Guidance for Industry 
 


Q4B Evaluation and Recommendation 
 


of Pharmacopoeial Texts for Use in the 
 


ICH Regions 
 


Annex 3 
 


Test for Particulate Contamination: 
 


Subvisible Particles General Chapter 
 


U.S. Department of Health and Human Services 
 


Food and Drug Administration 
 


Center for Drug Evaluation and Research (CDER) 
 


Center for Biologics Evaluation and Research (CBER) 
 


January 2009 
 


ICH
 
 
 

 

Guidance for Industry 
 


Q4B Evaluation and Recommendation of 
 


Pharmacopoeial Texts for Use in the 
 


ICH Regions 
 


Annex 3 
 


Test for Particulate Contamination: 
 


Subvisible Particles General Chapter 
 


Additional copies are available from: 
 


Office of Training and Communication 
 


Division of Drug Information
 
 

Center for Drug Evaluation and Research
 
 

Food and Drug Administration 
 


10903 New Hampshire Ave. 
 


Bldg. 51, Room 2201
 
 

Silver Spring, MD 20993-0002
 
 

(Tel) 301-796-3400

 http://www.fda.gov/cder/guidance/index.htm 
 


or 
 


Office of Communication, Training and
 

Manufacturers Assistance, HFM-40 
 

Center for Biologics Evaluation and Research 
 

Food and Drug Administration 
 

1401 Rockville Pike, Rockville, MD 20852-1448 

 http://www.fda.gov/cber/guidelines.htm. 
 

U.S. Department of Health and Human Services 
 


Food and Drug Administration 
 


Center for Drug Evaluation and Research (CDER) 
 


Center for Biologics Evaluation and Research (CBER) 
 


January 2009 
 


ICH 
 

TABLE OF CONTENTS 
 


I. INTRODUCTION (1)....................................................................................................... 1
 
 

II. Q4B OUTCOME (2)......................................................................................................... 2
 
 

A. Analytical Procedures (2.1) ...........................................................................................................2
 
 

B. Acceptance Criteria (2.2)...............................................................................................................2
 
 

III. TIMING OF ANNEX IMPLEMENTATION (3) .......................................................... 2
 
 

IV. CONSIDERATIONS FOR IMPLEMENTATION (4).................................................. 2
 
 

A. General Consideration (4.1)..........................................................................................................2
 
 

B. FDA Consideration (4.2) ...............................................................................................................2
 
 

C. EU Consideration (4.3) ..................................................................................................................3
 
 

D. MHLW Consideration (4.4) ..........................................................................................................3
 
 

V. REFERENCES USED FOR THE Q4B EVALUATION (5) ........................................ 3
 
 

ATTACHMMENT........................................................................................................................ 4
 
 

i 
 

 

 

 

 

Contains Nonbinding Recommendations 

Guidance for Industry1
 
 

Q4B Evaluation and Recommendation of Pharmacopoeial Texts 
 


for Use in the ICH Regions 
 


Annex 3 
 


Test for Particulate Contamination: Subvisible Particles 
 


General Chapter 
 


This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION (1)2 

This annex is one in a series of guidance documents that describe the evaluations and 

recommendations by the Q4B Expert Working Group (EWG) of selected pharmacopoeial texts 

to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH 

regions. Implementation of the Q4B annexes is intended to avoid redundant testing by industry. 

For general information on the Q4B process, the reader is referred to the core guidance Q4B 

Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions.

3 

This annex is the result of the Q4B process for the Test for Particulate Contamination: Subvisible 

Particles General Chapter. The proposed texts were submitted by the Pharmacopoeial 

Discussion Group (PDG). 

1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on 

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been 

endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2008. At Step 4 of the process, the final 

draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 

2

 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at 

Step 4 of the ICH process, June 2008. 

3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance page at http://www.fda.gov/cder/guidance/index.htm or the CBER guidance page at 

http://www.fda.gov/cber/guidelines.htm.. 

1
 
 
 

 

Contains Nonbinding Recommendations 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. Q4B OUTCOME (2) 

A. Analytical Procedures (2.1) 

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group 

(EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 2.9.19. Particulate 

Contamination: Sub-visible Particles, JP 6.07 Insoluble Particulate Matter Test for Injections, 

and USP <788> Particulate Matter in Injections, can be used as interchangeable in the ICH 

regions subject to the following condition: 

•	 Condition (2.1.1): Instrument calibration and system suitability measurements should 

follow regional good manufacturing practice (GMP) requirements. 

B. Acceptance Criteria (2.2) 

Except for nominal 100-milliliter (mL) parenteral products, the acceptance criteria are 

interchangeable. At the 100-mL nominal volume, the criteria specified in JP are more stringent 

than those in the Ph. Eur. and the USP pharmacopoeias; therefore, the criteria are not 

interchangeable in all three regions at that volume. 

III. TIMING OF ANNEX IMPLEMENTATION (3) 

When this annex has been implemented (incorporated into the regulatory process at ICH Step 5) 

in a region, it can be used in that region. Timing might differ for each region. 

IV. CONSIDERATIONS FOR IMPLEMENTATION (4) 

A. General Consideration (4.1) 

When sponsors or manufacturers change their existing methods to the implemented Q4Bevaluated pharmacopoeial texts that are referenced in section II.A (2.1) of this annex, any change 

notification, variation, and/or prior approval procedures should be handled in accordance with 

established regional regulatory mechanisms pertaining to compendial changes. 

B. FDA Consideration (4.2) 

2
 
 
 

Contains Nonbinding Recommendations 

Based on the recommendation above, and with reference to the conditions set forth in this annex, 

the pharmacopoeial texts referenced in section II.A (2.1) of this annex can be considered 

interchangeable. However, FDA might request that a company demonstrate that the chosen 

method is acceptable and suitable for a specific material or product, irrespective of the origin of 

the method. For nominal 100-mL parenteral products, the FDA considers testing criteria from all 

three pharmacopoeias as interchangeable. 

C. EU Consideration (4.3) 

For the European Union, the monographs of the Ph. Eur. have mandatory applicability. 

Regulatory authorities can accept the reference in a marketing authorization application, renewal 

or variation application citing the use of the corresponding text from another pharmacopoeia as 

referenced in section II.A (2.1), in accordance with the conditions set out in this annex, as 

fulfilling the requirements for compliance with the Ph. Eur. Chapter, Particulate Contamination: 

Sub-visible Particles: 2.9.19., on the basis of the declaration of interchangeability made above. 

For nominal 100-mL parenteral products, the EU considers testing criteria from all three 

pharmacopoeias as interchangeable. 

D. MHLW Consideration (4.4) 

The pharmacopoeial texts referenced in section II.A (2.1) of this annex can be used as 

interchangeable in accordance with the conditions set out in this annex. Details of 

implementation requirements will be provided in the notification by MHLW when this annex is 

implemented. 

V. REFERENCES USED FOR THE Q4B EVALUATION (5) 

A. (5.1) The PDG Stage 5B sign-off document: Japanese Pharmacopoeial Forum, 

Volume 13, Number 3 (August 2004). 

B. (5.2) The pharmacopoeial references for Particulate Matter for this annex are: 

1. (5.2.1) European Pharmacopoeia (Ph. Eur.): 5th Edition (official on January 

2005), Particulate Contamination: Sub-visible Particles (reference 01/2005:20919). 

2. (5.2.2) Japanese Pharmacopoeia (JP): 6.07 Insoluble Particulate Matter Test for 

Injections as it appears in the JP Fifteenth Edition (March 31, 2006, The Ministry of 

Health, Labour and Welfare Ministerial Notification No. 285). The method was 

changed in September 2007 to correct a sentence in the introduction as underlined in the text 

that is provided by MHLW which is attached. 

3. (5.2.3) United States Pharmacopeia (USP): <788> Particulate Matter in Injections, 

Revision Bulletin, April 4, 2007. 

3
 
 
Meiliod l. tighl Obsc"ratioll rar!kle Corml Tnt

Usc, suitable apparatus based on th" prin"iple of lighl

blockaile which allows all automatic delermin'lliull of tbe siz.c

of pllrticles and the numher ui I'prticle~ accnrding 10 siT-e. ·It

is tlCcessary to ptrform callbration, as well as 10 demonnrate

Ihe sample ~olunl( accuracy, lamplc flow rate, particle siLe

response wrve, sel\SO( Icsoilitiotl, and coullline accuracy, at

leu! once a year.•

·CalillraLion

rartitJes to bt u.~ed fOT calibration mould be subject to

lIaltide sit.e sensiri~ity mC~Sllre~t, ,,~ine: ,pherial Jloly<ly·

rme particles huinl: al iea.l1 5, 10 and 15 ~m in di~m.e!Cl'"

(I'SL parucLcs) ill munu-,Ji.pencd suspcnsion. Thc PSL parLicks should have dthu" domeslieor international traeeabil·

ity in lerms of Iellt;th, "'itn a Ievd of unanainly ill 001 s.rtiltcr than 3%_ The putides 10 be \l~ for ealibrat:on should he

dispersed inpanic!t-frn WIlIt<.

Mall"al mClhotl

Tbe particle Si1.e resporu~ or thc sYl!:em to be applied

.nould be deterrnilll..d using ar leaSl ) chanrttls fo' Ihre.shtlkl­

"01131<: setrlnt. accordint to tbe half cDunlint merhod of

windo.. moville. type. The Ihredlold-volla;:e ..indo,", sh;)uId

This lUI is htmonlzt<1 ...illllht P.uropun P:'..Clni>COpoci.

alld Ihe U. S. Pharmacopeia. l1\e paru of Ihe tul that art

nOI harmonized art marked with symbols (. .l.

Tht insoluble particulale m.illteT teSI for injauou Dr infu·

sions is the method to teu fOf inwluble p;uticllla!tS, to confinn thai they art flCIl preswl in c:ICeS$ of specifi~ Ievel~ in

tl'.t solutions. For the deurmlnalinn of panicnlol1t tflnrami~

nalion 1 proculurn, ).1C1hcxl I (Litht Ohscurallon Parrick

Coo:!1 Ten) and Method 1 (Micrl»l:Ollic Particle Cour't

Tesl), are sp«ili.ed bercillafttt. When ClI:;unininl: iujc>;tions

"lid pa:altaal iufusiulls fUI wb ,isiblt:: particles M=lhod I iii

prcfrrnbly "";llkd. Hl,)lIIelfl:r r ~t lDay be nc=al)' to tes!

some preparalions by Method I Iollovred by Mdhod 2 10

rucll a conclusion on ccnformana 10 !he requirr..meQts.

NOI all pIlJenterll prepalltlollS czn be examined for rub­

~isib!e pinkies by one or both of t~e.se m"'-hods. When

Method 1 is nO\ applicable, e.l. in east of prcp.ar-ations hvina rMooed cbril)' or incrascd ~isoo.<ity, the ~e>1 ~OIJld be:

carried out aceordhl& to Method 2. Emulsions, colluids, .,ld

lijlO10nll.I I1lepBrlltions all.. Ul\lnpll,'$. Siruilf..dy, prOOucl.li

Llull IIrtxluce air or ps bubbles ...hen dra...n into Ihe "",nSllT

may lbo require microscopic particle couol tu!i.o~. If the vU~

cosily of (he preparaLiOD 10 be (aiM is ~ulficicully w u

to predude its eumination by eithu lest melbQC!, a quantil"·

live uilution wilh an appropliate d;)<>enl rna, bc malle to

decrease visco~ily. lIS ncee.U;I;ry. to allow the analysis 10 be

perfOlmed.

The results oblained in cumin;n! a dio;aele unil or trOup

of unin for pan!Clllale oomouninatiol\ callnot IJ,: t:Ktlallolated

with Oo::llaiJ1Ly IU IILher units thai rCllla;n unkskd_ Thus,

5tmi~ticaU)' SIIUU\! samp1inl' plJns musl be d""doped if ""lid

inferenccs 'Ie 10 be drawn from ubiil:n'ed dala 10 charaCltri~c

the level of particulale contamination in a lnll:e jl,roup of

units.

6.07

< Co(~cAr..d.. >

Jnsoluhle l)artjculate i\latler

Test for Injections

be .L 20% of the me~\lrine particle nn. AfLer rneaAJrinc- lhe

sensilivity ofresponse for the desit,n.ued paThde SI1.e, the gU

respnme curve is prepared by tht methnr! indie:lled by thc

lnan..fll('lUrer from plITtle\e-lcsponse ffiaosuri"t poim, :led

Ihres.hold.volt'le of S, 10 and 15 joIm of rbe apPilur"s is nl>­

lained.

Electrollie mdtJo.d

In the use of multichannel peat hcipl andyuT, the p;trliell.. fiu re~poon$e i5 measured by half·oount mClhcd of moving

WIndow system S3mt 3.5 tilt mOlnual method, and the parlicle

s.iu reipoD5e .:uI"'e is pr~rC'\l by lhe: lIlCIbod desiVo'l.lM by

tbe: instrument manufaclurer, then, the tbreshold·volLlge of

5, 10 and 23 11m ofthe aPllllalUS is obtained. Ir.lbis e.ue, the

instrument manufacturer 01 the uu:r diould "alidate tbe

obtain.abilil)' uf the samc rerult as tholl of the mal:ual

"""'od.

Altlomllfcorl method

The particle siu rapoMc curve of the IpplUllhli rna)' be:

obtained by u5ine Ihe sofl.l..are developed by Ihe U!lCl" Or ~upplied by lhl: instrument manuhctUrcf. wllU<:lIS, the" IDlInufacIW"er (If the USCI should Vlllidate tht obl3inabilily of the same

result as !hill of the manual method. , SaJllple volume fltCar1iC)'

Sample. ~olume accnracy should fall wilbin 5% of the

menuT;n, value tn case muwrillJt the dtcrea5e of test wlution by Ihe mass melhod aria meuurins the te:l;l ~ntution of

IOmL.

Stll"l'lt nn.....It

TIle now rate of the $atllplc iorlicaled hllo the sensor

~hO<J.lrI be caleulated from ltIe obser~ed lample volume IInrl

tU:ne, ltn<.1 shuuld be confotmed within lhe range of Ibe

:n~nufatturcr's spco;i!ieation'f"r ~ni"r used.

Scn~or

There is a possibility or changes of pUlitle ,ize resolution

and eountin. rate of particle-detecting sensor in each sensor

lry "ucml>1inj;: ac.;uracy ,,"d llllrtil at:(;ufacy even in lhe ~ame

type sensor. Tht,thre$holoi ~ttl\rncy alSll neeoil to bl' ~on·

firmer!. T~s!ing should Accordingly be pelformed for each. of

particle size relohrlion, Ileet,rlley in eOlJnring anoi in Ihre<hnld

selling. using Particle Cnunt Reference Standard Su<pension

(PSL 5pllerel havin, llIean diameter of approltimMely 10 "m,

or II con<:etltfllril)ll.IlT 1000 parritlc';mL =:10%, nOf more

than S% uf CV ~.luel.

Dunne mea1urement, Sllrring should be made for auurinl::

tbe uniformity ill samllle concentration.

Scnsor runllllinn (p/lrtlele aiu ruolulion of appa-ratus)

Measuremtlll1honld be made by dthtr ont of the follow­

;nlt m~1hods..

1. Manual method 10 oblain Ihe spread of hiJtogT3m prepared from Inc coonling ..alIM of the IIppllutUS.

2. Electronic method 10 obt..in the $prr:>ltl of histogram of

the clauification of iystem·rcspondint: sil:nal by \lSinC the

multir:tJannc! peltk Itcicht analyr.tr.

J. A.utomated llIelhod to oblain the spre~d of his!D&fllm of

re.spotuive sir.n.al of lhe te5l-particle by usilll the software

p,eparcd hy tbe manuflclurcr or the Ula".

The rli!fefmce belwcen the lhl"l'shold or pltrlir..le oi7.<: I;r)'Imlini: 16 and 8'1% of lhe lotal toIlrtLI and the Iti!-l;artidc size

sho\lld be wilhin 10%. IIInerea.s, electronic melbod alld aUIOmated methnd $bnul:i he blllh \·aJid.uc::l fOf ob'lain;ng the

MCiliod l. tighl Ob'cnratloll rlrtlcl~ CUlml Tnl

Usc :II. luilabl. Illpaulus blud on the principle or li~hL

blocka!:e which allows im :aulomatie tlclcrminalioll of lhe siu

or pllrliclCllnd the numher nl plrtidC'l .<en.din/: 10 .liT.<:.• 11

is necenary 10 perform calibration, u ",ell IS to drnlon~trate

lhe JlImpk "ol\lrnt Icc'lrlc)'. ,.mpk: l'Iow rale. particle 'i«

tl'Sponse <:ur~. ItnlOr Iewlutioo. JIld caunlint aa:urxy. al

IUlII ;a )'eat••

'Ctlibratioa

l'ani:ks 10 be used lor c:llibnatioo ,,",ould be subject 10

p;ulicle m 5e'IlririYilJ _U~l, mine ~pmical(101J'lrreM pertlclcs h,ull'lc at Icut S, 10 and 25 Jr.rl io. diameta-

(PS!. puudcs) in moau-dUpencd ,.spcns::on. PSL IlartIl:lu d'.ould bneatha' a 6omestico' i..faoati;)n.a.llf2cubiJity in lenni ofJwOh. witlt. a ~I of "nanilinly .. ...,1 crelli_

n' lhall)% The p.lrtid~1 10 b~ fo' aJibr.at>oo 'lhcu'd be

d~scd ia ponirl../rtr _lIr

Mu"al "el\od

'T'h.e p:Il'l.ide IUe rupONc of the 'J'Slem 10 h applied

should be cktCllllined URn, III kafl ) d!a"niI, for threshlJ!d

\"Quae s-etrine. acca,dlnC lit lht hall tounfinc _"Ind of

""indow n'IOYUt,I)"pC The tftleshold·...olta;e .indo.. s!;;>uId

This lUI: b harmonlled .lIh fhe P.utllpCOlll P".l;Utnxopori.

'lid fhe U S. Plarm.ucpeia. The p;ilrt.i 01 the lJ:ICl lhou ZIC

JlC1 harmaniud ..'1: mulcd ...illl srmbols (. .l.

Thot inw'ubk pvlicul.llc malltt k:!t fill illjuriOln Ilr inill'

,ions is the mnhod to tal (Of illSlllubk putic.!a!cs. to cml·

fum thai tlrq' 001 ~EkOJ In dUSS of specifi~ Jevd' in

t},e solutions. For Ihe dwnnln.tlon of panicllblC malam;.

nllion 1 proea:!U(cs. )'1e1hod I (Lithl Ob$Cuntion hrrick

C:iourll Ten) Illd MClbod 2 (MicrO$Cllpi<: Partide Coulll

TC;5I). tlfe ~!Lcd b«dllwla. Wbo:" I:I.uniuilll: injcl;tiunJ

'Nd palalla:al infusiulls fUI ""' ,;sib" particles Mclhod I is

prdcnb!r ap"licd. Huwe'tCt , <it mar be nc=.!}' to fa!

tllIJle preparllions bJ Mclbod I foUo-d by Mdhod 2 10

le:adl a coaduJion on OOIIfonnallC1: til the la:julrc:IPl'llls.

Not an lIlUeritenl pnplliltiOlIJ QJl be u,;uai.ned rDr lilt..

...iJib~ pallides br O~ III botll af lhesc m~ Whr:J,

M~hod I i5 not .pptiC8bIe, e.,_ I.D case of pcepantio<>s ......._

illl red~ darilY or I_sed ~. IhI:: 5hou14

anted 0lIl1 accolCtin. 10 Method 1. F.mulsions, o::OlloIdl, .ood

llpos:)mal f~IU arc Q.Il;npla. Similllir. pruducu

tlIlrl lI'uducc aiT 0: pI bubbles wbm c!I...n iniD Ih IIl:tlmI"

may abo require llUao5eopk palUde C'tIUDI l~. Ifthe riJ~

eo5lt, ul lb: prcpant>ollio be ICliled illlI&i.C11l1l' m.b 10"

to pHd'JOe its a..min.lion by cilba tal cUbod. a qu;mtita.

,"c dl.1ulicD ..ith an approp.iMc diJuarl may be maCc 10

d«reue riscusil,. as IIKGU". 10 ano.. 1hc. analysis In be

perfcmned.

'The rQUlls obt.ined in cllIminina a d;K:lCle unit or (',:rtIup

of unill fOI pSJtkulaLe COIllaulma!ion cannot br: atrapo1.a\ed

....1Ih OI:ltainty I~ Olher Unitl lhll mullin unLnt".,- Thill.

ItallUM:aUy luuntlliUllpllnl: plllni mlJlL be uevdopo:rl if valid

infercutel arc 10 be dnlwn from obSC1vcd dill. La characterise

Ihe level of llarcic1JlalC contamination in :a lujte !troup of

unill.

6.07

< C"frc.)r.... >

Insoluble Particulate Matler

Test for Injections

be J,l()-" of the me:Nll:lI ~rticle sile. AIle mn:;urirtclhe

_lml1 olleliprlm.c for lbe dallr!aled ~nlrkSlU.lheAU

.esrom- allnic li pr'qIII,erl "" 1M malwld Iftdlawt hJ lIIe

""Il"'","urer florn plIf1Ide·U:lJIOIlIe mmnrfElt IlOirll. ar:d

Ihr~·..oltale of S. 10.Dd 15 I'm of !be ~r~ is nh--

l:lined.

1\1Klrolllt .elbocl

In llle we of mtllll:ha.l1nd peat heldtt U1alyur. l.Ilor: IlUti~

dl:.lu respOnse It measured by half-allllll method of mavinr;

wmdnw systclll .Amt as lbe mallu.:alllluhod. 2IId the pntitk

m ,elpolIK C\IJ'VC is P'C'pa'N b, the mdbod dClipl.lllcd by

lhe: inmUll'l(t\1 manulacturer. Ihen, the tlu'eshold."oh..lo,;C or

S. 10 I.nd 1S I'm ofthe aPllllalUI is oblained. In this ~~ lbc

inllrumcnt mauufaetu~r 01 the uu:r mould ,·.lidate the

obtlirUlbllily ur tlte SiUIle rdUlI as thai of the milr.ual

"""'''''

".IO.,kit method

Tht partidt silL rapcmsc: CUO"t of the apparIllll may be

obtained b, IIliot IbelOltWll't deYelo~ by the 111ft" or 11Ippial by lhe: Ulsllllmmi marl\llllCtuftf. -btl.... IhemanllfKlurn cr Ihe Woe! shook! "",lidlIlt ttlt obtai_b1'lily of lbe sam.c

rauh ., thai 01 tt.t lirlnu:&l CleUocI.

, .sa_pte ,ot._

Sampk.lfOlume aetDrary should r.loU within S,," of u--t

mcISl1rint ....I~ in caJoo:: musurinl; the dCO'UIC of tal 10111-

!ion b)' lhe mass mt:ehod ana- meullrlna tbc: lea R1tonoo of

101llL.

S..pl~ I "f~

The: /10 rile 01 lbe PUlIl~ iIldicaltd 11110 tbe Ia>lCr

~Id be c:l1cu\.lIIed from lhe obserYed IlImple: ..olume IiIlId

tUne. Ill1tl s.huuld he tonfullned wilrnl\ the Ilnte of !be

manllr"<~U.n·ISptQfi,,;"'lion·'OI senior UKtl.

St1l10f

There il a pouibilil)' of changes or plnide siu ruolution

and eO\lntinl rile of \Hlrlie!e·tlclcclinIIeRSOr in eacll sensor

liy "llocllllJlinl: I\C\:UHICy ~lld parll lICCLllllty even ill lhe same

type sensor. The.lltresholl! ~¢¢"rn¢y ...Iso ne..l!i It> b" ~"n"

filmed. T~ninl shnuld Accordingly be p~tfOlmed for each of

parlide lize reSOlulion, ~tCtlrney in [oulllini an" ;n Iltre<hold

lellin;. usinll'artlele Count Refuenee Siandard Surpem.ion

(PSL Ililicrel havin, lUt8Q dilllllClcl of apprOJlimalel)' 10 i'm.

of a canec.nH.riOll 111 1000 partideslml. r 10%, nOl mort

lhan S% uf CV ....Iud.

Durinl mCI.I\II"ClnClll. uurinSlhOllld be made fOI"lurin~

the vniro'mit)' in IlImplc: eaocenllalion.

Stnsor flU.liIli.lJl (parr;cl. lilt rUIOlotl.1I of .ppantllS)

McasuraoCill dlou.kl be IIlIde by alher oue or lht f0l.1o",,-

inr; rncthods.

1. MmuaJ method to obtain the 19fe.ad of hittop3lD P=-

~ed f10lJ1 the WIlQtillc ..alDC of tM: ap~raltU1. !:lco::tn,XIfC method 10 obt..Iill Ute tplud of blllo&1am of

rho: daatication of i)'llcm-rGpOodiJI, Aco;u by u:slnt tbe

II1Ultlcltar.-.d peall hci&hl analy=-.

l. AUlomated method 10 attain 1M Ip,ead ofhh1otram or

lapomiO'C Iisul 01 tlte uu-pnticlc by 1W1I.I th.:: mrt'il'l.[e

P'feparal b)' the manllf8C:NI'a' 01 [he IUa'

T1lc dlll'c.rmoe haWCll:fllhe IhlUboId or plUfidr.1iu. COUOt10.1 16 and .." or lbe: torn courtlr lind I~C tat-particle IQc

sholi\d within 10')(,. whereas. tlctlronir: 'Il:ethod. n.d ;lutO"-

malea mtlhnd JhD\lld I':e bOlh n1id.lled fOf obIalninl the

Contains Nonbinding Recommendations 

ATTACHMMENT 
 


4
 
 
-

saine fesu!1 35 tint of Ihe I:i3Il\lal method.

Particle cu.utliu: :l«_rKl

Dala ubtained by l:Ollutir.II/a,tieks of SJII'IlInd :J~aleT

$hollid be 763 to lISS pllllide$ ptf 1 ml..

Tllrt$ko!d UCll'••r

"lIrticle ,in: tlilNlatcd flonl a Ihn:5bo);i a,llfesvondint ro

sO')(, coI'nl$ for panide-\ or SI'TIl and grul.. sho"k! fall ..,1·

thin ±S% of the :»ean "'iarnete, of thc t~ parlil:les_

Reagent.

Parlicl~fri'ewall!: The purified water conUlining not morc

than S particles of JO I,m or ~teatcr lite, and not mOTl: Ihan 2

particles of 2S 11m or lr<:altr sitt in 10 mL of tbe :'15<.>luble

IlMtide nnmber mUil1rcd by Ihe Ilaht olW:IJTation parlide

counter.•

Gcneral ~rtc"utio"s

The test i. carried out under ~umlitlull' li<nitiu.lt pHf1i..~,lutc

conlamination, preferably in a l"minar-f1ow cabinet.

Vuy <::orcfll1ly .·a,b Ibc ~lau",are lInd Iiltrlll;oll cquip,uclll

U5Cd, ""cqlr for the rnc:mbrane fittus, wilh a .... arm ddcll\eut

solutiuo and rin>.e wilh abunl1anr amounls nf ...~Ier 10 rl:­

lTIOVC all traca of delersenl. Immcd~tdybefore usc, rinse

the "ctuil'lIlcnL frOU'l top to bottom. outside and rhm insido,

with partic~Ircc wale.

Take C:Il.re DOl 10 introlluce';r bubble$ ;'11'0 I"" l'rc:p:l.l'aticlIl

10 be Clllmincd. opccialll' wben ffaetiull5 ofth" prcp:Ilfat;on

arc. belli' traD.lfen'C.d to tile COlltalnc:. in ...hicll. thc delamina·

lion ;s 10 be canial. out.

I'll order tD chec.t t!'lat t!'lt ~viroIHnt:ll.t is .uitablc fur the

I~. Iha'lhe glaJIO'.rt is properly deaned. ar.d tlu.t the water

10 be uKd is ~rtick-lrec. tht rollowinC tat is canted OUI: dl:­

term;ne: thc palticubte eOllwoination of :; S:ll.mp~ of paT

ride-Inc ",{ale, tath of SmL, :.tCl.,mljIl~ to Ihe ml;lhtld described heloll'. If Ih~ !lumber or parlicler: ur lOot'm <II .,ccate,

sjze eJlceeds lS for the oombincd II mL, lht preaulious

taken for Ihe test are not sufficient. The preparatory .tep,

muu 'oc rtpede<! until the envirornne"" &!a$.$wUt and lI'atel

are .nitabl. for the le51.

Method

Mix th~ contents of theumflle by ,Jowly inverting the eonl~iJt~r:llJ t,mes ,uccdsively. If nt\:cn~ry, "aulio,,~ly rcmovc

the ~eal;ng closure. Clean lhr. OilIer 'Uffl1Ce~ ur the ronta:lIer

opcnins llsinll :II. jet of fJan;(;/e-fru water /lnd remove thc

clusu're, ayoiuinl allY contllllliIlaUOtl of Ihc COntCllts.

E~minalc ,as bubbles by appropriate mealu,u ~udt as allowinc 10 5tand ror 2 m:n or KlnicalinC.

For b.rge_voh'ec parenterals or for small-volume parenteralsh.avi::J~a...u1umc of2' rot 01 more, single unit. arc test·

ed. FOf smaU-vohlmc parenterlll1leu thar: 25 mL in volumo!:;,

the contents of ID 01 more nnlll ire l"Ombilled ill a deaoed

oont/l;ner 10 oblll!n a volume of nOl Ic$. lhao :l. ml_; whert

jUltified and authorU.cd. the tclt soh/lion ID-/IY be IJfeptred by

mixin~ Iheeonlents of a suitable nnn:ber of villil and dilut;nl!

to 25 mL 'lritb particft·/rtt WIIIt!" IT! with an 3(1plopriate solvent without COllIami:nation of paniclo when JNlrlicle-frtt

W(lfeT i5 not ""iullie.

POWdCfl for pllcole..t use IIle teoonWlutcd ....ithJHIrride­

/rt!C wtJlU 01' with an apP'opri.'I~IoOh'en~wilhout contamination <.If panicles WhCll pIlrride-/r« l~,,:e( b 1101 suitabloe.

The rl1lmber of tesl speeimens must he adequate 10 provide

a )lll.tiitically sound a~SCnl!lClll. I'or hlfte-~olllmeparentClal~

; f------l-o-----~: -.J!,.'k't'tIlo;l;'tm:Jl;

\~l~....

Fie. 6.1t7-' Circular diamch,r rraticu)e

I), for STull-volume pa,.nlera!s hoI"in, a volume of 25 rIlL 0:

1J.olt, It'IItr rhan 10 units m~y be tatal, based on an appropriate ~rnplint plan.

Rcmowcl4 porlioll$. each of !lO' len thin S mi., lttId CIluot

the nllmbc1' ofpa.rtieirs cqualto Or Itleater Ilt.an 10 j.lm and 2.S

j.lm. Disn;iard tllc raul! obtained. for thc lirst portion. and

tal.."tlblt lhe mean [lumber of partkles fur the pecpacalion 10

be ea:atn:ntd.

Enluatlol

If lbe avcraae number of particles aceeds lhe lirnilli. tal

lhe preparation by Melhod 2 (Microscopic Panicle Couot

Teu).

Test 1.A-Sollllir11ls for pJTl!nlf:7ol itr/iJ,S/on orSC/uti01U/or

IJVtctfon :rupplicd in cot:laintQ "'iIIl 0 f1flfniflaf OOllknr of

·cQual 10 or. mo'e Ihall 100 mL

The prepl-ralion complies \\ith thc lest ,f Ihe liverale number

or putitles IITCscnl in Ihe units lesled ~oes nOI e~teed 25 per

millilltel equ~1 to or greater than 10 jJm and dues not ellc«d J

per milliliter equal 10 or Ircaltr than 2S IIrn.

Te.il I.B_Sollltions for paren/ernl ill/usion or solutions for

illitel/on SllppUr:d in conrainers \f"r}, a nomiflal cont"nl uf

Iw lhan JOO mL.

'Ole IIrep:tr~tiou complj..,~ with tM.: le51 if the avcral(e number

of partiela prCSCllt itt the unit~ tested doxs oot exteed 6000

per eonlaine' <'<tualto or greater than 10 lI,n and does nOI cxotcd 600 IJ(:r container <:qual 10 or greater Ihan 2SjOm.

Method 2. MICTo~opic PlIrtkk ('..nul Tnt

Use a suitable binocubr micros<:~, filltr auembly fM

retainina p""iculale contamination and membrane liller for

o::arninl!tion.

TI-.e microscope i. equipped ..-itb all OQIlar miclolneter

calibrated wil.h an objedi~t micrometer. II rc«hanieal Ita&<:

capable of holtlillt lind Ifawr:r,;na the enl,re filtration areOll of

the n:embrane ilter, t...o 'wtabie iJlum;n1tDU 10 provide

episropic illumination ill lIddition to obliqltt illuminatioll,

and ia lldjwted to 100± 10 maa;nilll;:llions. The ocular

microm~r::r i, a circular di:ltnere' &ulieuk (l« FiC. 6.01 I)

and conWlJ or a lar&e circlo: di~ided by cronlla;n inlO quadrants, tTampa,enl and b1a"k fcfC1l'1tl'f: cireles 10 j.lm and 25

",m in diameter at tOO rna~ifi~ntiotl\. and .lincill :lCi!lc~adualcd ia HI."rn ;ncrement•. It 'I c.alibtaled tlsina a staze

microm:!er lhal il cerlified by eilher a domeltic of inte.nasame result Lhal of the m u

P rlide collliling ucu :I

Datil obtained by cou Ill.iIlI P .liclC$ of 5)11!l and :;reater

should be 763 to 11>5 pan per I mL

TbrtShold ceuraq

Partiel!: sUr cakulatctl from llucshold couespon in£ to

50% co\U\ts for pmiclc< of 5 pm ll/ld greatu should fall within ± 5% of Lhe mean tli3mtter 0 f the 1 t particle .

Rea tuts

Particle-free waler: The puriJied water containing not more

Lhan 5 particles of 1U11m or grealer size, and not more U,an 2

panicles of 25 pm Dr greater sitc in 10 mL of Lhe insoluble

panicle number mCllsured by the !lSh! obscuration parlide

counter.•

General preelluliollS

The test is carried oUt untler I;utldiliulls lirnilillg particulllle

contamination, preferably in a laminar-flow cabine .

Very carefully wash lhe gl w re alld ftltnllion t:quiplUelll

uo;ed, execp' for Ihe membnlOe filters, wilh a warm dd.tI tilt

solution and riIUe wilh ftbundnnl amounts of valer to remove all rraces 01 deler ent. Immcdialcly before $C, rin~

the equipment from lOP to bo om. outride and then insirk,

with panic~free If'aIU.

Take care oOtlO introtfoce air bubb~ inlo the pnparntioo

10 be examined, esp«i3IIy ra inns of Lhc preparation

an: being ransfcrred to the: container in wbich Lhc drtc:rminJI.-

lion is 10 iIO' clIJTicd ouL

In orda In c.hed" that I e covir ment is suitable fex the

I ,Ihat the gla are is properly cleaned and thaI the ",aID

to be used is piuliclc-frcx. the folio "n: tc:sl is carried ou . delennine the particulate conwninatlOll or 5 sa.mp~ nf p=

tide-free water, Qcl1 of 5 mL. a~vnJinll 10 he method described below. If the number of particles of 10 JIm or gJcalcr

size exceeds 25 lor Ihe combined 25 mL, tile precaurions

1aken for the test an nOI sufficienl. The JlTCparalOry steps

must be repeated un1iIth .:nvirollmcnt, glassware and water

are suilable for the tcst.

Method

Mix the contents of l.hesam('lle hy slowly inverting thc conlaiJler:W limes successively. Jf ne\~eSSary, cautiously remove

Ihe sealing closure, Clean the outer surfaces of the container

opening u.,ing II jet of "article-free 'Warer and remove the

dosu-re, avoiding ny tOlllwninauon of the cootents.

Elimimue gas bubbles hy appropriate mearures such as allowing to stand for 2 roin or sonicating.

For large-volu e parcollT.\ls ar for small-v lume pa.renteral.s having a vulume 00 m'" or more:, 'ngle units are tesled. For small-v lume palen eraIs I than 2S mL in ~olume.

the conknts of 10 or mort: units lIrt: l'OmbiJled in a cleaned

COIlt~ to oblJLn a oJume of not less rhan 25 mL; here

justified and authorised. the lest solution ~y be lI~cpared by

mixiot lhe<Xlnleots of a suitable nnmber of -ials and di1utin

to 25 mL with pQrtidelra lI'OIU r ith an IIPropri31e

veilI ...ilhoDI <Xlntaminalion of particles when jNlT1' e-fra:

"'flur is nn! mi "Le_

Powder for p renlCflll u are t njtituted with parlidefro lWlter or with an :lppropri.~lesoh ent wilhout conlaminatiun of particles when parlide·ffCJ: water is nol suitable.

The number of I .r p<:l:im~ muS! he adequate to provide

a statistically ~Dund asses mCnl. for I Il:e·~olume parenterals

htll

Fig. 6.07-1 Circular dj meter gTaticuJe

or for sruan-v lume pare.oterols hving a volume uf 2S mL or

more. fewer lboln 10 units may be: tested. baSl:d on an :lPproprillie ~p1ine plan.

Remove" portions. each of Jl lhan mL, d count

the number of particles equal 10 Or ~re tet than 10 Jim and 25

pm. ~itard the result obtained for the firsl p rtiAm. and

aleul3tt Ihe mean munber of particles for lbe pteparanon to

be examined.

1 liOD

If lbe 8\'erqe number of pa..rticles ceeds tile limits.

the prep ration by "'klhorl 2 ~Icroscopk Particle Cou t

Test).

Test J.A-Sofuno7l:S for pannceraf iIlfu on or solutionsfor

InJea/oll supplied in c:omainl!Z3 "'ith a nominat conlent of

°c uoJ 10 or 0 more Iban 100 ml.

llle prep..rarion complies with he lest if the average number

oi parlicles present illlhc unilS lested does ot exceed 25 )lcr

lnilliliter equal to or grealer than 10 JJm and does not exceed 3

pcr milliliter cQual to or grcat.er than 25 pm.

Te. t 1.8-8011lIion:s for parcntcrol infusion or so/ulions jor

inJuCion supph'cd in (,o/lroiners wlrh I1nminal conlenl of

less lhall JDD /1)L.

'OIC prep!\r~lion complies with the lest i the av.:ralle number

of partid present in lhe units lc leu \loes 11 t ~"(eeed 6000

per container equal to or greater lhall 10 pm and does not exoeed 600 per container equal to or greGter than 2S JlIll.

elbod 2. Mie~oscopic Partl Ie C lunl Te I

Use a suitable bwocul:ar micruscupe. filler assembly for

reu.inins pamculate contamination lUld memhrane filter far

tllamin Ii n.

The miCIO$COpe is equipped 'th an oc:ul r microlJ)ClCl

c:alibr.ued ith an objecth-e micrometer. 3 m hanicaJ age

pable of bo iog and tra\-cmng the entire Iillr.oti n area of

lhe membr:ane 1iJ1eI, IYrO suilable ilJUlUin wr. to provide

~piscopic U1wniuation i:l addition 10 0 lique illumination,

cd is 3djusted to IOO± JO m:a.pilli lions. Th ocnl:ar

micTom!:ler is a cirrol r diamaer 8l'alicule see Fig. 6.07 I)

and consists of a Jarx<' circle w\ided by erosshairs mto quadr nu. transparent and blacl rcfacnn: i les 10 m and 25

Jim in diamerer 31 100 ma£l'ifi;:n io <. IInti II line SCllle 1:1a -

uated i.n 10 JLl'I increments. It is cslibraled using a stnge

microm- er Ihat is cerlified by eil leT iI domesli or imemaContains Nonbinding Recommendations 

5
 
 
liollal st.ndard 'nSliluliun. A rd:l1i.-e tirOI or the lir.car l.Cak

of lhe tUliculo: ""ithin t. 2 flC1' oerlt il Ia:~ptlhle. 1bc );ute

cin:1c is dd'J:lWCd Ihe 1'1lir:ulc Ildd of ri,:... {GFOV}.

Two il1Ulll'n.IlOrs are r1:quirtd. One il In tpiscopie hrit/ltftdd iHummatur inlernal to tl:e mkloWl!X. the olher Is an

e:llelnll. foeusuble IllIiIi::uy iIluminatur adjustable lu lin

rd\ecled oblique illuminll;On II III lll~e of 10· to 20-.

The filler aucmbly for rttlilliol plrtK:ulate oonlaminal>on

eolUisu of a r.lrer ~er made of Clau or olher suilable

mllluial. and is equippad with a ~-ao;uum "",rCC al,d" suilable: membune fillet.

The membrane fiher is or luitable si7.c. black or <lark lItay

in color, nnn-triddcd or gridde<l. and 1.0 ....m or nner ill

nominll pore size.

Gene...1 preeauliun1

The lelt is eanitl;! QUI "nder conditions ~milinll parli<:uloIC.

CQlIlIunillation, preferably ill a laminar·I!Ow cabinet.

Very carefully wllsh the C1a$l'>/are anI;! filler alsembly u~ed,

ueepl for the membrane r,lter, wIth iI warm detergclll 501u·

tion and rinse "ith abum.lant a.nounts or water to remove.n

l.au:s of detc'e""\. lmlllediatt1y before use. ,in.., both sidcs

of the membrane !iller Rnd tlK: ~l)uipmeOI from lOp to bot10m. ouuide 1Il1d then inside. with 1H1r1ir./I,..frw; lWIt"r.

In order lO chc<:k that lhe en",rl/llmenl i$ ,uiable for lhe

test, that the &!Ilnware and llIe memb~ne fdlel' are Pfopc:rly

el~ned and Ihatlbe ...atr:r LO be uKd il p:trl.idc-fr«, lhe fot10winC ICSI is c;;r,nied aut: detetmine the panicub.te contamination 01. }O m.L vq''''''~ of pl1rlicWi-fr. _ta aa:ordinl:!O

the tnCIhod d=ibtd below. If more lhan 20 partidr::$ 10 JOtTl

or lar~r in size cr if more IMn) ~rtide$ H /<m Of br~ in

lill: are pu:sml within lhe 1I111I:ion are.a, !he pr«:illlllWm

tall:en for lbe lest are aot wltieienl. The ....q:>I.Il10'y "CJl5

must te repealed until the eJ.monrnenl, Vauware. membrane filter ..nd ...atet" Ire wit,Me roo llac IQI.

MEllaod

Mix the conl~nU of Ihe liamples by $lo....ly inveninr: lhe

eonlaineT 20 timrs liUCttStively. If nCQ:liiary, cautious!}' reo

lIIo~e lb~ sw!'& elusUle. Clean the OUtel liurfaeQ ollheeon·

t:liner opening using a jd of p(/rric~ Ir~ wal" and remo"e

lhe dOlUIt, avoiding any contaminalion of the eonlents.

For larr:e-volume palenlc:rals, ,irl$le units arc tested. For

liman-~olumeparentelals len lhan 25 mL in volume, thee(ln·

tenlS of 10 or mort unill is eombined in a cleaned container;

where jU$ti/ied ancl alllhnri5td, rhe ICII lolutiun may be vrepared by mixing the wnlents uf a 'uit..blc llumber 01 yiall

and dilulini to 2j mL ...ilh partlclr-frer k--fTIer or with an appropriate solvent without contamin..tion or particles whe"

panicltofrN vralu is nOI lllit~blf:. Small·volume parenterals

b~vin: a volume of 25 mL or mort may be ltlttrl individu1tl·

I,.

T'o",dc-rs ror patentall Uk ale eonstituled ",ilh. pIlrtiC'lefra:: ,n,lD" or ....ith;:n :OPPll:plialc- loOlvc-lII withoul eonta:nina·

lion of pa.ticb ...hen parrid,.frN I&'alrr is; nel suilable.

The Dumber oi eest sjlCCimer.l mull be adequale to pro~;cl~

a stalis;tia.ll~ Iculld aueumeDt. ~-o( brce·volume )l.unacrals

or for 5mall'YlJlume palallc1a1i h;tvint a ,·olume or25 f:lL 01

more. fewer lhan 10 units m:.r tit IClled, h!Cd OD ~n ;ap.

propriale gmpllnl pbn.

W~ Ihc- ir.Dde of thef.ller holder /iliad with the membullc

ftlter with SC'''Cn1 millillel of pgnieJt..frte ,",ler. TralUftl to

lhe fillration funndllte lotll "olume of 1II $11lulion jJIJl)\ 01 of

I 5inl,Ir. un,e, and apply Vl\COUOnl. H needed :odd S1ep'4'Uc: a

portion of the sntulion unLillbe entile volume is lil.ercd. Af

let lhe lallllddilion of solution. b<:lin riustullhe inner .....Ih

or .". 611er h..,1<"r by usi"<l a jet uf portid*-fr. _~. Main_

laiu tht 'KlIum ullt;1 l~'" $IIrfa;;c of thl: mclnb""ne fill« is

Ita:: from liQuid Pbec rhe litter in a pclri di5h and aUuw Ihl:

filter 10 lu-ciry 'I'ilh tbe cover s.Jizhtly aj.r. Aherlhe !ilkr tas

betll dlied, plxe Ihe pelfi dUh on lhe fl~,e or It'.c Dlit:ro­

~. seto Ihe entire memblane limr un:ler tile lellecled.

li&hl f,om the iIIum;n.;l.linl device, and counl lhe: nombcr of

particles lhal are equal 10 or yntr:r than 10I/m and :heOUlllber of particles tltlllTe eq"al to 01 createt Ihan 2S ....m. Alternalively, parlial filter counl and determlOalion of rhe LOlal

ftlter count by eak:ul~lion il allowed. Calculale Ihe mean

number of particle, for Ihe pt"e~ut;on to be eumined.

The PMlide silins procus with the \Ire of the ci,eular di­

:omeler e.ralicule is ea"ied OUI by IrandorminJ mentally the

ima,e of each puticle inlO a eirclc ..nd then cnmparinK il 10

the lO,t'm and 2:S Illn g,alioule refeltnCl! eircles. Thereby Ihc

parlielC-ll ..re not moved from lheir iniliallocntion$ Wilhin lhe

lllalicule fteltl oi view and are not suptrimposocl on the reference cilcles for eomparison. The inner diameler of the transparent J:.tiliculc rtl'erenee eildes is used to 5i.... whitt .lncl

tramparenl plrlic:lel, while d;u-k particles Ire si7.ed by IIsing

the outer diamtltt of {he black ol)3l)l'e ttl/kule rderence

ci.clel.

In pafu.min,lht microscopic p.arlide eollnt lest (Mctho<!

2) do lllll auempt t.., Jizc o. enumerate ..morphous, KDlI·lil)­

uid, Dr Ulher...i;e morpholockaPJ indwinet mllterials lhat

have lIac appeuana of a >lain or diseoloralion OD the maDbraoe fillet. malerials. w:)w little or nO s\ll"fa<:e lelil::f

.llld p,oeol a cdatinoos or film-like llpptlt..nec. 10 sueh

ca5t:& Ihe inlerprd.alion of alumeration mI.)' be: aided by IC-Stin,l gmple of the wluli:)n by Metbod I.

En.tu.tioll

Tnt 2.A-Soru!i/lM for ptlreJlI"",l/rtfwsio1l or IOlliriOllSfor

il\l«lioll $Uppr~d itt con!lIinrrt witlt II "omiNlI COlliei'll of

"CQual to Of _ Illon than tOO mL

The preparation complies with tbe lest if tlte.~craee number

of ~rtidCl preic:ot ill the units tr:liled does nOI e..""cd 12 per

milliliterequil to nr crc"ler than 10 ~r.l and does nOl C-Il.a:ed 2

per millili1l:r equal to or pcatet than 2.} ,llUl..

Ten 2.n-Solu"Ort.f for partnrurzt lrr/udon or .roIulions fOJ

Injecr/oll supplied in cOlflai/ll!TS with a nominul conrcn! of

I/'.t~ Iltan 100 mL

The pteparation cnmplies with Ihe lesl if Ihe average !lumber

of patliele$ prescnt in Ihe units tClted does nor e~cer:d 3000

ptr eonlainer equ;t] to Or ll,ealC1' llun 10 11m and doe5 nol ex·

ceed 300 per cont..iner cqu:,llo 0' IIrearer lh.." 25 ,..lIt.

lioall wlllbrlt mSl;WIMl. A r$livoe tlnl. of Iht Er..ar sak

Ilf lhe cnriolle ....tun :1:2 ptr IXZIIII IilXQUlbk. Tbc: "'ICt

WdI: i> daipwlcd W: ....ueuk tick! of ....... (G}'O\l

Two i~l3nItt f'CqlIlItd. Ont It Il.ll cpUoopit bri&lli.

Add lIIiuIar iflttfIUJ 10 I!:r; ~. lbt otbI:r is all

Qltl foxusublt .III:liliary if.-m:8D1 u!iusUbit 10

rdkdtd cbliqae iIbmi.ID.1 •• aqJc of 10· to 2l)".

'J"!w ill...........bly f;r:' n:UlII1U1a par1loC".lLau iXlOID1Uu.t>on

COflSilu of a 1Ib...- hoI«r !Ill&: of SJan 01 otbu ili.!ablc

mllwl. ~nd i$ tqu~ -iltl a ."lCU1IIll_r=bd:l. nlli.

hie rncmbrane filltl.

The me::nbl"ilM Ahu iJ of PIn_blot lin. "lad: or dui; sur

in mint. nnn-s,rid<kd or &ridded. and I-OJIPI ()I" inti 1JI

nominal pon: !.itt,

G~ntl'21 "cnlutiul.

The lt~t is canied OUI llnckr eanditionllim;lin,l p~rtic"lllte,

CIllll~minalion, prefer.bly'" !amlna(·now eabinel.

Very ~llrcfully ....1I~h Ibe clMll'lnrf. anti filter ;u~emhly u~td,

excepl f(,)r lhe membrane filler....1111 n ...arm detergcrll 501u·

tioll Ind ,in..: "ith abulluant ~lnOunLJ of .....ltT 10 remOve an

IlaCuo' (!(;\C,!:tfIL. Immedialely before Uie. I;n.., both sides

01 tbe membrane Iiller anti the cq"ip11l(nl from lop La bel'

tom. oulside and lben i:ll,dt. "irh fIilNir.t.-/~ _tu.

III orda [0 Wed IbM the <:n\"l'UUmcllt is ,u,uble for lhe

tea.. Ilw. Ihe sbu"att and t1Ic nIiCIIIbnnc fllta arc properl,

dcanaS.ad. that the...:cr "' be \lied is p¥tidc-frtt. tho:. fofblrina. us: is anicd CIIoll: ckurmil1e lhe ~r~axu..csi-

...rioo Of' }(I1I\l. O'OIuoc of,..lir"",/,.....r.:r la:DUR& to

!be: mdhod dcsaibcd. bdow. Ifmcn lila 20 ~'1ieks IOptn

01 msizs:cr:f IIIO!'C tba) partjdcs lSsaao: brJr:r m

5_ ,n, pro:seal. ..1l1U.rI tM 6hn:iaa area. the

IUeD for the 15 u-e aot sd:atal Tbc prcplJatOJy .5leP5 _ b:. .otiJ the a1ri1..-ou. &!oaSlWL"C. IDC_

mile t11e1' we __!sk rM llot: lac.

MfIt.lllMI

Mb: lhe CfJlI!:rfIU of lht uz:;pIcs II, 110""" invcniD& lbe

eclnairr.er 26 times ,"occcssively. If rtCCICi5IlT. cautious" relIlO\Ie the .d.IiIlS eloswe. OcJIllhc IlUtez 5\lrface:5 of the COil·

l.tiner opcnint uriJlt' of"".rkkJ'fIr "",1... and rcmO¥e

lbe dOlun. ayoid;IIS JIll' CIllllamlNlrion or the CQII\tnts.

Fllr I"SCo,'olume pllcnlcnh. iiTl$.lt unils ale tested Fill

5m~1I.volumepllcnletab Icn lhan ml. in ,"olume, tbecIIIIlelll' of 10 or more unllli. combined In a cleaned COIll3incr:

"'here jll~rificd anti ~1I1hor4ed, the lelliolulion may be VIepaled by mixi"ll the wnrfnLI ur a ~uilablc Illlmbe. 01 vi~11

and dilulinll. 10 lS mI. Wilh PIII'IIc!t-jrc. 1o111e, Dr wilh an .p.

propriate $olvent wilhout conl.mlnation of parlides when

fNlrtkft-/rH _er is nOl ,ulnblt. Sm.U volume plIrcnler.rl,

b.vin: a ¥oJUIllC" or 1J m.L Ot male m:ay be lPltd ind'9idual.

~.

rOW'dl:Jl 'or pa.nla.1 IlJC ..e (OnllflU(cd willi ptltfickfr• •..,Uror ...ilh III '1IPf"'pt"iUe:IOhc:ru withol;!. eootaroi....•

tm of partida "hell ,.rtfrl".fr« _1ft" is llCt suiWllot.

Th.. Dumber oj tc1t 1pccQmc:1:S ..... be adtqC2."~ to prll\oidc

asotisIiaIJJ 1C\Iod ·..,'....1. f'or IaIse--"Ohr1tliC JliUft'~

IX fOf IlUaH-wt11tllC ~CUklah ba.;Ula' .-vl:smc of 15 Cll. 01

_e. fC'l'!:% lban 10 .., oa, tit rcs:tl1. IRsaI 11II I.ll ;lp.

propriatt S1l1lplns plu.

Wet t:>e iJ::!;iU Df lhttl.cr bo:da filled wirb rk membra"

IlIta wittlll:\"Cnl PliJlihn of pantdft,.JrIIt ,,0". Tr.nmCf 10

the fil1ralion focnd 11M: u",I ..oNmc' Ilf _ SlIbtioR;ruol or of

a pnp ."'t. and apply ...."1111 II oca!cd -..:id •

Domon or ItIc $dulion tlllill l!re cnIue volufol.c IIl1hered. Af

Itr lbe 1.11. IiCdiliOll of so!uuotl. bqin r,~ the mnu .ah

oft.....'t. holdor by usi....JClofportld./.....,.· MaioIJil5 tbt ~m u_ti1 rt.e sulf~ of the .aEbllllc: fiIlu is

flce'rOllllir:lokl Pbec tbe Iiher ifI, petri dish aMi ..nu_1bc

ilia 10 ...-dry _ith IbcCQ'¥lC1' disfllly 'IN Mtez Ibt ilia baI

bte-. dlkd.. pIxt the prtri di5.b • lite II'P: of rte

'IaIIpl'. kaJ$ lhe mm _hi'.,., fth.."f UDZ Ute leleered

lijbt hom lloc: ilIuPlin.at:nr; dtYic:e, and ClIlUIil llIc Dumber of

ptmf!e:s thai areeqlAl tD Of pa:cr tbll.llIO,lllll.1ld th.cIlVC·

her of partldeu....... arecqeallOOl' srUlcrrt-.u 25"",. AhaoatiYd,. parrillI fj..,.er COWlI and ddcnn:uoon of!l'lc lOW

filler UMlIIl by glkllbtion il .!lowed. Calcall.lc [lie mean

number of pllticlci for the prtpalllKm I(> be ex.mined.

TIle ~nicle $irinS prDCtU ,,'ith Lhe "It: of ltoo:: circular di.

.meler V;llicultl iii !;lI!I;c(\ Out by trandoltJlinr; mel'll~lly Ihe

im."e uf each pUl!d~ inlO a cirde .nd thl:l'l CIlm~rin~ il 10

the 10 pm and 15 pm 8,alicule rererenot circlel, Thereby the

pArtielfi are nnl moved froln ,hell illili~llo~ations wilhin lhe

_,ukule tleJ<; of view and arc nllt JupelirnpulCd on Ihe rder.

enet ~rd<:l fOI ~omparison, 'flte InnCf dialneler of the In-nJp..enL .,tllicule reference cud" ;s uled 10 I;" "hitc u,d

lIanlp.,el'll ""ricks, ...hilt dark pafliclclare siud by u~lnll

lhe outer dial1l<.ltr of /.ht black OS-lJue t:I'.Iic\lle rdcrrnce

cilck.,.

I~ podocmil't: I"" JIIicrosc:oplc parlklt CC1VI'II lell (M<:thod

2)lSo ~ot ,uanpl to No: or CIIltRicrau _....pboua, 1Cmi-1i'I-

.Id. Ill" oI.hcrwiiC mIlrphcloPcal)' iJrdisiincl _,criab thaI

Jr.-c !he ~ppe..-aa: of Ilain Ill" di_lol'l.ltoD n the_~

bra_ Uter. l'bcsr:: m-tcriab d:ww IitlJc Cf IMI 11.II'faee. rdici

and prClGlt a ccbtillDtlS or Dtn-tikc: appurazrcc-. hI su:tr

QId rbr:: .t~ of anrmcatiaa ...., be ailkd by 1C5li:I, a _pk of the liOktti:Ja bot Melllod I

£glutloa

Tnt1.A-$obr:....../w pcrvrttral frtftlsiort 0' fOiv.bu!(}f

iltJ«riQn ~p["'Jf:d ill crm:ftn(n ,,;111 • /IOIfI1uI ~-r 0/

.cqua)IOOf. oorethan l00mL

The: preparation OIllJ]pIics ll"ilh lhe lell d Ihe .....,..lIumbl::-

of pIIrtldcl pn1m1 i~ lbc mUu lQled docs no1. CIlc.ccd 12 pel

millililer cquallDor ve"la Ihlln 10.6o!J:I an~ dor:Ii not uoccd 2-

per milliliter eq:tallo or Vellcr than 1) ,,'1'1,

Ttsf 1.S-SolurfolU for ptlrtnlerrz( flifurfoll or :o!llf;OIlS/01

i1t}«l101l rllpplicd ill cOllll1ill/.'f"r wirh II III/millol rollient of

I",u Iholl 100 mL

The prtp~r'llna complies with tILe lesl if lhe lIver~ie nllmber

01 parrlde, presenl in Ihe unitJ taltd ,JI)CS nOl CICcul. 3000

per conl.iner eqllaJ 10 0' I,talcr lhan 101'1"1'1 ;:md dOtS not u·

c«d 300 per contmincr ~I::'l 10 0' l:fnler lhln 15 JIm,

Contains Nonbinding Recommendations 

6