Analytical methods validation as per ich & usp

Analytical Methods Validation as per ICH & USP, Analytical Methods Validation

1. Analytical Methods Validation
as per ICH & USP Guidelines
Mr. Ganesh B. Nigade,
Assistant Professor,
Dept. of Pharmaceutical Chemistry
PDEA’s S G R S College of Pharmacy, Saswad

2. Contents
•Introduction
•QSEM
•Validation
•Analytical Method validation
•Types of Analytical Procedures to be Validated
•Validation Parameters
•References

3. Introduction
InternationalCouncilforHarmonisation(ICH):-
TheInternationalCouncilforHarmonisationofTechnical
RequirementsforPharmaceuticalsforHumanUse.
(ICH)isuniqueinbringingtogethertheregulatoryauthoritiesand
pharmaceuticalindustrytodiscussscientificandtechnicalaspects
ofpharmaceuticalsanddevelopICHguidelines.
Sinceitsinceptionin1990,ICHhasgraduallyevolved,torespondto
increasinglyglobaldevelopmentsinthepharmaceuticalsectorand
theseICHguidelinesareappliedbyagrowingnumberofregulatory
authorities.
ICH'smissionistoachievegreaterharmonisationworldwideto
ensurethatsafe,effectiveandhighqualitymedicinesare
developed,andregisteredandmaintainedinthemostresource
efficientmannerwhilstmeetinghighstandards.
•ICH Secretariat office is at Geneva, Switzerland

4. The ICH topics are divided into the four categories-QSEM
Quality Guidelines
in the Quality area including stability
studies, impurities testingand a
more flexible approach to
pharmaceutical quality based on
GMPrisk management.
Safety Guidelines
safetyGuidelinestouncoverpotential
riskslikecarcinogenicity,genotoxicity
andreprotoxicity
non-clinicaltestingstrategyfor
assessingtheQTintervalprolongation
liability.
Efficacy Guidelines
the Efficacy heading is concerned
with the design, conduct, safety and
reporting of clinical trials.
It also covers novel types of
medicines derived from
biotechnological processes and the
use of pharmacogenetics/genomics
techniques to produce better
targeted medicines.
Multidisciplinary Guidelines
Cross-cutting topics which do not fit
uniquely into one of the Quality,
Safety and Efficacy categories.
It includes the ICH medical
terminology (MedDRA), the Common
Technical Document (CTD)and the
development of Electronic Standards
for the Transfer of Regulatory
Information (ESTRI).

5. Validation
•Validationistheprocessofestablishing
documentaryevidencedemonstratingthata
procedure,process,oractivitycarriedoutin
testingandthenproductionmaintainsthe
desiredlevelofcomplianceatallstages.
•Inthepharmaceuticalindustry,itisveryimportantthatin
additiontofinaltestingandcomplianceofproducts,itisalso
assuredthattheprocesswillconsistentlyproducethe
expectedresults.

6. Analytical Method Validation
•istheprocessofdemonstratingthatan
analyticalprocedureissuitableforits
intendedpurpose.

7. Types of Analytical Procedures to be
Validated
Identification tests
Quantitative tests for impurities content
Limit tests for the control of impurities
Quantitative tests of the active moiety in
samples of drug substance or drug product or
other selected component(s) in the drug
product (Assay)

8. Validation Parameters as per ICH & USP
ICH
Accuracy
Precision
Repeatability
Intermediate Precision
Reproducibility
Specificity
Detection Limit
Quantitation Limit
Linearity
Range
Robustness
System Suitability
USP
Accuracy
Precision
Specificity
Detection Limit
Quantitation Limit
Linearity & Range
Ruggedness
Robustness

9. Accuracy
Theaccuracyofananalyticalprocedureexpressesthe
closenessofagreementbetweenthevaluewhichisaccepted
eitherasaconventionaltruevalueoranacceptedreference
valueandthevaluefound.
Thisissometimestermedtrueness.
Determination:-
1. Assay
Drug Substance
Drug Product
2. Impurities
Accuracy is calculated as % Recovery

10. Precision
Theprecisionofananalyticalprocedureexpressesthe
closenessofagreement(degreeofscatter)betweenaseries
ofmeasurementsobtainedfrommultiplesamplingofthe
samehomogeneoussampleundertheprescribedconditions.
Precisionmaybeconsideredatthreelevels:
1.Repeatability
2.Intermediateprecision
3.Reproducibility
Determination:-byassayingofsufficientnumberofaliquotsof
homogeneoussamples

11. Repeatability:-Repeatabilityexpressestheprecisionunderthe
sameoperatingconditionsoverashortintervaloftime.
Repeatabilityisalsotermedintra-assayprecision.
Intermediateprecision:-Intermediateprecisionexpresses
within-laboratoriesvariations:differentdays,different
analysts,differentequipment,etc.
Reproducibility:-Reproducibilityexpressestheprecision
betweenlaboratories(collaborativestudies,usuallyappliedto
standardizationofmethodology).

12. Specificity
Specificityistheabilitytoassessunequivocallytheanalytein
thepresenceofcomponentswhichmaybeexpectedtobe
present.Typicallythesemightincludeimpurities,degradants,
matrix,etc.
Lackofspecificityofanindividualanalyticalproceduremaybe
compensatedbyothersupportinganalyticalprocedure(s).
Thisdefinitionhasthefollowingimplications:
–Identification:toensuretheidentityofananalyte.
–PurityTests:toensurethatalltheanalyticalproceduresperformed
allowanaccuratestatementofthecontentofimpuritiesofananalyte,
i.e.relatedsubstancestest,heavymetals,residualsolventscontent,
etc.
–Assay(contentorpotency):toprovideanexactresultwhichallows
anaccuratestatementonthecontentorpotencyoftheanalyteina
sample.

13. Detection Limit
Thedetectionlimitofanindividualanalyticalprocedureis
thelowestamountofanalyteinasamplewhichcanbe
detectedbutnotnecessarilyquantitatedasanexactvalue.
Formula:-
DL=3.3σ
S
where,σ=thestandarddeviationoftheresponse
S=theslopeofthecalibrationcurve

14. Quantitation Limit
Thequantitationlimitofanindividualanalyticalprocedureis
thelowestamountofanalyteinasamplewhichcanbe
quantitativelydeterminedwithsuitableprecisionand
accuracy.
Thequantitationlimitisaparameterofquantitativeassaysfor
lowlevelsofcompoundsinsamplematrices,andisused
particularlyforthedeterminationofimpuritiesand/or
degradationproducts.
Formula:-
QL=10σ
S
Where,σ=thestandarddeviationoftheresponse
S=theslopeofthecalibrationcurve

15. Linearity
Thelinearityofananalyticalprocedureisitsability(withina
givenrange)toobtaintestresultswhicharedirectly
proportionaltotheconcentration(amount)ofanalyteinthe
sample.
ForestablishmentofLinearityminimumofFive
concentrationsnormallyused.
y = 0.0749x -0.001
R² = 0.9998
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 5 10 15
Abs
Conc
Abs
Linear (Abs)

16. Range
Therangeofananalyticalprocedureistheintervalbetween
theupperandlowerconcentration(amounts)ofanalytein
thesample(includingtheseconcentrations)forwhichithas
beendemonstratedthattheanalyticalprocedurehasa
suitablelevelofprecision,accuracyandlinearity.
Assay:-80-120%
Impurity:-50-120%
Contentuniformity:-70–130%
Dissolution:-20–110%

17. Ruggedness
•Theruggednessoftheanalyticalmethodisthedegreeof
reproducibilityoftestresultsobtainedbytheanalysisofthe
samesamplesunderavarietyofconditionssuchasdifferent
laboratories,analyst,instruments,lotsofreagents,elapsed
assaytime,assaytemperaturesorday.

18. Robustness
•Therobustnessofananalyticalprocedureisameasureofits
capacitytoremainunaffectedbysmall,butdeliberate
variationsinmethodparametersandprovidesanindicationof
itsreliabilityduringnormalusage.

19. System Suitability
•Systemsuitabilitytestingisanintegralpartofmanyanalytical
procedures.
•Thetestsarebasedupontheconceptthattheequipment,
electronics,analyticaloperationsandsamplestobeanalysed
constituteanintegralsystemthatcanbeevaluatedassuch.
•Systemsuitabilitytestparameterstobeestablishedfora
particularproceduredependuponthetypeofprocedure
beingvalidated

20. Type of
analytical
procedure
characteristics
IDENTIFICATION
TESTING FOR
IMPURITIES
ASSAY
-dissolution
(measurement
only)
-content/potency
Performance
(Dissolution, Drug
Release )
QuantitativeLimit
Accuracy - + - + -
Precision - + - + +
Repeatability - + - + -
Internal
Precision
- + (1) - + (1) -
Specificity (2) + + + + -
Detection Limit - -(3) + - -
Quantitation
Limit
- + - - -
Linearity - + - + -
Range - + - + -
-signifies that this characteristic is not normally evaluated
+ signifies that this characteristic is normally evaluated
(1)incaseswherereproducibility(seeglossary)hasbeenperformed,intermediateprecisionisnotneeded
(2)lackofspecificityofoneanalyticalprocedurecouldbecompensatedbyothersupportinganalyticalprocedure(s)
(3)maybeneededinsomecases

21. References
ValidationofAnalyticalProcedures:TextAndMethodologyQ2(r1);
InternationalConferenceOnHarmonisationofTechnicalRequirementsFor
RegistrationOfPharmaceuticalsForHumanUseIchHarmonisedTripartite
;CurrentStep4VersionParentGuidelineDated27October1994
(ComplementaryGuidelineOnMethodologyDated6November1996
IncorporatedInNovember2005).
GeneralChapter<1225>,ValidationofCompendialProcedures,USP.