Whi

tePaper
Coni
calMil
l
ing:Howtoeff
ect
i
vel
yscal
e-up
f
rom l
abtopil
ott
oproduct
i
on
Scale-upmi
ll
ingi
sani mportantconsi
derat
ionwhenlooki
ng
tointr
oduceanew pharmaceuti
calproduct
,ormake
changestoanexi
stingfor
mul a.

Thet est
ingshouldaimf orapar
ticularpar
ticl
esize
dist
ributi
onbyi denti
fyi
ngthecorrecttool
ingsetup,aswel
l
asflaggingpotenti
alissuest
hatoccurwhenmi l
ledunder
cert
ai ncondi
ti
ons.

Star
tingwi
thasmallscalemachineenabl esthelaborator
y
test
ingoft
hesevar
iables,wit
houtsacrif
icinglar
geamount s
ofexpensi
vemater
ialduringthet
rial
-and-err
orpr ocess.

Onceasuitablesetuphasbeensel ected,thiscanbetest
ed
onaslight
lylargermachineunderpi l
otplantcondit
ions;
thi
shelpstoidentif
ypotenti
alscale-
updevi ati
ons.Theaim
istofi
nali
sescr een/impell
ercombi nati
on,machinespeed
andevenroom condi t
ions,befor
ecommi tti
ngtoproducti
on.

Finall
y,theproductcanmovet oproducti
on.Theprevious
tr
ialswillhel
pexpeditetheval
idat
ionprocess,mi
nimising
downt i
mebef oreproducti
oncanbegin.

Thiswhi t
epaperwi l
lhelpprovi
destructureandguidance.
Awel ldesignedscale-
upwi l
lsaveti
meandmoney ,whil
e
improvingt heover
allchanceofeventualproduct
ion
success.

2 Whi
tePaper|Coni
calMi
l
li
ng:Howt
oef
fect
ivel
yscal
e-upf
rom l
abt
opi
l
ott
opr
oduct
ion
I
ntr
oduct
ion

Inmanyphar maceut icalprocesses,whatwor ksinthelabdoesn’talwaysscale-upseaml esslyi

ntoproduct
ion;
thi
sistrueinconi calmi l
li
ng.Lar gerbatches,di
ff
erentprocesscondit
ions,andvaryingmat eri
alcharact
eri
sti
cs
canallcreateunf oreseenpr oblemst hatult
imat
elyimpactperfor
mance.Despi tethi
s,labandpi l
otmi l
li
ngcan
sti
l
lbeagr eatindicatorofscal e- upoutput
,andcer t
ainstepscanbet akentomaxi mizethelikel
ihoodof
successfulproduction.Cer tainly,whenunder t
akencor r
ectl
y,small
-scal
emi l
li
ngcangi veanext remelyaccurat
e
for
ecastofevent ualpar ti
cl
esi ze,shapeandmachi necapacit
y.

Thiswhitepaperwil
laimtohelpyouscal
e-upwithmini
mum disr
upti
onordevi
ati
on.Whil
ethereisnosi
lver
bull
et,i
denti
fyi
ngpotenti
alpi
tf
all
swhi
leunderst
andi
ngbestpract
icecanatl
eastprovi
dealogi
calroadmapfor
achievi
ngmilli
ngsuccess.

Obj
ect
iveofScal
e-UpMi
ll
ing

Thepar t
icl
esi
zeandshapeofmat eriali
svitalt
othepr oduct
ionofpharmaceut i
calproduct
s.Thesevar i
abl
es
areaff
ectedbyt heorigi
nalingredi
ents,t
heirphysicalandmol ecul
arint
eract
ions,andtheprocessesthey
encounter.Mi
l
lingistheprimar ypr
ocedureusedf orsizereductionofpart
icl
espriortotabl
etandcapsule
for
mation.Materiali
sbrokendowni ntosmal ler
,mor econsi
stentpart
icl
es,whichwi l
lbelat
erblended,
compressedandcoat edi
ntot hefi
naldosageuni t
.

Theai misformateri
alunif
ormi t
y,asagoodpar t
icl
esizedist
ri
but
ion(PSD)willdel
iverabetterpowderf or
compressionorencapsulati
on.I mpor
tantl
y,thi
swi l
lal
soimproveproductsol
ubil
it
yandbi oavai
labil
i
ty,ul
timatel
y
deli
veri
ngimproveddrugper formance.Att hesamet i
me,t hesel
ectedmill
i
ngmet hodmustbepr acti
cablefor
producti
on,bal
ancingalldesi
r ableat
tr
ibut
es.I nthi
sregard,coni
calmil
li
ngoff
ersnumer ousbenef i
tsover
alt
ernati
vemill
i
ngmachi nes:

•Comparedwithosci
l
lati
ngmill
s,coni
calmill
swi
llachi
eveasimi
larPSD,butof
ferdr
amat
ical
lyhi
gher
t
hroughputonanequival
entsi
zemachi ne,f
ast
ertocleanandr
e-assembl
eandgivebet
terdur
abil
i
ty.

•Compar edwithhammermi l
l
s,conicalmil
l
swi l
lproducelessfi
nestogiveat i
ghterPSD,beeasiertocl
ean
andreassemble,andwi l
lproducelessheat,noi
seanddust( manyhammermi l
l
sr equi
rededi
cated
extr
act
ion).Iti
spar t
icul
arl
yimportantt
ounderstandthesebenefi
tsinor dert
oselecttheri
ghtt
echnol
ogy
foranewpr ocess,orwhenl ooki
ngtoupgradefrom anexisti
ngoscil
l
atingorhammermi l
l
.

Ifyoursel
ecti
onpr ocessdetermi nestheconicalmil
listhemostsuit
ablemachine,t
herearemanyvar iabl
est
o
experimentwith.Thesei ncludescr eent
ype,impellertype,i
mpell
erspeedandmat eri
alpressur
eont he
screen.Indeed,thereissignif
icantworktounder t
akeint heear
lyl
abstages,asscreenspecifi
cat
ionscan
becomever ydetail
edwi thvari
ationsinholesize,holeshape,pl
atethi
cknessandopenar ea-allofwhichwi
l
l
i
mpactf i
nalparti
cl
esi ze,shapeandmachi necapacity.

Thereareusual
lythreestepsinthepr ocess:labmi ll
ing,pil
otmi l
l
ing,andpr oducti
onmi l
li
ng.Although
thr
oughputsvar
ywi theachindivi
dualappl i
cati
on,apl ausi
bleexampl eofbat chesthroughscal e-upwouldbe
1-10kgsinthelab,25-100kgsi nthepilotplantand400- 800kgsi nproducti
on.Breaki ngitdowni nthisway
helpstoremi
ndust hatscale-
upi ssimplyamet hodicalandstagger edincreaseinmi lli
ngthroughput.The
emphasisshoul
dbet owardsi
dent i
fyi
ngandover comi ngdeviati
onbet weeneachst age,withtheul t
imate
object
iveofmanufactur
ingahigh-qualit
yandr eproducibleoutput,att
hel owestpossi bl
ecost .

Hanni
ngf
iel
dPr
ocessSyst
emsLt
d 3
LabMi
ll
ing

Labmi l
li
ngisthediscover
yphaseofpr oductscal
e-up,pr
ovidi
ngR&Dwi thaplatf
ormtotestandst
udymateri
al
behaviourduri
ngconicalmil
l
ing.Thisenablesthem tomicr
o-moni
tormateri
alpr
operti
es(par
ti
cl
esize
di
str
ibuti
on,parti
cl
eshape)andi dent
if
yprocessfactor
swhichimpactorareimpactedbythemater
ial(
heat
generati
on,capacit
y).

Forexampl e,afasterimpellerspeedwillproduceasmal lerparti

cl
eandhigherthroughput,butwi l
lal
so
gener atemor eheat.Manymat eri
al
sar etemper at
uresensiti
ve,sowhil
epushingapar t
icl
etoi t
sli
mitmaybe
suit
abl eonal aboratorysizedbatch,inthecont extofproduct i
onthesel
imit
ati
onscoul dprovedebi l
i
tati
ng.
Similarly,ascreenwi t
hasmal lhol
ewi l
lgiveaf inerpart
icle,butwil
lal
sorest
ri
ctcapacityandgener atemore
heat.Hence,asi gnifi
cantroleoflabmi l
li
ngi stopr ovi
deabal ancebetweenadesi rabl
epar t
icleanda
real
isticall
yachievableprocess-akeydel iverableshouldbehandi ngovercri
ti
calprocesspar ametersfort
he
l
arger -scal
epilotandpr oducti
onmi l
lstofollow.

Thet ar
getparti
cl
esizedi
stri
buti
onshouldbegui dedbyt heintendedpur poseofeachi ngredi
entandi t
s
contri
buti
ontothefi
nalpr
oduct. Toal ar
geextent,theoutputofpost mi
lledmateri
alswi l
ldependont hedegree
ofaggregati
onofthepremil
ledingr
edients.Togiveanaccur atei ndi
cat
ionofeventualpar t
icl
esizedi st
ri
but
ion,
i
tisrecommendedyoupl ant osurr
enderasmal lmat er
iall
ossf oreachlabmi l
l
ingbatch( approximately
equival
enttoascreenful
lofmat er
ial
).Thisshouldber egardedasanecessar yevi
l;itisimportanttoremember
thatthepurposeofl
abmill
ingistoaccuratel
yforecasttheoutcomeofamuchl ar
gerpr oducti
onbat ch.

Tobespecif
ic,attheendofabat cht hereisnotenoughdownwardgravi
tat
ionalf
orcepushi
ngmat eri
ali
ntothe
mil
l
ingchamber .Consequent l
y,alt
hought hismateri
alwoul
deventual
lypassthroughthescr
een,theproduct
wouldbe'st
ir
ring'rat
herthanmi l
l
ing,t aki
nganexcessiveamountofti
me,therebyproduci
ngadispropor
ti
onate
amountofsmal lpart
icul
ateorf
ines.1

Forexample,onal absizemachine~50gofa1kgbat chmayber etainedinthescreenunderthesecondi t

ions
(5%).Meanwhi l
e,inproduct
ion,onl
ythelast~1kgof600kgswoul
dmi l
lunderthesamecondi t
ions(0.166%) .
Hence,ifbot
hwer elef
ttomillt
heentir
etyofthebat
ch,thelabmachinewoul dshowasignif
icantl
ylarger
propor
ti
onoffinesandover -
mill
edmateri
althanwouldbethereal
i
tyinpr oduct
ion.

Itisobvioustonot ethatthemorerigorousandr obustthesmal l

-scalework,theeasi erprocessscal
e-upwi l
lbe.
Labmi l
l
ingresult
sar eusedtodrawcor r
elat
ionstoproposedpi l
otandpr oducti
onmi ll
ingsetups,soshouldtest
allrel
evantvariablesandgenerateinformati
vedat asets.Thisispar ti
cul
arl
ypertinentforconicalmil
li
ng,where
somanypar amet erscanbechangedonasi nglemachi ne;hol
esi ze,hol
eshape,i mpellertypeandimpell
er
rotati
onspeed.Bypr obi
ngtheoutcomeofeachvar iable,R&Dst affcannotonlyidentif
yapat htoproducti
on,
butalsogainanunder st
andi
ngofpot ent
ialprobl
emst hatcouldoccuri nascale-upsituati
on.

1
Pr
essurefrom theweightofmateri
alonthescreenmightnotseem rel
evantt
oaver agepar
ti
cl
esizeand
par
ticl
esizedist
ri
buti
on.However,themor epressur
eexertedonthescreen,t
helessresi
denceti
meofthe
materi
alduri
ngmi l
li
ng.Thisresul
tsinlessfr
equentimpactbytheimpel
ler,mi
nimi
singfi
nesorover-
mil
l
ed
par
ticl
es.

Pressureiscont
rol
ledbythefeedrateandthef eederdesi
gn;f
loodfeedi
ngofmat eri
alexer
tsaconstant
pressureonthescreengivi
ngatighter
,moreuni f
orm PSD.Thismakesf l
oodf eedingtheeasi
estt
or epr
oduce
i
nscal e-
up,alt
houghitmaynotalwaysbepr acti
cableandther
emaybej ust
if
iedreasoningtousediscont
inuous
feedi
ng.Forexampl e,i
fthemateri
alispr
onet ocaking/
bli
ndi
ngorifthefeedratef r
om anupstr
eam machineis
notsuffi
ci
ent,arot
aryval
veorsimilarmaybei nstal
l
edtocontr
olmateri
alfl
ow.

What
everprocessi
sul
ti
matel
ydesignedmustbewor
kabl
einareal
-wor
ldscenar
io,buti
tisi
mportantt
o
r
ememberthatthemor
einconsi
st
entthepr
essur
eonthescr
een,t
hemoreinconsist
entt
hesizeandshapeof
t
hepart
icl
e.

4 Whi
tePaper|Coni
calMi
l
li
ng:Howt
oef
fect
ivel
yscal
e-upf
rom l
abt
opi
l
ott
opr
oduct
ion
Pi
lotMi
ll
ing

Pil
otmi l
li
ngisacaut iousstepbetweenl abmi ll
i
ngandpr oducti
onmi l
li
ng.Itisthestagethatall
owsfur t
her
i
nvestigati
onofyourpr oductandyourpr ocessatani nter
medi atescale,beforelargeamount sofmoneyar e
commi tt
edtof ul
l-
scaleproducti
on.Equi pmentshoul daimt oprovider esult
sthatcanbeeasi l
ycor r
elatedto
producti
onlots,withoutrequi
ri
ngt hesignifi
cantoutlayoff undsf orpreciousingredi
entsandcapitalequipment.
Usingscalablemi l
l
ingequi pment,whichhasbeent estedviapr otocolinthelabwi t
hrefer
encemat erial
s,wil
l
minimiseexper i
ment at
ionandreducet heover alldurationofthepi lotphase.

Theequi pmentusedatt hisst ageshoul dsubjectthephar maceuti

calmat erialtoaddi t
ionalstr
essesofdi f
fer
ent
typesanddegr eest hanwer epr esentinthelab.Thepi l
otplantshouldpr ovidef orenvi ronment alandpr ocess
control
st hatwer eunl ikel
yt obepr esentinthel abor
atory.Si
nceheatandhumi dityar esot i
ghtlytiedtopar t
icl
e
aggregationordi ssociati
on,i tiseasyt oseet hatmachinepar ametersmi ghtneedt obechangedi nthemor e
control
ledpilotenvi ronment .Forexampl e,iftheroom conditi
onssuchast emper atureorhumi dit
yar ediff
erent
i
nt hepi l
otplantt othosei nt hel aborat
ory,themat eri
almaybehavedi f
ferent l
y( e.g.mor eorl essaggr egated,
mor eorlesspr onet obl i
nding) .Consequent ly,aprocesschangemayber equi redt ocompensat e,suchas
runningatal ower/hi gheri mpel lerspeedorusi ngascr eenwi t
hsmal l
er/l argerhol estogetcl osertothe
origi
nalpar t
iclesizedi str
ibution.Accor dingly
,room conditi
onsfrom pil
ottopr oduct ionshouldvar yasl i
tt
leas
possibl
e.Thesamei struei ftryi
ngt orepli
cateapr ocessbetweendi f
ferentgeogr aphicalsi
tes.

Ther awingredientsusedi nscale-upshouldclosel

yorexact l
yresembl ethoseusedi nt hepr
eviousst ageof
mill
i
ng,ori funf
easible,thennewi ngredi
entsneedt obet horoughlytestedandcor rel
atedwit
ht heoriginal
material
.Ideall
y,newi ngredientswil
lbetestedinthelabpriortointroduct
ionatt hepilotorproducti
onpl ant
.If
ther
ear elargeclumpsi nt hebulkmat er
ialt
hatwer eabsentinthelabor at
orytesting(e.g.duetocompact i
onin
stor
age),thenther esult
ingpar t
icl
esizedist
ribut
ionofmill
edmat erialmaydi f
fer.Shoul dsuchvariancesoccur,
i
nsightcanbegai nedbyst udyi
ngpatter
nsorpar al
lel
sinthedevel opment ,val
idationandbat chreports.

Onceal ltesti
ngiscomplete,thepil
otpl
antprovidesaf i
nalpl
atfor
mf orR&Dst afft
ointermi
nglewit
hpr oduct
ion
st
affbeforemanuf act
ure.Itisanoppor t
unit
ytot r
ansferknowledgeandconcer ns;t
hisall
owsallgroupsto
analyzeandcompar edata,togivetherequi
redconfidencethattheprocessiscompar abl
eandscal abl
e.Atthi
s
st
age,cl oseliai
sonwit
htheconi calmil
lsuppl
ierisal
sor ecommendedf ordrawingonpr ocessknowledgeand
understandingthecapabil
iti
esandl i
mit
ati
onsoft hemachinepr i
ortoproduct
ioncommi tments.

Hanni
ngf
iel
dPr
ocessSyst
emsLt
d 5
Pr
oduct
ionMi
ll
ing

Aft
ercompletionofpi
lott
est
ing,ther
equir
edsetupforpr
oduct
ionshouldnowbecl earl
yidenti
fi
ed,wit
han
accur
ateforecastofPSDandmachi necapaci
ty
.Thisisnott
osaythateverythi
ngwi l
lworkfi
rstt
ime,butt
he
majori
tyofproblemsshoul
dalreadyhavebeenovercomeandanyout st
andingissuesshoul
dbesol vabl
eduri
ng
theval
idat
ionprocess(e.
g.FAT,SAT,IQ,OQ,PQ) .

Onceal lpr
oducti
onparameter
sareagreedandf i
xed,t
hreetof
ivebatchesshoul dbeproducedtoprove
consist
encyandalignmentwit
hanti
ci
patedper
formance.Assumingthesear esuccessf
ul,t
henoncet he
processisval
idat
edandt heequi
pmentisqual
i
fied,mil
l
ingwil
lbecomej ustanotherst
andardoperat
ing
procedureatyourfaci
l
it
y.

Tomi nimiset hevari

abil
i
tyoft hi
spr ocessandt oensuret hehard- workunder t
akeninscale-upisnotwast ed,
closecont rolofmachineoper at
ionisr ecommended.Agoodexampl emaybet heuseofanHMI ,whichli
mits
theoper atortothesimpleexecut i
onofpr esetcondit
ions,whileaf f
ordingtheadmi ni
strat
oralargedegr eeof
fl
exibil
it
yifr equi
red.Thisgivestightercont r
oloffuncti
onssuchasspeed;asl ear
nedi nthelaborator
yimpeller
rotat
ionspeedcanhaveasi gnifi
cantimpactonpar ti
clesi zeandheatgener ati
on.Iftheoperatorhascont r
olof
machi nespeed,t henabat chcoul dber unonani ncorrectsett
ing( accident
alorotherwise)
.I ndeed,two
operatorsmayhavedi ff
eri
ngi deasof' whatwor ksbest '
,regardlessofappr ovedprocedure.

Iti
sessenti
althatt
hedocumentedprocedureisfol
lowedbytechnical
lyqual
ifi
edandadequatel
ytrai
ned
personnel
.Iti
sapr ocesst
hatwi
llbeint
egratedwit
ht heover
allpharmaceut
icalpr
oduct
ionplanandbe
support
edby QualityCont
rol
,Quali
tyAssurance,HealthSaf
etyEnvironmentandEngineer
ing.

Attent
ionshoul
dal sobef ocusedonaplannedmai ntenanceschedul
e,usi
ngmil
estonessetintheOperati
on
Manualf orr
egularinspecti
onsandwear-partr
eplacement.Fur t
her
more,t
opreventaproducti
onstandst
il
l
,iti
s
recommendedt hatvitalsparepar
tsar
ekepti nthemai nt
enancedepart
ment.Specif
ical
l
y,r
egularl
yused
screensandimpel l
ersshouldbekeptinstockforimmediaterepl
acementi
ncaseofloss,damageorwear .

6 Whi
tePaper|Coni
calMi
l
li
ng:Howt
oef
fect
ivel
yscal
e-upf
rom l
abt
opi
l
ott
opr
oduct
ion
Concl
usi
on

Itisperhapsunreal
i
sti
ctoexpectt
hatscal
e-upwi
l
loccurwi t
houtf
ine-
tuni
ngandt hatsuccessinthelabwil
l
transl
atedir
ect
lyint
osuccessinpr
oducti
on.Nonethel
ess,planni
ngforscal
e-upshouldbeginbeforelabstudi
es
haveevencommenced.Thepl ancanthenbeadaptedthrougheachstep,asmor edetail
edinf
ormationand
knowledgeisgained.

Aftereachstageiscomplete,i
ti
sessenti
alf
ort
her ecei
vi
ngteam tost
udyt hebatchrecordreport
s,i
nordert
o
betterunderst
andtheissuesexperi
encedi
nthedevelopmentphase.Itisalsoimperat
ivethatt
eamsengagein
cross-depar
tmentalcommunicati
on,t
oensurel
essonslear
nedarecarriedforwardtomaximisethechanceof
scale-upsuccess.

Byt het i
meapr oductreachesproduct
ion,acomprehensiveandthoroughscal
e-upwil
laff
ordahighdegr eeof
confidencetobeshar edbyt hedevel
opmentandmanuf acturingt
eams,aswellasoutsi
deregulat
ors.Fr om l
ab
topilot,andfr
om pil
ottoproducti
on,amaj ordel
i
verabl
eshoul dbetoputfor
wardspecif
icr
ecommendat ions
withregar dt
otherequiredcombinati
onofscreen,i
mpellertypeandmachinespeedforachievi
ngar epeatabl
e
process.

Overall
,coni
calmil
lsof
ferexcel
lentscal
abil
i
ty,producingpredi
ctabl
eandcompar abl
eresul
tsasyoupr ogr
ess
towardslar
gerbat
ches.Foll
owingtheabovegui deli
neswillsmoothandacceler
atethi
spath;ul
ti
mat elythi
s
helpstoachievet
heori
ginalobj
ecti
veofdeliver
ingt henecessar
yproductspeci
fi
cati
on,whil
esati
sfyingthe
requi
rementsofahighl
yregulat
edpr oduct
i
onenvi ronment.

Hanni
ngf
iel
dPr
ocessSyst
emsLt
d 7
 UK and Worldwide USA, Canada, Mexico Australasia and
(Headquarters) and North America South-East Asia

Hanningfield Process Systems Ltd Hanningfield (North America) LLC Hanningfield (Asia-Pacific) Pty Ltd
17 Millhead Way PO Box 1178 PO Box 362
Purdeys Industrial Estate Hillsborough Kenmore
Rochford, Essex North Carolina Queensland
SS4 1LB 27278 4069
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