BPSA 2017 Design, Control & Monitoring of Single-Use Systems For Integrity Assurance

DESIGN, CONTROL, AND
MONITORING OF SINGLE-USE
SYSTEMS FOR
INTEGRITY ASSURANCE
This document would not be possible
without the generous support of the
following BPSA sponsors:
!
Table&of&Contents&
&&&&&&&&&Page&
&
Executive&Summary& & & & & & & & & & 4&
Part&1.&Introduction& & & & & & & & & & 5&
The!Bio(Process!Systems!Alliance!(BPSA)!! ! ! ! ! ! 5!
Background!and!Objective! ! ! ! ! ! ! ! 5&
Part&2.&Approach&to&Assessing&Integrity&of&SingleCuse&Systems& & & & 5&
2.1&RiskCbased&Approach&to&Integrity&of&SingleCuse&Systems& & & & & 5&
Industry!Guidance!and!Standards! ! ! ! ! ! ! 8&
Integrity!Assurance!and!SUS!Product!Life!Cycle! ! ! ! ! ! 8&
&&&&2.1.1.&Supplier&Evaluation&& & & & & & & & 8&
a.!SUS!Product!Development!and!Validation!Stage! ! ! ! ! 9!
b.!SUS!Product!Manufacturing!Stage! ! ! ! ! ! ! 10!
c.!Transportation!Stage! ! ! ! ! ! ! ! ! 11&
&&&2.1.2.&EndCuser&Evaluation&& & & & & & & & 11&
a.!Design!and!Development! ! ! ! ! ! ! ! 12!
b.!Implementation!–!Validation!and!Training! ! ! ! ! ! 12!
c.!SU!System!Transportation!from!Supplier!–!Incoming!Inspection! ! ! 13&
!!!!!!!!!!!!!!!!!!!!!Package!Integrity! ! ! ! ! ! ! ! ! 13&&!
!!!!!!!!!!!!!!!!!!!!!QC!Inspection! ! ! ! ! ! ! ! ! 13&
d.!Pre(use!(Installation)!Stage! ! ! ! ! ! ! ! 13&
e.!Post(use!Stage! ! ! ! ! ! ! ! ! 13&
2.2.&Practical&Testing&for&Assurance&of&Integrity& & & & & & 14&
2.2.1.&Definitions& & & & & & & & & 14&
Barrier!Properties! ! ! ! ! ! ! ! ! 14!
Integrity!test!! ! ! ! ! ! ! ! & 14&
Leak!Test! ! ! ! ! ! ! ! ! ! 14!
Visual!Inspection! ! ! ! ! ! ! ! ! 14!
!
!
2.2.2.&Leak&detection&in&SingleCuse&Systems& & & & & & 14!!
2.2.3.&Integrity&and&Leak&Test&Methods& & & & & & & 15!
a.!Pressure!Tests! ! ! ! ! ! ! ! ! 15!
Pressure!Decay!Method!! ! ! ! ! ! ! 15!!
Flow!measurement!Method! ! ! ! ! ! ! 18&
!b.!Trace!Gas!Integrity!Test! ! ! ! ! ! ! ! 19&
Part&3.&Critical&Defect&Size&(Shape,&Type)&and&Correlation&by&Microbial&Challenge&& 22!
&&&&&3.1.&Creation&of&Defects&for&Correlation&Studies& & & & & & 22&
3.1.1.!Laser!Drilling! ! ! ! ! ! ! ! ! 22!
3.1.2.!Use!of!Microcapillaries! ! ! ! ! ! ! ! 23&
&&&&&3.2.&Microbial&Challenge&Tests& & & & & & & & 24&
3.2.1.!Aerosol!Challenge!Test! ! ! ! ! ! ! ! 24!
3.2.2.!Liquid!Immersion!Challenge!Test! ! ! ! ! ! ! 26&
Part&4.&Implementation&of&Integrity&Tests&by&the&Supplier&and&EndCuser& & & 28&
&&&&&4.1.&When&to&Test&and&What&Type&of&Test& & & & & & & 28&
&&&&&4.2.&Detection&Capabilities&of&NonCdestructive&Integrity&Tests&& & & & 30&
&&&&&4.3.&Effect&of&System&Complexity&on&Suitability&of&Integrity&Test&Methods& & & 31&
&&&&&4.4.&Level&of&Risk&in&Implementation&of&Integrity&Test&at&Different&Stages&in&the&Process& 32&
4.4.1.!Risk!of!Product!Contamination! ! ! ! ! ! !
! 4.2.1.!Risk!of!Damage! ! ! ! ! ! ! ! !
! 4.4.3.!Sensitivity!and!Reliability! ! ! ! ! ! ! ! 32&
Part&5.&Discussion&and&Conclusions& & & & & & & & 33&
Part&6.&Summary& & & & & & & & & & 34&
Part&7.&References& & & & & & & & & & 34&
Disclaimer& & & & & & & & & & & 36&
Part&8.&Acknowledgements& & & & & & & & & 36&
& &
!
Design, Control, and Monitoring of Single-use Systems for Integrity Assurance
!
Executive&Summary&
The!Bio(Process!Systems!Alliance!(BPSA)!recognised!the!need!for!a!guide!on!the!integrity!assurance!
of!single(use!systems!and!formed!a!working!group!from!supplier!and!end(user!companies!to!discuss!
the!topic!and!recommend!best!practices.!
!
This!document!divides!best!practices!into!two!separate!but!complementary!sections!
1.!A!risk(based!approach!requiring!a!risk!assessment!of!the!total!process!from!design,!development!
and! manufacture! by! the! supplier! through! to! packaging! and! transportation,! and! finally! installation!
and!operation!by!the!end(user.!!
!
The!risk!management!plan!contains!four!key!elements!–!Business,!Product,!Operator!&!Environment,!
and! Integrity.! ! The! latter! involves! a! Quality! by! Design! (QbD)! approach!including! a! road! map! of! the!
product!life!cycle!to!identify!the!quality!attributes!that!are!important!for!the!achievement!of!system!
integrity.!!The!guide!highlights!the!importance!of!a!shared!responsibility!by!the!supplier!and!end(user!
in! the! evaluation! and! implementation! of! the! plan,! and! gives! detailed! recommendations! on! issues!
relevant!to!system!integrity!such!as!process!validation,!packaging,!QC!testing,!installation,!training,!
etc.!
!
2.! The! complementary! section! covers! practical! testing! of! components! and! systems.! ! Two! types! of!
tests!are!described.!
• Pressure(based!tests,!using!either!a!pressure!decay!or!flow!measurement!method!
• Trace!gas!tests,!typically!using!helium.!
!
The!critical!features!of!each!method!are!identified!and!the!strengths!and!limitations!of!each!method!
compared,!including!experimental!data!on!the!critical!defect!sizes!that!can!be!detected!by!the!test!in!
a!single(use!system!under!various!conditions.!!
!
The!significance!of!the!critical!defect!size!in!relation!to!the!risk!of!microbial!ingress!or!loss!of!liquid!is!
assessed!by!examples!of!studies!on!the!correlation!of!the!integrity!test!to!microbial!challenge!tests,!
using!either!aerosol!or!liquid!immersion!methods.!!!
!
In!the!last!section!of!the!guide,!the!detection!capabilities!and!suitability!of!leak!or!integrity!tests!for!
different! types,! sizes! and! complexities! of! single(use! systems! are! assessed.! The! importance! of!
integrity!testing!by!the!supplier!is!highlighted!together!with!the!decision!process!by!the!end(user!on!
the!option!of!testing!at!point!of!use.!!The!decision!on!whether!to!test!takes!account!of!the!sensitivity,!
suitability!and!practicality!of!the!test!as!well!as!the!potential!risks!of!testing!to!the!single(use!system!
CQA’s,!process,!operators!or!environment.!!!
!
!
!!
!
! !
© 2017 Bio-Process Systems Alliance. Copying and Distribution Prohibited. 4

!
!
Part&I:&Introduction&
The&BioCProcess&Systems&Alliance&(BPSA)&
The! Bio(Process! Systems! Alliance! (BPSA)! is! an! industry! association! whose! mission! is! dedicated! to!
encouraging! and! accelerating! the! adoption! of! single(use! manufacturing! technologies! used! in! the!
production! of! pharmaceuticals! and! vaccines.! ! BPSA! facilitates! education,! sharing! of! best! practices,!
development! of! consensus! guides,! and! business(to(business! networking! opportunities! among! its!
member! company! employees.! ! Corporate! members! include! single(use! system! (SUS)! suppliers,!
service!providers!and!users!in!the!biopharmaceutical!industry!who!share!this!mission.!A!key!focus!of!
BPSA’s! core! activities! is! to! educate! its! members! and! others! through! sharing! of! information! and!
development! of! guides! to! best! practice! that! help! suppliers,! users! and! regulators! to! safeguard! the!
quality! of! drugs! produced! with! single(use! process! technologies.! The! absence! of! any! industry!
standards! on! the! verification! of! integrity! for! single(use! systems! presented! an! opportunity! for! the!
BPSA!to!produce!this!guide.!
!
Background&and&Objective&&
The! increasing! uptake! of! single(use! technologies! (SUT)! in! the! more! critical! cGMP! processes! and!
applications,!especially!the!development!of!larger!and!complex,!multi(component!systems!has!made!
assurance! of! integrity! a! critical! quality!attribute! for! both! suppliers! and! end(users.! ! The! Bio(Process!
Systems! Alliance! (BPSA)! recognized! a! need! in! the! SUT! industry! to! address! this! complex! and!
challenging!subject!and!a!working!group!comprised!of!subject!matter!experts!(SMEs)!from!supplier!
and!end(user!companies!was!formed!to!discuss!the!topic!and!recommend!best!practices.!!
!
This!document’s!intended!audience!is!a!combination!of!
those! who! are! new! to! SUT! as! well! as! those! who! are!
already!familiar!with!the!technologies.!It!is!anticipated!
that!the!document!will!provide!a!base!for!both!groups!
to!gain!a!common!understanding!of!this!topic.!
!
The! document! provides! recommendations! to! both!
suppliers! and! end(users! in! the! SUT! industry! regarding!
strategies,! tools! and! procedures! that! can! assist! in!
providing!enhanced!assurance!of!integrity!of!single(use!
systems.! It! can! help! end(users! convey! their! specific!
requirements!to!the!supplier.!!In!turn,!suppliers!can!use!
Figure&1.&SingleCuse&bag&assemblies&
the!document!to!demonstrate!what!they!can!provide!to!
the!end(user.!
! !
Part&2.&Approach&to&Assessing&Integrity&of&SingleCuse&Systems&
This!guidance!document!to!best!practices!is!divided!into!two!separate!but!complementary!sections!
1.!Risk(based!approach!to!integrity!of!single(use!systems!!
2.!Practical!testing!of!components!and!systems!–!challenges!and!solutions!!!
!
2.1&RiskCbased&approach&to&Integrity&of&SingleCuse&Systems&
In! a! traditional! multi(use! stainless! steel! system,! the! end(user! has! significant! responsibility! and!
control! over! the! design,! construction,! integrity,! operation! and! maintenance! of! the! system.! In!
contrast,!for!a!single(use!system,!a!turnkey!or!off(the(shelf!SUS!is!frequently!used.!In!this!case,!the!
supplier!or!integrator!has!an!increased!responsibility!and!role!to!play!in!many!of!these!operations,!
starting!at!the!earliest!design!stage!through!to!the!manufacture,!assembly,!sterilization,!packaging,!
validation,!certification!and!shipping!of!the!system!to!the!end(user.!In!addition,!the!supplier!needs!to!
provide! the! end(user! with! assistance! in! areas! such! as! application! studies,! operator! training! and!
procedures!to!verify!and!maintain!the!integrity!of!the!system!both!pre(use!and!post(use.!!

!
!
This!shared!responsibility!demands!a!collaborative!effort!and!even!a!close!partnership!between!the!
supplier!and!end(user!to!achieve!the!critical!objectives.!The!complex!and!often!customised!design!of!
many!single(use!systems!makes!this!task!particularly!challenging!and!it!is!important!to!identify!and!
address!the!potential!risks!both!at!the!system!manufacturing!stages!and!in!the!end!user’s!process.!
These! requirements! can! be! assessed! by! developing! a! risk! management! plan! for! the! single(use!
system,!as!shown!in!Figure!2.!!!
!
Figure! 2! highlights! four! key! elements! that! contribute! to! the! risk! assessment,! not! only! to! ensure!
safety! for! the! patient! for! a! pharmaceutical! product,! but! also! for! the! process! operators! (e.g.! risks!
from! cytotoxic! products)! and! for! the! environment! (e.g.! biosafety).! ! The! plan! also! includes! the!
economic!and!regulatory!risks!to!the!business.!
!!!
•  Life!Cycle! •  QbD!Approach!
Management!
•  Visual!inspec]on!
•  Cost!Beneﬁt!
•  Leak!Tes]ng!
Analysis!
•  Integrity!Tes]ng!
Business! Integrity&
Patient'Risk &
•  Supplier/End(user! Operator!&!
Product!
Environment! •  Health,!safety!and!
•  Materials!Science!
environment!
•  Barrier!Proper]es!
•  Containment!
•  Control!Strategies! Strategy!
•  Veriﬁca]on/Valida]on! •  Transport/Storage!
•  Process! •  Operator!Training!
•  SAL!10(6! •  Assembly/Disposal!
!
!
!
! Figure&2.&Risk&management&of&singleCuse&systems&
!A! risk(based! approach! to! manufacture,! assembly! and! use! involves! process! mapping! of! design,!
manufacturing!and!end!use!to!identify!high!risk!activities.!Process!failure!mode!and!effects!analyses!
(FMEA)!typically!addresses!steps!such!as!assembly,!testing,!packaging!and!shipping!of!empty!SUS!by!
the!supplier!and!unpacking,!handling,!installation!and!processing!by!the!end(user.!!!
!
An! important! consideration! is! the! role! of! visual! inspection! and! leak! testing! in! manufacturing!
validation!for!components!and!single(use!systems.!These!procedures!would!normally!be!included!in!
the!supplier’s!manufacturing!controls!but!when!technically!feasible,!implementation!of!leak!testing!
and! integrity! testing! in! the! process! may! be! valuable! to! the! end(user.! It! may! be! unacceptable,!
however,!if!testing!by!the!user!adds!undesirable!complexity!to!the!system!and!operating!procedures.!!
User! testing! may! even! introduce! a! risk! of! a! false! failure! result.! For! large! or! complex! single(use!
systems,!current!integrity!test!methods!may!not!be!able!to!provide!the!required!level!of!sensitivity!to!
confirm!the!presence!of!a!total!barrier!against!microbial!ingress!or!liquid!loss!but!may!still!provide!a!
valuable!test!for!gross!defects.!!

!
!
Some! of! these! limitations! can! be! accommodated! by! the! introduction! of! other! practices! and! risk!
assessments.!The!integrity!component!of!the!plan!contains:!
• Controls! involving! practical! procedures! such! as! visual! inspection! and! integrity! testing,! as!
discussed!in!more!detail!in!Section!2.2.!
• A! Quality! by! Design! (QbD)! approach.! ! QbD! is! a! systematic! approach! to! development! of!
single(use!technologies!based!on!sound!science!and!quality!risk!management.!!It!begins!with!
pre(defined! objectives! with! emphasis! on! a! full! understanding! of! the! raw! materials,!
components,! product! and! process! controls.! ! Guidelines! in! ICH! Q9! (1)! provide! examples! of!
tools! of! quality! risk! management! that! can! be! applied! to! all! aspects! of! pharmaceutical!
quality.!
!
QbD!demands!understanding!of!the!risks!and!potential!defects!associated!with!each!stage!of!the!SUS!
life! cycle,! as! shown! in! Figure! 3,! starting! with! the! supplier! in! the! design! and! development! stages!
through!to!assembly!manufacture!and!validation,!and!packaging.!!After!irradiation!and!shipment,!the!
end(user!is!responsible!for!deployment,!operator!training,!assembly!installation,!use!and!disposal.!!
!
Most!importantly,!QbD!for!single(use!technology!requires!a!strong!working!relationship!between!the!
supplier!and!end(user.!!
Supplier(Integration!
SU&critical&
component&
Assembly&& Packaging&
Other&
components&
Irradiation&&
EndCuser!Deployment!!
Disposal&& Use&& Installation&& Shipment&
Figure&3.&&Product&life&cycle&of&singleCuse&system&
!
!
&
&
&
&

!
!
Industry&Guidance&and&Standards&
Implementation! of! QbD! and! preparation! of! life! cycle! road! maps! can! be! assisted! by! reference! to!
industry!guidance!and!standards!on!integrity,!as!summarised!in!Table!I.!!!
!!
!
Organization! Status!
!
! ASTM&2095.&Standard&Test&Methods&for&Pressure&Decay&Leak&Test&for&
Flexible&Packages&with&and&without&Restraining&Plates&(2)&
ASTM%E55! ASTM&F2391C05.&Standard&Test&Method&for&measuring&Package&and&Seal&
! Integrity&using&Helium&as&the&Tracer&Gas&(3)&
&
!
PDA$!
&
TR&66.&Application&of&SingleCUse&Systems&in Pharmaceutical&Manufacture&(4)&
! TR&27.&Pharmaceutical&Package&Integrity&(5) &
!
USP&<381>.&&&Elastomeric&Closures&for&Injections.&(6)&&&&&&&
!
USP! USP&<1207>.&Sterile&Product&Packaging&C&Integrity&evaluation.&(7)&
USP&<1223.&&&&Validation&of&alternative&microbiological&methods&(8)&
!
EP&3.2.9.&Rubber&closures&for&containers&for&aqueous&parenteral&preparations&
EP! for&powders&and&freezeCdried&powders&(9)&
!
!
ISO&11607.& Packaging&for& terminally& sterilized& medical&devices&CC& Part&1:&
ISO! Requirements& for& materials,& sterile& barrier& systems& and& packaging&
& systems&(10)&
& ISO&15747:2010.&Plastic&containers&for&intravenous&injections&(11)&
&
&
Table&I.&Industry&guidance&and&standards&on&integrity&&
&
Integrity&Assurance&and&SUS&Product&Life&Cycle&
The!quality!attributes!that!are!important!for!the!achievement!of!system!integrity!should!be!added!to!
the! road! map! at! each! stage! along! with! an! explanation! of! how! those! attributes! are! monitored! and!
controlled.!!
!
Evaluation!of!integrity!assurance!throughout!the!SUS!product!life!cycle!can!be!conveniently!divided!
into!two!sections,!the!supplier!evaluation!and!the!end(user!evaluation.!!!
!
2.1.1.&Supplier&Evaluation&
The! supplier! evaluation,! shown! in! Table! II,! lists! in! the! first! column! the! process! steps! and! their!
criticality,!as!defined!by!the!risk!class!for!breach!of!integrity!from!low!to!high.!Where!sterile!filtration!
is!possible!at!the!final!stage!of!the!process,!the!risk!class!is!defined!as!low!to!medium.!However,!for!
those!formulations!where!sterile!filtration!is!not!possible,!such!as!suspension!products!or!some!types!
of!vaccines,!gene!therapy!and!cell!therapy!products,!the!risk!class!is!defined!as!high!and!additional!
testing!during!manufacture!may!be!specified.!
!
!
!
!
!
!
!
!

!
!
!
!
SU&System& SU&System&
Development&&& SU&System& Transportation&
! Validation& Manufacturing& (nonCused&empty&
systems)&
Criticality,&Intended& QbD,&Risk& Statistical&Process& Design&&&Packaging&&

Use&(i.e.&End&user& Assessment&&& Control&&&& (SU&Systems&before&
process&step)& Process&Validation& QC&Testing& Use)&
1.!Individual!component! 1.!Individual!component! 1.!Packaging!validation!!
Upstream!!
validation!! testing!(e.g.!filters,!sterile! 2.!ASTM/ISTA!
! 2.!Mechanical!tests!! connectors,!bags)! transportation!validation!
3.!Assembly!validation! 2.!Seal!quality!tests!(e.g.!
Sterile&filtration&possible& !Junction!test!! bags)!
! 4.!Shelf!life! 3.!Visual!inspections!of!
Low&Risk& ! system!assembly!
!
1.!Individual!component! 1.!Individual!component! 1.!Packaging!validation!!
Downstream!!
! 2.!Mechanical!tests!! connectors,!bags)! transportation!validation!
Sterile&filtration&possible& 3.!Assembly!validation! 2.!Seal!quality!tests!(e.g.!!
!Junction!test!! bags)!
! 4.!Shelf!life! 3.!Leak!testing!of!bags!
Medium&Risk& depending!on!joint!brisk!
!
! assessment!
4.!Visual!inspection!of!
system!assembly!
Final!Formulation!&! 1.!Individual!component! 1.!Individual!component!!! 1.!Packaging!validation!!
Compounding! validation!! testing!(e.g.!filters,!sterile! 2.!ASTM/ISTA!
! 2.!Mechanical!tests!! connectors)! transportation!validation!
3.!Assembly!validation! 2.!Seal!quality!tests!(e.g.!
Sterile&filtration&possible&
!Junction!test!! bags)!
! 4.!Shelf!life! 3.!Leak!testing!of!bags!
Medium&Risk& ! depending!on!joint!risk!
! assessment!
4.!Visual!inspections!of!
system!assembly!!
!
1.!Individual!component! 1.!Individual!component!!! 1.!Packaging!validation!!
Filling!
&
2.!Mechanical!tests! connectors)! transportation!validation!
No!sterile&filtration& 3.!Assembly!validation! 2.!Seal!quality!tests!(e.g.!
possible& !Junction!test!! bags)!
4.!Shelf!life! 4.!Visual!inspections!of!
! 5.!Microbial!aerosol!or! system!assembly!!
High&Risk& immersion!challenge!test! 5.!Integrity!testing!of!
! system!assembly!with!
sensitive!test!method!
(e.g.!helium,!gas!tracer)!
!
! Table&II.&Potential&testing/qualification&approach&performed&by&the&SUS&supplier&for&
! integrity&assurance.&
&
a.&SUS&Product&Development&and&Validation&Stage&
In! SUS! development! and! in! the! process! validation,! QbD! plays! a! key! role! together! with! risk!
assessment,! when! assessed! against! the! user! requirement! specification! (URS).! Other! critical!
requirements!such!as!quality!and!consistency!from!batch!to!batch!and!change!control!management!
must!also!be!evaluated,!as!well!as!biocompatibility!and!shelf!life.!

!
!
Test!methods!relevant!to!integrity!and!robustness!of!the!single(use!product,!described!in!more!detail!
in!Part!3,!include!microbial!challenge!and!mechanical!tests!on!components!and!assemblies,!including!
connections!and!seals!which!can!be!‘design!qualified’!to!show!that!they!function!as!intended.!For!a!
high(risk! class! (e.g.! where! terminal! sterile! filtration! of! the! product! is! not! possible),! it! is! highly!
desirable! to! perform! either! an! aerosol! or! an! immersion! microbial! challenge! test.! The! microbial!
challenge!levels!in!an!aerosol!test!are!orders!of!magnitude!higher!than!the!microbial! limits!for!the!
cleanroom! environments! associated! with! operation! of! single(use! systems;! for! example,! the! WHO!
recommended! limits! for! a! Grade! D! environment! (12)! are! shown! in! Table! III.! ! Depending! on!
applications! and! risk! assessment,! a! more! challenging! liquid! immersion! test! may! be! required,! as!
discussed! in! Part! 3.! ! Implementation! of! microbial! challenge! tests! is! a! very! complex! procedure.! It!
should,! therefore,! be! limited! solely! to! very! critical! components! (e.g.! sterile! connectors),! highly!
critical! applications! such! as! operations! after! the! sterilising! filter! in! filling! applications,! processes!
where!sterile!filtration!is!not!possible!(e.g.!certain!vaccines),!or!when!containment!is!requested.!!
Grade! Air!sample! 90!mm!diameter! 55!mm!diameter! Glove!print!(!!!!!!

(CFU/m3)! settle!plates! contact!plates! 5!fingers!
(CFU/4hours)! (CFU/plate)! (CFU/glove)!
A! <1! <1! <1! <1!
B! 10! 5! 5! 5!
C! 100! 50! 25! (!
D! 200! 100! 50! (!
&
Table&III.&&WHO&recommended&limits&for&microorganisms&during&operation&
!
Integrity! testing! including! gross! leak! detection,! both! destructive! and! non(destructive,! may! also! be!
valuable! in! the! development! stage.! For! individual! components,! validation! and! control! strategy! are!
extensively!described!in!the!Quality!Matrices!from!BPSA!(13).!
!
The! testing! could! be! either! on! samples! from! each! lot! or! on! every! product.! ! Some! testing! may! be!
performed! during! development! and! validation! and/or! routinely! during! manufacturing.! For! any!
specific!process,!the!decision!on!where!to!test!and!what!type!of!test!will!be!determined!by!several!
factors,!discussed!later!in!Part!4!of!this!guide.!!!
!
Validation!of!the!SUS!development!process!should!be!completed,!including!evidence!of!product!and!
process!capability!and!variability,!as!well!as!statistical!process!control!(SPC)!and!trend!analysis.!This!
process! assessment! will! be! of! greater! significance! in! the! product! manufacturing! stage! described!
below.!!!!
!
Packaging! and! shipping! procedures! of! the! single(use! systems! to! the! end(user! site! should! also! be!
validated!per!international!standards!(ISTA!or!ASTM).!!Testing!standards!prescribe!various!methods!
depending! on! the! classification! (parcel! or! unitized)! of! the! packaging! containing! the! single(use!
systems,!the!shipment!route!(road,!train,!air),!and!other!factors.!!
!
Finally,!validation!data!should!be!fully!documented!and!available!to!the!end(user!and,!if!required,!to!
regulatory!authorities.!
!
b.&SUS&Product&Manufacturing&Stage&
In! the! single(use! system! manufacturing! stage,! statistical! process! control! (SPC)! for! large!
manufacturing! runs! associated! with! trending! and/or! QC! testing! provide! data! and! assurances! on!
integrity!and!reproducibility,!especially!when!supported!by!detailed!standard!operating!procedures!
(SOPs)!and!operator!training.!Testing!could!be!performed!on!individual!components!such!as!filters,!

!
!
connectors! and! bags! for! all! risk! classes.! In! addition,! seal! quality! tests! (e.g.! for! bags)! and! visual!
inspections!of!system!assembly!could!be!performed.!!!
For! the! high(risk! class,! integrity! testing! of! bags! by! a! sensitive! non(destructive! method! such! as! a!
helium! leak! test! could! be! considered! although! the! difficulty! of! performing! a! helium! leak! test! may!
make!this!test!impractical.!!!A!qualified!leak!test!of!the!full!system!assembly,!where!possible,!could!
confirm! proper! assembly.! Tests! should! be! supported! by! documented! qualification! studies,! and!
should!be!referenced!in!the!quality!control!procedures.!!!
!
c.&Transportation&Stage&
Supplier! evaluation! of! the! transportation! stage! is! strongly! linked! to! the! packaging! and! shipping!
validation!referred!to!in!the!product!development!and!validation!stage.!!Assistance!with!evaluation!
of! transportation! can! be! found! in! guidance! and! standards! documents! published! by! various!
organizations! including! ASTM! and! ISTA.! As! part! of! this! exercise,! packaging! requires! a! great! deal! of!
attention.!Special!attention!is!demanded!for!the!following!points:!folding!of!bags,!protection!of!the!
bag!from!sharp!objects!(e.g.!clamps),!coiling!of!tubing!and!stacking!of!multiple!systems!in!a!single!box!
and!appropriate!procedural!controls!to!ensure!adherence!to!qualified!packaging!methods.!The!use!of!
detailed!packaging!drawings!along!with!clear!instructions!on!packaging!and!unpacking!instructions!is!
recommended.!!!
&
2.1.2.&EndCuser&Evaluation&
The!end(user!section!on!integrity!assurance!and!single(use!system!life!cycle!is!summarised!in!Table!
IV!and!defines!five!stages.!
!
EndCuser& EndCuser& SU&Product& SU&Commercial& SU&Commercial&
! Evaluation& Implementation& Transportation& PreCuse& PostCuse&
Design&&& Validation&&& Incoming& PreCuse& PostCuse&

Development& Training& Inspection& Installation&
Process/application! User!qualification! Check!at!reception! Visual!inspection!of! Visual!inspection!
mapping!for! package.! and!any! packaging!and!SUS! for!absence!of!
intended!use.! ! intermediate! (gross!defects,! liquid!leaks!(also!
! IQPQ!&!Aseptic!broth! storage!location!for! integrity!of! during!operation).!
Design!space.!! validation.! any!visible!damage.! secondary! !
Review!of!existing! ! ! packaging).! Sterility!testing!of!
validation!&!gaps! Consistency!batches.! QC!Inspection.! ! product.!
identification.! ! ! Non(destructive! !
! Training!by!supplier! Documentation.! testing.! Additional!testing!
Definition!of! and/or!end(user!SME! ! ! as!per!user’s!
expected! Visual!inspection!of! ! Visual!checks!during! requirements.!
manufacturing! SUS.! ! use:!! !
control!strategy! ! Connectivity,!tubing! !
(supplier!and!end! Verification!of! installation,!clamps,!
user).! integrity:!non( special!attention!to!
! destructive!and! sterile!connections.!
Verification!of! destructive!testing.!
supplier!validation! !
package.! For!critical!
! applications,!submit!
Establish!process! SUS!to!full!life!cycle!
and!storage! and!verify!integrity!at!
conditions!for! the!end.!
unused!SUS,!based!
on!supplier!
recommendations.!!
!
!
!

!
!
Visual!inspection.!
Verification!of!
integrity:!Non(
destructive!and!
destructive!testing.!
!
&
Table&IV.&Potential&endCuser&strategy&to&ensure&integrity&assurance&throughout&SUS&
&
product&life&cycle&based&on&risk&assessment&
&
a.&Design&and&Development&
In! the! design! and! development! stage,! it! is! essential! to! understand! fully! the! application! and! the!
process! in! which! the! SUS! will! be! used.! In! addition,! storage! conditions! and! associated! operations!
should! be! evaluated! to! verify! that! there! is! a! suitable! environment! for! storage,! as! defined! by! the!
supplier,!and!that!integrity!can!be!maintained!during!storage!as!well!as!during!transfers!to!and!from!
the!storage!areas.!!
!
Methods! for! visual! inspection! should! be! set! up.! ! In! addition,! destructive! and! non(destructive! tests!
should! be! performed! to! verify! that! there! are! no! breaches! of! integrity.!!
The!methods!could!be!applicable!at!the!quality!control!or!pre(use!stages.!!
This!control!can!be!supplemented!by!a!leak!test,!if!possible!or!desirable,!
to! confirm! that! the! assembly! prototypes! or! final! versions! have! no! gross!
leaks.!
!
b.&Implementation&C&Validation&and&Training&
There! should! be! verification,! in! collaborative! evaluations,! that! the!
supplier! and/or! end(user! have! performed! the! necessary! validation! Figure&4.&Packaged&
studies! involving! destructive! or! non(destructive! testing! depending! on! SUS&assembly&&
applications!such!as:!
• Junction!testing!for!single(use!system!assembly.!
• System/chamber!integrity!by!an!appropriate!method.!
• Seal!integrity!by!peel!test!per!ASTM!F88/F88M(09!(14)!or!by!risk!assessment.!!
• Package!testing!and!integrity!during!transport!and!shipping!per!ASTM!D4169(14!(15)!or!ISTA!
standards.!
• Shelf!life!by!accelerated!aging!tests!backed!by!strong!rationale!or!real!time!tests.!
• Bacterial! challenge! and! soiling! tests! defined! either! by! manufacturer! or! by! ISO! 15747! (11).!
Further!guidance!can!be!obtained!from!PDA!TR27!(5).!
• Aseptic! broth! simulation! studies! (also! known! as! sterile! challenges! or! Media! Process! Tests!
(MPTs).!
• Chemical! compatibility! per! ASTM! D543(14! (16)! or! by! risk! assessment! or! other! applicable!
procedures.!
!
Aseptic! simulations! and! bacterial! challenges! need! only! be! considered! if! indicated! by! a! risk(based!
approach! to! process! validation.! The! assembly! set! up,! frequency! and! operation! for! aseptic! broth!
simulations! should! be! established! during! installation,! operation! and! performance! qualification!
(IOPQ)!studies.!This!validation!requirement!should!refer!to!internal!user!SOP!or,!if!not!available,!to!
standard! guidance! documents! for! process! simulations! described! in! FDA! and! EMA! guidelines! or! in!
interpretations!of!the!guidelines!issued!by!the!PDA,!ISPE!and!other!organizations.!
!The!supplier!should!verify!that!the!consistency!of!batches!established!during!the!end(user’s!product!
development! stage! is! maintained! and! not! compromised,! thereby! verifying! the! robustness! of! the!
process,!operations!and!controls.!
!

!
!
Training! on! effective! handling! procedures! by! the! supplier! and/or! by! the! end(user’s! subject! matter!
experts!(SMEs)!can!provide!assurance!that!integrity!is!maintained!(!and!has!been!demonstrated!to!be!
of!paramount!importance!to!provide!assurance!that!integrity!is!maintained!during!use.!
!
Shipping!qualification!and!testing!procedures!should!also!be!established!and,!if!necessary,!additional!
testing!and!validation!requirements!should!be!discussed!with!the!supplier.!
&
c.&SU&System&Transportation&from&Supplier&–&Incoming&Inspection&
Package& Integrity.! ! When! shipped! from! the! supplier,! the! end(user! should! verify! that! the! shipping!
configuration!has!not!been!compromised.!This!verification!should!also!be!obtained!when!a!single(use!
system! filled! with! pharmaceutical! product! is! shipped! from! end(user! to! end(user.! ! For! this! type! of!
transportation! application! (e.g.! media,! buffer,! bulk! product),! specific! shipping! qualification! and!
testing!procedures!should!be!established.!
!
QC& Inspection.! Visual! inspection! of! the! single(use! assembly,! either! on! selected! lots! or! individual!
units,! can! ensure! that! integrity! of! inner! packaging! is! maintained! during! transportation.! Testing! for!
integrity! is! not! essential! at! this! stage! if! there! is! an! adequate! level! of! integrity! assurance! from! risk!
assessment! studies.! Some! users! may,! however,! choose! to! conduct! some! form! of! documented!
testing.!!
&
d.&PreCuse&(Installation)&Stage&&
After! removal! of! the! packaging! and! prior! to! installation! and! use! of! the! single(use! assembly,! a!
systematic!visual!inspection!for!gross!defects!should!be!performed.!Special!attention!should!be!given!
to! visual! inspection! of! the! assembly! of! the! system! including! clamps,! tubing! etc.! with! particular!
emphasis!on!sterile!connections.!!
!
The! supplier! will! have! fully! qualified! the! manufacturing! process! to!
ensure!absence!of!defects.!In!addition,!in!some!cases,!the!supplier!may!
have! performed! a! leak/integrity! test! on! the! SUS! before! shipment.!!
Potential! damages! could! occur! to! the! single(use! system! between! its!
manufacturing! and! its! actual! use! by! the! end(user.! A! risk! assessment!
will!help!the!end(user!to!evaluate!and!determine!if!a!pre(use!leak!test!
should!be!performed!at!the!point(of(use!or!not.!
If! testing! is! considered! necessary! for! further! risk! mitigation,! non(
destructive! methods! on! selected! lots! or! on! individual! units! can! be!
performed! using! suitable! methods! such! as! pressure! decay,! flow!
measurement,! hydrostatic! leak! and! hydrostatic! pressure! tests.! ! In! Figure&5.&Installing&
principle,!these!tests!can!be!performed!on!sterile!systems!when!using! SUS&assembly&&
well(designed! methodology! but,! in! practice,! limitations! due! to! system!
size,!complexity!or!other!factors!may!make!testing!less!sensitive!or!even!impractical.!!For!a!testable!
system,!any!additional!complexity!and!risks!that!may!be!introduced!to!the!sterile!system!by!the!test!
procedures! should! be! assessed! and! balanced! against! the! practicality! and! benefits! of! testing! at! this!
stage!(!and!against!the!testing!strategy!of!the!supplier.!!!
!
e.&PostCuse&Stage&
Visual! verification! for! holes! or! breaches! in! seals! may! be! performed! at! this! stage.! A! post(use!
destructive! or! non(destructive! leak! test! could! be! incorporated! if! the! bag! or! assembly! is! clean! and!
dried,!but!only!if!it!is!technically!feasible!with!a!qualified!test!that!provides!better!sensitivity!and!if!a!
risk!assessment!has!determined!that!it!is!necessary.!!!
!

!
!
Sterility! testing! of! final! product! can! provide! supportive! information! contributing! to! assurance! of!
system!integrity.!!Further!qualification!of!the!assembly!design!and!construction!to!provide!a!sterile!
and/or!containment!barrier!can!be!obtained!with!aseptic!process!simulations!or!MPT!challenges!for!
critical! applications.! ! When! repeated! annually! or! sometimes! more! frequently,! media! challenges!
provide!a!check!on!robustness!as!well!as!consistency!of!the!manufacturing!process.!!They!also!offer!a!
test!of!the!user’s!technique.!
!
&
2.2.&Practical&Testing&for&Assurance&of&Integrity&
&
2.2.1.&Definitions&&
Before!assessing!the!methods!and!technologies!available!for!determination!of!the!integrity!of!single(
use!systems!(SUS),!it!is!important!to!review!some!key!definitions.!
!
Barrier&properties&
The!physical!properties!of!the!barrier!which!maintains!the!structural!and!mechanical!integrity!of!the!
SUS,! i.e.! the! state! of! the! contact! surface! area! which! acts! as! the! physical! partition! and! sterility! and!
biosafety! barrier.! These! properties! are! defined! according! to! the! intended! use! or! process!
compatibility! of! the! SUS! (4,17).! Examples! of! such! parameters! would! be! transparency! to! light,!
microbial!ingress,!liquid!loss!or!gas!permeability.!The!barrier!properties!can!be!evaluated!by!different!
test! methods,! such! as! those! described! below,! which! are! progressively! more! rigorous! and! so! have!
different!probabilities!of!failure!detection.&
&
Integrity&Test&
A! test! used! to! confirm! the! barrier! properties! of! the! single<use! system.! It! assesses! functional!
performance,! taking! into! account! the! process! environment! and! considerations.! It! must! be!
correlated,!directly!or!indirectly,!to!the!ability!of!the!test!to!detect!a!breach!i.e.!correlated!to!a!study!
or! challenge! test! showing! the! ability! of! the! single(use! system! to! provide! the! specified! barrier!
properties!under!defined!conditions!(5,18,19,20).!The!test!may!be!performed!pre(use!i.e.!if!it!is!non(
destructive,! or! post(use! if! destructive,! because! in! this! second! case,! the! test! may! compromise! the!
sterility!or!other!essential!properties!of!the!system.!
&
Leak&test&
A! test! used! to! check! the! single<use! system! for! leaks! of! any! size,! independent! from! the! barrier!
properties.!A!leak!test!is!developed!according!to!a!risk(based!approach!and!can!be!unique!to!a!given!
assembly.!It!is!often!assessed!according!to!an!allowable!pressure!drop!and!the!sensitivity!of!this!test!
is!correlated!to!the!phase!in!the!SUS!product!lifecycle,!such!as!process!control!at!the!supplier’s!site!
or!gross!leak!testing!after!shipping!and/or!handling!at!the!end!user’s!site.!(18,21,22).!
&
Visual&inspection&
A!qualitative!test!that!confirms!conformity!to!design.!Visual!inspection!can!also!detect!contamination!
and!gross!failures,!or!visual!imperfections!that!may!be!suspected!of!causing!a!leak.!
!It!consists!of!a!visual!inspection!by!a!trained!operator!and!provides!verification!of!the!structure!of!
the!single(use!system,!before!or!after!final!assembly.!(18,23).!
!
2.2.2.&Leak&Detection&in&SingleCuse&Systems&&
For! a! major! flaw! generating! a! gross! leak! in! a! single(use! flexible! container! or! tubing,! detection! by!
visual!inspection!may!be!possible!but,!in!many!cases,!the!location!of!the!flaw!may!not!be!visible!or!
the! hole! too! small! to! be! detectable! with! the! human! eye.! ! More! sensitive! methods! are! therefore!
essential! to! prevent! the! consequential! effects! of! a! leak! in! the! system! such! as! microbial!
contamination!or!loss!of!samples,!media!and!buffer!(24(30).!Leaks!also!present!potential!hazards!to!

!
!
operations!personnel!and!the!production!area!hygiene.!In!addition,!there!could!be!severe!financial!
costs! from! loss! of! high! value! products,! replacement! of! single(use! components! and! lost!
manufacturing!time.!!!
!
Ways! of! avoiding! system! leaks! have! already! been! described! in! the! risk(based! approach! detailed! in!
Part!1,!such!as!robust!design!(QbD!in!single(use!system!design!and!development),!supplier!in(process!
and! release! testing,! robust! (and! validated)! packaging! and! shipping! process,! and! effective! handling!
procedures.! In! most! cases,! however,! some! form! of! practical! testing! may! be! required! and! ideally!
carried!out!pre(use!to!prevent!consequential!effects!or!losses!from!a!system!leak.!!!
!
When!selecting!a!suitable!test,!the!decision!can!be!influenced!by!a!number!of!factors!and!user!
requirements!such!as:!!
• Destructive!or!non(destructive! • Test!time!
• Pre(use!or!post(use! • Test!cost!
• No!addition!of!contaminants! • Ease!of!operation!
• Detection!limit!(size!of!leak)! • 21!CFR!Part!11!compliance!
!
2.2.3.&Integrity&and&Leak&Test&Methods&
The!usual!requirement!for!an!integrity!test!is!that!it!should!be!non(destructive!when!planned!to!be!
implemented!in!routine!production.!!The!two!types!of!tests!meeting!this!requirement!and!suitable!
for!single(use!components!or!systems!are:!
1.!Pressure(based!tests.!!
2.!Trace!gas(based!(typically!helium)!tests.!!
!
a. Pressure&Tests&
With!portions!of!the!single(use!assembly!containing!a!sterile!product!and!being!used!in!a!Grade!D!
environment,!integrity!of!the!system!is!critical.!!As!30!µm!has!been!shown!to!be!the!defect!size!that!
would! allow! ingress! of! bacteria! under! process! conditions,! leak! testing! capable! of! detecting! 30! µm!
would!be!of!value!as!part!of!a!risk!mitigation!approach.!!!
!
The!basic!principle!of!a!pressure!test!is!to!detect!leaks!in!the!system!by!pressurisation!to!a!defined!
pressure! with! air! (or! sometimes! some! other! gas! such! as! Nitrogen).! ! The! flow! of! air! through! any!
defects! in! the! system! can! be! detected! either! by! a! pressure! decay! method! after! isolation! of! the!
supply! pressure! or! by! direct! flow! measurement! at! a! constant! system! pressure! using! suitable!
equipment!upstream!of!the!system!under!test.!
&
Pressure&Decay&Method&
The!procedure!for!a!pressure!decay!test!is!shown!in!Figure!6.!!!!
!
! Filling&and& Isolate&pressure& Measure&pressure&
Maintain&pressure&
! pressurization&of& supply&&&allow& decay&and&confirm&
for&set&time&to&
! isolated&system&to& whether&above&or&
the&system& stabilize&system&&
settle& within&limit&value&&
!!
!
Figure&6.&Test&procedure&for&a&pressure&decay&test&
Pressure!decay!and!flow!measurement!tests!depend!on!the!ideal!gas!law!PV=nRT.!!Higher!pressure!
and!lower!test!volumes!enhance!sensitivity,!while!constant!temperature!is!required!during!the!test.!
!
The! test! can! be! performed! using! pressure! gauges! and! manually(controlled! valves! but! purpose(
designed!automated!instruments!are!available!to!give!improved!control!and!sensitivity!of!the!test,!
elimination!of!operator!error!and!printed!documentation!of!test!parameters!and!results.!!

!
!
In!production!environments,!it!may!be!possible!to!use!existing!pressure!decay!instruments!designed!
for!integrity!testing!of!membrane!filters.!!A!typical!automated!test!set!up!is!shown!in!Figure!7.!!
The! pressure! decay! test! is! used! widely! for! leak! testing! of! multi(use! components! such! as! stainless!
steel! vessels.! The! high! test! pressures! possible! in! these! rigid,! pressure(rated! vessels! increases! the!
sensitivity!of!detection,!especially!for!finer!leaks,!and!also!allows!accurate!testing!of!larger!volume!
systems.!!
! Regulated&air& SingleCuse&system&
supply&&
under&test&
!
Automated&test&
equipment&&
!
!
!
!
!
Downstream&
! Air&supply&valve& Optional&
shut&off&valve&
! sterile&air&
filter& Optional&
! restraining&plate&
!
! Figure&7.&&Pressure&decay&test&system&
!
!
!
A! major! difference! between! a! rigid! system! and! a! flexible! single(use!
system! is! that! the! latter! cannot! withstand!high! test! pressures! due! to!
the! pressure! limits! of! the! flexible! materials,! and! often! is! deformable!
(31).! ! This! pressure! restriction! substantially! reduces! the! test!
sensitivity,!as!less!air!flow!will!pass!through!a!hole!of!fixed!diameter!at!
a!lower!test!pressure.!Pressures!of!up!to!300!mbar!may!be!achievable!
with!2D!bags!when!using!restraining!plates!but!test!pressures!will!be!
significantly! lower! for! unrestrained! or! 3D! systems! thus! reducing! the!
sensitivity!of!the!test.!!!
!
Figure&8.&&Pressure&decay&
Qualification!studies!should!assess:!
test&system&
1. Temperature! and,! where! necessary,! recommended! extended!
stabilization!times!to!ensure!constant!temperature!during!the!pressure!decay!measurement!
phase.!
2. The!polymeric!bag!film!expansion!over!time!due!to!the!polymer’s!viscoelastic!properties.!The!
decay!of!the!pressure!during!stabilization!is!mainly!caused!by!film!expansion.!!!
!
Another! parameter! to! consider! is! possible! diffusion! of! air! through! the! flexible! barrier! as! it! could!
contribute!to!the!pressure!decay!value.!!Most!flexible!materials,!however,!in!single(use!systems!have!
very!low!permeability!for!air,!and!diffusion!would!not!normally!be!a!significant!factor!over!the!short!
test!time!(15!(!30!minutes).!
!
When! testing! a! sterilized! system,! a! sterilizing! grade! air! filter! should! be! incorporated! into! the!
manifold!prior!to!system!sterilization!to!prevent!contamination!and!to!ensure!that!the!air!used!for!
the!test!does!not!compromise!the!sterility!of!the!system.!

!
!
!!
Typical!pressure!curves,!as!shown!in!Figure!9,!demonstrate!the!four!phases.!!
1.!Initial!pressurisation!or!inflation!phase.!!
2.!Pressure!stabilization!phase!when!constant!test!pressure!is!being!established.!
3.!Pressure!decay!stabilization!phase!following!isolation!of!the!supply!pressure.!!
4.!Pressure!decay!measurement!phase!when!pressure!decay!is!measured!over!a!specified!time.!!!
!
The!defective!bag!shows,!as!expected,!a!larger!pressure!decay!than!the!intact!bag.!
!
A&
Pressure&
isolated&
Pressure&
Intact&bag&
Defective&bag&
Pressurisation& Pressure& Pressure&decay& Pressure&decay&&

inflation&& stabilization& stabilization&phase& measurement&
phase& phase& phase&
& !
! Time&&
!
! Figure&9.&Pressure&decay&test&on&singleCuse&flexible&systems&
!
The!measured!pressure!decay!and!the!validated!maximum!allowable!limit!are!dependent!on!system!
volume!of!the!pressurised!test!system.!The!volume!should!therefore!be!defined!and!fixed!for!each!
type! and! size! of! system! when! qualifying! the! method! and! establishing! the! maximum! allowable!
pressure!decay!for!a!pass!result.!!
!!!
As! SUS! volume! increases,! the! sensitivity! of! the! test! method! decreases.! This! relationship! limits! the!
accuracy! and! volume! of! the! system! that! can! be! tested! to! ensure! that! any! critical! defects! are!
detected.! The! use! of! restraining! plates! for! two(dimensional! (2D)! bags! can! significantly! reduce! the!
test!volume!and!in!this!way,!increase!the!allowable!pressure!decay!limit!to!maintain!an!acceptable!
level! of! sensitivity! for! detection! of! defects.! The! restraining! plates! also! reduce! stress! on! the! bag.!
Insertion! of! porous! spacers! between! the! bag! and! restraining! plates! allows! free! passage! of! air!
through!any!defects!without!restriction!by!the!impermeable!restraining!plates.!!

!
!
!
The! impact! of! attachments! to! the! system! such! as! tubing! and! connectors! must! also! be! taken! into!
account!as!they!may!significantly!change!the!system!volume!and!potentially!lead!to!erroneous!test!
results!if!not!assessed!in!qualification!studies.!!Their!diameter,!wall!thickness,!length,!and!material!
type! should! all! be! taken! into! account! since! these! properties! can! affect! the! stiffness! of! the! tubing!
under! pressure! and! therefore! have! an! effect! on! the! pressure! measurements.! ! Any! permeable!
membranes!such!as!vent!filters!or!hydrophobic!peel!strips!on!connectors!must!be!isolated!from!the!
tested!SUS!by!shut(off!valves!or!clamps.!
!
An! important! consideration! unique! to! flexible! systems! such! as! 2D! and! 3D! bags! is! the! increase! in!
volume!in!the!test!system!during!the!pressure!decay!stage!due!to!flexing!and!stretching!of!the!bag.!
The!effect!of!this!changing!volume!is!a!decrease!in!pressure!during!the!pressure!decay!stabilization!
phase.! This! effect! is! clearly! shown! in! Figure! 9! when! significant! decrease! in! pressure! occurs! after!
isolation!of!the!supply!pressure,!even!with!an!intact!bag.!!
!
Conversely,!the!fall!in!pressure!in!a!pressure!decay!test!may!cause!slight!relaxation!or!deflation!of!
the!flexible!system!which!would!reduce!the!volume!during!the!measurement!phase!and!impact!on!
the! accuracy! of! the! pressure! decay! values.! ! It! is! more! likely! to! be! a! factor! in! larger! unrestrained!
systems!and!where!the!maximum!allowable!pressure!decay!limit!is!very!small.! The!contribution!of!
this!effect,!if!any,!could!be!explored!in!qualification!studies.!!
!
Some!control!over!maintenance!of!constant!volume!may!be!achieved!when!using!restraining!plates!
for!2D!bags!during!the!test!or!when!supported!in!customised!stainless!steel!totes!or!holders!for!3D!
containers.!!
!
The!effects!from!flexing!of!the!test!system!can!be!mitigated!to!some!extent!by!measuring!pressure!
decay!values!from!an!identical!single(use!system!with!no!defects!to!provide!a!baseline!control!value.!
This!value!is!then!deducted!from!the!pressure!decay!value!obtained!in!the!test!system!to!give!a!net!
pressure!decay!value,!shown!as!A!in!Figure!9.!In!this!way,!any!difference!between!the!two!values!can!
be! considered! as! a! more! accurate! representation! of! the! pressure! decay! due! to! any! defects! in! the!
barrier!of!the!test!system.!
!
&Flow&Measurement&Method!
!An! alternative! method! monitors! the! gas! flow! rate! required! to! maintain! system! pressure! during!
testing!(36).!!The!test!set!up!is!shown!in!Figure!10.!!
!
!
Figure&10.&&Flow&measurement&integrity&test&
Automated&flow& Optional&
measurement& sterile&air&
equipment&& filter&
SingleCuse&bag&
with&defect& Air&flow&
Regulated&air& Constant& through&
supply&& test& defect&&
pressure&P&
!
!
!
!

!
!
!
The!main!differences!between!this!method!and!the!
pressure!decay!method!are:!
• The!air!supply!is!not!isolated!during!the!test.!!
• The!test!pressure!is!held!constant.!
• Air!flow!due!to!a!defect!in!the!barrier!of!the!
single(use! system! is! measured! directly! on! the!
upstream!side.!!!
!
An! optional! sterilizing! air! filter! can! be! incorporated!
into! the! manifold! for! testing! sterile! single(use!
Figure&11.&&Flow&measurement&instrument& systems!without!compromising!sterility.!
!
The!main!benefits!are:!
1.! Different! configurations! or! geometry! of! single(use! systems! can! be! accurately! tested! without!
determining!the!exact!volume!of!the!system!!
2.!Constant!pressure!throughout!the!test!minimises!any!changes!in!the!geometry!and!volume!due!to!
flexing!of!the!system.!!!
!
Constant!temperature!during!the!measurement!phase!is!an!essential!requirement.!!
!
In! small! single(use! systems,! such! as! 2D! bags,! the! pressure! decay! and! flow! measurement! integrity!
tests!can!detect,!under!ideal!conditions,!defects!in!the!barrier!down!to!approximately!30!µm!(32,!36,!
37).!The!sensitivity!decreases!with!increasing!size!of!system.!For!large!volume!3D!systems,!the!limit!
could! be! upwards! of! 100! µm.! As! defects! of! this! size! in! the! barrier! may! allow! ingress! of! microbial!
contaminants!under!some!process!conditions,!as!described!later,!the!pressure(based!tests!for!larger!
systems!may!be!better!defined!as!a!gross!leak!test.!!Nevertheless,!these!tests!can!play!an!important!
role! in! a! risk(based! QbD! approach! to! system! integrity! as! discussed! in! Part! 2.! The! sensitivity! of!
pressure! methods! will! be! enhanced! by! other! factors! such! as! the! presence! of! restraining! plates! or!
holders,!strict!control!of!temperature,!and!extended!stabilization!and!test!times.!
!
The! detection! sensitivity! of! the! pressure(based! tests! and! the! relationship! between! defect! size! and!
microbial!ingress!are!discussed!in!Part!3.!The!studies!show!that!microbial!contaminants!may!be!able!
to!penetrate!a!film!barrier!with!a!defect!of!2.65!µm!or!greater!in!size.!Therefore,!for!sterile!products,!
an!additional!integrity!test!with!detection!levels!in!this!range!could!be!beneficial!to!reduce!the!risk!of!
non(sterility.!
!
b.&Trace&Gas&Integrity&Test!
The!trace!gas!integrity!test,!typically!a!helium!leak!test!as!described!below,!has!been!used!widely!in!
various!industries!for!detecting!defects!in!solid!structures!with!a!detection!limit!down!to!2!µm!under!
industrial! manufacturing! conditions! (33,! 34).! Although! not! yet! widely! used! for! testing! of! flexible,!
non(rigid!systems,!it!offers!a!potentially!suitable!method!for!single(use!systems!in!the!bioprocessing!
industry!where!the!highest!possible!level!of!sterility!assurance!may!be!required!to!complement!a!risk!
management!and!QbD!approach!to!system!integrity,!as!described!earlier!in!this!section!
The!set!up!for!a!helium!integrity!test!(HIT)!is!shown!in!Figure!12.!
!

!
!
!
! Figure&12.&&Helium&integrity&test&&
!
The!principle!of!the!method!is!to!measure!the!amount!of!a!tracer!gas!leaking!through!any!defect!in!a!
barrier.!To!carry!out!the!test,!the!container!under!test!is!placed!inside!a!well(sealed,!rigid!chamber,!
as!shown!in!Figure!13,!and!connected!to!a!helium!inlet!valve.!The!chamber!seals!ensure!that!no!air!
or! other! gas! can! enter! or! leave! while! the! test! is! in! progress.! For! a! flexible! bag! system,! restraining!
plates! can! be! fitted! to! reduce! stress! on! the! bag! while!
increasing!allowable!test!pressures.!Porous!spacers!can!
be! inserted! to! avoid! masking! of! any! defects! by! the!
restraining! plates.! ! The! air! is! then! pulled! from! the!
chamber! and! helium! is! injected! into! the! single(use! bag!
or!system.!!
!
If! there! are! no! defects! in! the! barrier! of! the! single(use!
system,! the! helium! will! remain! inside! the! system,!
except! for! possible! helium! diffusion! through! intact!
polymeric! films! or! tubing.! Diffusion! needs! to! be!
accounted! for! in! the! baseline! control! and! calibration!
samples.!If!there!are!defects!in!the!barrier,!the!vacuum!
will! pull! helium! from! the! single(use! system! into! the! Figure&13.&Helium&integrity&test&system&
vacuum! chamber.! The! helium! in! the! chamber! is! then!
detected! and! quantified! using! a! mass! spectrometer! and! the! amount! of! helium! detected! can! be!
correlated!with!defect!size.!The!helium!test!does!not!require!constant!temperature!conditions.!!
!
!
!
!
!
!
!
!
!
!
!
!
! Figure&14.&&Helium&integrity&test&leak&rates&

!
!
Interference! from! diffusion! of! helium! through! the! film! of! the! flexible! barrier! can! increase! the!
concentration! of! helium! in! the! vacuum! chamber! during! the! test,! as! shown! in! the! “non(defective”!
curve! in! Figure! 14.! This! phenomenon! limits! the! defect! size! resolution! of! the! test! method.! It! is!
essential! therefore! to! ensure! the! shortest! possible! test! time! to! minimize! the! accumulation! of!
diffused!helium!in!the!vacuum!chamber.!
Helium! integrity! testing! is! less! sensitive! to! system! volume! than! pressure(based! tests! and! can!
currently!accommodate!both!2D!and!3D!systems!as!shown!in!Figure!15.!!In!this!study,!a!SUS!provider!
was!able!to!show!that!a!5!µm!defect!can!be!detected!in!50!L!2D!and!200!L!3D!biocontainers.!(37)!
Further!developments!may!extend!this!range!to!larger!systems.!!
14&
12&
RELATIVE&HELIUM&LEAK&RATE&
10&
8&
6&
4&
2&
0&
50L&CONTROL& 50L&with&5&µm& 200L&CONTROL& 200L&with&5&µm&
DEFECT& DEFECT&
! ! ! !
! Figure&15.&&Helium&integrity&test&on&2D&and&3D&biocontainers&
The!capital!and!maintenance!costs!for!helium!testing!are!higher!than!those!for!pressure!tests,!and!
operator! handling! procedures! are! more! complex.! The! test! can! therefore! be! considered! mainly! for!
validation!testing!both!at!the!supplier!or!end(user!site,!or!for!routine!testing!of!small!assemblies!at!
the!supplier!site.!
A!comparative!summary!of!the!features!of!helium!and!pressure(based!tests!is!presented!in!Table!V!
(36,37).!!!
! !

!
!
Feature! Helium Test Pressure Tests
Sensitivity! ≥ 2 µm! ≥ 30 µm!
Environmental!effects! Low! Medium!(temperature)!
Volume!impact! Low!to!Medium! Medium!to!High!
Material! Medium!to!High! Low!→!Medium!
Handling! Complex! Simple!
Test!time! Low! Medium!
Maintenance! Complex! Low!
Cost! High! Low!
!
Table&V.&Comparative&features&of&helium&and&pressureCbased&tests&
!
From!these!comparative!data,!it!is!evident!that!decisions!on!which!type!of!test!to!use!for!each!
individual!operation!must!take!into!account!not!only!detection!limits!but!safety,!financial!and!other!
operational!or!practical!considerations.!
!
Part&3.&&Critical&Defect&Size&(Shape,&Type)&and&Correlation&by&Microbial&Challenge&!
Having! described! the! attributes! of! various! test! methods! in! Part! 2,! the! higher! sensitivity! tests! will!
have! limited! significance! if! they! are! not! correlated! to! some! form! of! microbial! challenge! at! the!
validation!phase!to!assess!the!risk!of!microbial!ingress.!These!correlation!studies!can!determine!the!
critical! defect! size! which! is! defined! as! the! smallest! size! of! defect! below! which! microbial! ingress!
cannot!occur.!!
!
3.1.&Creation&of&Defects&for&Correlation&Studies&
In! order! to! investigate! this! relationship,! it! is! first! necessary! to! create! holes! or! defects! of! different!
sizes!in!a!solid!substrate.!!Various!techniques!have!been!proposed!and!evaluated!but!the!two!most!
widely!used!methods!are:!
!
3.1.1.&Laser&Drilling&&&
This!technique!involves!the!use!of!focused!laser!light!with!appropriate!energy!levels!to!create!holes!
of! different! sizes! in! flexible! film,! as! shown! in! Figure! 16.! ! The! film,! with! or! without! the! artificially(
created!defects,!can!then!be!used!to!manufacture!flexible!bags!for!correlation!studies.!!For!example,!
the! bag! in! Figure! 17! has! a! 10! µm! defect! in! the! centre.! Alternatively,! a! metal! plate! with! standard!
laser(drilled!holes!can!be!attached!to!the!SUS!under!test.!
Laser& !
entry& !
!
!
!
! 10&µm&
! defect!
!
Nominal& !
orifice&size& !
!
!
!
!
!
! Figure&17.&&Bag&with&10&µm&
Laser& !
exit& laserCdrilled&defect!
! &&
Figure&16.&&Laser&drilling&&
!
!
!
!
The!shape!of!the!orifice!at!the!surface!viewed!from!both!the!entry!and!exit!points,!shown!in!Figure!
18,! is! typically! not! a! perfect! circular! hole.! ! The! net! flow! area! is! described! as! a! nominal! defect! size!
based!on!flow!rate!measurement,!calculation!and!pinhole!equivalent.!!
!
10&µm 2&µm
!
!
!
!
!
! Laser&
! entry&
! points&
!
!
!
!
!
!
! Laser&
! exit&
! points&
!
!
!
Figure&18.&&Laser&entry&and&exit&points&
!
!
!
The!air!flow!rate!through!a!known!size!of!orifice,!as!certified!by!the!National!Institute!of!Standards!
and!Technology!(NIST),!can!be!compared!with!the!air!flow!rate!through!the!defect!in!the!film!from!
which!the!defect!size!can!be!calculated.!
!
Data!from!studies!with!laser(drilled!holes!are!presented!in!a!later!section.!
&
&
3.1.2.&Use&of&Microcapillaries&&
!Various! techniques! and! materials! may! be!
used! to! manufacture! microcapillaries! with!
different! core! diameters! and! these! can! be!
used! in! microbial! challenge! tests! to!
determine! critical! defect! size! for! microbial!
ingress.!Microcapillaries!used!in!these!studies!
include! glass! micro(pipettes,! poly(coated!
glass! micro(tubes! and! nickel! micro(tubes.!
Examples! of! microcapillaries! inserted! into! a!
tubing! attachment! and! a! container! cap! are!
shown!in!Figure!19.!! Figure&19.&&Microcapillaries&inserted&into&a&
! tubing&attachment&and&a&container&cap&
&
&
&
&
&

!
!
&
3.2.&Microbial&Challenge&Tests&
It!is!a!misconception!to!define!the!critical!defect!size!as!the!size!of!the!smallest!organism!that!could!
compromise! the! sterility! of! a! product.! For! example,! a! so! called! ‘0.2! µm’! sterilizing! grade! filter! has!
some!pores!much!greater!than!0.2!µm!and!these!pores!are!also!larger!than!the!minimum!dimension!
of! the! rod(shaped! organism! Brevundimonas! diminuta! of! approximately! 0.3! µm! used! to! qualify! the!
filter! as! a! sterilizing! grade.! The! only! meaningful! way! to! define! critical! defect! size! is! to! perform!
microbial! challenge! tests! on! defective! systems! with! known! defect! sizes! and! to! establish! the! size!
above!which!microbial!ingress!occurs.!!!
!
This!critical!size!can!vary!according!to!the!type!of!challenge!test!and!its!detailed!parameters,!as!well!
as! the! size! and! shape! of! the! organism,! the! differential! pressure! across! the! defect! and! many! other!
factors.!!The!critical!defect!size!may!also!vary!according!to!the!process!and!product!–!for!example,!a!
corrosive! fluid! with! no! susceptibility! to! bacterial! infection! but! requiring! zero! liquid! loss! for! safety!
reasons! may! tolerate! a! bag! with! a! relatively! large! critical! defect! size.! ! Sterile! products! however!
present!the!most!demanding!requirements!for!system!integrity.!Single(use!systems!for!the!storage!
of! sterile! products! must! therefore! be! validated! using! high! sensitivity! bacterial! challenge! tests! to!
determine! the! smallest! critical! defect! size! for! prevention! of! microbial! ingress,! either! under! worst!
case!conditions!or!conditions!simulating!typical!process!applications.!
!
Two!basic!tests!methods!are!currently!used!for!microbial!challenge:!
1.!Aerosol!challenge!
2.!Liquid!immersion!!!
These!two!methods!differ!in!their!sensitivity!to!microbial!ingress!which!is!highly!dependent!on!test!
conditions.! The! bacterial! ingress! experiments! and! results! described! below! for! aerosol! and! liquid!
testing!are!examples!meant!to!guide!the!end(user.!The!results!are!not!intended!to!provide!definitive!
guidelines.!!!
&
3.2.1.&Aerosol&Challenge&Test&
This! type! of! test! is! less! challenging! than! liquid! immersion! and! will! be! appropriate! for! most!
applications,!as!the!single(use!system!will!be!operating!at!worst!in!a!class!D!environment,!as!shown!
previously! in! Table! III.! ! The! choice! of! an! aerosol! test! would! be! assisted! by! the! risk! assessment!
procedure!for!the!process!from!which!selection!of!test!conditions!could!also!be!established!such!as!
test!organisms!and!challenge!levels,!exposure!times,!sampling!methods!etc.!
!
Details! of! an! experimental! study! for! aerosol! challenge! are! shown! in! Figure! 20! and! Table! VI! as! an!
example.!
!
!
!
!
!
!
!
!
!
!
!
!
!

!
!
Air&supply& Microbial&
! suspension&
!
!
! Nebulizer&
!
!
Vent&
!
filter&
! Glove&
2D&bags&with&sized&defects&plus&nonC port&
! Support& defective&control&bags&
! rail&
!
!
!
!
!
! Petri&dish&
!
! Figure&20.&Test&system&for&aerosol&microbial&challenge&on&singleCuse&2D&bags&
!
!
Feature& Properties&
Test!bag!! 2D!with!2!L!volume!!
Defect!size!range! 4!µm!(!20!µm!
Growth!media! 600!mL!trypticase!soy!broth!
Challenge!organisms! Escherichia!coli!
! ! Staphylococcus!aureus!
! Bacillus!spizizenii!
Candida!albicans!
Aspergillus!brasiliensis!
Microbial!aerosol! 106!cfu/mL!
concentration!
Aerosol!exposure!times! 60!minutes!
Incubation!temperature! 300!–!350!C!
Incubation!time!! 14!days!
&
Table&VI.&Aerosol&microbial&challenge&test&
!
!
Bags! with! known! sizes! of! defects,! produced! by! laser! drilling,! were! filled! with! growth! media.! Bags!
with!no!defects!were!included!to!act!as!negative!controls!and!
all!bags!were!sterilized!by!gamma!irradiation.!Positive!controls!
were! introduced! by! inoculating! a! sample! bag! with! the! test!
organism.!!!
!
The!chamber!was!fitted!with!feeds!for!air!and!liquid!microbial!
suspension! which! were! passed! through! a! nebulizer! to! create!
the! aerosolized! challenge.! Vent! filters! allowed! escape! of! air.!!
Petri! dishes! with! growth! media! were! positioned! at! suitable!
locations! throughout! the! chamber! to! quantify! the! incident!
Figure&21.&Bag&inside&chamber&

!
!
microbial!challenge!levels.!Glove!ports!enabled!operator!handling!of!the!chamber!contents.!!
!
After! exposing! the! bags! to! aerosolized! microbial! suspension! for! the! specified! time,! the! bags! were!
removed!and!incubated!under!appropriate!conditions!to!ensure!maximum!growth!of!the!challenge!
organism.!!The!media!was!then!sampled!for!presence!of!any!bacterial!growth.!The!Petri!dishes!were!
incubated! to! determine! the! incident! aerosol! challenge! levels! in! the! chamber.! The! microbial!
challenge!fed!to!the!chamber! was!also!calculated!from!the!volume!and!microbial!concentration!of!
the!suspension.!!
!
The!negative!control!bags!with!no!laser(drilled!defects!showed!no!growth!confirming!the!sterility!of!
the!media!and!lack!of!critical!defects!in!normal!production!bags.&
The! positive! control! bags! inoculated! with! 100! cfu! showed! growth,! confirming! suitability! of! the!
incubation!conditions.!
!
Results! from! defective! bags! after! 60! minutes! of! exposure! to! the! aerosol! challenge! are! shown! in!
Number&of&
bags&tested&&
Defect&size&(µm)&
&
Figure&22.&Microbial&results&from&aerosol&challenge&test&for&60&minutes&
Figure!22.!!Microbial!growth!was!not!detected!in!any!of!the!test!bags!with!defects!smaller!than!12.65!
µm.!!Growth!was!present!in!bags!with!defects!of!12.65!µm!and!greater.!!
!
From!this!experimental!study,!it!was!concluded!that!the!critical!defect!size!for!this!type!of!bag,!when!
tested!under!these!specific!aerosol!challenge!conditions,!was!less!than!12.65!µm.!!
!
3.2.2.&Liquid&Immersion&Challenge&Test&
The! liquid! immersion! test! offers! more! severe! test! conditions! than! an! aerosolized! challenge! and!
therefore!has!a!higher!probability!of!detecting!microbial!ingress!through!defects!smaller!in!size!than!
those! detected! by! the! aerosol! test.! This! type! of! test! is! therefore! typically! applicable! to! sterile!
products!in!their!final!dosage!containers!(5).!

!
!
Details! of! an! experimental! study! on! the! liquid! immersion! challenge! test! are! presented!in! Table! VII!
and!Figures!23.!!
!
The!test!set!up!and!procedures!had!two!major!differences!to!those!used!in!the!aerosol!test:!
1.! Replacement! of! the! nebulizer! and! aerosolized! microbial! environment! by! a! microbial! liquid!
suspension!in!the!chamber!to!enable!immersion!of!the!bags,!as!shown!in!Figure!23.!
2.! Replacement! of! a! mixed! microbial! suspension! by! a! single! organism,! Brevundimonas! diminuta,!
which!is!a!diminutive!and!highly!penetrative!rod(shaped!bacterium!approximately!0.3!µm!x!0.8!µm!
in! size.! ! It! is! used! widely! for! other! liquid! challenge! tests! such! as! in! validation! of! sterilizing! grade!
filters.!!
!
Feature& Properties&
Test!bag!! 2D!with!2!L!volume!!
Defect!size!range! 4!µm!(!20!µm!
Growth!media! 600!mL!trypticase!soy!broth!
Challenge!organism! Brevundimonas!diminuta!
Microbial!concentration! 9.7!x!106!cfu/mL!!
Immersion!times! 180!minutes!!!
Incubation!temperature! 300!–!350!C!
Incubation!time!! 14!days!
!
Table&VII.&Liquid&immersion&microbial&challenge&
!
test&
Bag&with&
growth&
medium&
Defect&&
&
Figure&23.&Liquid&microbial&immersion&test&&
Microbial&
suspension&&
The! defective! bags! filled! with! sterile! growth! &
media! were! immersed! in! the! liquid! to! the! level!
shown! in! Figure! 24! so! that! the! defective! region!
Figure&24.&Defective&bag&in&
was!fully!covered.!!!
! microbial&immersion&test&&
!
The!negative!control!bags!with!no!laser(drilled!defects!showed!no!growth,!confirming!the!sterility!of!
the!media!and!lack!of!critical!defects!in!normal!production!bags.!The!positive!control!bags!inoculated!
with!100!cfu!showed!growth,!confirming!suitability!of!incubation!conditions.!
!
The!results!from!defective!bags!are!presented!in!Figure!25.!!

!
!
Number&of&
bags&tested&&
Defect&size&(µm)&
&
Figure&25.&Microbial&results&after&3&hours&liquid&immersion&
When!compared!to!the!aerosol!data!in!Figure!22,!the!graphs!showed!a!substantial!shift!in!the!critical!
defect!size!from!12.65!µm!for!the!aerosol!challenge!to!2.65!µm!for!the!liquid!immersion!challenge.!!
The! five(fold! reduction! in! the! critical! defect! size! confirms! the! more! severe! conditions! in! a! liquid!
immersion! test! as! well! as! the! more! penetrating! nature! of! the! challenge! organism! Brevundimonas!
diminuta.! In! this! context,! it! is! important! to! note! that! the! critical! defect! sizes! determined! in! these!
microbial!challenge!tests!relate!to!pinhole!defects!only.!!!
!
For!most!applications,!an!aerosol!challenge!test!would!represent!the!worst(case!challenge!condition!
for! typical! manufacturing! environments! (see! Table! III),! but! in! some! highly! critical! applications,! an!
immersion! challenge! test! might! be! relevant.! ! This! destructive! test! does! provide! a! powerful! tool! in!
validation!of!the!manufacturing!process!to!offer!a!high!level!of!assurance!of!product!integrity!prior!
to!shipment.!!!!
!
Part&4.&Implementation&of&Integrity&Tests&by&the&Supplier&and&EndCuser&
&
4.1.&When&to&Test&and&What&Type&of&Test&
Having! described! the! various! types! of! test,! their! detection! capabilities,! suitability,! risks! and! other!
considerations,! it! is! evident! that! control! of! integrity! assurance! can! only! be! achieved! by! a!
combination!of!a!risk(based!QbD!approach!and,!when!technically!practicable,!a!selective!application!
of!integrity!tests!and!gross!leak!tests!together!with!visual!inspection.&
!
There!are!three!stages!where!testing!may!be!considered:!
• Component!testing!by!manufacturer!
• Assembly!testing!by!supplier/integrator!
• Assembly!testing!by!end(user!at!the!point!of!use!
!
The!options!available!for!implementation!of!testing!in!the!SUS!product!life!cycle!are!shown!in!Figure!
26.!

!
!
Assembly(Supplier/Integrator!
Validated&by&
component&
manufacture Qualified&&assembly&
r&& processs&
Other&
components&
Assembly&& Packaging&
SU&critical&
component&
Optional&leak&or&integrity& Irradiation&&
Optional&leak& test,&dependent&on&
or&integrity&test&& system&size/complexity&
and&practicality&
EndCuser%Deployment!
Disposal&& Use&& Installation&& Shipment&
Optional&preC&or&postCuse&
leak&or&integrity&test.&& Operator&
Dependent&on&system& training&&
size/complexity,&practicality,&
and&criticality&of&application&
Figure&26.&&Integrity&assurance&in&SUS&product&life&cycle&&
For! some! components,! the! system! manufacturer! or! integrator! is! dependent! on! the! testing! and!
validation!performed!by!the!component!supplier.!Testing!by!the!system!supplier!may!be!performed!
on!a!sample!basis!during!manufacture,!but!testing!on!a!100%!basis!may!be!achievable!or!desirable!
for! specific! components! or! systems! such! as! bags,! filter! capsules! or! sterile! connectors! to! offer! the!
highest! assurance! of! integrity.! ! The! choice! will! depend! on! the! system! size! and! complexity,! the!
practicality!and!limitations!on!sensitivity!and!the!criticality!of!the!application.!!!!
!
For! single(use! assemblies! in! critical! processes,! it! is! essential! to! ensure! system! integrity! at! the! very!
highest!level.!!Qualification!studies!show!that!this!level!may!be!achievable!for!small!systems!(<200!L)!
by! performing! a! high! sensitivity! integrity! test! at! the! manufacturing! site! by! the! supplier! on! a! 100%!
basis.!!At!the!end!of!the!manufacturing!process!prior!to!shipping,!the!test!may!have!the!sensitivity!to!
detect! small! defects! that! potentially! could! compromise! sterility! in! the! application.! ! However,! with!
increasing!size!and!complexity!of!the!assembly,!a!high!sensitivity!integrity!test!may!not!be!available!

!
!
or! possible.! ! Risk! assessment! may! conclude! that,! under! end(user’s! responsibility,! this! limitation! in!
testing! technology! can! be! overcome! by! QbD,! supportive! validation! and! other! qualifying! data!
combined!with!adequate!audits.!Similarly,!this!approach!may!be!applicable!for!less!critical!as!well!as!
smaller,!less!complex!systems!to!eliminate!the!need!for!routine!QC!testing!for!integrity.!
!
As! discussed! previously,! packaging! and! transportation! are! vital! components! in! risk! assessment! as!
this!is!an!area!where!damage!could!occur!with!poorly!designed!packaging!together!with!inadequate!
evaluation! of! shipment! and/! or! environmental! conditions! and! their! effect! on! product! integrity.!
Additional! risk! may! be! present! during! subsequent! handling! and! deployment! by! the! end(user.!!
Training,!often!in!conjunction!with!the!product!supplier,!together!with!well(documented!operating!
procedures!is!extremely!important!to!prevent!damage!due!to!handling!errors!by!the!end(user!(35).!!
.!!!!
The!size!of!defect!that!could!be!created!from!transportation!damage!or!mishandling!by!an!operator!
may!be!much!larger!than!those!detected!by!the!supplier!at!the!manufacturing!stages!when!using!a!
high!sensitivity!test.!These!‘gross!defects’!could!have!a!substantial!impact!on!the!production!process,!
such!as!loss!of!high!value!product,!contamination!of!an!operator!and/or!the!environment!with!toxic!
product! or! microbial! contamination! of! sterile! product.! Unfortunately,! these! gross! defects! might!
remain! undetected! by! visual! inspection! by! the! end(user.! ! They! may! be! identifiable! however! by!
performing!a!gross!leak!test!before!use.!!!!
!
This!combination!of!an!integrity!test!at!the!supplier’s!manufacturing!site!for!critical!components!and!
assemblies!and!the!pre(use!gross!leak!test!by!the!end(user,!if!technically!feasible!and!supported!by!
risk!assessment,!can!contribute!to!a!safe!and!practical!way!to!ensure!integrity!of!a!single(use!system!
in!critical!applications.!!!
&
4.2.&Detection&Capabilities&of&NonCdestructive&Integrity&Tests&
In! Parts! 2! and! 3,! the! risk(based! approach! to! integrity! assurance! for! single(use! systems! has! been!
described! together! with! the! practical! methods! available! for! integrity! testing! (including! those! that!
can! be! used! as! pre(installation! tests)! and! the! correlation! of! these! tests! to! microbial! challenge! and!
critical!defect!size.!
&
However,!it!is!necessary!to!establish!from!this!information!which!of!the!practical!tests!are!suitable!
for!integrity!assurance!by!the!supplier!and!by!the!end(user.!!The!sensitivity!as!well!as!limitations!of!
each! method! needs! to! be! assessed! with! regard! to! the! application,! the! size! and! complexity! of! the!
system,!the!possible!causes!and!nature!of!defects,!and!other!factors.!
!
The!defect!detection!capabilities!of!pressure!and!helium!tests!are!summarized!in!Table!VIII.!!
!
! !

!
!
Location&of&defect& Pressure&tests! Helium&Test&
Detection!limit! ≥ 30!µm! ≥ 2!µm!
Defect!in!bag!1! !! !!
Defect!in!tubing! !! !!
Defect!in!sterile!connector!2! X!& X!!
Defect!in!T!or!Y!piece! !! !!
Defect!in!quick!connector! !& !!
Non(integral!filter! X& X!
Defect!in!filling!needle3! X! X!
Absence!of!cable!ties4! X! X!
Cable!tie!not!tightened! X! X!
X& =! Does! not! detect! defect.! !& =! Detects! defects! but! different! levels! of! sensitivity!
!! depending! on! application.! 1.! Volume! and! test! pressure! dependent.! ! 2.! Dependent! on!
type! of! connector! (! with! or! without! membrane;! male! or! female! part;! before! or! after!
actuation.!male!or!female!part;!before!or!after!actuation.!!3.!Need!to!be!isolated!from!
&& the!SUS.!4.!Because!of!test!pressure.!!
! Table&VIII.&Defect&detection&capabilities&of&integrity&tests&&
!
For!defects!in!bags,!tubing!and!T!or!Y!pieces,!both!tests!have!capability!for!detection!whereas!none!
can! provide! detection! capability! for! defects! in! filter! integrity,! filling! needles,! and! absence! of! cable!
ties! or! ties! not! sufficiently! tightened.! For! some! defects,! such! as! those! in! bags! or! tubing,! there! are!
differences!in!levels!of!detection!capabilities!between!the!tests.!Even!for!those!defects!where!a!test!
may!in!principle!be!capable!of!detection,!consideration!must!also!be!given!to!the!ability!to!perform!
the!test!effectively!and!without!risk!in!the!specific!process!stage!or!environment.!!This!consideration!
is!discussed!later.!
It!is!evident!therefore!that!integrity!testing!alone!cannot!provide!the!defect!detection!capability!for!
all! system! components! and! that! integrity! control! strategy! must! be! supported! by! detailed! risk!
assessment,!QbD!and!full!validation!of!the!individual!component!manufacturing!and!of!the!assembly!
process.!!
4.3.&Effect&of&System&Complexity&on&Suitability&of&Integrity&Test&Methods&
The!level!of!complexity!of!the!system!can!have!a!significant!impact!on!the!suitability!of!an!integrity!
test!method,!as!shown!in!Table!IX.!!Although!the!helium!test!can!potentially!offer!sensitivity!down!to!
2!µm!for!simple!bag!systems,!it!is!not!suitable!for!complex!systems!where!pressure!tests!are!the!only!
option,!but!the!sensitivity!will!be!largely!dependent!on!system!volume.!There!will!also!be!differences!
in!sensitivity!for!either!test!within!the!various!types!of!systems!shown!in!Table!IX.!!
System& Suitability&
Pressure!tests! Helium!Test!
Lower! Higher!sensitivity!
sensitivity!
Tubing!sets1! !! !!
Simple!bag!sets1!! !! !!
Bioreactor!chamber1! !! !!
Mixing!chamber1!! !! !!
Complex!system!with!filters1!! !! X&!
Complex!system!with!sterile!connectors1,2! !! X!
Final!filling!sets1,2! !! X!
!
X& =! Not! suitable.! 1! =! Volume! and! test! pressure! dependent.! 2! =! Open! ended!
components!such!as!filling!needles!and!sterile!connectors!need!to!be!clamped!
!
Table&IX.&Level&of&system&complexity&and&experience&of&integrity&test&methods&
!
!
The!SUS!can!be!designed!to!make!the!system!more!easily!testable!by!the!end(user.!!The!increased!
adoption! of! integrity! testable,! standard! systems! rather! than! customised! systems! would! facilitate!
factory!testing!by!the!supplier!under!controlled!test!conditions.!
4.4.&Level&of&Risk&in&Implementation&of&Integrity&Test&at&Different&Stages&in&the&Process&
Having!established!the!sensitivity!of!the!test!and!what!type!of!system!can!be!tested,!implementation!
cannot! be! considered! before! completion! of! a! risk! assessment.! ! In! addition,! although! the! pressure!
and! helium! tests! are! non(destructive,! they! can! potentially! introduce! risks! to! the! product,! process,!
operator!or!environment!in!specific!situations.!!
!
4.4.1.&Risk&of&product&contamination&
An!integrity!test!performed!before!sterilization!of!the!single(use!system!will!present!a!very!low!risk!
of! contamination! and! non(sterility,! as! any! microbial! contaminants! introduced! during! the! test!
presents! a! low! risk! if! the! step! is! qualified! and! performed! according! to! a! qualified! procedure.! ! In!
contrast,!a!test!on!the!sterilized!system!before!use!will!require!aseptic!techniques!and!therefore!has!
a! potentially! higher! risk! of! contamination! and! product! non(sterility.! ! Testing! after! use! and! before!
disposal! will! have! zero! risk! in! this! context,! except! for! systems! containing! hazardous! final! product!
where!risks!to!the!operator!or!environment!could!be!introduced!by!leaks!from!a!defect!or!from!poor!
management!of!the!used!system.!
!
4.4.2.&Risk&of&damage&
An! integrity! test! could! also! potentially! introduce! physical! damage! to! the! system.! ! A! supplier! test!
before! sterilization! can! be! performed! under! conditions! that! offer! easier! handling! of! the! non(
sterilized!system!and!designed!to!avoid!any!risk!of!single(use!system!damage.!
!
Once!at!the!end(user,!the!single(use!system!will!have!gone!through!sterilization,!packing,!shipment,!
unpacking! and! deployment.! ! These! sequential! steps! should! have! a! minimal! impact! on! the! system,!
provided! it! has! been! well! designed! with! good! packaging,! shipment! conditions! and! handling! by!
trained!operator.!!The!risk!of!damage!by!pre(use!integrity!testing!would!therefore!be!expected!to!be!
low,! but! when! these! parameters! are! compromised,! damage! from! integrity! testing! could! occur! in!
areas!such!as!weakened!connections,!abraded!bags!or!materials!weakened!by!gamma!irradiation.!!In!
such! cases,! the! risk! of! damage! could! be! medium! to! high.! In! addition,! design! of! single(use! system!
which!is!tested!at!point!of!use!should!include!an!air!inlet!fitted!with!a!sterilising!grade!filter!to!ensure!
absence!of!microbial!contamination!during!testing!and!air!or!gas!of!an!appropriate!quality.!
!
4.4.3.&Sensitivity&and&reliability&
The! user! must! also! consider! the! sensitivity! and! reliability! of! the! test! at! different! stages! in! the!
process,!as!shown!in!Table!X.!!!
!
Stage&in&Process! Sensitivity&&&Reliability!
Before!sterilization! High&
Before!use! Medium&
After!use! Low1&
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!1!=!Due!to!drying!conditions!
!
! Table&X.&Sensitivity&and&reliability&of&testing&at&different&process&stages&
testing&singleCuse&systems&
The!higher!sensitivity!and!reliability!before!sterilization!can!be!attributed!to!the!more!favourable!and!
controllable! test! conditions,! in! addition! to! the! potential! use! of! a! helium(based! test;! for! example,!
control! of! temperature,! optimization! of! test! time,! access! to! and! connection! of! test! equipment.!!
Nevertheless,! the! sensitivity! of! the! test! will! always! decrease! as! the! system! size! and! complexity!
increase,!as!shown!in!table!IX,!and!therefore!the!implementation!of!this!type!of!test!for!large!system!
volumes!should!be!questioned.!&

!
!
Part&5.&Discussion&and&Conclusions&
Integrity!testing!methods!for!single(use!systems!clearly!have!some!significant!limitations!which!pose!!
three!fundamental!questions:!
• Is!integrity!testing!necessary!at!all?!
• Is!integrity!testing!by!the!supplier!necessary?!
• Is!integrity!testing!by!the!end(user!necessary?!!
!
The!complexity!of!many!single(use!systems!introduces!a!risk!of!creating!defects!during!manufacture,!
shipment! and! use.! ! These! risks! can! be! mitigated! to! a! great! extent! by! QbD! during! design! and!
development,!as!shown!in!Figure!27,!as!well!as!a!very!strict!validation!of!the!assembly!manufacturing!
and! packaging! process.! ! ! Routine! leak! or! integrity! testing! during! manufacture,! either! on! a! sample!
basis!or!100%,!may!be!performed!especially!for!less!complex!or!low!volume!systems.!
!
Development&& & &

Design& Manufacturing& User&
Validation&
&&QbD/Risk&Assessment& QC,&Visual&Control& QbD/Risk&Assessment&

&&Mechanical,& Documentation& &&&&&Operator&Training&
&&Microbial,& Optional)Supplier) &&&&&QC,&Visual&Inspection&
&&Shipping&Tests& Leak/Integrity)Test)) &&Optional)Point)of)Use))
&&Integrity&tests& Leak)or)Integrity)Test)
SUS&Fit&for&Purpose& ! &
&
&
Figure&27.&&Best&practices&for&risk&mitigation&
For! the! end(user,! operator! training! is! essential! supported! by! detailed! technical! due! diligence,!
procedural!and!engineering!controls.!!Integrity!assurance!by!visual!inspection!for!gross!defects!is!a!
simple!and!beneficial!procedure!but!for!some!highly!critical!applications,!additional!controls!could!be!
considered!and!evaluated!to!ensure!a!higher!level!of!integrity!assurance.!For!example,!some!form!of!
integrity!or!leak!test!by!the!end(user!may!be!desirable!for!systems!downstream!of!sterile!filtration!or!
if! the! drug! product! cannot! be! sterile! filtered,! but! the! practicality,! added! complexity! and! potential!
risks!of!testing!a!sterile!system!at!point!of!use!must!be!carefully!evaluated.!!
If! an! integrity! test! is! performed! by! the! end(user,! the! test! must! be! shown! to! have! a! meaningful!
sensitivity!for!detection!of!defects.!!However,!the!sensitivity!of!current!integrity!testing!technologies!
is!highly!dependent!on!system!size!or!complexity!and!therefore!not!all!systems!can!be!tested!to!this!
highest! level! of! integrity! assurance.! In! addition,! the! test! must! not! introduce! contamination! nor!
damage!the!system.!!Where!appropriate,!it!could!be!argued!that!further!testing!by!the!end(user!is!
not!required!and!may!even!be!meaningless!for!some!systems!because!of!the!sensitivity!limitations!in!
testing!at!point!of!use.!!This!route!can!be!a!justifiable!option!provided!that!a!high!level!of!assurance!
of!integrity!has!been!established!by!the!supplier’s!QbD!and!validation,!as!well!as!the!end(user’s!IOPQ!
and!operator!training.!
!

!
!
Part&6.&Summary&
A! risk(based! approach! provides! the! foundation! for! integrity! assurance! of! Single(Use! Systems! and!
requires!a!risk!management!plan.!!This!plan!has!five!components!–!business,!product,!operator!and!
environment,!and!integrity.!!!
!
For! the! integrity! component,! a! Quality! by! Design! (QbD)! approach! demands! understanding! of! the!
single(use! system’s! life! cycle! from! the! earliest! design! stages! through! to! manufacture,! assembly,!
deployment! and! exploitation.! QbD! for! single(use! technology! also! requires! a! strong! working!
relationship!between!the!supplier!and!end(user.!!A!joint!FMEA!performed!by!supplier!and!end(user!
will!enhance!the!QbD!results!and!help!to!identify!an!appropriate!Manufacturing!Control!Strategy.!
!
Integrity! testing! of! components! and! systems! by! the! supplier! during! manufacture! of! the! assembly!
and! supported! by! full! validation! of! the! assembly! process! are! vital! elements! providing! system!
integrity! assurance! for! the! SUT.! Packaging! and! transportation! operations! and! conditions! must! be!
designed!carefully!to!maintain!integrity!on!the!SUS!in!transit.!!
!
The! end(user! must! ensure! that! integrity! is! maintained! during! installation! and! operation! by!
implementation!of!detailed!standard!operating!procedures!and!operator!training.!!Further!assurance!
of!integrity!may!be!achieved!by!optional!testing!at!point!of!use.!The!decision!to!test!at!point!of!use!
depends! on! the! criticality! of! the! application! and! the! ability! to! perform! a! meaningful! test! without!
adding! risk! to! the! process,! operators! or! environment.! ! Where! justified! by! risk! assessment! and!
validation,!and!supported!by!the!QbD!approach,!a!single(use!system!may!be!safely!used!without!the!
need!for!integrity!testing!by!the!end(user.!!!
!
Part&7.&References&
&&
1. ICH!guideline!Q9!on!quality!risk!management.!!
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50
0002873.pdf!
2. ASTM!2095.!Standard!Test!Methods!for!Pressure!Decay!Leak!Test!for!Flexible!Packages!with!and!
without!Restraining!Plates!http://www.astm.org/Standards/F2095.htm
3. ASTM!F2391(05.!Standard!Test!Method!for!measuring!Package!and!Seal!Integrity!using!Helium!as!
the!Tracer!Gas.!http://www.astm.org/Standards/F2391.htm!
4. PDA!Technical!Report!TR!66.!Application!of!Single(Use!Systems!in!Pharmaceutical!Manufacturing.!
http://store.pda.org/TableOfContents/TR66_TOC.pdf!
5. PDA!Technical!Report!TR!27.!Pharmaceutical!Package!Integrity.!J!Pharm.!Sci.!and!
Tech.,!Supplement!Vol.!52,!No.!S2,!1998.!
http://store.pda.org/ProductCatalog/Product.aspx?ID=1185!
6. USP!<381>.!!Elastomeric!closures!for!injections.!http://www.usp.org/usp(nf/notices/elastomeric(
closure(injections.!
7. USP!<1207>.!Sterile!product!packaging!–!Integrity!evaluation.!
http://pharmacopeia.cn/v29240/usp29nf24s0_c1207.html!
8. USP!<123>.!Validation!of!alternative!microbiological!methods.!http://www.usp.org/usp(
nf/notices/validation(alternative(methods!!
9. EP!3.2.9.!Rubber!closures!for!containers!for!aqueous!parenteral!preparations!for!powders!and!
form!freeze(dried!powders.!!!
http://library.njucm.edu.cn/yaodian/ep/EP5.0/03_materials_and_containers/3.2.__containers/3.
2.9.%20Rubber%20closures%20for%20containers%20for%20aqueous%20parenteral%20preparat
ions,%20for%20powders%20and%20for%20freeze(dried%20powders.pdf!
10. ISO!11607.!Packaging!for!terminally!sterilized!medical!devices!–!Part!1:!Requirements!for!
materials,!sterile!barrier!systems!and!packaging!systems.!
http://www.iso.org/standard/38712.html.!!

!
!
11. ISO!15747:2010.!Plastic!containers!for!intravenous!injections.!
https://www.iso.org/standard/51479.html.!!
12. Cleanroom!monitoring!–!regulatory!standards.!http://www.a2f(
filters.com/files/Air%20Classification.pdf!
13. Quality!matrices!from!BPSA.!http://www.bpsalliance.org/technical(guides/!
14. ASTM!F!88(00!Standard!test!method!for!seal!strength!of!flexible!barrier!materials.!
http://www.astm.org/Standards/F88.htm!
15. ASTM!D4169(14.!Standard!Practice!for!Performance!Testing!of!Shipping!Containers!and!Systems!
http://www.astm.org/Standards/D4169.htm.!
16. ASTM!D534(14.!Standard!Practices!for!Evaluating!the!Resistance!of!Plastics!to!Chemical!Reagents!
http://www.astm.org/Standards/D543.htm!
17. ASTM!WK43741.!New!Practice!for!Testing!Integrity!of!Single(Use!Systems!at!Suppliers!
Manufacturing!Facilities.!!https://www.astm.org/DATABASE.CART/WORKITEMS/WK43741.htm.!
18. PDA!Technical!Report!TR26!revised!2009.Sterile!filtration!of!liquids.!
https://store.pda.org/ProductCatalog/Product.aspx?ID=1184!
19. PDA!Technical!Report!TR!45.!Filtration!of!liquids!using!cellulose(based!depth!filters.!
http://trarchive.pda.org/i/84275(tr(45(2008#!
20. PDA!Points!to!consider!for!aseptic!processing.!Part!1.!https://trarchive.pda.org/i/489604(ptc(
part(1(jan2015/21#!
21. PDA!Technical!Report!TR!15.!!Validation!of!tangential!flow!filtration!in!biopharmaceutical!
applications.!http://trarchive.pda.org/i/120057(tr15(2009#!!
22. ASTM!E2930.!Standard!Practice!for!Pressure!Decay!Leak!Test!Method.!
http://www.astm.org/Standards/E2930.htm!
23. ISPE.!Risk!in!pharmaceutical!packaging.!Shifting!the!industry!from!a!compliance!culture!to!a!
quality!culture!in!pharmaceutical!packaging!
http://vertassets.blob.core.windows.net/download/9874a97c/9874a97c(4e5d(4a3b(9b5c(
92fc4ad78fab/packagingriskarticle.pdf!
24. ASTM!E!432(91!Standard!guide!for!selection!of!a!leak!testing!method.!
https://www.astm.org/DATABASE.CART/HISTORICAL/E432(91R04.htm!
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"Pharmaceutical!container!closure!integrity!IV:!Development!of!an!indirect!correlation!
between!vacuum!decay!leak!measurement!and!microbial!ingress".!PDA!J!Pharm!Sci!
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33. Kirsch,!L.E.,!Nguyen,!L.,!Moeckly,!C.S.!and!Gerth,!R.!1997.!"Pharmaceutical!container!
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34. Kirsch,!L.E.,!Nguyen,!L.!and!Moeckly,!C.S.!1997.!"Pharmaceutical!Container!Closure!

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35. PDA!J.Pharm.!Sci!and!Tech,!2007,!61,!154(159!!
Beh,!W.!Operational!considerations!for!robust!single(use!systems.!IBC’s!5th!Single(use!
applications!for!biopharmaceutical!manufacturing.!June!2,!2008,!San!Diego,!California!
36. Pall!Leak!Testing!of!Single(use!Systems!with!the!Palltronic®!Flowstar!LGR!Test!Instrument,!
Technical!Report!USTR!3147!
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Assemblies!by!Implementing!Helium!Integrity!Test!and!a!New!Point(of(Use!Leak!Test!using!
Palltronic®!Flowstar!LGR!Instrument!for!Critical!Formulation!and!Filling!Applications,!Leesburg,!
VA,!USA,!ECI!conference!!
!
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&
Part&8.&Acknowledgements&&
&
Janmeet!Anant,!!Millipore!Sigma!
Stephen!Brown,!Biological!E!Ltd!
Patrick!Evrard,!GSK!Vaccines!
Patrick!Gerst,!CPC!
Marc!Hogreve,!Sartorius!Stedim!Biotech!
Carole!Langlois,!!Sartorius!Stedim!Biotech!
Doug!Norris,!Charter!Medical!
Mark!Petrich,!Merck!&!Co.,!Inc.!
Hélène!Pora,!!Pall!Life!Sciences!!
Christopher!S.!Shields,!Saint<Gobain!
Adam!Sokolnicki,!Millipore!Sigma!
Kirsten!Strahlendorf,!Sanofi!Pasteur!
Alain!Vanhecke,!Pall!Life!Sciences!!
!
!
!
!
!

!

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DESIGN, CONTROL, AND

Part&2.&Approach&to&Assessing&Integrity&of&SingleCuse&Systems& & & & 5&

2.1&RiskCbased&Approach&to&Integrity&of&SingleCuse&Systems& & & & & 5&

&&&&2.1.1.&Supplier&Evaluation&& & & & & & & & 8&

&&&2.1.2.&EndCuser&Evaluation&& & & & & & & & 11&

2.2.&Practical&Testing&for&Assurance&of&Integrity& & & & & & 14&

Integrity!test!! ! ! ! ! ! ! ! & 14&

2.2.2.&Leak&detection&in&SingleCuse&Systems& & & & & & 14!!

2.2.3.&Integrity&and&Leak&Test&Methods& & & & & & & 15!

&&&&&3.1.&Creation&of&Defects&for&Correlation&Studies& & & & & & 22&

&&&&&3.2.&Microbial&Challenge&Tests& & & & & & & & 24&

Part&4.&Implementation&of&Integrity&Tests&by&the&Supplier&and&EndCuser& & & 28&

&&&&&4.1.&When&to&Test&and&What&Type&of&Test& & & & & & & 28&

&&&&&4.2.&Detection&Capabilities&of&NonCdestructive&Integrity&Tests&& & & & 30&

&&&&&4.3.&Effect&of&System&Complexity&on&Suitability&of&Integrity&Test&Methods& & & 31&

Part&5.&Discussion&and&Conclusions& & & & & & & & 33&

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Criticality,&Intended& QbD,&Risk& Statistical&Process& Design&&&Packaging&&

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Grade! Air!sample! 90!mm!diameter! 55!mm!diameter! Glove!print!(!!!!!!

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Design&&& Validation&&& Incoming& PreCuse& PostCuse&

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Pressurisation& Pressure& Pressure&decay& Pressure&decay&&

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Development&& & &

&&QbD/Risk&Assessment& QC,&Visual&Control& QbD/Risk&Assessment&

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