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VALIDATION!
!
Validation! is! defined! as! the! verification,! by! data! and! analysis,! that! the! design! objectives! of! a! given! facility,! system,!
apparatus,! or! procedures! are! reliably! fulfilled! in! routine! operation.! It! is! a! planned! series! of! interactive! tests! and!
inspection!designed!to!describe!and!reduce!uncertainty!in!an!important!process.!!
!
A!validated!product!is!one!that!has!been!shown!by!appropriate!scientific!means!to!be!uniform!within!a!lot,!consistent!
between!lots,!and!meeting!design!criteria!within!defined!limits.!
!
!
I.!PROCESS!VALIDATION!
!
The! FDA! defines! process! validation! as! ‘‘...! a! documented! program! which! provides! a! high! degree! of! assurance! that! a!
specific!process!will!consistently!produce!a!product!meeting!its!predetermined!specification!and!quality!attributes.’’!
Pharmaceutical! process! validation! consists! of! well! documented,! written! procedures! that! define! processes! which!
ensure!that!a!specific!pharmaceutical!technology!is!capable!of!and!is!attaining!that!which!is!specified!in!official!or!inP
house!specifications,!e.g.,!a!specified!precision!and!accuracy!of!an!assay!procedure!or!the!characteristics!of!a!finished!
pharmaceutical!product.!Validation!can!be!categorized!as!either!prospective*or!retrospective.!
!
Retrospective*validation! would! be! applicable! for! a! product! that! has! been! on! the! market! for! which! adequate! data! is!
available! for! evaluation.! Although! there! is! no! theoretical! lower! limit! on! the! number! of! lots! needed! for! such! an!
evaluation,! 20! lots! has! been! suggested! as! an! approximate! lower! limit.! Retrospective! validation! consists! of! an!
evaluation! of! product! characteristics! over! time.! The! most! simple! and! direct! way! of! evaluating! and! displaying! these!
characteristics!is!via!control!charts.!Each!attribute!could!be!charted!giving!a!visual!display!of!the!batch!history.!The!
control! chart! not! only! allows! an! evaluation! of! the! consistency! of! the! process,! but! can! be! helpful! in! identifying!
problems!and!as!an!aid!in!setting!practical!inPhouse!release!limits.!Thus,!retrospective!validation!is!a!useful!evaluative!
procedure,! and,! representing! a! relatively! large! number! of! batches! over! a! long! period! of! time,! gives! detailed!
information!on!the!product!performance.!
!
On!the!other!hand,!prospective*validation!must!always!be!performed!for!a!new!product!during!initial!development!and!
production.! Usually,! the! first! three! production! batches! are! evaluated! in! great! detail! in! order! to! demonstrate!
consistency!and!accuracy.!The!important!feature!of!prospective!validation!is!that!the!attributes!measured!reflect!the!
important!or!critical!characteristics!of!the!process.!This!requires!a!knowledge!of!the!process.!Having!identified!these!
features,!an!experimental!design!and!sampling!plan!that!captures!the!relevant!measurements!is!needed.!Each!type!of!
dosage!form!or!product!is!different!and!may!require!different!considerations.!
!
Statistical!analysis!of!the!data!is!useful.!However,!statistical!methods!should!be!used!to!aid!in!an!understanding!of!the!
data!only.!Hypothesis!testing!may!not!be!useful,!in!part!because!of!power!considerations.!Scientific!judgement!should!
prevail.!
!
An! example! is! given! with! solutions! to! illustrate! the! ‘‘validation’’! train! of! thought.! There! is! no! unique! statistical!
approach!to!any!single!problem!in!most!practical!situations.!In!validation!procedures,!in!particular,!there!will!be!more!
than!one!way!of!attacking!a!problem.!Different!statistical!methods!will!be!used.!
!
Example!
Quality!control!data!are!available!for!an!ointment!that!has!been!manufactured!during!a!period!of!approximately!one!
year.! The! inPprocess! (bulk)! product! is! assayed! in! triplicate! for! each! batch! (top,! middle,! and! bottom! of! the! mixing!
tank).! The! finished! product! consists! of! either! a! 2Pounce! container! or! a! 4Pounce! container,! or! both.! A! single! assay! is!
performed! on! each! size! of! the! finished! product.! The! assay! results! for! the! eight! batches! manufactured! are! shown! in!
Table!1.!
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The!following!questions!must!be!answered!to!pursue!the!process!validation!of!this!product:!
1. Are!the!assays!within!limits!as!stated!in!the!inPhouse!specifications?!!
2. Do!the!average!results!differ!for!the!top,!middle,!and!bottom!of!the!bulk?!This!can!be!considered!as!a!measure!
of! drug! homogeneity.! If! the! results! are! (statistically! or! practically)! different! in! different! parts! of! the! bulk!
container,!mixing!heterogeneity!is!indicated.!!
3. Are! the! average! drug! concentration! and! homogeneity! in! the! bulk! mix! different! !from! the! average!
concentration!and!homogeneity!of!the!product!in!the!final!container?!!
4. Are!batches!in!control!based!on!the!charting!of!averages!using!control!charts?!!
!
!
Table!1.!Results!of!Bulk!and!Finished!Tablet!Assays!of!Eight!Batches!
!

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Answers:!
Question*1.*The!inPhouse!specifications!call!for!an!average!assay!between!100!and!120%.!All!batches!pass!based!on!the!
average! results! of! both! the! bulk! and! finished! products.! Batch! 8! has! a! relatively! high! assay,! but! still! falls! within! the!
specifications.!
Question*2.*A!twoPway!analysis!of!variance!is!used!to!test!for!equality!of!means!from!the!top,!middle,!and!bottom!of!the!
bulk!container.!The!average!results!are!shown!in!Table!1,!and!the!ANOVA!table!is!shown!in!Table!2.!The!F!test!shows!
lack!of!significance!at!the!5%!level,!and!the!product!can!be!considered!to!be!homogeneous.!
!
Table!2.!ANOVA!for!Top,!Middle,!and!Bottom!of!Bulk!

!
*
Question*3.*The!average!results!of!the!bulk!and!finished!product!can!be!compared!using!a!paired!t*test.!For!this!test!we!
first! compute! the! average! result! of! the! bulk! and! finished! material! for! each! batch.! The! average! results! are! shown! in!
Table! 1.! The! t* test! (Table! 3)! shows! no! significant! difference! between! the! average! results! of! the! bulk! and! finished!
material.!
!
Table!3.!Paired!t*Test!Comparing!the!Average!of!the!Bulk!and!Finished!Product!

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Question*4.*A!control!chart!can!be!constructed!to!monitor!the!process!based!on!the!data!available.!A!control!chart!with!
3!sigma!limits!could!be!set!up!based!on!the!average!of!the!top,!middle,!and!bottom!assays.!
!
!
II.!VALIDATION!OF!ANALYTICAL!PROCEDURE!
!
The!analytical*procedure!refers!to!the!way!of!performing!the!analysis.!It!should!describe!in!detail!the!steps!necessary!
to! perform! each! analytical! test.! This! may! include! but! is! not! limited! to:! the! sample,! the! reference! standard! and! the!
reagents! preparations,! use! of! the! apparatus,! generation! of! the! calibration! curve,! use! of! the! formulae! for! the!
calculation,!etc.!
!
Validation!of!analytical!procedures!is!directed!to!the!most!common!types!of!analytical!procedures:!
!
1. Identification*tests!are!intended!to!ensure!the!identity!of!an!analyte!in!a!sample.!This!is!normally!achieved!by!
comparison!of!a!property!of!the!sample!(e.g.,!spectrum,!chromatographic!behavior,!chemical!reactivity,!etc)!to!
that!of!a!reference!standard;!
2. Testing*for*impurities!can!be!either!a!quantitative!test!or!a!limit!test!for!the!impurity!in!a!sample.!Either!test!is!
intended!to!accurately!reflect!the!purity!characteristics!of!the!sample.!Different!validation!characteristics!are!
required!for!a!quantitative!test!than!for!a!limit!test;!!
3. Assay! procedures! are! intended! to! measure! the! analyte! present! in! a! given! sample.! In! the! context! of! this!
document,! the! assay! represents! a! quantitative! measurement! of! the! major! component(s)! in! the! drug!
substance.!For!the!drug!product,!similar!validation!characteristics!also!apply!when!assaying!for!the!active!or!
other! selected! component(s).! The! same! validation! characteristics! may! also! apply! to! assays! associated! with!
other!analytical!procedures!(e.g.,!dissolution).!!
!
The! objective! of! the! analytical! procedure! should! be! clearly! understood! since! this! will! govern! the! validation!
characteristics! which! need! to! be! evaluated.! Typical! validation! characteristics! which! should! be! considered! are!
Accuracy,! Precision! (Repeatability! and! Intermediate! Precision),! Specificity,! Detection! Limit,! Quantitation! Limit,!
Linearity,!!and!Range.!
!
Table! 4! lists! those! validation! characteristics! regarded! as! the! most! important! for! the! validation! of! different! types! of!
analytical! procedures.! This! list! should! be! considered! typical! for! the! analytical! procedures! cited! but! occasional!
exceptions!should!be!dealt!with!on!a!casePbyPcase!basis.!It!should!be!noted!that!robustness!is!not!listed!in!the!table!
but!should!be!considered!at!an!appropriate!stage!in!the!development!of!the!analytical!procedure.!
!
Specificity*
Specificity!is!the!ability!to!assess!unequivocally!the!analyte!in!the!presence!of!components!which!may!be!expected!to!
be!present.!Typically!these!might!include!impurities,!degradants,!matrix,!etc.!
!
This!definition!has!the!following!implications:!!
• Identification:!to!ensure!the!identity!of!an!analyte.!
• Purity! Tests:! to! ensure! that! all! the! analytical! procedures! performed! allow! an! accurate! statement! of! the!
content!of!impurities!of!an!analyte,!i.e.!related!substances!test,!heavy!metals,!residual!solvents!content,!etc.!
• Assay!(content!or!potency):!to!provide!an!exact!result!which!allows!an!accurate!statement!on!the!content!or!
potency!of!the!analyte!in!a!sample.!
!
Accuracy*
The!accuracy!of!an!analytical!procedure!expresses!the!closeness!of!agreement!between!the!value!which!is!accepted!
either! as! a! conventional! true! value! or! an! accepted! reference! value! and! the! value! found.! This! is! sometimes! termed!
trueness.*
!
Accuracy! should! be! assessed! using! a! minimum! of! 9! determinations! over! a! minimum! of! 3! concentration! levels!
covering!the!specified!range!(e.g.,!3!concentrations/3!replicates!each!of!the!total!analytical!procedure).!
Accuracy!should!be!reported!as!percent!recovery!by!the!assay!of!known!added!amount!of!analyte!in!the!sample!or!as!
the!difference!between!the!mean!and!the!accepted!true!value!together!with!the!confidence!intervals.!
!
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Table!4.!Validation!characteristics!for!different!types!of!analytical!procedures!

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Precision!
The!precision!of!an!analytical!procedure!expresses!the!closeness!of!agreement!(degree!of!scatter)!between!a!series!of!
measurements!obtained!from!multiple!sampling!of!the!same!homogeneous!sample!under!the!prescribed!conditions.!
Precision!may!be!considered!at!three!levels:!repeatability,!intermediate!precision!and!reproducibility.!
!
Repeatability! expresses! the! precision! under! the! same! operating! conditions! over! a! short! interval! of! time.!
Repeatability!is!also!termed!intraPassay!precision.!!
!
Repeatability!should!be!assessed!using:!
a)! a! minimum! of! 9! determinations! covering! the! specified! range! for! the! procedure! (e.g.,! 3! concentrations/3!
replicates!each);!or!b)!a!minimum!of!6!determinations!at!100%!of!the!test!concentration.!
!
Intermediate* precision! expresses! withinPlaboratories! variations:! different! days,! different! analysts,! different!
equipment,!etc.!
!
Reproducibility! expresses! the! precision! between! laboratories! (collaborative! studies,! usually! applied! to!
standardization!of!methodology).!
!
Precision! should! be! investigated! using! homogeneous,! authentic! samples.! However,! if! it! is! not! possible! to! obtain! a!
homogeneous!sample!it!may!be!investigated!using!artificially!prepared!samples!or!a!sample!solution.!The!precision!of!
an! analytical! procedure! is! usually! expressed! as! the! variance,! standard! deviation! or! coefficient! of! variation! (relative!
standard!deviation)!of!a!series!of!measurements.!
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Detection*Limit*
The! detection! limit! of! an! individual! analytical! procedure! is! the! lowest! amount! of! analyte! in! a! sample! which! can! be!
detected!but!not!necessarily!quantitated!as!an!exact!value.!
!
Quantitation*Limit*
The!quantitation!limit!of!an!individual!analytical!procedure!is!the!lowest!amount!of!analyte!in!a!sample!which!can!be!
quantitatively!determined!with!suitable!precision!and!accuracy.!The!quantitation!limit!is!a!parameter!of!quantitative!
assays!for!low!levels!of!compounds!in!sample!matrices,!and!is!used!particularly!for!the!determination!of!impurities!
and/or!degradation!products.!
!
Linearity*
The!linearity!of!an!analytical!procedure!is!its!ability!(within!a!given!range)!to!obtain!test!results!which!are!directly!
proportional! to! the! concentration! (amount)! of! analyte! in! the! sample.! If! there! is! a! linear! relationship,! test! results!
should!be!evaluated!by!appropriate!statistical!methods,!for!example,!by!calculation!of!a!regression!line!by!the!method!
of! least! squares.! The! correlation! coefficient,! yPintercept,! slope! of! the! regression! line! and! residual! sum! of! squares!
should!be!submitted.!A!plot!of!the!data!should!be!included.!In!addition,!an!analysis!of!the!deviation!of!the!actual!data!
points! from! the! regression! line! may! also! be! helpful! for! evaluating! linearity.! For! the! establishment! of! linearity,! a!
minimum!of!5!concentrations!is!recommended.!Other!approaches!should!be!justified.!
!
Range*
The!range!of!an!analytical!procedure!is!the!interval!between!the!upper!and!lower!concentration!(amounts)!of!analyte!
in!the!sample!(including!these!concentrations)!for!which!it!has!been!demonstrated!that!the!analytical!procedure!has!a!
suitable!level!of!precision,!accuracy!and!linearity.!
!
Robustness*
The!robustness!of!an!analytical!procedure!is!a!measure!of!its!capacity!to!remain!unaffected!by!small,!but!deliberate!
variations!in!method!parameters!and!provides!an!indication!of!its!reliability!during!normal!usage.!
!
!
ASSAY!VALIDATION!
!
Assay! validation! is! a! method! that! provides! an! estimate! of! assay! accuracy! and! precision.! To! challenge! the! assay!
procedure,!the!following!steps!are!done:!
1. Preparation!of!samples!
2. Analysis!of!samples!
3. Calculation!of!percent!relative!deviation!
4. Calculation!of!percent!relative!error!
5. Disposition!
6. Documentation!
!
!
Preparation!of!Samples!
!
Prepare!a!total!of!6!validation!samples!(or!3!pairs!for!duplicate!determination)!as!follows:!
1. Prepare!two!samples!to!contain!the!nominal!product!formula!quantity!of!the!substance!to!be!assayed.!
2. Prepare! two! samples! to! contain! an! amount! equal! to! the! nominal! product! formula! minus! 1.5! times! the!
difference!between!the!nominal!formula!quantity!and!the!lower!assay!specification!limit.!
3. Prepare! two! samples! to! contain! an! amount! equal! to! the! nominal! product! formula! plus! 1.5! times! the!
difference!between!the!nominal!formula!quantity!and!the!upper!assay!specification!limit.!
!
Sample!A!
XA!=!label!claim!–!1.5!(label!claim!–!lower!claim)!
!
Sample!B!
XB!=!label!claim!
!
!
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 Sample!C!
XC!=!label!claim!+!1.5!(upper!limit!–!label!claim)!
!
!
Analysis!
!
Two! different! analysts! should! carry! out! a! single! determination! on! each! of! the! three! drug! levels! by! the! assay!
method!prescribed!for!the!product.!The!analysts!should!carry!out!the!assay!validation!analysis!on!different!days.!
Results!of!the!analyses!should!be!reported!as!percent!of!formula!quantity.!
!
Calculation!
!
The!percentage!relative!deviation!(D)!is!a!measure!of!the!precision!of!the!method.!In!using!the!formula,!ignore!
the!negative!sign!from!subtraction.!The!percentage!relative!error!(E)!is!a!measure!of!the!accuracy!of!the!method.!
Here,!any!negative!sign!is!taken!into!account!during!the!calculation.!!
!
The!symbol!Z!stands!for!the!average!of!the!two!determinations!per!drug!level.!
!
! !!! ! !!! ! !!!
! !! = ! ! ! ! !!!!!!!!!!!!! = ! ! ! ! !!!!!!!!!!!!! = ! ! ! ! !!!!!!!!!!!!
!
! %!Relative!Deviation!(D)!! ! ! ! %!Relative!Error!(E)!
! !
!! !!!! !(!! !!!! )! !"" !! !!!! !(!! !!!! )! !""
!! = ! !
!!! !!
! ! ! !! = ! !
!!! !!
!
!
!! !!!! !(!! !!!! )! !"" !! !!!! !(!! !!!! )! !""
!! = ! !
!!! !!
! ! ! !! = ! !
!!! !!
!
!
!
!! !!!! !(!! !!!! )! !"" !! !!!! !(!! !!!! )! !""
!! = ! !
!!! !!
! ! ! !! = ! !
!!! !!
!
!
!
where!! XA,!XB,!and!XC!are!the!three!drug!level!concentrations!(Samples!A,!B,!and!C)!in!percent!added!in!the!
analysis!
! a1!and!a2!in!percent!are!the!drug!levels!found!after!the!analysis!of!Sample!A!
! ! b1!and!b2!in!percent!are!the!drug!levels!found!after!the!analysis!of!Sample!B!
! ! c1!and!c2!in!percent!are!the!drug!levels!found!after!the!analysis!of!Sample!C!
!
The! lower! the! values! for! %! Relative! Deviation! and! %! Relative! Error,! the! better! the! method.! All! values! of! %!
Relative!Deviation!(DA,!DB,!and!Dc)!and!the!%!Relative!Error!(EA,!EB,!and!EC)!must!be!below!an!acceptable!limit.!
!
It! is! difficult! to! set! of! an! acceptable! limit! for! the! required! accuracy! and! precision! of! a! method,! since! there! are!
variables! that! depend! on! the! method! being! used! and! the! product! being! tested.! There! is! no! substitute! for!
knowledge!of!analytical!chemistry!and!good!scientific!judgment.!Most!modern!analytical!procedures!should!have!
an!accuracy!and!precision!in!the!range!of!1!to!2!percent.!If!a!value!greater!than!2.0!(ignoring!the!sign)!is!obtained!
for!(D)!and!(E)!when!the!monograph!limits!are!90%!and!110%,!a!problem!with!the!assay!method!is!indicated.!A!
value!of!1.0%!is!used!if!the!monograph!limits!are!95%!and!105%.!
!
!
!
!
!
!
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 Disposition!
!
When! estimates! for! assay! accuracy! and! precision! are! not! satisfactory,! it! will! be! necessary! to! subject! the!
procedure!to!appropriate!review,!designedPstudy,!revision!or!replacement.!
!
When!validation!results!are!satisfactory,!the!assay!method!should!be!left!alone.!
!
Documentation!
!
The!evidence!that!an!assay!method!really!works!can!be!provided!in!the!form!of!a!written!validation!profile.!
!
!
III.!VALIDATION!OF!MANUFACTURING!EQUIPMENTS!
!
Facility! or! equipment! validation! is! the! confirmation! that! the! specified! process! conditions! are! reliably! fulfilled! in! a!
given! apparatus.! The! validation! program! consists! of! several! phases! such! as! installation! qualification,! operational!
qualification!and!actual!validation.!
!
Installation!qualification!must!cover!a!number!of!items!such!as:!
1. utilities! connection! (steam,! water,! electrical,! etc.)! to! determine! if! they! comply! to! regulatory! requirements!
(national!codes,!GMP)!and!all!applicable!corporate!standards,!
2. equipment! features! and! characteristics:! description! (model! number,! serial! number,! location)! and!
specifications,!
3. sanitation!program,!
4. maintenance,!and!
5. drawings.!
!
The! objective! of! operation! qualification! is! to! obtain! adequate! assurance! that! the! equipment! when! operated! by! the!
approved!SOP’s!does!perform!its!assigned!limits.!The!items!covered!by!operational!qualification!are:!
1. applicable!SOP’s!(e.g.,!operation!of!equipment,!sanitation),!
2. utilization!list!(e.g.,!product!to!be!sterilized,!temperature),!
3. process!description,!
4. key!process!variables!(e.g.,!heat!cycle,!cycle!length),!and!
5. test! functions! –! the! items! to! be! tested! are! indicated! (e.g.,! cycle! timer,! air! velocity,! instrument! air,! empty!
chamber!distribution).!
!
The!third!phase!which!is!validation!consists!of!the!following!steps:!
1. state!objectives,!
2. indicate!procedure,!
3. perform!tests,!and!
4. evaluate!data!and!draw!conclusions.!
!
!
IV.!CLEANING!VALIDATION!
!
Contamination!is!a!critical!factor!leading!to!product!failure.!For!this!reason,!cleaning!procedures!must!be!adequate!as!
well!as!effective.!The!principal!concern!is!for!residual!contaminants!which!could!alter!or!adversely!affect!a!subsequent!
product!and!cannot!be!detected!by!ordinary!SOP!methods!(e.g.,!visual!inspection).!
!
Cleaning!validation!program!consists!of!three!phrases:!
1. PreCvalidation!–!to!evaluate!the!cleaning,!sampling!and!analytical!testing!procedures.!
2. Validation*–!to!establish!that!the!cleaning!results!are!repeatedly!acceptable.!
3. ReCvalidation!–!to!ensure!continuing!validity!of!the!cleaning!procedures.!
!
Some!approaches!to!validation!of!cleaning!procedures!are:!
1. Product*line:!which!is!based!on!the!assumption!that!the!active!ingredient!is!the!most!deleterious!contaminant!
and!that!the!mix!ratio!of!active!to!excipient!is!indicative!of!excipient!residue!levels.!Prioritization!of!product!
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 lines! chosen! for! validation! is! governed! by! toxicity! of! the! active! ingredient! and/or! frequency! (volume)! of!
production.!
2. Detergent*residue*levels:*which!are!assumed!to!be!independent!of!the!product!and!are!validated!by!equipment!
piece!and!detergent.!
!
Cleaning!SOP’s!must!exist!for!every!piece!of!equipment.!All!productionPwashed!equipment!must!be!tested!using!either!
approach.! The! analytical! method! selected! must! be! sensitive! to! detect! microgram! levels! of! contaminants.! ThinPlayer!
chromatography!(TLC),!high!performance!liquid!chromatography!(HPLC),!ultraviolet!spectrophotometry!and!infrared!
spectroscopy!are!suitable!for!this!purpose.!
!
!
V.!POSTPVALIDATION!
!
Post! validation! efforts! are! required! whenever! there! is! a! change! in! formulation,! processing! conditions,! analytical!
methods,!cleaning!procedures!or!materials.!
!
!
Exercise!
1. The!assay!procedure!of!an!active!drug!with!an!assay!acceptance!criterion!of!not!less!than!90%!and!not!more!
than!110%!is!challenged.!!
a. Compute!the!three!drug!level!concentrations!for!the!analysis.!
b. Compute!for!(D)!and!(E)!given!that!a1!is!84.8,!a2!is!86.0,!b1!is!98.6,!b2!is!99.3,!c1!is!115.2,!and!c2!is!116.!
c. Is!the!assay!procedure!precise!and!accurate?!
!
!
!
!
References:!
!
Bolton,! Sanford! and! Charles! Bon.! Pharmaceutical* Statistics* –* Practical* and* Clinical* Applications,* 4th* Ed.,* Revised* and*
Expanded.!USA:!Marcel!Dekker,!Inc.,!2004.!
!
ICH! Harmonised! Tripartite! Guideline! on! Validation! Of! Analytical! Procedures:! Text! And! Methodology! Q2(R1).! In:!
International*Conference*On*Harmonisation*Of*Technical*Requirements*For*Registration*Of*Pharmaceuticals*For*Human*
Use.*Step*4*version.*ICH!Expert!Working!Group,!2005.!
!
Lerma,! Norma! V.! and! Marina! O.! Osi.! Drug* and* Cosmetic* Quality* Control* with* Instrumentation,! 2nd! ed.! Manila,!
Philippines:!UST!Publishing!House,!1996.!
!
Sarker,!Dipak!K.!Quality*Systems*and*Controls*for*Pharmaceuticals.!United!Kingdom.!John!Wiley!&!Sons,!Ltd.,!2008.!

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