o& gradients 'an a&&e't baseline dri&t and dete'tion 'apability. )he limits o&dete'tion 'an be higher than other dete'tor types d(e to ba'>gro(nd inter&eren'es.

@%aporati%e $ight S'attering "ete'tion6n @$S" the 'ompo(nd is separated on an H!$C 'ol(mn as (s(al and then enters aneb(lizer that is 'ombined #ith a gas stream and passed thro(gh a heated 'ol(mn. )heheated 'ol(mn e%aporates the mobile phase lea%ing the solid analyte in the 'ol(mn. )hesolid analyte then passes thro(gh a dete'tor that 'onsists o& a laser or light so(r'e. )helaser or light so(r'e is s'attered #hen it hits the solid analyte. )he dete'tor then pi'>s (pthis s'attering.

)here are many ad%antages asso'iated #ith e%aporati%e light s'attering dete'tors. @$S"is 'laimed to be (ni%ersal. 6t is 'alled (ni%ersal be'a(se it 'an dete't any type o&'ompo(nd. @$S"s are simple %ersatile and r(gged in (se. Sin'e it is a mass dete'tor all'ompo(nds prod('e similar responses. Additionally there is no baseline dri&t d(e to mobilephase e&&e'ts.)here are t#o primary disad%antages o& @$S". Dirst there is a %ery limited 'hoi'e o& b(&&ersalts that 'an be (sed. +e'all that the mobile phase is e%aporated or remo%ed lea%ing theanalyte. Any b(&&ers that #ill not e%aporate #ill also prod('e solid parti'les that #ill then bedete'ted and 'a(se inter&eren'es. )he se'ond disad%antage is that the neb(lizer anddete'tor m(st prod('e 'onsistent parti'le sizes. )his re*(ires 'are&(l 'leaning andmonitoring o& the neb(lizer.

Actives and Detergent )here are many types o& resid(es that 'an be analyzed (sing H!$C te'hni*(es. )hese


4/13

in'l(de both a'ti%es and detergent resid(es. When dealing #ith detergent resid(es it isimportant to identi&y #hat is being analyzed: s(r&a'tant b(ilder 'omponents 'helatingagents et'. )he separation and *(antitation o& s(r&a'tants at lo# le%els is di&&i'(lt at best.6nd(stry literat(re is &(ll o& re&eren'es &or s(r&a'tant analyses (sing H!$C. )he %astma=ority o& te'hni*(es des'ribed in the literat(re are &or the determination o& s(r&a'tants in

'on'entrated prod('ts.-/-0

)here&ore the limits o& *(antitation and the limits o& dete'tionare rather high. )here are also re&eren'es &or the analysis o& s(r&a'tants related to theen%ironment.-3-4 6n en%ironmental analysis the sample is pre,'on'entrated so that thelimits o& *(antitation are %ery lo#. )he pre,'on'entration 'an be (p to one tho(sand &old.

Suggested ReadingA(thors $in et. al. 'ompared the analysis o& anioni' 'ationi' and amphoteri' s(r&a'tants'ontaining n,dode'yl gro(ps (sing H!$C and 'apillary ele'trophoresis.-5 )hey &o(nd thatH!$C #as best &or all 'lasses o& s(r&a'tants espe'ially &or &orm(lated s(r&a'tants. A(thorsCarrer et. al. (tilized @$S" &or amphoteri' type s(r&a'tants.-7 Amphoteri' s(r&a'tants are a'lass o& s(r&a'tants that display 'ationi' beha%ior in an a'idi' sol(tion and anioni' beha%ior

in an al>aline sol(tion. )he lo#est 'alibration standard that they (tilized #as 3< ppm b(tthey probably 'o(ld ha%e gone m('h lo#er. A(thors F(erro et. al. obtained a limit o&*(antitation o& yl polyethylene gly'ol ethers (sing @$S".-8

Capillary @le'trophoresisAn interesting method o& analysis is Capillary @le'trophoresis C@;. )here are manydi&&erent types o& C@. Capillary Gone @le'trophoresis CG@; is by &ar the most 'ommon. C@instr(mentation is &airly simple 'onsisting o& a high %oltage so(r'e a 'apillary and adete'tor. )he high %oltage so(r'e is (sed to apply a potential a'ross t#o sol(tions. ne o&the sol(tions 'ontains the analyte and the potential applied to the sol(tions 'a(ses theanalyte to migrate thro(gh the 'apillary thro(gh the dete'tor and into the other sol(tion.)he 'ol(mn or 'apillary is typi'ally 'omposed o& &(sed sili'a #ith a polyimide 'oating. )hediameter o& the 'apillary is typi'ally 3,53mm in diameter. )he 'apillary has a polyimide'oating simply to ma>e it more r(gged. All 'ommon dete'tion te'hni*(es EV&l(ores'en'e et'.; 'an be (sed in 'apillary ele'trophoresis dete'tion. )he 'apillary itsel&ser%es as the dete'tor 'ell. A small portion o& the polyimide 'oating is s'raped o&& prior to(se and the bare portion o& the 'apillary is pla'ed in the light path. )his dete'tion isdi&&erent &rom that seen in H!$C be'a(se the dete'tion o''(rs #hile the separation ista>ing pla'e rather than a&ter separation has been 'ompleted. Esing a G,'ell 'an in'reasethe sensiti%ity o& the te'hni*(e. )his is a''omplished by (sing a spe'ial a''essory thatbends the 'apillary 'a(sing the so(r'e radiation to penetrate length#ise thro(gh the

'apillary rather than a 'ross,se'tional sampling. )his in e&&e't in'reases the path length o&the 'ell. )he G,'ell 'an be (sed in all types o& C@ #here EV dete'tion is (sed. C@ 'an be (sed &or many di&&erent types o& analyses. S(r&a'tants 'an be determined*(ite readily (sing this te'hni*(e.


5/13

resid(es./

Suggested Reading Vogt et. al. pro%ided a good o%er%ie# o& the separation o& 'ationi' anioni' and nonioni's(r&a'tants (sing 'apillary ele'trophoresis.0 )hey indi'ated that one 'an easily ad=(st the

parameters o& the separation to 'oel(te or separate oligomers. Coel(tion o& the oligomersin'reased the sensiti%ity at the e2pense o& in'reasing the potential &or 'oel(ting positi%einter&eren'es. "ire't EV dete'tion 'o(ld be (sed &or EV,absorbing materials and indire't ornon,EV absorbing materials. Heinig et. al. (tilized mi'ellar ele'tro>ineti' 'apillary 'hromatography &or the separationo& non,ioni' al>ylphenol polyo2yethylene type s(r&a'tants.3 Ho#e%er the (se o& thismethod #as limited be'a(se o& ins(&&i'ient pea> resol(tion and relati%ely lo# dete'tionsensiti%ity. Heinig et. al. also 'ompared H!$C and C@ analyses o& s(r&a'tants.4 )hes(r&a'tant types they st(died #ere linear al>ylbenzenes(l&onatesnonylphenolpolyetho2ylates 'etylpyridini(m 'hloride and al>yls(l&onates. Dor the C@analyses they (tilized EV dete'tion either in the dire't or indire't modes depending on the

nat(re o& the s(r&a'tant. Dor the H!$C analyses they (tilized either dire't EV dete'tion or'ond('ti%ity dete'tion. Anioni' s(r&a'tant samples #ere pre,'on'entrated one tho(sand&old thro(gh the (se o& solid phase e2tra'tion. )his allo#ed &or dete'tion limits in the partsper billion range to be obtained. Kelly et. al. (tilized C@ #ith indire't dete'tion to determine sodi(m dode'yls(l&ate'on'entrations.5 )hey also indi'ated that it is important to loo> at the absorption o& thes(r&a'tants onto &ilters i& the samples are indeed &iltered prior to analysis. )his is mostimportant in dil(te sol(tions. Diltering large %ol(mes o& sample 'an minimize this. Againappropriate st(dies need to be done to determine i& this indeed is a problem. Altria et. al. e2amined the (se o& C@ in the analysis o& sodi(mdode'ylbenzenes(lphonate.7 )hey obtained a limit o& *(antitation o&


6/13

mean that the 'ompo(nd m(st be sol(ble in the h(ndreds o& parts per million range b(tsol(ble in the lo# parts per million range. Another disad%antage is that organi' sol%ents'annot be (sed. 6& organi' sol%ents #ere (sed the )C o& the sol%ents #o(ld bemeas(red instead o& the resid(e. )here are also many so(r'es o& 'ontamination that 'ano''(r (sing )C. )hese so(r'es 'an in'l(de the atmosphere the s#ab itsel& personnel

and many other so(r'es. Methods de%eloped (sing )C sho(ld be #ritten to in'l(de'ontrols and blan>s to identi&y or a''o(nt &or possible 'ontamination. Dor e2ample a'ommon so(r'e o& 'ontamination is the te'hni*(e (sed to '(t the handles o& the s#abs sothat they &it into the )C %ials. Many times the s'issors or (tensils are not 'lean eno(gh&or )C (se. )his introd('es 'ontamination into the sampling %ial #hen the s#ab is '(t.

Excipients Some methodste'hni*(es 'an be (sed in 'ertain sit(ations to 'omplement ea'h other.@2amples in'l(de )C and H!$C. Consider the 'ase o& a dr(g in the presen'e o&e2'ipients. )he e2'ipients are %ery sol(ble in #ater #hile the dr(g a'ti%e has e2tremely lo#sol(bility in #ater. )he e2'ipients 'ontrib(te to the )C %al(es be'a(se they are %ery

sol(ble in #ater ho#e%er the dr(g a'ti%e does not sho# (p in the )C analysis. An H!$Canalysis is per&ormed to monitor the loss o& the dr(g. )he e2'ipients are remo%ed m('h&aster &rom a s(r&a'e d(ring 'leaning than the dr(g a'ti%e is remo%ed. 6n this 'ase )Canalysis is not a good stand,alone method. 6t is ho#e%er a good 'omplement &or theH!$C assay. )he )C analysis enables the analyst to see #hat #ater sol(ble matter isle&t behind i& any.

Suggested Reading F(azzaroni et. al. e2amined the (se o& total organi' 'arbon &or the analysis o&detergents endoto2ins biologi'al media and polyethylene gly'ol./0 Dor detergents they #ere able to obtain a


7/13

Suggested Reading 6n determining s(r&a'tants an e2'ellent re%ie# 'on'erning their analysis #as done byVogt et. al..0 )hey 'ompared the (se o& H!$C C@ ion 'hromatography $i*(idChromatography,Mass Spe'tros'opy $C,MS; and Fas Chromatography,MassSpe'tros'opy FC,MS;. )hey also dis'(ssed pre,'on'entration o& the samples. )hey

'ompared the (se o& solid phase e2tra'tion s(per 'riti'al &l(id e2tra'tion So2hlete2tra'tion and steam distillation as means o& pre,'on'entrating samples. )hey &o(nd by&ar that the best method #as solid phase e2tra'tions &or the pre,'on'entration o&s(r&a'tants. )hey also e2amined the (se o& titrimetri' methods o& analysis &or s(r&a'tants.Dor dete'ting anioni's s(bstan'es li>e methylene bl(e pyridini(m azo andtriphenylmethane dye #as (sed to 'omple2 the s(r&a'tants prior to photometri'determination. onioni's #ere determined indire'tly by &orming a 'ationi' 'omple2 #ithbari(m. )his 'omple2 #as then pre'ipitated by bism(th tetraiodide ion in a'idi' a'id. )hebism(th #as then *(anti&ied by potentiometri' titrations. Cationi's #ere 'omple2ed #ithanioni' dyes s('h as dis(l&ine bl(e.

)heile et. al. bro(ght (p an e2'ellent point that s(r&a'tants tend to 'on'entrate at

inter&a'es.0/ )his 'an be a problem in e2tremely dil(te sol(tions o& s(r&a'tants. )hes(r&a'tants 'an 'olle't at the s(r&a'e o& the 'ontainers that they are stored in. )his may'a(se errors in analysis. !roper 'ontrols in st(dies sho(ld be done to determine i& this is aproblem. )he a(thors indi'ated that pre,'on'entration #as re*(ired to determine %ery lo#le%els o& s(r&a'tant. Solid phase e2tra'tion #as the best method &or this. )hey #ere alsoable to obtain dete'tion limits &or linear al>ylbenzenes(l&onates o& .< ppb #ith&l(ores'en'e dete'tion and - o& portability o& D)6+e*(ipment and the semi,*(antitati%e nat(re o& the re&le'tan'e te'hni*(es (sed &or thesetypes o& analyses. Ho#e%er it is %ery (se&(l in per&orming s'reening st(dies and in

e%al(ating potential 'leaning agents. )his is done by soiling standard 'o(pons #ith the'leaning agent allo#ing them to dry and per&orming stati' rinsing st(dies. )hese types o&st(dies 'an indi'ate #hether or not the 'leaning agent is readily remo%ed &rom s(r&a'es.


8/13

)he height or area o& a parti'(lar pea> is meas(red %ers(s the 'on'entration o& thestandard 'o(pon.

Biol(mines'en'e Biol(mines'en'e is *(ite (se&(l &or biologi'als. )his type o& analysis (s(ally (ses

Adenosine )riphosphate A)!; biol(mines'en'e.3<

)his is based on the rea'tion o& A)! #ith $('i&erin$('i&erase. )his te'hni*(e is o&ten (sed in biopharma'e(ti'al &a'ilities. 6t hase2tremely high sensiti%ity and a %ery high reprod('ibility. 6n many 'ases the instr(ments'an be (sed at the e*(ipment site. )his te'hni*(e (tilizes s#abs &or s(r&a'e analyses.

pti'ally Stim(lated @le'tron @mission 6n some 'ases a 'ompany1s established limits o& resid(e are so lo# that they 'annot bedete'ted by 'on%entional methods. A %ery sensiti%e method that may be appli'able ispti'ally Stim(lated @le'tron @mission S@@;.3- )he instr(mentation &or S@@ is &airlyportable and 'an be readily ta>en to tan> side &or analysis. )he te'hni*(e (ses a probethat is pla'ed against a s(r&a'e and a EV so(r'e ill(minates and a'ti%ates the s(r&a'e.

When some s(r&a'es are e2posed to EV light at 'ertain #a%elengths ele'trons are emitted&rom the s(r&a'e. )he instr(ment meas(res the '(rrent that is prod('ed. 6& e%en smallamo(nts o& resid(es are present on the s(r&a'e the '(rrent #ill be a&&e'ted. )he '(rrent'an be a&&e'ted either in a positi%e or negati%e #ay depending on the nat(re o& the resid(e.)his is an e2tremely sensiti%e te'hni*(e. 6t 'an be (sed in either a *(alitati%e or*(antitati%e manner.

!ortable Mass Spe'trometer Dor those 'ompanies that re*(ire (ltrasensiti%e meas(rements and identi&i'ation o& theresid(es a te'hni*(e has been de%eloped I $a#ren'e $i%ermore ational $aboratorieshas de%eloped a portable mass spe'trometer.3 )he (nit 'onsists o& a g(n portion o& theinstr(ment that is 'onne'ted #ith 'ables to %a'((m p(mps. )he g(n portion is held againstthe s(r&a'e to be analyzed. A seal is &ormed and the s(r&a'e is heated to %olatilize any'ompo(nds that are present. )his instr(ment is (sed not only to meas(re ho# m('h o&something is present b(t also #hat that something is. )his pie'e o& e*(ipment has been(tilized in the aerospa'e ind(stry. ne dra#ba'> o& the portable mass spe'trometer is thatit re*(ires relati%ely &lat s(r&a'es. Ho#e%er they are '(rrently #or>ing on adaptors to be(sed on non,&lat s(r&a'es.

Additional Techniques 6n the biopharma'e(ti'al ind(stry a #ide %ariety o& te'hni*(es are (tilized.3/ )hese

in'l(de the @nzyme,$in>ed 6mm(nosorbent Assay @$6SA;30

the $im(l(s Amoebo'yte$ysate $A$; and a #ide %ariety o& protein determinations. )hese are all 'ontaminantspe'i&i' assays. Dor e2ample the $A$ test meas(res the le%el o& endoto2ins present.)here is also the anthrone assay that 'an be (sed to monitor the le%els o& 'arbohydrateson s(r&a'es. )hese te'hni*(es are (s(ally (sed in 'ombination #ith )C. )he nonspe'i&i' te'hni*(es o& pH 'ond('ti%ity and titrations 'an be (sed thro(gho(t allareas o& pharma'e(ti'al man(&a't(ring. b%io(sly these te'hni*(es are most o&ten(tilized in rinse #ater monitoring. )he 'ond('ti%ity and pH o& rinse #ater is typi'allymonitored and 'ompared to the 'ond('ti%ity and pH o& the #ater prior to introd('tion to thee*(ipment. 6& a'idi' or al>aline materials are being meas(red titration is a %ery (se&(lte'hni*(e. 6n some 'ases titration 'an be more sensiti%e than per&orming )C analyses.

)he sample size 'an be ad=(sted andor the normality o& the titrant 'an be ad=(sted toin'rease the sensiti%ity o& the titration.


9/13

Method Validation

6t is %ery important to s'ienti&i'ally establish the resid(e limit prior to 'hoosing the methodo& analysis. )his in'l(des the limit in the analyti'al sample and the limit in the ne2t prod('t.)his #ill ens(re that the method 'hosen #ill be able to dete't and *(antitate the limit

'hosen. n'e the te'hni*(e &or analysis has been 'hosen it is %ery important to %alidatethe method (sed.33,4no#n #eight per'ent o& a sol(tion'ontaining the analyte 'an be sprayed &airly e%enly o%er the s(r&a'e o& a 'o(pon. )he'o(pon 'an be s#abbed (sing a standard te'hni*(e. 6t does not matter ho# yo( s#ab the'o(pon as long as the 'omplete s(r&a'e is 'o%ered and that the 'o(pons are s#abbed thesame #ay I ea'h and e%ery time. )he type o& s#abs (sed in re'o%ery st(dies m(st be thesame as those (sed in the %alidation proto'ol. 6& this is a sim(lated rinse pro'ed(re thenthe 'o(pons are rinsed and the rinse #ater is analyzed.

Dor s#abs a desorption pro'ess is 'arried o(t. )his 'an 'onsist o& simply sha>ing thesample %ial or (sing an (ltrasoni' bath. )he samples are then analyzed. +e'o%ery st(diesare al#ays done belo# a''eptan'e limits in the test sol(tion. )his ens(res that the limit #ill

be or 'an be; meas(red in the analysis. A re'o%ery o& greater than 7< per'ent is good. 6&the re'o%ery is greater than 3< per'ent it may be a''eptable. Ho#e%er i& the re'o%ery isless than 3< per'ent *(estions arise and the so(r'e o& the poor re'o%ery sho(ld bein%estigated. A possible 'a(se o& a poor re'o%ery 'an be that the resid(e is being tootightly held by the s#ab. )his 'an be in%estigated by spi>ing a s#ab #ith a >no#n amo(nto& resid(e allo#ing it to dry trying to desorb the resid(e and &ollo#ing (p #ith analysis. 6&the analyte is held too tightly by the s#ab another type o& s#ab material sho(ld bein%estigated. )he re'o%ery &a'tor sho(ld be in'l(ded in analyti'al 'al'(lations or in thea''eptan'e limit 'al'(lation. 6t sho(ld not be in'l(ded in both o& the 'al'(lations.

Containers

)he 'hoi'e o& 'ontainers (sed in the analysis o& samples is %ery important. 6t has beensho#n that in %ery dil(te sol(tions s(r&a'tants 'an adsorb onto the s(r&a'es o& sample%ials. )his #ill prod('e arti&i'ially lo# res(lts in the analysis. )his ho#e%er typi'ally only


10/13

o''(rs in stati' systems. )here is no need to #orry abo(t the adsorption o& the s(r&a'tanton the #alls o& man(&a't(ring e*(ipment. )his is be'a(se the agitation that is in%ol%ed in'leaning remo%es the s(r&a'tants &rom the s(r&a'es. )his is another matter in sample %ials.Appropriate spi>ing st(dies sho(ld be per&ormed to ens(re that this phenomenon is noto''(rring and #ill not inter&ere #ith the analyti'al method. )his in'l(des both H!$C or ion

'hromatography sample %ials as #ell as )C sample %ials. )his phenomenon is notlimited to s(r&a'tants. !roteins ha%e been sho#n to adsorb readily onto glass s(r&a'es.)hese proteins are m('h more di&&i'(lt to remo%e &rom s(r&a'es than s(r&a'tants.

Spe'i&i' Vers(s onspe'i&i'

)he 'hoi'e o& (sing a spe'i&i' or nonspe'i&i' method 'an be di&&i'(lt. 6& a dr(g a'ti%e ishighly to2i' a spe'i&i' method is al#ays re'ommended.4-"etergents 'an be *(antitatedeither (sing spe'i&i' or nonspe'i&i' methods ho#e%er 'are m(st be ta>en in 'hoosing #hi'h 'omponent is meas(red. Dor e2ample a detergent may 'ontain &i%e per'ent o& as(r&a'tant and < per'ent o& another organi' ingredient. Ass(ming e*(al sensiti%ities o& the

analyti'al methods the limit o& *(antitation o& the #hole detergent system #ill be lo#eredby a &a'tor o& &o(r i& the ingredient present in the greater amo(nt is determined. 6& a nonspe'i&i' method i.e. )C; is (sed &or the same system a m('h lo#er limit o&*(antitation 'o(ld be determined simply be'a(se there #o(ld be a tremendo(s amo(nt o&'arbon present in the sample. 6n addition i& detergent systems are 'ombined s('h as inthe 'ase o& adding a detergent additi%e to another prod('t the 'hoi'e o& a spe'i&i' method #o(ld be made e%en more di&&i'(lt. )he *(estion #o(ld be Whi'h detergent do 6determine? A disad%antage o& (sing a nonspe'i&i' method &or the entire 'leaning%alidation analysis is that i& there is a &ail(re in the &(t(re it #o(ld not be >no#n #here the&ail(re originally o''(rred. )he &ail(re 'o(ld be d(e to the a'ti%e e2'ipients detergentsystem or e%en an (n>no#n so(r'e.

Con'l(sion

)here are many di&&erent analyti'al te'hni*(es a%ailable that 'an be (sed to dete'tresid(es. )hese range &rom simple titrations to more 'omple2 $C,MS. )he 'hoi'e o&te'hni*(e sho(ld be based on #hat e*(ipment is a%ailable the type o& resid(e and thes'ienti&i'ally established resid(e limit. 6t is important &or an analyti'al 'hemist to >eepabreast o& the literat(re and #hat te'hni*(es are a%ailable. )here are te'hni*(es a%ailablethat #ill analyze any resid(e at any le%el. At the end o& the day ho#e%er it is al#ays #iseto 'hoose the simplest te'hni*(e that 'an be (sed to rea'h the desired goal. o

About the Authorser!ert "# $aiser% &h#D# is 'anager ( ard Surface &roducts at STERIS )orporation# ehas *+ ,ears of experience in cleaning and surface technologies% -hich includesdeveloping products and methods for the cleaning and anal,.ing of a -ide variet, ofsurfaces# Dr# $aiser has developed a -ide variet, of products for the healthcare% industrial%and pharmaceutical mar/ets# e is the sole inventor listed in five 0nited States &atents forvarious industrial treatment schemes# Dr# $aiser received his 1#A# degree from St# 'ar,2s0niversit, in San Antonio% Texas% his '#S#3R4 from St# Louis 0niversit,% and his &h#D# fromthe 0niversit, of 'issouri# e is a mem!er of the American )hemical Societ, and the

Association for the Advancement of 'edical Instrumentation# Dr# $aiser can !e reached !, phone at 5*6789:76;8


11/13

'aria 'ino-it.% '#L#S#% Information Associate at STERIS )orporation% has *: ,ears ofexperience in corporate research and development li!rarianship# She has !eenresponsi!le for information management in the disciplines of chemistr,% medicine% andengineering# 'ino-it. received her A#1# degree from St# Louis 0niversit, and an '#L#S#from the 0niversit, of 'issouri7)olum!ia# She is a mem!er of the Special Li!raries Association% 'idcontinental )hapter of the 'edical Li!rar, Association% and the St# Louis

'edical Li!rarians#

References-. Falato#its'h S. )he 6mportan'e o& Cleaning Validation. Cleanrooms >er 6n'.: e# 9or>. -887. pp.578,7. -880. pp. 78,/4.-3. Jandera !. H!$C o& S(r&a'tants and +elated Compo(nds. $i*(id Chromatography in @n%ironmentalAnalysis. @d. $a#ren'e J. H(mana !ress: e# Jersey. -870. pp. --3,-45.-4. Waters J. Analysis o& $o# Con'entrations o& Cationi' S(r&a'tants in $aboratory )est $i*(ors and@n%ironmental Samples. Cationi' S(r&a'tants. @ds. Cross J. Singer @. S(r&a'tant S'ien'e. Series 3/.Mar'el "e>>er 6n'.: e# 9or>. -880. pp. /3,34.-5. $in W. $in S. Sh( S. Comparison o& Analyses o& S(r&a'tants in Cosmeti's Esing High,!er&orman'e$i*(id Chromatography and High !er&orman'e Capillary @le'trophoresis. Jo(rnal o& S(r&a'tants and"etergents. Vol. /-;.


12/13

3. Heinig K. Vogt C. Werner F. Separation o& onioni' S(r&a'tants o& the !olyo2yethylene )ype byCapillary @le'trophoresis. Dreseni(s Jo(rnal o& Analyti'al Chemistry. Vol. /35. -885. pp. 483,5 W. K. Ese o& )otal rgani' Carbon Analysis and Do(rier,)rans&orm 6n&raredSpe'tros'opy to "etermine +esid(es o& Cleaning Agents on S(r&a'es. Jo(rnal o& AAC 6nternational. Vol.7


13/13

3. Meltzer M. Koester C. Ste&&ani C. Criteria @%al(ation &or Cleanliness !hase et. A''reditation and (ality Ass(ran'e. -885 /; -0

Documents

Analyzing Cleaning Validation Samples What Method