Guidance 1-6

GHTF/SG3/N99-10:2004 (Edition 2)
FINAL DOCUMENT
Title: Quality Management Systems -
Process Validation Guidance
Authoring Group: SG3
Endorsed by: The Global Harmonization Task
Force
Date: dition ! - "anuary !##$

Taisuke Hojo,
GHTF Chair
The document herein %as &roduced by the Global Harmonization Task Force' a
(oluntary grou& o) re&resentati(es )rom medical de(ice regulatory agencies and
the regulated industry* The document is intended to &ro(ide non-binding
guidance to regulatory authorities )or use in the regulation o) medical de(ices'
and has been sub+ect to consultation throughout its de(elo&ment*
There are no restrictions on the re&roduction' distribution or use o) this
document, ho%e(er' incor&oration o) this document' in &art or in %hole' into any
other document' or its translation into languages other than nglish' does not
con(ey or re&resent an endorsement o) any kind by the Global Harmonization
Task Force*
GHTF Study Group 3 - Quality Management Systems
Proess !alidation Guidane " #anuary $%%&
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Process Validation Guidance
Contents
0 Introduction
1 Purpose and scope
1.1 Purpose
1.2 Scope
2 Definitions
3 Processes that should be validated
3.1 Special processes
3.2 Process validation within the ualit! "ana#e"ent s!ste"
3.3 Process validation decision
3.$ %&a"ples
$ Statistical "ethods and tools for process validation
' Conduct of a validation
'.1 Gettin# started
'.2 Protocol develop"ent
'.3 Installation ualification (I)*
'.$ +perational ualification (+)*
'.' Perfor"ance ualification (P)*
, -aintainin# a state of validation
,.1 -onitor and control
,.2 Chan#es in process and.or product
,.3 Continued state of control
,.$ %&a"ples of reasons for revalidation
/ 0se of historical data in process validation
1 Su""ar! of activities
2nne&es
2 Statistical "ethods and tools for process validation
3 %&a"ple validation
Proess !alidation Guidane" #anuary $%%&
Page 3
0 Introduction
'Quality Management Systems " Proess !alidation Guidane(, originally )inali*ed in +,,,, is -eing
repu-lished as 'GHTF.SG3./,,-+%0$%%& 12dition $3( a)ter re4isions due to the hanges in 5S6
+3&780$%%3, 9hih is utili*ed in some regulatory systems: The Proess !alidation Guidane has -een
re4ised in setions % through 3:&, Figure + and ;nne< =: The re4isions an -e generali*ed in t9o
ategories0 +:3 2ditorial re4ision o) terminology to -e onsistent 9ith 5S6 +3&780$%%3 1i:e:, '>uality
system( to '>uality management system( and 'design ontrols( to 'design and de4elopment
ontrols(3, and? $:3 Changes to Figure + and the orresponding te<t to re)let the ne9 proess
4alidation re>uirements )ound in lause @:8:$ o) 5S6 +3&780$%%3:
This proess 4alidation guidane is intended to assist manu)aturers in understanding >uality
management system re>uirements onerning proess 4alidation and has general applia-ility to
manu)aturing 1inluding ser4iing and installation3 proesses )or medial de4ies: The guidane
pro4ides general suggestions on 9ays manu)aturers may prepare )or and arry out proess
4alidations:
Proess 4alidation is a term used in the medial de4ie industry to indiate that a proess has -een
su-jet to suh srutiny that the result o) the proess 1a produt, a ser4ie or other outome3 an -e
pratially guaranteed: This is 4itally important i) the predetermined re>uirements o) the produt an
only -e assured -y destruti4e testing:
Proessing de)iienies may only -eome apparent a)ter an intermediate omponent is )urther
proessed or the )inished produt is in use: !alidation o) a proess entails demonstrating that, 9hen a
proess is operated 9ithin spei)ied limits, it 9ill onsistently produe produt omplying 9ith
predetermined 1design and de4elopment3 re>uirements:
The medial de4ie industry enompasses a 9ide range o) tehnologies and appliations, ranging
)rom simple hand tools to omple< omputer-ontrolled surgial mahines, )rom implanta-le sre9s
to arti)iial organs, )rom -lood-gluose test strips to diagnosti imaging systems and la-oratory test
e>uipment: These de4ies are manu)atured -y ompanies o) 4aried si*e, struture, 4olume o)
prodution, manu)aturing proesses and management methods: These )ators, espeially prodution
4olume and num-er o) manu)aturing steps per unit 1e:g: soldering or 9elding steps3 signi)iantly
in)luene ho9 proess 4alidation is atually applied: Gi4en this di4ersity, this guidane does not
suggest partiular methods o) implementation, and there)ore, must not -e used to assess ompliane
9ith >uality management system re>uirements: Aather the intent is to e<pand on >uality management
system re>uirements 9ith pratial e<planations and e<amples o) proess 4alidation priniples:
Manu)aturers an and should seek out.selet tehnology-spei)i guidane on applying proess
4alidation to their partiular situation:
This guidane pro4ides general suggestions on 9ays manu)aturers may prepare )or and arry out
proess 4alidations: 6ther 9ays may -e e>ually aepta-le? some regulatory re>uirements plae the
responsi-ility on the manu)aturer to spei)y those proesses 9hih re>uire 4alidation and the
>uali)iation o) personnel 9ho operate 4alidated proesses: Aegardless o) the method used to 4alidate
the proess, reords o) all 4alidations ati4ities should -e kept and the )inal outome doumented:
Bhile the ompletion o) proess 4alidation is a regulatory re>uirement, a manu)aturer may deide to
4alidate a proess to impro4e o4erall >uality, eliminate srap, redue osts, impro4e ustomer
satis)ation, or other reasons: Coupled 9ith properly ontrolled design and de4elopment ati4ities? a
4alidated proess may 9ell result in a redued time to market )or ne9 produts:
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5n general, the 4alidation o) a proess is the mehanism or system used -y the manu)aturer to plan,
o-tain data, reord data, and interpret data: These ati4ities may -e onsidered to )all into three
phases0 +3 an initial >uali)iation o) the e>uipment used and pro4ision o) neessary ser4ies " also
kno9 as installation >uali)iation 15Q3? $3 a demonstration that the proess 9ill produe aepta-le
results and esta-lishment o) limits 19orst ase3 o) the proess parameters " also kno9n as operational
>uali)iation 16Q3? and 33 and esta-lishment o) long term proess sta-ility " also kno9n as
per)ormane >uali)iation 1PQ3:
Many proesses are ontrolled -y omputers: Bhile the omputer so)t9are may -e onsidered an
integral part o) the proess, this guideline does not o4er so)t9are 4alidation:
Bhile the theory o) proess 4alidation is reasona-ly straight)or9ard, the deision o) the manu)aturer
to e4aluate e4ery proess )or potential 4alidation may lead to unertainty: Some regulatory
re>uirements state that e4ery proess that annot -e 4eri)ied -y su-se>uent monitoring or
measurement -e 4alidated: Guidane is pro4ided )or reahing deisions on 9hether to 4alidate or not:
Page '
1 Purpose and scope
1.1 Purpose This proess 4alidation guidane is intended to assist manu)aturers in
understanding >uality management system re>uirements onerning proess 4alidation:
1.2 Scope This doument has general applia-ility to manu)aturing 1inluding ser4iing and
installation3 proesses )or medial de4ies: Spei)i reommendations )or 4eri)iation o) design
output and design 4alidation is inluded in the GHTF doument o4ering design ontrol:
2 Definitions
For this doument, the )ollo9ing de)initions apply: Terms other than those de)ined herein may -e
)ound in the literature:
2.1 Installation ualification (I)*4 esta-lishing -y o-jeti4e e4idene that all key aspets o) the
proess e>uipment and anillary system installation adhere to the manu)aturerCs appro4ed
spei)iation and that the reommendations o) the supplier o) the e>uipment are suita-ly onsidered:
2.2 +perational ualification (+)*4 esta-lishing -y o-jeti4e e4idene proess ontrol limits and
ation le4els 9hih result in produt that meets all predetermined re>uirements:
2.3 Perfor"ance ualification (P)*4 esta-lishing -y o-jeti4e e4idene that the proess, under
antiipated onditions, onsistently produes a produt 9hih meets all predetermined re>uirements:
2.$ Process validation4 esta-lishing -y o-jeti4e e4idene that a proess onsistently produes a
result or produt meeting its predetermined re>uirements:
2.' Process validation protocol4 a doument stating ho9 4alidation 9ill -e onduted, inluding
test parameters, produt harateristis, manu)aturing e>uipment, and deision points on 9hat
onstitutes aepta-le test results:
2., Verification4 on)irmation -y e<amination and pro4ision o) o-jeti4e e4idene that the
spei)ied re>uirements ha4e -een )ul)illed:
3 Process validation within the ualit! "ana#e"ent s!ste"
Proess 4alidation is part o) the integrated re>uirements o) a >uality management system: 5t is
onduted in the onte<t o) a system inluding design and de4elopment ontrol, >uality assurane,
proess ontrol, and orreti4e and pre4enti4e ation:
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The interrelationship o) design ontrol and proess de4elopment may, )or some tehnologies, -e 4ery
losely related: For others the relationship may -e remote: The produt should -e designed ro-ustly
enough to 9ithstand 4ariations in the manu)aturing proess and the manu)aturing proess should -e
apa-le and sta-le to assure ontinued sa)e produts that per)orm ade>uately: 6)ten this results in a
4ery interati4e produt de4elopment and proess de4elopment ati4ity:
Daily measuring and monitoring ati4ities are onduted as spei)ied -y the proess ontrol plan
9hih is o)ten largely de4eloped during proess 4alidation:
Correti4e ations o)ten identi)y inade>uate proesses.proess 4alidations: 2ah orreti4e ation
applied to a manu)aturing proess should inlude the onsideration )or onduting proess
4alidation.re4alidation:
3.1 Process validation decision
The )ollo9ing model may -e use)ul in determining 9hether or not a proess should -e 4alidated0

A
Is Process
Output
Verifiable
B
Is Verification
Sufficient &
Cost Effective
No No

E
Redesign
Product
and/or
Process
D
D
Validate

Yes Yes
C
Verify &
Control te
Process
Figure +0 Proess 4alidation deision tree
The model sho9n desri-es a deision tree that a manu)aturer an )ollo9 9hen deiding on 9hether
a proess needs to -e 4alidated: The proess under onsideration in this model is the simplest
possi-le - many proesses may -e large and.or a omple< set o) su--proesses:
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2ah proess should ha4e a spei)iation desri-ing -oth the proess parameters and the output
desired: The manu)aturer should onsider 9hether the output an -e 4eri)ied -y su-se>uent
monitoring or measurement 1A3: 5) the ans9er is positi4e, then the onsideration should -e made as to
9hether or not 4eri)iation alone is su))iient to eliminate unaepta-le risk and is a ost e))eti4e
solution 1B3: 5) yes, the output should -e 4eri)ied and the proess should -e appropriately ontrolled
1C3:
5) the output o) the proess is not 4eri)ia-le then the deision should -e to 4alidate the proess 1D3?
alternati4ely, it may -eome apparent that the produt or proess should -e redesigned to redue
4ariation and impro4e the produt or proess 1E3: ;lso, a hange in a manu)aturing proess may
result in the need )or proess 4alidation e4en though the proess )ormerly only re>uired 4eri)iation
and ontrol:
The risk or ost may also -e redued -y redesigning the produt or proess to a point 9here simple
4eri)iation is an aepta-le deision 1E3:
3.2 %&a"ples
The )ollo9ing ta-le is a list o) e<amples o) proesses 9hih0 1+3 should -e 4alidated, 1$3 may -e
satis)atorily o4ered -y 4eri)iation, and 133 proesses 9hih may -e 4eri)ia-le, -ut )or -usiness
purposes, 4alidation an -e hosen:
(1* Processes which should be validated
Sterili*ation proesses
Clean room am-ient onditions
;septi )illing proesses
Sterile pakaging sealing proesses
Eyophili*ation proess
Heat treating proesses
Plating proesses
Plasti injetion molding proesses
(2* Processes which "a! be satisfactoril! covered b! verification
Manual utting proesses
Testing )or olor, tur-idity, total pH )or solutions
!isual inspetion o) printed iruit -oards
Manu)aturing and testing o) 9iring harnesses
(3* Processes for which the above "odel "a! be useful in deter"inin# the need for
validation
Certain leaning proesses
Certain human assem-ly proesses
/umerial ontrol utting proesses
Certain )illing proesses
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Bhile the output o) a proess may -e 4eri)ia-le, appliation o) so)t9are used in that proess should -e
4alidated )or its intended use:
$ Statistical "ethods and tools for process validation
There are many methods and tools that an -e used in proess 4alidation: ; primer on statistis and
proess 4alidation is pro4ided in 2nne& 2 as a guide through the -asi onepts: Control harts,
apa-ility studies, designed e<periments, tolerane analysis, ro-ust design methods, )ailure modes and
e))ets analysis, sampling plans, and mistake proo)ing are some o) the e<amples:
' Conduct of a validation
'.1 Gettin# started
; onsideration should -e gi4en to )orm a multi-)untional team to plan and o4ersee the 4alidation
ati4ities: ; team approah 9ill help assure the 4alidation proesses are 9ell thought out, the
protools are omprehensi4e and that the )inal pakages are 9ell doumented and easy to )ollo9: The
team should ad4ise '9hat ould go 9rong(: The team also pro4ides an opportunity )or key )untional
areas to ommuniate early a-out important ne9 and hanged produts and proesses and an )oster
ooperation:
Mem-ers o) the 4alidation team ould inlude representati4es )rom or personnel 9ith e<pertise in0
Quality ;ssurane
2ngineering
Manu)aturing
6thers depending on ompany organi*ation and produt types0
Ea-oratory
Tehnial Ser4ies
Aesearh F De4elopment
Aegulatory ;))airs
Clinial 2ngineering
Purhasing.Planning
6ne the 4alidation team has -een )ormed, the ne<t step is to plan the approah and de)ine the
re>uirements: Many manu)aturers de4elop 9hat is re)erred to as a master 4alidation plan 9hih
identi)ies those proesses to -e 4alidated, the shedule )or 4alidations, interrelationships -et9een
proesses re>uiring 4alidation and timing )or re4alidations: 6ne these ha4e -een esta-lished, and the
purpose and sope )or 4alidations are learly stated and kno9n, protool de4elopment an ommene:
Follo9ing is a list o) ati4ities 9hih may -e used as a heklist to re4ie9 4alidation ati4ity0
Form multi-)untional team )or 4alidation
Plan the approah and de)ine the re>uirements
5denti)y and desri-e the proesses
Spei)y proess parameters and desired output
Deide on 4eri)iation and.or 4alidation
Create a master 4alidation plan
Selet methods and tools )or 4alidation
Create 4alidation protools
Per)orm 5Q, 6Q, PQ and doument results
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Determine ontinuous proess ontrols
Control the proess ontinuously
'.2 Protocol develop"ent
Detailed protools )or per)orming 4alidations are essential to ensure that the proess is ade>uately
4alidated: Proess 4alidation protools should inlude the )ollo9ing elements0
5denti)iation o) the proess to -e 4alidated
5denti)iation o) de4ie1s3 to -e manu)atured using this proess
6-jeti4e and measura-le riteria )or a suess)ul 4alidation
Eength and duration o) the 4alidation
Shi)ts, operators, e>uipment to -e used in the proess
5denti)iation o) utilities )or the proess e>uipment and >uality o) the utilities
5denti)iation o) operators and re>uired operator >uali)iation
Complete desription o) the proess
Aele4ant spei)iations that relate to the produt, omponents, manu)aturing materials, et:
;ny speial ontrols or onditions to -e plaed on preeding proesses during the 4alidation
Proess parameters to -e monitored, and methods )or ontrolling and monitoring
Produt harateristis to -e monitored and method )or monitoring
;ny su-jeti4e riteria used to e4aluate the produt
De)inition o) 9hat onstitutes non-on)ormane )or -oth measura-le and su-jeti4e riteria
Statistial methods )or data olletion and analysis
Consideration o) maintenane and repairs o) manu)aturing e>uipment
Criteria )or re4alidation
For all three phases, 5Q, 6Q, and PQ, -ased on produt.proess re>uirements0
Determine 9hat to 4eri)y.measure
Determine ho9 to 4eri)y.measure
Determine ho9 many to 4eri)y.measure, i:e: statistial signi)iane
Determine 9hen to 4eri)y.measure
De)ine aeptane.rejetion riteria
De)ine re>uired doumentation
Gno9ing e<atly 9hat the produt re>uirements are and 9hat key parameters 9ill -e neessary to
ans9er the >uestions o) 9hat to measure: Seal thikness, seal strength, pressure testing and 4isual
de)ets o) samples are e<amples o) measura-le parameters:
Htili*ing statistially 4alid tehni>ues suh as sampling, design e<periments, Taguhi methods,
response sur)ae studies and omponent s9apping are statistially 4alid tehni>ues to ans9er the
>uestions o) ho9 many to measure: Htili*ation o) standard test methods suh as suh as those
ontained in international or national standards 9ill pro4ide guidane in ho9 to measure spei)i
parameters: ;lso, it is important to ensure test methods repliate atual use onditions:
During the ondut o) 4arious phases o) 4alidation, the protool should address the resolution o)
disrepanies: Some de4iations in esta-lished protool may not negate the results: 2ah de4iation
should -e addressed, e4aluated and a onlusion dra9n as to aeptane or rejetion o) the results: ;s
a result, proess ontrol proedures may re>uire modi)iation and those modi)iations should -e
4alidated as part o) the o4erall proess:
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;ddressing all produt and proess re>uirements and the esta-lishment o) spei)i riteria )or eah
re>uirement, upper and lo9er limits -ased on produt spei)iations and esta-lished standards 9ill
help de)ine the aeptane.rejetion riteria:
'.3 Installation ualification (I)*
Simply put, 5Q means is it installed orretlyI 5mportant 5Q onsiderations are0
2>uipment design )eatures 1i:e: materials o) onstrution leana-ility, et:3
5nstallation onditions 19iring, utilities, )untionality, et:3
Cali-ration, pre4entati4e maintenane, leaning shedules
Sa)ety )eatures
Supplier doumentation, prints, dra9ings and manuals
So)t9are doumentation
Spare parts list
2n4ironmental onditions 1suh as lean room re>uirements, temperature, humidity3
Sometimes ati4ities are onduted at the e>uipment supplierCs site loation prior to e>uipment
shipment: 2>uipment suppliers may per)orm test runs at their )ailities and analy*e the results to
determine that the e>uipment is ready to -e deli4ered: Copies o) the suppliersC >uali)iation studies
should -e used as guides, to o-tain -asi data, and to supplement installation >uali)iation: Ho9e4er,
it is usually insu))iient to rely solely upon the 4alidation results o) the e>uipment supplier: 2ah
medial de4ie manu)aturer is ultimately responsi-le )or e4aluating, hallenging, and testing the
e>uipment and deiding 9hether the e>uipment is suita-le )or use in the manu)ature o) a spei)i
de4ie1s3: The e4aluations may result in hanges to the e>uipment or proess:
'.$ +perational ualification 6 (+)*
5n this phase the proess parameters should -e hallenged to assure that they 9ill result in a produt
that meets all de)ined re>uirements under all antiipated onditions o) manu)aturing, i:e:, 9orst ase
testing: During routine prodution and proess ontrol, it is desira-le to measure proess parameters
and.or produt harateristis to allo9 )or the adjustment o) the manu)aturing proess at 4arious
ation le4el1s3 and maintain a state o) ontrol: These ation le4els should -e e4aluated, esta-lished
and doumented during proess 4alidation to determine the ro-ustness o) the proess and a-ility to
a4oid approahing '9orst ase onditions:(
6Q onsiderations inlude0
Proess ontrol limits 1time, temperature, pressure, linespeed, setup onditions, et:3
So)t9are parameters
Aa9 material spei)iations
Proess operating proedures
Material handling re>uirements
Proess hange ontrol
Training
Short term sta-ility and apa-ility o) the proess, 1latitude studies or ontrol harts3
Potential )ailure modes, ation le4els and 9orst-ase onditions 1Failure Mode and 2))ets
;nalysis, Fault Tree ;nalysis3
The use o) statistially 4alid tehni>ues suh as sreening e<periments to esta-lish key
proess parameters and statistially designed e<periments to optimi*e the proess an -e
used during this phase:
Page 11
'.' Perfor"ance ualification 6 (P)*
5n this phase the key o-jeti4e is to demonstrate the proess 9ill onsistently produe aepta-le
produt under normal operating onditions: Please note the guidane )or proess sta-ility in ;nne<es
; and = 'Methods and tools )or proess 4alidation(:
PQ onsiderations inlude0
;tual produt and proess parameters and proedures esta-lished in 6Q
;epta-ility o) the produt
;ssurane o) proess apa-ility as esta-lished in 6Q
Proess repeata-ility, long term proess sta-ility
Challenges to the proess should simulate onditions that 9ill -e enountered during atual
manu)aturing: Challenges should inlude the range o) onditions as de)ined -y the 4arious ation
le4els allo9ed in 9ritten standard operating proedures as esta-lished in the 6Q phase: The
hallenges should -e repeated enough times to assure that the results are meaning)ul and onsistent:
Proess and produt data should -e analy*ed to determine 9hat the normal range o) 4ariation is )or
the proess output: Gno9ing the normal 4ariation o) the output is ruial in determining 9hether a
proess is operating in a state o) ontrol and is apa-le o) onsistently produing the spei)ied output:
6ne o) the outputs o) 6Q and PQ is the de4elopment o) attri-utes )or ontinuous monitoring and
maintenane: Proess and produt data should also -e analy*ed to identi)y any 4ariation due to
ontrolla-le auses: Depending on the nature o) the proess and its sensiti4ity, ontrolla-le auses o)
4ariation may inlude0
Temperature
Humidity
!ariations in eletrial supply
!i-ration
2n4ironmental ontaminants
Purity o) proess 9ater
Eight
Human )ators 1training, ergonomi )ators, stress, et:3
!aria-ility o) materials
Bear and tear o) e>uipment
;ppropriate measures should -e taken to eliminate ontrolla-le auses o) 4ariation: 2liminating
ontrolla-le auses o) 4ariation 9ill redue 4ariation in the proess output and result in a higher
degree o) assurane that the output 9ill onsistently meet spei)iations:
'., 7inal report
;t the onlusion o) 4alidation ati4ities, a )inal report should -e prepared: This report should
summari*e and re)erene all protools and results: 5t should deri4e onlusions regarding the
4alidation status o) the proess: The )inal report should -e re4ie9ed and appro4ed -y the 4alidation
team and appropriate management:
, -aintainin# a state of validation
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,.1 -onitor and control
Trends in the proess should -e monitored to ensure the proess remains 9ithin the esta-lished
parameters: Bhen monitoring data on >uality harateristis demonstrates a negati4e trend, the ause
should -e in4estigated, orreti4e ation may -e taken and re4alidation onsidered:
,.2 Chan#es in processes and.or product
;ny hanges in the proess and .or produt inluding hanges in proedures, e>uipment, personnel,
et: should -e e4aluated to determine the a))ets o) those hanges and the e<tent o) re4alidation
onsidered:
,.3 Continued state of control
!arious hanges may our in ra9 materials and.or proesses, 9hih are undeteted, or onsidered at
the time to -e inonse>uenial: 1;n e<ample o) this type o) proess is sterili*ation:3 These hanges
may umulati4ely a))et the 4alidation status o) the proess: Periodi re4alidation should -e
onsidered )or these types o) proesses:
,.$ %&a"ples of reasons for revalidation
Ae4alidation may -e neessary under suh onditions as0
hange1s3 in the atual proess that may a))et >uality or its 4alidation status
negati4e trend1s3 in >uality indiators
hange1s3 in the produt design 9hih a))ets the proess
trans)er o) proesses )rom one )aility to another
hange o) the appliation o) the proess
The need )or re4alidation should -e e4aluated and doumented: This e4aluation should inlude
historial results )rom >uality indiators, produt hanges, proess hanges, hanges in e<ternal
re>uirements 1regulations or standards3 and other suh irumstanes:
Ae4alidation may not -e as e<tensi4e as the initial 4alidation i) the situation does not re>uire that all
aspets o) the original 4alidation -e repeated: 5) a ne9 piee o) e>uipment is purhased )or a
4alidated proess, o-4iously the 5Q portion o) the 4alidation needs to -e repeated: Ho9e4er, most o)
the 6Q aspets are already esta-lished: Some elements o) PQ may need to -e repeated, depending on
the impat o) the ne9 e>uipment:
;nother e<ample might -e i) a ra9 material supplier is hanged, the impat o) that hange on the
proess and resultant produt should -e onsidered: Parts o) 6Q and PQ might need to -e redone, as
the interation -et9een the ne9 ra9 material and the proess may not -e )ully understood:
/ 0se of historical data for validation
!alidation o) a proess an -e partially -ased on aumulated historial manu)aturing, testing,
ontrol, and other data related to a produt or proess: This historial data may -e )ound in -ath
reords, manu)aturing log -ooks, lot reords, ontrol harts, test and inspetion results, ustomer
Page 13
)eed-ak, )ield )ailure reports, ser4ie reports, and audit reports: ; omplete 4alidation -ased on
historial data is not )easi-le i) all the appropriate data 9as not olleted, or appropriate data 9as not
olleted in a manner 9hih allo9s ade>uate analysis: Historial manu)aturing data o) a pass.)ail
nature is usually not ade>uate:
5) historial data is determined to -e ade>uate and representati4e, an analysis an -e onduted per a
9ritten protool to determine 9hether the proess has -een operating in a state o) ontrol and has
onsistently produed produt 9hih meets its predetermined re>uirements: The analysis should -e
doumented:
The terms 'retrospeti4e 4alidation(, 'onurrent 4alidation( and 'prospeti4e 4alidation( are o)ten
used: ;ny 4alidation an use historial data in the manner desri-ed a-o4e, regardless o) the term
used:
1 Su""ar! of activities
Initial considerations include4
Deide on 4eri)iation and.or 4alidation
If the decision is to validate4
Form multi-)untional team )or 4alidation
Plan the approah and de)ine the re>uirements
Spei)y proess parameters and desired output
Selet methods and tools )or 4alidation
Create 4alidation protools
Per)orm 5Q, 6Q, PQ and doument results
Determine ontinuous proess ontrols
Prepare )inal report and seure management appro4al
Control the proess ontinuously
-aintainin# a state of validation0
Monitor and ontrol the proess ontinuously
Ae4alidate as appropriate
Page 1$

2nne& 2 Statistical "ethods and tools for process validation
2.1 Introduction
Proess 4alidation re>uires that a proess is esta-lished that an onsistently on)orm to re>uirements
and then studies are onduted demonstrating that this is the ase: Proess de4elopment and
optimi*ation may lead diretly to the 4alidation o) the proess: 5n other 9ords, the methods )or
de4eloping and optimi*ing a proess may -e used 1and the data de4eloped3 to demonstrate proess
apa-ility and sta-ility: Thus there is o)ten not a lear distintion -et9een proess de4elopment and
proess 4alidation:
Ho9e4er, many proesses are 9ell esta-lished and su-jet to routine proess 4alidation: Many o) the
methods and tools desri-ed here may already -e used )or these proesses: ;s 4alidation methods and
tools are re4ie9ed )or e<isting proesses, some o) these may -e help)ul to impro4e 4alidation
protools and impro4e proesses:
This anne< desri-es the many ontri-utions that statistial methods and tools an make to 4alidation:
2ah tool appearing in -old is )urther desri-ed in 2nne& 2.3:
/onon)ormities o)ten our -eause o) errors made and -eause o) e<essi4e 4ariation: 6-taining a
proess that onsistently on)orms to re>uirements re>uires a -alaned approah using -oth mistake
proo)ing and 4ariation redution tools: Bhen a nonon)ormane ours -eause o) an error, "ista8e
proofin# "ethods should -e used: Mistake proo)ing attempts to make it impossi-le )or the error to
our or at least to go undeteted:
Ho9e4er, many nonon)ormities are not the result o) errors, instead they are the result o) e<essi4e
4ariation and o))-target proesses: Aeduing 4ariation and proper targeting o) a proess re>uires
identi)ying the key input 4aria-les and esta-lishing ontrols on these inputs to ensure that the outputs
on)orm to re>uirements:

6ne output o) proess 4alidation is the de4elopment o) a ontrol plan: The )inal phase o) 4alidation
re>uires demonstrating that this ontrol plan 9orks, i:e:, that it results in a proess that an
onsistently on)orm to re>uirements: 6ne key tool here is a capabilit! stud!: ; apa-ility study
measures the a-ility o) the proess to onsistently meet the spei)iations: 5t is appropriate )or
measura-le harateristis 9here nonon)ormities are due to 4ariation and o))-target onditions:
Testing should -e per)ormed not only at nominal, -ut also under 9orst-ase onditions: 5n the e4ent o)
potential errors, challen#e tests should -e per)ormed to demonstrate that mistake proo)ing methods
designed to detet or pre4ent suh errors are 9orking: 2cceptance sa"plin# plans an -e use)ul in
optimi*ing the num-er o) samples to -e tested and to demonstrate on)ormane to spei)iation:
2.2 Pri"er on statistics and process validation
2ah unit o) produt di))ers to some small degree )rom all other units o) produt: These di))erenes,
no matter ho9 small, are re)erred to as 4ariation: !ariation an -e harateri*ed -y measuring a
sample o) the produt and dra9ing a histogram: For e<ample, one operation in4ol4es utting 9ire
into +%% m lengths: The tolerane is +%% 8 m: ; sample o) +$ 9ires is seleted at random and the
)ollo9ing results o-tained0
,7:@ ,,:3 +%%:& ,@:J +%+:& +%$:%
+%%:$ ,J:& +%3:& +%$:% ,7:% +%%:8
; histogram o) this data is sho9n -elo9: The 9idth o) the histogram represents the 4ariation:
Page 1'
N
u
m
b
e
r
0
1
2
3
USL
LSL
100 105 95
Length (cm)
Figure $0 Histogram o) data
6) speial interest is 9hether the histogram is properly entered and 9hether the histogram is narro9
enough to easily )it 9ithin the spei)iation limits: The enter o) the histogram is estimated -y
alulating the a4erage o) the +$ readings: The a4erage is ,,:,, m: The 9idth o) the histogram is
estimated -y alulating either the range or standard de4iation: The range o) the a-o4e readings is @:%
m: The standard de4iation is $:%J m: The standard de4iation represents the typial distane a unit
is )rom the a4erage: ;ppro<imately hal) o) the units are 9ithin + standard de4iation o) the a4erage
and a-out hal) o) the units are more than one standard de4iation a9ay )rom the a4erage: 6n the other
hand, the range represents an inter4al ontaining all the units: The range is typially 3 to J times the
standard de4iation:
Fre>uently, histograms take on a -ell-shaped appearane that is re)erred to as the normal ur4e as
sho9n -elo9: For the normal ur4e, ,,:@3K o) the units )all 9ithin 3 standard de4iations o) the
a4erage:
Average Average - 3 St! Dev! Average " 3 St! Dev!
99!#3$
Figure 30 /ormal ur4e applied to histogram
For measura-le harateristis like 9ire length, )ill 4olume, and seal strength, the goal is to optimi*e
the a4erage and redue the 4ariation: 6ptimi*ation o) the a4erage may mean to enter the proess as
in the ase o) )ill 4olumes, to ma<imi*e the a4erage as is the ase 9ith seal strengths, or to minimi*e
the a4erage as is the ase 9ith harm)ul emissions: 5n all ases, 4ariation redution is also re>uired to
ensure all units are 9ithin spei)iations: Aeduing 4ariation re>uires the ahie4ement o) sta-le and
apa-le proesses: Figure & sho9s an unsta-le proess: The proess is onstantly hanging: The
a4erage shi)ts up and do9n: The 4ariation inreases and dereases: The total 4ariation inreases due
to the shi)ting:
Page 1,

!
i
"
e
UNS%ABLE &'(CESS
%)ta*
+ar,at,)n
Figure &0 Hnsta-le proess
5nstead, sta-le proesses are desired as sho9n in )igure 8: Sta-le proesses produe a onsistent le4el
o) per)ormane: The total 4ariation is redued: The proess is more predita-le:
%
,
m
e
S%ABLE &'(CESS
%)ta*
+ar,at,)n
Figure 80 Sta-le proess
Ho9e4er, sta-ility is not the only thing re>uired: 6ne a onsistent per)ormane has -een ahie4ed,
the remaining 4ariation must -e made to sa)ely )it 9ithin the upper and lo9er spei)iation limits:
Suh a proess is then said to -e sta-le and apa-le: Suh a proess an -e relied on to onsistently
produe good produt as illustrated in )igure J:
Page 1/
%
,
m
e
&'(CESS CA&AB-L-%.
CA&ABLE
N(%
CA&ABLE
S/ec
L,m,t0
Figure J0 Proess apa-ility
; capabilit! stud! is used to determine 9hether a proess is sta-le and apa-le: 5t in4ol4es
olleting samples o4er a period o) time: The a4erage and standard de4iation o) eah time period is
estimated and these estimates plotted in the )orm o) a control chart: These control charts are used to
determine i) the proess is sta-le: 5) it is, the data an -e om-ined into a single histogram to
determine its apa-ility: To help determine i) the proess is apa-le, se4eral apa-ility indies are
used to measure ho9 9ell the histogram )its 9ithin the spei)iation limits: 6ne inde< alled C
p
is
used to e4aluate the 4ariation: ;nother inde< C
pk
is used to e4aluate the entering o) the proess:
Together these t9o indies are used to deide 9hether the proess meets its re>uirements: The 4alues
re>uired to pass depend on the se4erity o) the de)et 1major, minor, ritial3 that the manu)aturer
onsiders aepta-le:
Bhile apa-ility studies e4aluate the a-ility o) a proess to onsistently produe good produt, these
studies do little to help ahie4e suh proesses: Aeduing 4ariation and the ahie4ement o) sta-le
proesses re>uires the use o) numerous 4ariation redution tools: !ariation o) the output is aused -y
4ariation o) the inputs: Consider the e<ample o) a simple system, suh as a pump )or mo4ing )luids0

Figure @0 The pump
;n output is )lo9 rate: The pump uses a piston to dra9 a )luid into a ham-er through one opening
and then pushes it -ak out another opening: !al4es are used to keep the )luid mo4ing in the right
diretion: Flo9 rate 9ill -e a))eted -y piston radius, stroke length, motor speed and 4al4e -ak)lo9
to name a )e9: The target )lo9 rate is ahie4ed -y designing the piston radius, stroke length, motor
speed, et: The atual )lo9 rate 9ill 4ary due to 4ariation in 9ear o) the piston, 9ear o) the -earings,
9ear o) the 4al4es, 4ariation o) the motor speed, temperature.4isosity o) the )luid, et: !ariation o)
the inputs is transmitted to the output as sho9n -elo9:
Page 11

%'ANS1-SS-(N (2 +A'-A%-(N
(
U
%
&
U
%
-N&U%
'e*at,)n0h,/ Bet3een
-n/ut an (ut/ut
+ar,at,)n )4 -n/ut
%ran0m,tte
+ar,at,)n
Figure 70 Transmission o) 4ariation
Aeduing 4ariation re>uires identi)ying the key input 4aria-les a))eting the outputs, designing the
proess to take ad4antage o) relati4e input sensiti4ities 1the relationships -et9een ylinder radius,
stroke length, motor speed and output3 and esta-lishing ontrols on input 4ariation 19ear, motor
speed, temperature.4isosity, et:3 to ensure that the outputs on)orm to their esta-lished
spei)iations: 5n general one should, identi)y the key input 4aria-les, understand the e))et o) these
inputs on the output, understand ho9 the inputs -eha4e and )inally, use this in)ormation to esta-lish
targets 1nominals3 and toleranes 19indo9s3 )or the inputs: !arious tehni>ues an -e used:
6ne type o) designed e<periment alled a screenin# e&peri"ent an -e used to identi)y the key
inputs: ;nother type o) designed e<periment alled a response surface stud! an -e used to o-tain a
detailed understanding o) the e))ets o) the key inputs on the outputs: Capabilit! studies an -e used
to understand the -eha4ior o) the key inputs: ;rmed 9ith this kno9ledge, robust desi#n "ethods
an -e used to identi)y optimal targets )or the inputs and tolerance anal!sis an -e used to esta-lish
operating 9indo9s or ontrol shemes that ensure the output onsistently on)orms to re>uirements:
The o-4ious approah to reduing 4ariation is to tighten toleranes on the inputs: This impro4es
>uality -ut generally dri4es up osts: The ro-ust design methods pro4ide an alternati4e: Ao-ust
design 9orks -y seleting targets )or the inputs that make the outputs less sensiti4e 1more ro-ust3 to
the 4ariation o) the inputs as sho9n -elo9: The result is less 4ariation and higher >uality -ut 9ithout
the added osts: Se4eral approahes to ro-ust design e<ist inluding 9a#uchi "ethods, dual
response approach and robust tolerance anal!sis:
Page 15
(
U
%
&
U
%
-N&U%
'(BUS% DES-5N
Sen0,t,ve
')bu0t
Figure ,0 Ao-ust design
;nother important tool is a control chart:
Figure +%0 Control Chart
=y monitoring the results o) hanges o) inputs through ontrol harting, the resultant 4ariation in
output an -e determined and inherent 4ariation o) the proess identi)ied: Hltimately, ontrol harting
may -e used to ontinuously monitor the proess and assure a state o) 4alidated ontrol: Control or
ation le4els an -e determined to adjust the proess and maintain the proess 9ithin the ontrol
limits:

!arget
#pper Spec $%cceptance& 'i"it
'o(er Spec $%cceptance& 'i"it

C)ntr)* Chart
)orst Case
)orst Case
Control $%ction& 'evel
Control $%ction& 'evel
!i"e 6 * average of a set of observations
Page 20

Many other tools also e<ist )or identi)ying key inputs and soures o) 4ariation inluding co"ponent
swappin# studies, "ulti6vari charts, anal!sis of "eans 1;/6M3, and variance co"ponents
anal!sis, and anal!sis of variance 1;/6!;3:
Bhen studying 4ariation, good measurements are re>uired: Many times an e4aluation o) the
measurement system should -e per)ormed using a #au#e :;: or similar study:
2.3 Descriptions of the tools
; -rie) desription o) eah o) the ited tools )ollo9s0
2cceptance Sa"plin# Plan " ;n aeptane sampling plan takes a sample o) produt and uses this
sample to make an aept or rejet deision: ;eptane sampling plans are ommonly used in
manu)aturing to deide 9hether to aept 1release3 or to rejet 1hold3 lots o) produt: Ho9e4er, they
an also -e used during 4alidation to aept 1pass3 or to rejet 1)ail3 the proess: Follo9ing the
aeptane -y a sampling plan, one an make a on)idene statement suh as0 'Bith ,8K on)idene,
the de)et rate is -elo9 +K de)eti4e:(
2nal!sis of -eans (2<+-* " Statistial study )or determining i) signi)iant di))erenes e<ist
-et9een a4ities, instruments, et: 5t has many uses inluding determining i) a measurement de4ie is
reprodui-le 9ith respet to operators and determining i) di))erenes e<ists -et9een )ill heads, et:
Simpler and more graphial alternati4e to ;nalysis o) !ariane 1;/6!;3:
2nal!sis of Variance (2<+V2* " Statistial study )or determining i) signi)iant di))erenes e<ist
-et9een a4ities, instruments, et: Statistially, this is de)ined as a methodology )or e4aluating the
results o) )atorial e<periments designed to determine the relati4e in)luene o) the )ators and
interations 9hih ause 4ariation in a proess: ;lternati4e to ;nalysis o) Means 1;/6M3:
Capabilit! Stud! " Capa-ility studies are per)ormed to e4aluate the a-ility o) a proess to
onsistently meet a spei)iation: ; apa-ility study is per)ormed -y seleting a small num-er o)
units periodially o4er time: 2ah period o) time is alled a su-group: For eah su-group, the
a4erage and range is alulated: The a4erages and ranges are plotted o4er time using a ontrol hart
to determine i) the proess is sta-le or onsistent o4er time: 5) so, the samples are then om-ined to
determine 9hether the proess is ade>uately entered and the 4ariation is su))iiently small: This is
aomplished -y alulating apa-ility inde<es: The most ommonly used apa-ility indies are C
p

and C
pk
: 5) aepta-le 4alues are o-tained, the proess onsistently produes produt that meets the
spei)iation limits: Capa-ility studies are )re>uently used to9ards the end o) the 4alidation to
demonstrate that the outputs onsistently meet the spei)iations: Ho9e4er, they an also -e used to
study the -eha4ior o) the inputs in order to per)orm a tolerane analysis:
Challen#e 9est " ; hallenge test is a test or hek per)ormed to demonstrate that a )eature or
)untion is 9orking: For e<ample, to demonstrate that the po9er -akup is )untioning, po9er ould
-e ut to the proess: To demonstrate that a sensor designed to detet -u--les in a line 9orks, -u--les
ould -e purposely introdued:
Co"ponent Swappin# Stud! " Study to isolate the ause o) a di))erene -et9een t9o units o)
produt or t9o piees o) e>uipment: Ae>uires the a-ility to disassem-le units and s9ap omponents
in order to determine i) the di))erene remains 9ith original units or mo4es 9ith the s9apped
omponents:
Page 21
Control Chart " Control harts are used to detet hanges in the proess: ; sample, typially
onsisting o) 8 onseuti4e units, is seleted periodially: The a4erage and range o) eah sample is
alulated and plotted: The plot o) the a4erages is used to determine i) the proess a4erage hanges:
The plot o) the ranges is used to determine i) the proess 4ariation hanges: To aid in determining i) a
hange has ourred, ontrol limits are alulated and added to the plots: The ontrol limits represent
the ma<imum amount that the a4erage or range should 4ary i) the proess does not hange: ; point
outside the ontrol limits indiates that the proess has hanged: Bhen a hange is identi)ied -y the
ontrol hart, an in4estigation should -e made as to the ause o) the hange: Control harts help to
identi)y key input 4aria-les ausing the proess to shi)t and aid in the redution o) the 4ariation:
Control harts are also used as part o) a apa-ility study to demonstrate that the proess is sta-le or
onsistent:
Desi#ned %&peri"ent 1Design o) 2<periments or D623 " The term designed e<periment is a general
term that enompasses sreening e<periments, response sur)ae studies, and analysis o) 4ariane: 5n
general, a designed e<periment in4ol4es purposely hanging one or more inputs and measuring
resulting e))et on one or more outputs:
Dual :esponse 2pproach to :obust Desi#n " 6ne o) three approahes to ro-ust design: 5n4ol4es
running response sur)ae studies to model the a4erage and 4ariation o) the outputs separately: The
results are then used to selet targets )or the inputs that minimi*e the 4ariation 9hile entering the
a4erage on the target: Ae>uires that the 4ariation during the study -e representati4e o) long term
manu)aturing: ;lternati4es are Taguhi methods and ro-ust tolerane analysis:
7ailure -odes and %ffects 2nal!sis (7-%2* " ;n FM2; is systemati analysis o) the potential
)ailure modes: 5t inludes the identi)iation o) possi-le )ailure modes, determination o) the potential
auses and onse>uenes and an analysis o) the assoiated risk: 5t also inludes a reord o) orreti4e
ations or ontrols implemented resulting in a detailed ontrol plan: FM2;s an -e per)ormed on
-oth the produt and the proess: Typially an FM2; is per)ormed at the omponent le4el, starting
9ith potential )ailures and then traing up to the onse>uenes: This is a -ottom up approah: ;
4ariation is a Fault Tree ;nalysis, 9hih starts 9ith possi-le onse>uenes and traes do9n to the
potential auses: This is the top do9n approah: ;n FM2; tends to -e more detailed and -etter at
identi)ying potential pro-lems: Ho9e4er, a )ault tree analysis an -e per)ormed earlier in the design
proess -e)ore the design has -een resol4ed do9n to indi4idual omponents:
7ault 9ree 2nal!sis (792* " ; 4ariation o) a )ailure analysis: See FM2; )or a omparison:
Gau#e :;: Stud! " Study )or e4aluating the preision and auray o) a measurement de4ie and
the reprodui-ility o) the de4ie 9ith respet to operators:
-ista8e Proofin# -ethods " Mistake proo)ing re)ers to the -road array o) methods used to either
make the ourrene o) a de)et impossi-le or to ensure that the de)et does not pass undeteted: The
#apanese re)er to mistake proo)ing as Poka-Loke: The general strategy is to )irst attempt to make it
impossi-le )or the de)et to our: For e<ample, to make it impossi-le )or a part to -e assem-led
-ak9ards, make the ends o) the part di))erent si*es or shapes so that the part only )its one 9ay: 5)
this is not possi-le, attempt to ensure the de)et is deteted: This might in4ol4e mounting a -ar a-o4e
a hute that 9ill stop any parts that are too high )rom ontinuing do9n the line: 6ther possi-ilities
inlude mitigating the e))et o) a de)et 1seat -elts in ars3 and to lessen the hane o) human errors
-y implementing sel)-heks:
-ulti6Vari Chart " Graphial proedure )or isolating the largest soure o) 4ariation so that )urther
e))orts onentrate on the largest soure o) 4ariation:
:esponse Surface Stud! " ; response sur)ae study is a speial type o) designed e<periment 9hose
purpose is to model the relationship -et9een the key input 4aria-les and the outputs: Per)orming a
response sur)ae study in4ol4es running the proess at di))erent settings )or the inputs, alled trials,
Page 22

and measuring the resulting outputs: ;n e>uation an then -e )it to the data to model the a))ets o) the
inputs on the outputs: This e>uation an then -e used to )ind optimal targets using ro-ust design
methods and to esta-lish targets or operating 9indo9s using a tolerane analysis: The num-er o)
trials re>uired -y a response sur)ae study inreases e<ponentially 9ith the num-er o) inputs: 5t is
desira-le to keep the num-er o) inputs studied to a minimum: Ho9e4er, )ailure to inlude a key input
an ompromise the results: To ensure that only the key input 4aria-les are inluded in the study, a
sreening e<periment is )re>uently per)ormed )irst:
:obust Desi#n -ethods " Ao-ust design methods re)ers olleti4ely to the di))erent methods o)
seleting optimal targets )or the inputs: Generally, 9hen one thinks o) reduing 4ariation, tightening
toleranes omes to mind: Ho9e4er, as demonstrated -y Taguhi, 4ariation an also -e redued -y
the are)ul seletion o) targets: Bhen nonlinear relationships e<ist -et9een the inputs and the
outputs, one an selet targets )or the inputs that make the outputs less sensiti4e to the inputs: The
result is that 9hile the inputs ontinue to 4ary, less o) this 4ariation is transmitted to the output: The
result is that the output 4aries less: Aeduing 4ariation -y adjusting targets is alled ro-ust design: 5n
ro-ust design the o-jeti4e is to selet targets )or the inputs that result in on-target per)ormane 9ith
minimum 4ariation: Se4eral methods o) o-taining ro-ust designs e<ist inluding ro-ust tolerane
analysis, dual response approah and Taguhi methods:
:obust 9olerance 2nal!sis " 6ne o) three approahes to ro-ust design: 5n4ol4es running a designed
e<periment to model the outputCs a4erage and then using the statistial approah to tolerane analysis
to predit the outputCs 4ariation: Ae>uires estimates o) the amounts that the inputs 9ill 4ary during
long-term manu)aturing: ;lternati4es are Taguhi methods and ro-ust tolerane analysis:
Screenin# %&peri"ent " ; sreening e<periment is a speial type o) designed e<periment 9hose
primary purpose is to identi)y the key input 4aria-les: Sreening e<periments are also re)erred to as
)rational )atorial e<periments or Taguhi E-arrays: Per)orming a sreening e<periment in4ol4es
running the proess at di))erent settings )or the inputs, alled trials, and measuring the resulting
outputs: From this, it an -e determined 9hih inputs a))et the outputs: Sreening e<periments
typially re>uire t9ie as many trials as input 4aria-les: For e<ample, 7 4aria-les an -e studied in +J
trials: This makes it possi-le to study a large num-er o) inputs in a reasona-le amount o) time:
Starting 9ith a larger num-er o) 4aria-les redues the hanes o) missing an important 4aria-le:
Fre>uently a response sur)ae study is per)ormed )ollo9ing a sreening e<periment to gain )urther
understanding o) the a))ets o) the key input 4aria-les on the outputs:
9a#uchi -ethods " 6ne o) three approahes to ro-ust design: 5n4ol4es running a designed
e<periment to get a rough understanding o) the e))ets o) the input targets on the a4erage and
4ariation: The results are then used to selet targets )or the inputs that minimi*e the 4ariation 9hile
entering the a4erage on the target: Similar to the dual response approah e<ept that 9hile the study
is -eing per)ormed, the inputs are purposely adjusted -y small amounts to mimi long-term
manu)aturing 4ariation: ;lternati4es are the dual response approah and ro-ust tolerane analysis:
9olerance 2nal!sis " Hsing tolerane analysis, operating 9indo9s an -e set )or the inputs that
ensure the outputs 9ill on)orm to re>uirements: Per)orming a tolerane analysis re>uires an e>uation
desri-ing the e))ets o) the inputs on the output: 5) suh an e>uation is not a4aila-le, a response
sur)ae study an -e per)ormed to o-tain one: To help ensure manu)atura-ility, toleranes )or the
inputs should initially -e -ased on the plants and suppliers a-ility to ontrol them: Capa-ility studies
an -e used to estimate the ranges that the inputs urrently 4ary o4er: 5) this does not result in an
aepta-le range )or the output, the tolerane o) at least one input must -e tightened: Ho9e4er,
tightening a tolerane -eyond the urrent apa-ility o) the plant or supplier re>uires that
impro4ements -e made or that a ne9 plant or supplier -e seleted: =e)ore tightening any toleranes,
ro-ust design methods should -e onsidered:
Variance Co"ponents 2nal!sis " Statistial study used to estimate the relati4e ontri-utions o)
Page 23
se4eral soures o) 4ariation: For e<ample, 4ariation on a multi-head )iller ould -e the result o)
shi)ting o) the proess a4erage o4er time, )illing head di))erenes and short-term 4ariation 9ithin a )ill
head: ; 4ariane omponents analysis an -e used to estimate the amount o) 4ariation ontri-uted -y
eah soure:
Page 2$

2nne& 3 %&a"ple validation
7oreword
Heat sealing proesses, as desri-ed in this e<ample, use e>uipment to seal plasti pouhes 9hih
per)orm as sterility -arriers )or disposa-le medial de4ies: Seal integrity is ruial )or maintenane
o) sterility: Testing o) seal integrity is usually destruti4e testing, and the proess there)or is a speial
proess 9hih re>uires 4alidation:
This ;nne< is presented only to gi4e a simple and -rie) e<ample o) the nature o) a proess 4alidation:
The heat seal proess desri-ed should not -e onsidered a model )or all heat seal 4alidations:
;dditionally, this e<ample may -e modi)ied aording to di))erent >uality management systems,
doumentation methods and ultures o) regions and.or ountries 9hih use this guidane:
There are many other irumstanes and 4aria-les that might -e onsidered 9hen 4alidating an atual
heat seal proess: This e<ample uses only three simple input 4aria-les0 time, temperature and
pressure: There may -e many more input 4aria-les, suh as operator training, material thikness and
melt inde<es o) the plasti pouhes: ;dditionally, all the details surrounding the rationale )or spei)i
sample si*es, ontrol limits, et: are not gi4en:
Page 2'
23C -edical Device Co"pan!
Process Validation Protocol
PVP 516101
Title0 Heat Sealer !alidation
Produts to -e o4ered0 Sterile Gi*mos " Codes +$3&8 through +$@7,
2>uipment.Proess to -e !alidated0 Supplier Co:, Model <y*, ;=C Manu)aturing 2>uipment
Aegister0 M2A ,7-+$&7 . Heat Sealing Proess0 S6P $%-+$-+&
Proess.Produt Change Control /um-er0 PPC/ ,7-3J&
6-jeti4e0
Supplier Co: has de4eloped a ne9 and impro4ed heat sealer, 9hih should impro4e proess )lo9 and
redue setup time: The heat sealer 9ill -e 4alidated to assure it per)orms 9ith e<isting sterile -arrier
pouh materials and e<isting proess proedure S6P $%-+$-+&: S6P $%-+$-+& identi)ies a design
re>uirement )or a seal strength o) $ to & kg and a target o) 3 kg: The most di))iult pouhes to seal are
the smallest 1P/ ,J-+$$3 and the largest 1P/ 77-%+%3: The target proess apa-ility is a C
pk
o) M+:
Ae)erene Douments0
+: Heat Seal Proess Proedure, S6P $%-+$-+&
$: Statistial Methodologies, S6P 3-7-8+, S6P 3-,-+$, S6P 3-+3-7+
3: Master De4ie Aeords, Codes +$<<<
&: Manu)aturing 2>uipment Aegister, M2A ,7-+$&7
8: Supplier Co: Model <y* Heat Sealer 6perating Manual
J: Proess !alidation Master Plan0 P!P-,7%%+
@: Ea- Proesses and Cali-ration0 S6P ,-$-8
7: Prodution Proesses and Cali-ration0 S6P $%-+-$
,: Clean Aoom Proedures0 S6P +-+$-@@
!alidation Plan0
The Supplier Co: Model <y* Heat Sealer 9ill -e su-jeted to the 5nstallation Quali)iation,
6perational Quali)iation and Per)ormane Quali)iation proedures outlined in the Master !alidation
Plan0 P!P-,7%%+: Statistial methods in S6P 3-<-< 9ill -e used as appropriate:
The 5nstallation Quali)iation 9ill utili*e the heat sealer operating manual to de)ine re>uirements )or
eletrial and air pressure re>uirements: The heat sealer 9ill -e installed, heked and ali-rated in
Clean Aoom 3 during a 9eekend, -e)ore the 9eekend sru--do9n: Partiular attention 9ill -e paid to
the e<haust o) pressuri*ed air into the lean room, so that the re>uirement )or integrity o) the
en4ironment is not ompromised: ; heklist o) re>uirements 9ill -e ompleted and results
appro4ed:
6perational Quali)iation 9ill -e ompleted in three phases: First, during prodution do9n time, the
heat sealer 9ill -e su-jeted to an initial -urn-in to o-ser4e the sta-ility o) the measurements o) lamp
losure time, temperature -uild and pressures: Pouhes 9ill -e sealed, -ut detailed assessments o)
seal integrity 9ill not -e ompleted: Data )or lamp losure time, temperature -uild and pressures
9ill -e reorded: !ariations in these measures 9ill -e su-jeted to a sreening e<periment 1S6P 3-7-
8+3 to determine possi-le 9orst ase situations and the risk o) 9eak seals or o4er-urning o) the
pouhes: 5nitial optimal heat seal settings 9ill also -e esta-lished:
Page 2,

The seond phase o) operational >uali)iation 9ill enter the proess and determine initial proess
apa-ility: The proess 9ill -e onduted o)) line, -ut during prodution, in the lean room and 9ith
prodution personnel: Prodution personnel 9ill -e trained on the use o) the ne9 heat sealer: Heat
seals 9ill -e ompleted )or pouhes P/ ,J-+$$ and P/ 77-%+%: Heat sealer settings )or the time,
temperature and pressure 9ill -e used 9hih 9ere determined to -e optimal during the initial phase o)
operational >uali)iation: ;elerated sampling plan +-; )rom S6P 3-,-+$ 9ill -e used and the
results ontrol harted: The seal strength target result 9ill -e 3 kg and the 4ariation monitored: The
num-er o) runs, samples and e4aluations 9ill ontinue until it is determined that the C
p
is M+ per S6P
3-+3-7+: 6ptimal heat sealer settings 9ill -e determined )or the ne<t phase:
The third phase o) operational >uali)iation 9ill determine the sensiti4ity o) the proess to 4ariations
in time, temperature and pressure: The normal prodution proess 9ill -e used: Prodution personnel
9ill -e trained on the use o) the ne9 heat sealer: Borst ase om-inations o) time, temperature and
pressure 9ill -e e4aluated: Auns 9ill -e ompleted +3 9ith the optimal settings, $3 9ith a short d9ell
time, lo9 temperature and lo9 pressure? and 33 long d9ell time, high temperature and high pressure:
;tion le4els )or adjustment o) the heat sealer 9ill -e determined as a result o) this phase:
Per)ormane >uali)iation 9ill ommene a)ter satis)atory ompletion o) operational >uali)iation:
6ptimal settings )or the heat sealer 9ill -e used and the heat seal ation le4els )or adjustment o) time,
temperature and pressure 9ill -e used: ;elerated sampling plan $-C )rom S6P 3-,-+$ 9ill -e used
and the results ontrol harted: !ariations in seal strength 9ill -e in4estigated and root auses
determined: Bhen proess sta-ility is demonstrated, and the proess 4ariation demonstrates a 4alue
o) C
pk
M + per S6P 3-+3-7+, the proess 9ill -e onsidered 4alidated and S6P $%-+$-+& 9ill -e used
to ontrol the proess:
Measurement . Testing 2>uipment and Cali-ration0
+: Stop9ath, Proess De4elopment Ea-, Cali-rated per S6P ,-$-8
$: Aemote 5A Thermometer AST-+$, Proess De4elopment Ea-, Cali-rated per S6P ,-$-8
3: Pressure gauge, % " 8%%kPa, Proess De4elopment Ea-, Cali-rated per S6P ,-$-8
&: !;A meter, 5D J73, Proess De4elopment Ea-, Cali-rated per S6P ,-$-8
8: Heat Seal Pull Tester, P2 7+J@, Prodution, Cali-rated per S6P $%-+-$
2>uipment Maintenane0
During 4alidation the heat sealer 9ill -e maintained per the Supplier Co: 6perating Manual: Hpon
ompletion o) the 4alidation, Manu)aturing 2>uipment Aegister, M2A ,7-+$&7 9ill -e updated to
inlude maintenane and ali-ration o) the heat sealer:
Ae4alidation0
Hpon ompletion o) the 4alidation, the Proess !alidation Master Plan0 P!P-,7%%+ 9ill -e updated to
inlude the heat sealer in the master 4alidation shedule:
Page 2/
!alidation Team Protool ;ppro4al
!ohn "#ith
Date0 +8 /o4: +,,7 Title0 Sr: Quality 2ngineer
=ohn S"ith
$aula !ohnson Date0 +8 /o4: +,,7 Title0 Prodution
Super4isor
Paula =ohnson
%andy !a&oby
Date0 +8 /o4: +,,7 Title0 Plant Manager
:and! =acob!
"ue 'ro(n Date0 +8 /o4: +,,7 Title0 AFD Projet Eeader
Sue 3rown
Claudia 'e&)er Date0 +8 /o4: +,,7 Title0 Plant Quality
Manager
Claudia 3ec8er
Protool Aegistered in Do Center0
$ris&illa !ohnson Date0 +7 /o4: +,,7 Title0 Doument Center
Manager
Priscilla =ohnson
Page 21

Installation )ualification :esults
PVP 516101
5nstallation Cheklist
Ae>uirements 9ere esta-lished )rom the heat sealer operating manual, lean room proedures 1S6P +-+$-@@3
and heat seal proess proedure 1S6P $%-+$-+&3:
Ae>uirement Soure Status
2letrial supply heat sealer operating manual on)orms
;ir pressure heat sealer operating manual on)orms
2rgonomi positioning heat sealer operating manual on)orms
Spare parts heat sealer operating manual
F S6P $%-+$-+& on)orms
Clean air e<haust S6P +-+$-@@ on)orms
Cleana-ility around e>uipment S6P +-+$-@@ on)orms
;essi-ility )or maintenane S6P $%-+$-+& on)orms
Capa-ility )or si*es o) pouhes S6P $%-+$-+& on)orms
5nitial =urn-in
The heat sealer operated as desri-ed in the heat sealer operating manual and as re>uired -y S6P $%-
+$-+&:
Cali-ration
;ll gauges and measuring de4ies on the heat sealer 9ere suess)ully ali-rated per S6P $%-+-$:
Ea- /ote-ook Ae)erene
Quality 2ngineering Ea- /ote-ook, #BS, ,7-&, pages &J " J$:
5ssues . Commentary
/o ne9 issues 9ere identi)ied:
The en4ironmental hallenge o) the air e<haust 9as met -y adding an oil -ased air )ilter to the e<haust
line o) the heat sealer: The partiulate matter 9as monitored per S6P ,-+8-7& and no hanges )rom
normal le4els 9ere deteted:
The heat sealer installation 9as suess)ul:
Page 25
!alidation Team 5Q Aesults ;ppro4al
!ohn "#ith
Date0 +8 De: +,,7 Title0 Sr: Quality 2ngineer
=ohn S"ith
Paula "ohnson Date0 +8 De: +,,7 Title0 Prodution
Super4isor
Paula #ohnson
%andy !a&oby
Date0 +8 De: +,,7 Title0 Plant Manager
:and! =acob!
"ue 'ro(n Date0 +8 De: +,,7 Title0 AFD Projet Eeader
Sue 3rown
Claudia 'e&)er Date0 +8 De: +,,7 Title0 Plant Quality
Manager
Claudia 3ec8er
5Q Aesults Aegistered in Do Center0
$ris&illa !ohnson Date0 +7 De: +,,7 Title0 Doument Center
Manager
Priscilla =ohnson
Page 30

+perational )ualification :esults
PVP 516101
Phase 6ne
Clamp losure time, temperature -uild and pressures 9ere measured o4er a )our-hour time )rame 9ith
initial heat seal settings )or time, temperature and pressure: Control harts 9ere ompleted as )ollo9s0
Clamp Closure Time in Seonds

Target - +:8 Seonds
Hpper Eimit - $:%
Seonds
Eo9er Eimit - +:%
Seonds
Temperature in Degrees Centigrade Centigrade

Target - +J%
o
C
Hpper Eimit - +@%
o
C
Eo9er Eimit - +8%
o
C

Target " 3$8 kPa
Hpper Eimit - 38% kPa
Eo9er Eimit " 3%% kPa

Pressure in kPa
Page 31
From this analysis, it is apparent that the temperature is the most 4aria-le 9ithin the lo9er and upper
limits )or temperature: ;lso, temperatures 9ere under the limit )or the )irst )i)teen to t9enty minutes,
as the sealer re>uires this time to 9arm up: This sreening e<periment demonstrated that temperature
might -e the primary )ator in)luening heat seal integrity:
5nitial optimal heat sealer settings 9ere esta-lished0 temperature ontroller setting o) @:8, losure time
setting o) +:8 seonds and pressure setting o) 3$8 kPa:
Phase T9o
Aesponse sur)ae studies 9ere onduted to determine the e))ets o) key inputs on seal strength:
!ariations in settings 9ere used and the resultant seal strength )or ten pouhes 9as alulated: The
)ollo9ing ta-le summari*es the results0
Trial Aun Pouh Si*e Time Temperature Pressure Seal Strength
+ Small +:% +8% 3%% ;4erage $:+, J +:$
$ Earge +:% +8% 3%% ;4erage $:3, J +:7
3 Small +:8 +8% 3%% ;4erage $:$, J +:J
& Earge +:8 +8% 3%% ;4erage $:8, J +:3
8 Small $:% +8% 3%% ;4erage $:&, J +:8
J Earge $:% +8% 3%% ;4erage $:7, J +:%
@ Small +:% +J% 3%% ;4erage 3:%, J %:&
7 Earge +:% +J% 3%% ;4erage 3:+, J %:J
, Small +:8 +J% 3%% ;4erage 3:3, J %:8
+% Earge +:8 +J% 3%% ;4erage 3:&, J %:J
++ Small $:% +J% 3%% ;4erage $:,, J %:3
+$ Earge $:% +J% 3%% ;4erage $:7, J %:&
+3 Small +:% +@% 3%% ;4erage 3:+, J %:J
+& Earge +:% +@% 3%% ;4erage 3:$, J %:8
+8 Small +:8 +@% 3%% ;4erage $:@, J %:J
+J Earge +:8 +@% 3%% ;4erage $:,, J %:&
+@ Small $:% +@% 3%% ;4erage $:7, J %:J
+7 Earge $:% +@% 3%% ;4erage 3:%, J %:@
+, Small +:% +8% 3$8 ;4erage $:$, J +:@
$% Earge +:% +8% 3$8 ;4erage $:3, J +:8
$+ Small +:8 +8% 3$8 ;4erage $:$, J +:3
$$ Earge +:8 +8% 3$8 ;4erage $:8, J +:&
$3 Small $:% +8% 3$8 ;4erage $:&, J +:@
$& Earge $:% +8% 3$8 ;4erage $:7, J +:$
$8 Small +:% +J% 3$8 ;4erage 3:%, J %:3
$J Earge +:% +J% 3$8 ;4erage 3:+, J %:8
$@ Small +:8 +J% 3$8 ;4erage 3:3, J %:&
Page 32

Aesults, ontinued0
$7 Earge +:8 +J% 3$8 ;4erage 3:&, J %:3
$, Small $:% +J% 3$8 ;4erage $:,, J %:$
3% Earge $:% +J% 3$8 ;4erage $:7, J %:3
3+ Small +:% +@% 3$8 ;4erage 3:+, J %:8
3$ Earge +:% +@% 3$8 ;4erage 3:$, J %:&
37 Earge +:% +8% 38% ;4erage $:3, J +:7
3, Small +:8 +8% 38% ;4erage $:$, J +:J
&% Earge +:8 +8% 38% ;4erage $:8, J +:3
&+ Small $:% +8% 38% ;4erage $:&, J +:8
&$ Earge $:% +8% 38% ;4erage $:7, J +:%
&3 Small +:% +J% 38% ;4erage 3:%, J %:&
&& Earge +:% +J% 38% ;4erage 3:+, J %:J
&8 Small +:8 +J% 38% ;4erage 3:3, J %:8
&J Earge +:8 +J% 38% ;4erage 3:&, J %:J
&@ Small $:% +J% 38% ;4erage $:,, J %:3
&7 Earge $:% +J% 38% ;4erage $:7, J %:&
&, Small +:% +@% 38% ;4erage 3:+, J %:J
8% Earge +:% +@% 38% ;4erage 3:$, J %:8
8+ Small +:8 +@% 38% ;4erage $:@, J %:J
8$ Earge +:8 +@% 38% ;4erage $:,, J %:&
83 Small $:% +@% 38% ;4erage $:7, J %:J
8& Earge $:% +@% 38% ;4erage 3:%, J %:@
=ased on these results, it is apparent that the lo9er temperature limit o) +8%
o
C 9ill result in
unaepta-le 4ariations in seal strength 1o4erall a4erage o) $:37 kg, J o) +:&$3: !ariations in time
and pressure 9ithin spei)ied limits ha4e little to do 9ith seal strength:
;n additional 3J runs 9ere repeated 9ith a lo9er temperature limit o) +88
o
C and 4ariations o) time
and pressure similar to the )irst 8& runs: The data is not inluded in this report, -ut is a4aila-le in the
la- note-ook re)erened -elo9: The results o) these runs demonstrated an o4erall a4erage o) $:,$ kg,
J o) %:8: The C
p
)or these runs had a 4alue o) +:7: 6ptimal heat sealer settings 9ere determined to
-e a temperature ontroller setting o) 7:$, a time o) +:8 seonds and pressure o) 3$8 kPa:
Phase Three
/ormal prodution proesses 9ere used to seal pouhes 9ith produt and heat seal settings at +3
optimal le4els? $3 lo9 temperature, lo9 pressure and short time, and 33 high temperature, high
pressure and long time: +,% produts 9ere produed at eah om-ination o) settings:
Aesults0
The run 9ith optimal le4els resulted in an a4erage seal strength o) 3:%7 kg, J o) %:3, the run 9ith lo9
settings resulted in an a4erage seal strength o) $:7 kg, J o) %:8, and the run 9ith high settings
resulted in an a4erage seal strength o) $:, kg, J o) %:J:
Page 33
Ea- /ote-ook Ae)erene
Quality 2ngineering Ea- /ote-ook, #BS, ,7-&, pages J3-,7:
5ssues . Commentary
The input 9hih transmits the most 4ariation to the heat sealing proess is temperature: The lo9er
limit o) temperature 9as adjusted to +88
o
C )rom +8%
o
C:
The heat sealer must ha4e a 9arm-up time period o) at least t9enty minutes 9ith normal yling to
ha4e sta-le temperature ontrol:
=ased on these results, 9hen the proess is run 9ithin input limits, the seal strength target o) 3:% kg
should -e met 9ith a C
pk
o) +:7 per S6P 3-+3-7+: 5nitial ation le4els )or adjustment o) the heat sealer
should -e seal strengths o) $:J kg and 3:$ kg, 9hih should -e 3 4ariation )rom the a4erage o) $:,
during operational >uali)iation:
The heat sealer 6perational Quali)iation 9as suess)ul:
!alidation Team 6Q Aesults ;ppro4al
!ohn "#ith
Date0 8 #an: +,,, Title0 Sr: Quality 2ngineer
=ohn S"ith
$aula !ohnson Date0 8 #an: +,,, Title0 Prodution
Super4isor
Paula =ohnson
%andy !a&oby
Date0 8 #an: +,,, Title0 Plant Manager
:and! =acob!
"ue 'ro(n Date0 8 #an: +,,, Title0 AFD Projet Eeader
Sue 3rown
Claudia 'e&)er Date0 8 #an: +,,, Title0 Plant Quality
Manager
Claudia 3ec8er
6Q Aesults Aegistered in Do Center0
$ris&illa !ohnson Date0 +% #an: +,,, Title0 Doument Center
Manager
Priscilla =ohnson
Page 3$

Perfor"ance )ualification :esults
PVP 516101
/ormal prodution o) odes +$3&8 and +$@7, 9ere run utili*ing pouhes P/ ,J-+$$ and P/ 77-%+%:
6ptimal heat sealer settings 9ere used: The heat sealer 9as allo9ed to 9arm-up 9ith normal yling
)or one hal)-hour prior to use: ; 9eek o) prodution 9as ompleted )or eah ode: ;elerated
sampling plan $-C )rom S6P 3-,-+$ 9as used and the results ontrol harted: Follo9ing is a typial
ontrol hart0
The resultant C
pk
9as +:@8 )or the o4erall proess during this per)ormane >uali)iation: The
omparison o) the C
p
results )or eah day demonstrated that the proess 9as -oth sta-le and apa-le:
The )ollo9ing C
p
4alues 9ere alulated0
P/ ,J-+$$0 +:7, +:,, +:@, +:J, +:@?
P/ 77-%+%0 +:J, +:7, +:@, +:,, $:%:
The entering o) results a-out the target 9as 4ery lose0 o4erall a4erage seal strength 9as $:,3 kg
9ith a target o) 3:% kg
The ation le4els 9ere ne4er reahed, and there)ore no adjustments 9ere made and no root auses
identi)ied:
Ea- /ote-ook Ae)erene0
Quality 2ngineering Ea- /ote-ook, #BS, ,,-+, pages + " &7:
5ssues . Commentary
The proess has demonstrated sta-ility and apa-ility:
The Manu)aturing 2>uipment Aegister, M2A ,7-+$&7, has -een updated to inlude maintenane and
ali-ration o) the ne9 heat sealer:
The Proess !alidation Master Plan, P!P-,7%%+ has -een updated to inlude the ne9 heat sealer in
the re4alidation proess:

!arget +,- .g
#pper %cceptance 'i"it &:% kg
'o(er %cceptance 'i"it /,- .g

Seal Strength
%ction 'evel +,/ .g
%ction 'evel /,0 .g
Page 3'
The Heat Seal Proess Proedure, S6P $%-+$-+&, has -een updated to inlude the ne9 heat sealer and
the re4ised operating proedure )or temperature 9arm-up and lo9er temperature ontrol limit has
-een hanged )rom +8%
o
C to +88
o
C:
;ll prodution and Q; employees ha4e -een trained and the training shedule in S6P $%-+$-+& has
-een re4ised aordingly:
!alidation Team PQ Aesults ;ppro4al
!ohn "#ith
Date0 3+ #an: +,,, Title0 Sr: Quality 2ngineer
=ohn S"ith
$aula !ohnson Date0 3+ #an: +,,, Title0 Prodution
Super4isor
Paula =ohnson
%andy !a&oby
Date0 3+ #an: +,,, Title0 Plant Manager
:and! =acob!
"ue 'ro(n Date0 3+ #an: +,,, Title0 AFD Projet Eeader
Sue 3rown
Claudia 'e&)er Date0 3+ #an: +,,, Title0 Plant Quality
Manager
Claudia 3ec8er
PQ Aesults Aegistered in Do Center0
$ris&illa !ohnson Date0 8 Fe-: +,,, Title0 Doument Center
Manager
Priscilla =ohnson
Page 3,

7inal :eport
PVP 516101
Be ha4e re4ie9ed the re>uirements o) the protool? the 5Q, 6Q and PQ reports and ompared these to
the re>uirements o) the re)erene douments: ;ll re>uirements ha4e -een met and the proess is
4alidated:
!alidation Team Final Aeport ;ppro4al
!ohn "#ith
Date0 8 Fe-: +,,, Title0 Sr: Quality 2ngineer
=ohn S"ith
$aula !ohnson Date0 8 Fe-: +,,, Title0 Prodution
Super4isor
Paula =ohnson
%andy !a&oby
Date0 8 Fe-: +,,, Title0 Plant Manager
:and! =acob!
"ue 'ro(n Date0 8 Fe-: +,,, Title0 AFD Projet Eeader
Sue 3rown
Claudia 'e&)er Date0 8 Fe-: +,,, Title0 Plant Quality
Manager
Claudia 3ec8er
Final Aeport Aegistered in Do Center0
$ris&illa !ohnson Date0 +% Fe-: +,,, Title0 Doument Center
Manager
Priscilla =ohnson

Guidance 1-6

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GHTF/SG3/N99-10:2004 (Edition 2)

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