3/13/12

1
lSL Commlsslonlng and
Cuallcauon Culdance
An Cvervlew of new Culdance

1lmoLhy . Poward, Cl, L
vlce resldenL
Commlsslonlng AgenLs, lnc.

Agenda
!"#$% PlsLory Lesson
Sclence and 8lsk 8ased Approach
lCP C8 / C9
AS1M L2300
new Culdance uocumenLs
lSL Culdance uocumenL
lSL Cood racuce Culde
3/13/12
2
In the 8eg|nn|ng.
A number of semlnal documenLs
esLabllshed Lhe prlnclples of a 8lsk
8ased Approach Lo C&C:
lSL 8asellne Culde 3 (2001)
harmaceuucal cCMs for Lhe 21
sL
CenLury
- A 8lsk 8ased Approach" - luA (2004)
lSL WhlLe aper - 8lsk 8ased Cuallcauon
for Lhe 21
sL
CenLury" (2003)
lCP C8 harmaceuucal uevelopmenL (2003)
lCP C9 CuallLy 8lsk ManagemenL (2006)
AS1M L 2300 (2007)









1987 2000 2002 2004 2006 2008 2010
ss2222222222222222201020102010220112010204321093248 0932148 093218420394820934802 93840293842010
ICH Q9
FDA:
Pharmaceutical
CGMPs For
The 21st
Century
FDA
Guide to
Process
Validation
ISPE
C&Q
Baseline
5 Guide
ICH Q8
ISPE 21
st

Century
Qualification
White Paper
EU
Annex
15
FDA: Quality
Systems
Approach to
Pharmaceutical
cGMP
Regulations
ASTM
E2500-
07
ICH
Q10
FDA
Process
Val.
Guidanc
e
ISPE
Guide
FSE
ICH
Q9
ASTM
ISPE GPG
(Draft)

2011
Lvo|unon Cf Comm|ss|on|ng & ua||hcanon
3/13/12
3
lSL 8asellne Culde - volume 3
uened Commlsslonlng
lnLroduced SysLem and ComponenL Level
lmpacL AssessmenLs
SysLems 8ased Approach
3/13/12
4
10 r|nc|p|es for k|sk-8ased ua||hcanon

1. locus on LhaL whlch aecLs producL quallLy
2. rocess user 8equlremenLs key Lo accepLablllLy (lC/CC subordlnaLe Lo C)
3. 8lsk assessmenLs and process knowledge used Lo ldenufy crlucal elemenLs
4. Cnly crlucal feaLures/funcuons Lo be qualled
3. All acuvlues musL conLrlbuLe value
6. 8lsk-based asseL dellvery - noL cookbook" requlremenLs
7. value-added documenLs based on Lechnlcal merlL
8. use of suppller documenLauon
9. 1esL plannlng (and one-ume Lesung)
10. losLer lnnovauon - all change ls noL bad
ISPE White Paper Risk Based Qualification for the 21
st
Century
March 2005
lCP C9 - CuallLy 8lsk ManagemenL
.Lhe proLecuon of Lhe pauenL by managlng
Lhe rlsk Lo quallLy should be consldered of
prlme lmporLance.
8lsk evaluaLed based on sclenuc knowledge
Level of eorL commensuraLe wlLh level of rlsk
3/13/12
3
lCP C8 - harmaceuucal uevelopmenL
Crlucal CuallLy AurlbuLes
A physlcal, chemlcal, blologlcal or mlcroblologlcal
properLy or characLerlsuc LhaL should be wlLhln an
approprlaLe llmlL, range, or dlsLrlbuuon Lo ensure
Lhe deslred producL quallLy.
Crlucal rocess arameLers
A process parameLer whose varlablllLy has an
lmpacL on a crlucal quallLy aurlbuLe and Lherefore
should be monlLored or conLrolled Lo ensure Lhe
process produces Lhe deslred quallLy.
luA CuallLy SysLems Culdance
CuallLy rlsk managemenL lnLegral Lo quallLy
sysLems
Lncourage conunuous lmprovemenL
LqulpmenL and faclllues
use of Lechnlcal experLs
CuallLy unlL revlew basls for deslgn: process
requlremenLs, rlsk Lo pauenL
3/13/12
6
AS1M L2300-07
SLandard Culde for Lhe
Speclcauon, ueslgn and
verlcauon of
harmaceuucal and
8lopharmaceuucal
LqulpmenL, SysLems and
laclllues
AS1M key rlnclpals
#1 8lsk 8ased
#2 Sclence 8ased
#3 Crlucal CuallLy AurlbuLes (CCA)
#4 CuallLy by ueslgn (Cbu)
#3 Cood Lnglneerlng racuces (CL)
#6 Sub[ecL Mauer LxperLs (SML)
#7 use of vendor uocumenLs
3/13/12
7
AS1M rocess
8equlremenLs uenluon
Speclcauon and ueslgn
verlcauon
AccepLance and 8elease
Supporung Acuvlues
Cood Lnglneerlng racuce
8lsk ManagemenL
ueslgn 8evlew
Change ManagemenL
3/13/12
8
1he Speclcauon, ueslgn and
verlcauon rocess
Crlucal AspecLs of Mfg SysLems
.Lyplcally funcuons, feaLures, ablllues, and
performance or characLerlsucs necessary for Lhe
manufacLurlng process and sysLems Lo ensure
conslsLenL producL quallLy and pauenL safeLy.
1hey should be ldenued and documenLed based
on sclenuc producL and process undersLandlng.
.referred Lo as crlucal aspecLs."
verlcauon acuvlues should focus on Lhese
aspecLs of manufacLurlng sysLems and should be
documenLed.
3/13/12
9
new lSL Culdance uocumenLs
lSL CuluL:
- &'()*') ,*- .(&/0!,&)- ,11.2,'3
42. 53) -)6(7).8 24 4,'(6(5()&9
&8&5):&9 );<(1:)*5 =4&)>
lSL CCCu 8AC1lCL CuluL:
- ,116()- .(&/ :,*,?):)*5 42.
'2::(&&(2*(*? ,*- ;<,6(4(',5(2*
=?1?>
AS1M L2300-07
lmplemenLauon
Culdance


Wrluen by lSL
C&C CC
Worklng Croup
3/13/12
10
lSL- 8auonale for Lhe new lSL CuluL
resenLs a sLrucLured llfecycle approach Lo Lhe dellvery of
faclllues, sysLems and equlpmenL whlch supporL Lhese
regulaLory lnluauves

ueslgned Lo lmprove Lhe way ln whlch Lhe lndusLry dellvers
regulaLed manufacLurlng capaclLy

lmprove Lhe ablllLy Lo meeL documenLed process
requlremenLs
ConLrol rlsks wlLhln Lhe manufacLurlng process
roduce hlgh quallLy producLs whlch conslsLenLly meeL
producL user requlremenLs.
1he CuluL descrlbes Lhe 1"#@A#BC$D requlred when applylng a
sclence and rlsk based program.
ua||hcanon
"1rad|nona|" vs. k|sk 8ased Approach (k8A)
1rad|nona| Approach
(roducL) user 8equlremenLs
noL lormally uocumenLed
roLocols ueveloped from
1emplaLes"
lC/CC roLocols
reapproved"
Commlsslonlng noL Leveraged
Lnglneerlng and valldauon"
ersonnel Cen ulsuncL
Lmphasls on uocumenLs - noL
SysLem erformance

k8A 8ased on AS1M L 2S00
rocess 8equlremenLs
uocumenLed, Approved
8lsk AssessmenLs ueLermlne
Crlucal AspecLs of ueslgn
Lnglneerlng 1esung
(Commlsslonlng") verlcauon
All uocumenLs wlLh 1echnlcal
MerlL used as Lvldence of
llLness for use
Lmphasls on Meeung rocess
8equlremenLs
3/13/12
11
8G S
Gu|dance
New k|sk-based
Approach
rocess
valldauon
Lnglneerlng Change ManagemenL
CA Change ConLrol
lC & CC
Commlsslonlng
Lnhanced Des|gn
kev|ew
Des|gn
Deve|opment
C
rocess
valldauon
Lnglneerlng Change ManagemenL CA Change
ConLrol
erformance
1esung
verlcauon
1esung
Des|gn kev|ew
Des|gn
Deve|opment
1
8asellne Culde 3 vs. lSL Culde
lSL CuluL Cvervlew
Chapters 1|t|es
1 lnLroducuon
2 Cvervlew Cf 1he Llfecycle
3 8equlremenLs
4 Speclcauon & ueslgn
3 verlcauon, AccepLance and 8elease
6 Conunual lmprovemenL
7 CuallLy 8lsk ManagemenL
8 Cood Lnglneerlng racuce
9 ueslgn 8evlew
10 Change ManagemenL
11-13 Appendlces
16 Appendlx 6 Clossary and Acronyms
17 Appendlx 7 8eferences


noLe : AuLomauon dealL wlLh LhroughouL each chapLer
3/13/12
12
Scope

new commerclal manufacLurlng and
modlcauon Lo exlsung regulaLed mfg
faclllues

lannlng, speclcauon, deslgn, and dellvery
(harmonlzed) wlLh CAM 3

Addresses Lhe verlcauon (or quallcauon)
poruon of Lhe valldauon llfe cycle on whlch
process valldauon ls bullL


urpose
Sclenuc producL
and process
knowledge
uocumenLed
speclcauon,
deslgn, and
verlcauon of
equlpmenL/
sysLems/uullues
llL for lnLended
use, and mlnlmlze
rlsk Lo pauenL
safeLy and
producL quallLy
3/13/12
13
8eneLs

Lncourage Lhe lndusLry and lndlvldual
organlzauons Lo reassess Lhe Lermlnology,
pracuces, and roles and responslblllues
lnvolved ln dellverlng new manufacLurlng
capaclLy Lo focus on Lhe crlLerla requlred
Lo esLabllsh sulLablllLy for lnLended use."
key ConcepLs

&A#$@A$ !ED$F ;GEC#HI .#DJ :E@EK$L$@H
uescrlbes Lhe lmporLance of a C8M program
uocumenLed rlsk assessmenLs focused on rlsk Lo pauenL
locus on ldenufylng , assesslng and conLrolllng rlsk
1"MFGAH E@F 1"MA$DD <@F$"DHE@F#@K
8esulung from sclenuc lnvesugauon
Lnhanced conunually durlng ongolng operauons
8eglns wlLh knowlng Lhe producL CCAs and assoclaLed Cs
4MAGD M@ ,AN#$O#@K 4#H@$DD %M" (@H$@F$F <D$
verlcauon acuvlues focused on conrmlng LhaL CAs of equlpmenL/
sysLems and assoclaLed meeL accepLance crlLerla
verlcauon lnspecuons and LesLs are noL llmlLed Lo CAs

3/13/12
14
key ConcepLs (conL.)

4C$P#QC$ ,BB"MEAN$D HM &B$A#RAESM@ E@F
7$"#RAESM@
Several approaches Lo sLrucLure Lhe documenLs, lnspecuons, and
Lesung acuvlues
uemonsLrauon of L for lnLended use and sumclenL Lo meeL
regulaLory expecLauons
'CE"#RAESM@ M% .MC$D E@F .$DBM@D#Q#C#S$D
1he roles of CuallLy unlL and SML are descrlbed ln Lhe conLexL of
Lhe scope of acuvlues covered by Lhls Culde.
Sub[ecL Mauer LxperLs (SMLs) are dened as Lhose lndlvlduals wlLh
speclc experuse ln a parucular area or eld.
1he CuallLy unlL has a key role wlLhln Lhe quallLy managemenL
sysLem governlng faclllues, sysLems, and equlpmenL.
ln addluon Lo acung as a Sub[ecL Mauer LxperL (SML), Lhe CuallLy
unlL ls responslble for overseelng quallLy and compllance
ko|e of the ua||ty Un|t
1he CuallLy unlL ls expecLed Lo ldenufy, approve, and
verlfy Lhose aspecLs LhaL are necessary Lo manufacLure
a quallLy producL, and Lo ensure LhaL approprlaLe
procedures are followed Lo ensure LhaL rlsks Lo Lhe
pauenL ln Lhe manufacLurlng sysLems are adequaLely
conLrolled

1he Lerm CuallLy unlL ls used as an encompasslng Lerm
LhaL lncludes many quallLy-relaLed roles, lncludlng
Lhose responslblllues covered by Lhe role of Cualled
erson (as dened ln Arucle 31 of 387 Lu ulrecuve
2001/83/LC)
3/13/12
13





1he 8lsk-8ased verlcauon rocess
Concerns from &ML$ ln lndusLry
1oo 8lg of a Leap for us
1oo much ume spenL on lmplemenung quallLy
sysLems wlLh 8C3 model
l llke Lhe concepLs buL don'L see how l can
fully lmplemenL Lhls model
My faclllLy ls all legacy sysLems
3/13/12
16
lSL Cood racuce Culde #10
Applled 8lsk ManagemenL for
Commlsslonlng and
Cuallcauon
3/13/12
17
Good racnce Gu|de Structure
1 - lnLroducuon
2 - lundamenLals
3 - ConL. lmprovemenL
4 - Supporung racuces
3 - CuallLy 8lsk MgmL
6 - CosL ConLrol and
rocess erformance
7 - SpeclalLy Appllcauons

Appendlces
user 8equlremenLs
C&C lans
Crganlzauonal MaLurlLy
Commlsslonlng
8eferences
Clossary
SelecL PlghllghLs
Secuon 2.3 - rocess llow ulagram
llgure 2.3 - 1wo 1lered 8lsk AssessmenL
1able 3.2 - Legacy SysLem Challenges
1able 4.1 - CMS Challenge Lxamples
1able 10.1 - Crganlzauonal MaLurlLy Model
3/13/12
18
knowledge 8rlef (!an 2010)
lndusLry ls undergolng a sea of change wlLh
sclence and rlsk based pharmaceuucal
developmenL, valldauon, and manufacLurlng
8lsk 8ase C&C an lmporLanL parL of change
CuallLy SysLems musL adapL for commerclal
and compllance reasons
1he road for each rm wlll be dlerenL
1|mothy . noward, CI, L
vlce resldenL
Commlsslonlng AgenLs, lnc.

1lm.Poward[CagenLs.com
919-338-3482
3/13/12
19
8ACku SLluLS - lSL CuluL


ISL GUIDL CCN1LN1


SClLnCL-8ASLu A8CACP

Sclenuc knowledge should be Lhe basls on whlch rlsk assessmenLs
performed Lo supporL deslgn, developmenL, and verlcauon Lo ensure
LhaL pharmaceuucal sysLems are sulLable for lnLended use
ldenucauon of Lhe Cs and CCAs, along wlLh dened approprlaLe
operaung llmlLs or accepLance crlLerla, should be lncluded ln Lhe
documenLed producL developmenL daLa, process ow dlagram, and
producL quallLy sLraLegy
roducL and process requlremenLs should be used Lo dene approprlaLe
verlcauon acuvlues and accepLance crlLerla Lo ensure LhaL
manufacLurlng elemenLs are sulLable for Lhelr lnLended use
3/13/12
20
CuALl1? 8lSk MAnACLMLn1 ln 1PL
LllL C?CLL
C8M should underpln Lhe speclcauon, deslgn, and
verlcauon process, and be applled approprlaLely aL each
sLage

1wo prlmary prlnclples of quallLy rlsk managemenL are
ldenued ln lCP C9:
Lhe evaluauon of Lhe rlsk Lo quallLy should be based on sclenuc knowledge
and ulumaLely llnk Lo Lhe proLecuon of Lhe pauenL
Lhe level of eorL, formallLy and documenLauon of Lhe quallLy rlsk
managemenL process should be commensuraLe wlLh Lhe level of rlsk
CuALl1? 8? uLSlCn

CuallLy should be bullL lnLo Lhe deslgn LhroughouL Lhe speclcauon,
deslgn, and verlcauon process.

Assurance LhaL manufacLurlng elemenLs are sulLable for lnLended use
should noL rely solely upon verlcauon aer lnsLallauon.

1he process conLrol sLraLegy ls essenual Lo Lhe overall producL quallLy
conLrol sLraLegy:
Lo mlugaLe process rlsks by deslgn
Lo conLrol rlsks vla Lhe process conLrol sLraLegy
Lo deLecL fallure of Lhe process Lo meeL crlucal Lo quallLy aspecLs by measuremenL,
alarmlng and acuon as parL of an overall producL quallLy conLrol sLraLegy llmlLs
3/13/12
21
SLClllCA1lCn Anu vL8lllCA1lCn

1he process of speclcauon, deslgn, and verlcauon of
equlpmenL and sysLems should lnclude Lhe followlng
acuvlues:
requlremenLs denluon
speclcauon and deslgn
verlcauon
accepLance and release

CL, C8M, and deslgn revlews should be applled LhroughouL
Lhe process and LhroughouL Lhe llfecycle
CCCu LnClnLL8lnC 8AC1lCL

CL ls dened as esLabllshed englneerlng meLhods and sLandards LhaL
are applled LhroughouL Lhe pro[ecL llfe cycle and ensure Lhe eecuve
sausfacuon of sLakeholder requlremenLs
1hey dellver approprlaLe, cosL-eecuve soluuons Lo meeL user
requlremenLs and compllance wlLh all appllcable regulauons
CL should be applled Lo all sLages of Lhe speclcauon, deslgn, and
verlcauon process
CL ensures LhaL an englneerlng pro[ecL meeLs Lhe requlremenLs of Lhe
user whlle belng cosL eecuve, compllanL wlLh regulauons, and well
documenLed. LsLabllshed guldance and sLandards supporL eecuve CL.
lor CM pro[ecLs, lL ls crlucal Lo Lhe overall pro[ecL success, LhaL Lhe
prlnclples of CL are applled wlLh Lhe full cooperauon of suppllers,
englneerlng and consLrucuon companles, and an organlzauon's own
cross-funcuonal Leams.

3/13/12
22
CCn1lnuAL lM8CvLMLn1

Cnce Lhe verlcauon process ls compleLed, Lhe sysLem wlll be sub[ecL Lo
Lhe approprlaLe quallLy sysLem(s) for ongolng supporL and conunual
lmprovemenL
An evaluauon should be performed perlodlcally or upon speclc
lncldenLs, such as frequenL non-conformance of Lhe sysLem or producL,
Lo revlew Lhe performance of Lhe sysLem and lLs ablllLy Lo conunue
funcuonlng as requlred Lo meeL crlucal aspecLs of manufacLurlng
capablllLy. 1he revlew should conrm LhaL Lhe sysLem remalns sulLable
for lnLended use or recommend poLenual lmprovemenLs

Where sysLem lmprovemenLs are recommended, Lhls Culde may asslsL ln
Lhelr approprlaLe deslgn and lmplemenLauon
CPAnCL MAnACLMLn1

Change ManagemenL pracuces should be approprlaLe Lo Lhe acuvlues
performed and Lhe sLage wlLhln Lhe sysLem llfe cycle

Change ManagemenL pracuces may, generally, be ldenued as:
englneerlng change managemenL, based upon CLs
formal CA change conLrol, uslng slmllar CLs augmenLed wlLh pre- and posL- approvals
by Lhe CuallLy unlL, ls requlred durlng commerclal manufacLurlng
lmplemenung formal CA Change ConLrol, wlLh CuallLy unlL pre and posL
approvals, prlor Lo sLarung commerclal manufacLurlng operauons ls
unllkely Lo provlde beneL
3/13/12
23
Su8!LC1 MA11L8 LxL81S

Sub[ecL Mauer LxperLs (SMLs) are dened as Lhose lndlvlduals wlLh
speclc experuse ln a parucular area or eld

SMLs should Lake Lhe lead role ln Lhe verlcauon of manufacLurlng
elemenLs

SML responslblllues lnclude plannlng and denlng verlcauon sLraLegles,
denlng accepLance crlLerla, execuuon of verlcauon LesLs, and revlewlng
resulLs

SMLs are encouraged Lo undersLand, ldenufy, and leverage besL pracuces
and processes relaLed Lo auLomaLed equlpmenL sysLem.

SuLlL8 MAnACLMLn1

use of suppller documenLauon, lnspecuon resulLs, and LesL resulLs can
help Lo reduce dupllcauon of eorL
ln Lhe case of supplled equlpmenL or sysLems wlLh crlucal aspecLs,
approprlaLe SMLs should assess Lhe CMS of Lhe suppller Lo deLermlne
wheLher, and Lhe exLenL Lo whlch, suppller documenLauon, lnspecuons,
and LesL resulLs can be leveraged
1he regulaLed organlzauon should esLabllsh a clear approach for ensurlng
LhaL Lhe fabrlcaLed and dellvered sysLem or equlpmenL complles wlLh Lhe
pre-esLabllshed requlremenLs
1he regulaLed organlzauon should esLabllsh how compllance ls verled
and documenLed durlng verlcauon Lesung and performance Lesung
3/13/12
24
Au1CMA1lCn

AuLomauon should be an lnLegral parL of Lhe verlcauon
process for a manufacLurlng sysLem LhaL Lakes lnLo accounL
sysLems, process ows, auLomauon and equlpmenL elemenLs
of Lhe sysLem, as well as oLher funcuons such as daLa ow,
alarmlng, and reporung
Cnce crlucal aspecLs of manufacLurlng, Lhelr accepLance
crlLerla, and Lhe verlcauon plan are ln place, Lhe
developmenL and Lesung of Lhe auLomauon, boLh ln Lhe
developmenL envlronmenL and Lhe producuon envlronmenL,
become englneerlng acuvlues
verlcauon acuvlues may help deLermlne acLual operaung
ranges wlLhln whlch Lhe sysLem ls capable (process
capablllues)
Commlsslonlng
Commlsslonlng ls a managed and planned process of brlnglng a faclllLy
or equlpmenL from lLs lnsLalled or consLrucLed sLaLe lnLo operauonal
servlce. 1hls normally lnvolves a process of semng Lo work followed by
regulauon and ad[usLmenL. 1hese acuvlues should be based on Lhe
prlnclples of CL. Commlsslonlng acuvlues are based on Lhe prlnclples
of CL and lL should be a well planned, execuLed, and documenLed
process
Commlsslonlng ls a process execuLed by englneers, whlch applles Lo all
aspecLs of a faclllLy, equlpmenL, and servlces. 1he key acuvlues are
slmllar regardless of wheLher commlsslonlng ls applled Lo a new faclllLy
or a slmple plece of equlpmenL has been consLrucLed and lnsLalled, only
Lhe complexlLy ls dlerenL. key acuvlues lnclude:
o plannlng
o schedule
o lnspecuon and Lesung
o reporL
3/13/12
23
;GEC#RAESM@T
1he Lerm quallcauon" may conunue Lo be used

qGEC#RAESM@T should mean LhaL equlpmenL has been found Lo be
sulLable for lLs lnLended use, based on:
Lhe deslgn crlLerla (process requlremenLs or equlvalenL necessary Lo manufacLure a
quallLy producL)
demonsLrauon of sumclenL conLrol of rlsks Lo Lhe pauenL
documenLauon complled Lhrough Lhe verlcauon work performed LhroughouL Lhe
dellvery process and llfe cycle

1hls does noL lmply Lhe necesslLy Lo conducL addluonal work ln Lhe form
of separaLe uC, lC, and CC proLocols - Lhe denluon of uC, lC, and CC
ls based on provldlng documenLed verlcauon." 1hls gulde
recommends a compllanL yeL emclenL meLhod of produclng Lhls
verlcauon evldence
uened ln verlcauon lan(s)
Scope of work
verlcauon sLraLegy
AccepLance crlLerla for crlucal aspecLs
uocumenLauon requlremenLs
verlcauon 1esung (hases)
ueslgn 8evlews
lacLory AccepLance 1esung (lA1)
SlLe AccepLance 1esung (SA1)
lnsLallauon verlcauon (lv)
luncuonal verlcauon (lv)
erformance 1esung (1/C)
Ver|hcanon
3/13/12
26
Common CL racuces
Cood uocumenLauon racuces (Cu)
Lnglneerlng ro[ecL Change ManagemenL
ro[ecL AudlLs
lannlng 8elaLed Acuvlues
o ro[ecL lannlng
o CuallLy lannlng
o Communlcauon lan
o rocuremenL lan
ueslgn 8evlews
ManagemenL SysLems
ConsLrucuon CuallLy SLandards
ro[ecL SlLe Loglsucs
ro[ecL CuallLy ConLrol
non CM 8egulauon Compllance
1urnover and ro[ecL Closure