Roles and responsibilities in verification of traceability...

Roles and responsibilities in Roles and responsibilities in

verification of traceability of in vitro verification of traceability of in vitro

medical diagnostics (IVD)medical diagnostics (IVD)

Federica BragaFederica Braga

University of Milan Medical School University of Milan Medical School

Centre for Metrological Traceability in Laboratory Centre for Metrological Traceability in Laboratory

Medicine (CIRME)Medicine (CIRME)

Laboratory measurement paradigm:Laboratory measurement paradigm:

•• Assays that claim to measure the same Assays that claim to measure the same analyteanalyte

should give equivalent measurement results (for should give equivalent measurement results (for

long term and within clinically meaningful limits)long term and within clinically meaningful limits)

Measurement results should be independent of:Measurement results should be independent of:

−− TimeTime

−− Location/laboratoryLocation/laboratory

−− Assay systemAssay system

Laboratory results should be

equivalent no matter where

they are performed

ISO/EN 17511 ISO/EN 17511 -- MeasurementMeasurement of of quantitiesquantities in in samplessamples of of biologicalbiological originorigin -- MetrologicalMetrological traceabilitytraceability of of

valuesvalues assignedassigned toto calibratorscalibrators and control and control materialsmaterials..

→→ To becomeTo become equivalent for long equivalent for long termterm, results must be traceable to , results must be traceable to higherhigher--order references.order references.

ObjectiveObjective of of traceabilitytraceability

implementationimplementation::

toto enableenable the the resultsresults obtainedobtained byby the the

calibratedcalibrated routine procedure routine procedure toto bebe

expressedexpressed in in termsterms of the of the valuesvalues obtainedobtained at at

the the highesthighest availableavailable levellevel of the of the calibrationcalibration

hierarchyhierarchy..

EU 98/79/ECEU 98/79/EC--IVD IVD DirectiveDirective

•• Establishment of a calibration hierarchy Establishment of a calibration hierarchy

starting from the unequivocal definition of starting from the unequivocal definition of

the the measurandmeasurand

•• Elimination of measurement biasElimination of measurement bias

•• Adequate estimation of measurement Adequate estimation of measurement

uncertaintyuncertainty

Basic requirements to Basic requirements to

establish traceability establish traceability

Primary Ref. ProcedurePrimary Ref. Procedure

Secondary Ref. Secondary Ref.

ProcedureProcedure

ManufacturerManufacturer’’ss

Internal ProcedureInternal Procedure

EndEnd--useruser’’s Routines Routine

ProcedureProcedure

Primary Reference MaterialPrimary Reference Material

(e.g. pure (e.g. pure analyteanalyte))

Secondary Ref. MaterialSecondary Ref. Material

(matrix(matrix--based)based)

ManufacturerManufacturer’’s Calibrators Calibrator

Routine SampleRoutine Sample

Test ResultTest Result

SI UnitsSI Units

Tra

cea

bility

Tra

cea

bility

*Adapted from ISO 17511

Reference Measurement SystemReference Measurement SystemU

nce

rtain

tyU

nce

rtain

ty

ProfessionProfession (e.g., IFCC, JCTLM):(e.g., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference

measurementmeasurement systemssystems ((traceabilitytraceability chainchain) )

and and associatedassociated clinicallyclinically acceptableacceptable

uncertaintyuncertainty ((fitfit forfor purposepurpose))

DiagnosticDiagnostic manufacturersmanufacturers:: ImplementImplement suitablesuitable measuringmeasuring systemssystems

((platformplatform, , reagentsreagents, , calibratorscalibrators, , controlscontrols) )

fulfillingfulfilling the the aboveabove establishedestablished goalsgoals

End End usersusers ((clinicalclinical laboratorieslaboratories):): Survey assay and laboratory performance Survey assay and laboratory performance

through:through:

-- IQC component I: testing system controls IQC component I: testing system controls

to confirm and verify manufacturerto confirm and verify manufacturer’’s s

declared performance (CE marked declared performance (CE marked ––

virtually unbiased)virtually unbiased)

-- EQA: true value in commutable materials EQA: true value in commutable materials

for defining measurement error of for defining measurement error of

laboratorylaboratory

PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7









through:through:









�� UnequivocalUnequivocal definitiondefinition of the of the measurandmeasurand asas the the

quantityquantity subjectsubject toto measurementmeasurement

�� DefinitionDefinition of the of the referencereference measurementmeasurement systemsystem

�� DefinitionDefinition of of analyticalanalytical performance performance

specificationsspecifications

Role of ProfessionalRole of Professional OrganizationOrganization::

MeasurandMeasurand

TYPE A MEASURANDSTYPE A MEASURANDS

• Well defined compounds;• Traceable to SI units;• Results are not method-dependent;• Approx. 65 analytes(metabolites, electrolytes,steroid hormones);

TYPE B MEASURANDSTYPE B MEASURANDS

• Not well defined (often heterogeneous mixtures);• Analytes can be bound or in free state;• Not traceable to SI units, but to arbitrary units (e.g. WHO International Units);• Immunochemical procedures show inherent variability (different epitopes);• 400-600 analytes (tumour markers, viral antigens, clotting factors);

PanteghiniPanteghini M. M. ClinClin BiochemBiochem 2009;42:2362009;42:236

Joint Committee for Traceability in Joint Committee for Traceability in

Laboratory Medicine (JCTLM)Laboratory Medicine (JCTLM)

The WorldThe World’’s only qualitys only quality--assured database of:assured database of:

a)a) Higher Order Reference MaterialsHigher Order Reference Materials

b)b) Higher Order Reference Measurement ProceduresHigher Order Reference Measurement Procedures

c)c) Accredited Laboratory Reference Measurement Services Accredited Laboratory Reference Measurement Services

For use by (primarily):For use by (primarily):

a) IVD industry (a) IVD industry (to assist them in following the EU Directive on to assist them in following the EU Directive on

compliance and traceability of commercial systemscompliance and traceability of commercial systems))

b) Regulators (to verify that results produced by b) Regulators (to verify that results produced by IVDsIVDs are are

traceable to)traceable to)

Reference measurement systemReference measurement system

The definition and use of the reference systemThe definition and use of the reference system

concept for standardization of measurements must concept for standardization of measurements must

be closely associated with the setting of targets for be closely associated with the setting of targets for

uncertainty and error of measurement in order to uncertainty and error of measurement in order to

make it clinically acceptablemake it clinically acceptable

L L ThienpontThienpont et al., et al., ClinClin ChemChem Lab Med 2004;42:842Lab Med 2004;42:842

Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55

If these goals are not objectively defined and fulfilled, there If these goals are not objectively defined and fulfilled, there is a risk of letting is a risk of letting

error gain the upper hand, thus obscuring the clinical informatierror gain the upper hand, thus obscuring the clinical information supplied by on supplied by

the result and possibly nullifying the theoretical advantages ofthe result and possibly nullifying the theoretical advantages of metrological metrological

traceability and even causing negative effects on patients' outctraceability and even causing negative effects on patients' outcome.ome.

Analytical performance specificationsAnalytical performance specifications

Model 1: Based on the effect of analytical Model 1: Based on the effect of analytical

performance on clinical outcomeperformance on clinical outcome

Model 2: Based on components of biological Model 2: Based on components of biological

variation of the variation of the measurandmeasurand

Model 3: Based on state of the art of the Model 3: Based on state of the art of the

measurement (i.e., the highest level of measurement (i.e., the highest level of

analytical performance technically analytical performance technically

achievable) achievable)

Some models are better suited for certain Some models are better suited for certain

measurandsmeasurands than for others. The attention is than for others. The attention is

therefore primarily directed towards the therefore primarily directed towards the

measurandmeasurand and its biological and clinical and its biological and clinical

characteristics.characteristics.

1.1. The The measurandmeasurand hashas a a centralcentral rolerole in in diagnosisdiagnosis and and

monitoringmonitoring of a of a specificspecific diseasedisease⇒⇒ outcomeoutcome

modelmodel

2.2. The The measurandmeasurand hashas a high a high homeostatichomeostatic control control ⇒⇒biologicalbiological variabilityvariability modelmodel

3.3. NeitherNeither centralcentral diagnosticdiagnostic rolerole nornor sufficientsufficient

homeostatichomeostatic control control ⇒⇒ state state ofof--thethe--artart modelmodel

Biologic

al

Biologic

al

Variati

onVar

iation

approa

chapp

roach

a. Done by direct outcome studies – investigating the impact of analytical

performance of the test on clinical outcome.

b. Done by indirect outcome studies – investigating the impact of analytical

performance of the test on clinical classifications or decisions and thereby on

the probability of patient outcome, e.g., by simulation analysis.

a. Done by direct outcome studies a. Done by direct outcome studies –– investigating the impact of analytical investigating the impact of analytical

performance of the test on clinical outcome.performance of the test on clinical outcome.

b. Done by indirect outcome studies b. Done by indirect outcome studies –– investigating the impact of analytical investigating the impact of analytical

performance of the test on clinical classifications or decisionsperformance of the test on clinical classifications or decisions and thereby on and thereby on

the probability of patient outcome, e.g., by simulation analysisthe probability of patient outcome, e.g., by simulation analysis..

IMPRECISION:IMPRECISION: ≤≤ 0.25 CV0.25 CVII (O)(O)

≤≤ 0.5 CV0.5 CVII (D)(D)

≤≤ 0.75 CV0.75 CVI I (M)(M)

BIAS: BIAS: < 0.125 (CV< 0.125 (CVII22 + CV+ CV

GG22))1/21/2 (O)(O)

< 0.25 (CV< 0.25 (CVII22 + CV+ CV

GG22))1/21/2 (D)(D)

< 0.375 (CV< 0.375 (CVII22 + CV+ CV

GG22))1/21/2 (M) (M)

Outcome

Outcome

approach

approach

IntraIntra--individualindividual BV: BV: CVCVII%%

InterInter--individualindividual BV: BV: CVCVGG%%

<0.75 x CV<0.75 x CVII (Minimum)(Minimum)

<0.50 x CV<0.50 x CVII ((DesirableDesirable))

<0.25 x CV<0.25 x CVII (Optimum)(Optimum)

UNCERTAINTYUNCERTAINTYUNCERTAINTY [Note that these are goals for [Note that these are goals for random variabilityrandom variability, as , as at the at the

calibrator level the systematic error (bias), in agreement calibrator level the systematic error (bias), in agreement

with the metrological traceability theory, must be corrected with the metrological traceability theory, must be corrected

if present in a non negligible amount]if present in a non negligible amount]

<(0.75 x CV<(0.75 x CVII) x 2 (Minimum)) x 2 (Minimum)

<(0.50 x CV<(0.50 x CVII) x 2 () x 2 (DesirableDesirable))

<(0.25 x CV<(0.25 x CVII) x 2 (Optimum)) x 2 (Optimum)

kuU ×=EXPANDED UNCERTAINTYEXPANDED UNCERTAINTYEXPANDED UNCERTAINTY

Total uncertainty budget that should be fulfilled

when combining the uncertainty of the measuring

system employed in the individual laboratory

(random uncertainty) to that accumulated along all

the steps of metrological traceability chain.

Total uncertainty budget that should be fulfilled

when combining the uncertainty of the measuring

system employed in the individual laboratory

(random uncertainty) to that accumulated along all

the steps of metrological traceability chain.

Biological Biological

VariationVariation

approachapproach

UncertaintyUncertainty of of measurementmeasurement thatthat

fitsfits forfor purposepurpose mustmust bebe defineddefined

acrossacross the the entireentire traceabilitytraceability chainchain, ,

→→ startingstarting withwith the provider of the provider of

referencereference materialsmaterials, ,

→→ extendingextending through the IVD through the IVD

manufacturersmanufacturers and and theirtheir processesprocesses forfor

assignmentassignment of of calibratorcalibrator valuesvalues, and , and

→→ ultimatelyultimately toto the final the final resultresult

reportedreported toto cliniciansclinicians byby end end usersusers (i.e. (i.e.

clinicalclinical laboratorieslaboratories).).

[[PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2012;50:1237]2012;50:1237]

Braga F & Braga F & PanteghiniPanteghini M. M. ClinClin ChemChem Lab Lab MedMed 2013;51:17192013;51:1719

HbAHbA1c1c: Metrological traceability chain: Metrological traceability chain

Uncertainty budgetUncertainty budget

Clinical Clinical


IVD ManufacturerIVD ManufacturerReference providerReference provider

System imprecision

System calibration

uncertainty

Individual lab

performance

(IQC safety margin)

Total measurement

uncertainty

budget

Total measurement

uncertainty

budget

Uncertainty of

references

Patient result

33%33%

50%50%

100%100%

Measurand definitionMeasurand definition









through:through:









IVD manufacturers should IVD manufacturers should define adefine a calibration calibration

hierarchyhierarchy to assign traceable values to their system to assign traceable values to their system

calibrators and to fulfil during this processcalibrators and to fulfil during this process

uncertainty limits,uncertainty limits,

Role of IVD manufacturersRole of IVD manufacturers

which represent a proportion which represent a proportion

of the uncertainty budget of the uncertainty budget

allowed for clinical laboratory allowed for clinical laboratory

results.results.

ParadigmParadigm shiftshift in the in the thinkingthinking

•• IfIf the the manufacturermanufacturer assumesassumes total total responsibilityresponsibility forfor supplyingsupplying productsproducts of of acceptableacceptable qualityquality in in termsterms of of traceabilitytraceability and and uncertaintyuncertainty of the system (of the system (““CE CE markedmarked””), ), itit isisno no longerlonger possiblepossible toto considerconsider separatelyseparately the the componentscomponents of of eacheach measuringmeasuring system (system (i.ei.e., ., platformplatform, , reagentsreagents, , calibratorscalibrators and control and control materialsmaterials), ), whichwhich in in termsterms of performance can of performance can onlyonly bebe guaranteedguaranteed and and certifiedcertified byby the the manufacturermanufacturer asas a a wholewhole..

•• AnyAny changechange introducedintroduced byby usersusers or or thirdthirdpartiesparties ((e.ge.g., the ., the useuse of of reagentsreagents, , calibratorscalibrators or or control control materialsmaterials fromfrom otherother supplierssuppliers) ) maymaysignificantlysignificantly alter the alter the qualityquality of the of the measuringmeasuringsystem performance, system performance, removingremoving anyanyresponsibilityresponsibility fromfrom the the manufacturermanufacturer and and deprivingdepriving the system (and, the system (and, consequentlyconsequently, the , the producedproduced resultsresults) of the ) of the certificationcertification originallyoriginallyprovidedprovided through CE through CE markingmarking..

ProfessionProfession ((e.ge.g., IFCC, JCTLM):., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference







End End usersusers ((clinicalclinical laboratorieslaboratories):): SurveySurvey assayassay and and laboratorylaboratory

performance through:performance through:

-- IQC IQC componentcomponent I: I: testingtesting system system

controlscontrols toto confirmconfirm and and verifyverify

manufacturermanufacturer’’s s declareddeclared performance performance

(CE (CE markedmarked –– virtuallyvirtually unbiasedunbiased))

-- EQA: EQA: truetrue valuevalue in in commutablecommutable

materialsmaterials forfor definingdefining measurementmeasurement

error of error of laboratorylaboratory

PostPost--marketing marketing

surveillance of IVD surveillance of IVD

metrological traceabilitymetrological traceability

AdaptedAdapted fromfrom PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7

The role of the endThe role of the end--usersusers

1. Availability and quality of information about IVD

metrological traceability and uncertainty

2. Daily surveillance of IVD system traceability

3. Estimating the measurement uncertainty due to

the random effects


Post-marketingsurveillance

PostPost--marketing

marketingsurveillance

surveillance






the random effects



PostPost--marketing


surveillance

In principle, laboratory users should be able to In principle, laboratory users should be able to

access the following:access the following:

a) an indication of higher order references (materials and/or procedures) used to assign traceable values to calibrators,

b) which internal calibration hierarchy has been applied by the manufacturer, and

c) a detailed description of each step,

d) the expanded combined uncertainty value of commercial calibrators, and

e) which, if any, acceptable limits for uncertainty of calibrators were applied in the validation of the analytical system.

a) an indication of higher order references (materials and/or procedures) used to assign traceable values to calibrators,

b) which internal calibration hierarchy has been applied by the manufacturer, and

c) a detailed description of each step,

d) the expanded combined uncertainty value of commercial calibrators, and

e) which, if any, acceptable limits for uncertainty of calibrators were applied in the validation of the analytical system.


(ideally all this information should be available in (ideally all this information should be available in

the assay or calibrator package inserts)the assay or calibrator package inserts)

Currently, the full information about

calibration is usually not available

Some Some organisationsorganisations are are frequentlyfrequently

mentionedmentioned ((oftenoften withoutwithout explanationexplanation): ):

usedused asas a a ““trustedtrusted brandbrand””

•• NIST, IRMM, IFCC, CLSI (NIST, IRMM, IFCC, CLSI (protocolsprotocols))

GCGC--IDMS @ NISTIDMS @ NIST

NIST SRM 917NIST SRM 917

ManufacturerManufacturer’’s s

internal procedureinternal procedure

Commercial Commercial

systemsystem


(glucose in human serum)(glucose in human serum)

CommercialCommercial

calibratorcalibrator

PatientPatient’’s sample resultss sample results

GCGC--IDMS IDMS [accredited reference laboratory][accredited reference laboratory]

ManufacturerManufacturer’’s internals internal

procedureprocedure


systemsystem




ComparisonComparison onon

biologicalbiological samplessamples

AA BB

CC DD NIST SRM 917NIST SRM 917

ManufacturerManufacturer’’s s

internal procedureinternal procedure


CDC CDC HexokinaseHexokinase[accredited reference laboratory][accredited reference laboratory]

ManufacturerManufacturer’’s internals internal

procedureprocedure


systemsystem




ComparisonComparison onon

biologicalbiological samplessamples


Commercial Commercial

systemsystem




Types of metrological chains that can be used to implement the tTypes of metrological chains that can be used to implement the traceability of blood glucose results*raceability of blood glucose results*


*all*all JCTLM JCTLM recognizedrecognized

Chain A = 1.45% vs. Chain C = 3.26%

Are the Are the measuringmeasuring systemssystems commerciallycommercially availableavailable forfor glucoseglucose determinationdetermination ableable toto

achieveachieve the the desirabledesirable limitlimit forfor combinedcombined uncertaintyuncertainty in a in a clinicalclinical settingsetting??

uurefref

(u(u22refref ++ uu22

calcal))½½

((uu22ref ref + + uu22

calcal + + uu22randomrandom))½½

System imprecision

System calibration

uncertainty

Individual lab

performance

(IQC safety margin)

Measurement

uncertainty

budget

Uncertainty of

references

Measurand definition

Patient result

5.4%5.4% desirabledesirable


Pasqualetti S, Braga F, Panteghini M, Clin Biochem 2017 Mar 11. Pasqualetti S, Braga F, Panteghini M, Clin Biochem 2017 Mar 11. pii: S0009pii: S0009--9120(17)301169120(17)30116--99

L M H

•• Measured in triplicate in 3 consecutive Measured in triplicate in 3 consecutive

daysdays byby participatingparticipating laboratorieslaboratories59

.9 U

/L5

9.9

U/L

18

6.9

U/L

18

6.9

U/L

40

1.5

U/L

40

1.5

U/L

•• ALP target values ALP target values

assigned with assigned with IFCC RMPIFCC RMP

Desirable and minimum APS for bias: 8.3% and 5.5%Desirable and minimum APS for bias: 8.3% and 5.5%

The importance of the postThe importance of the post--marketing surveillancemarketing surveillance

EQA experimentEQA experiment

(performed 5(performed 5 years later years later the availability of the IFCC RMPthe availability of the IFCC RMP) )

to evaluate the level of ALP standardizationto evaluate the level of ALP standardization

ID

Lab

Measuring

system

Bias Regression parameters

Pool L Pool

M

Pool H Slope Intercepts

1 Roche

Cobas 6000

-7.2% -9.0% -9.6% 0.8998

(P=0.0005)

1.8

(P=0.065)

2 Roche

Cobas 6000

-5.4% -5.9% -7.0% 0.9271

(P=0.0029)

1.7

(P=0.37)

3 Beckman

AU5800

5.9% 6.6% 5.8% 1.0573

(P=0.0029)

0.7

(P=0.69)

4 Roche

Cobas 8000

-5.2% -6.8% -8.6% 0.9074

(P=0.0047)

3.3

(P=0.31)

5 Roche

Cobas

6000/8000

-3.0% -4.0% -5.1% 0.9452

(P=0.0028)

2.0

(P=0.32)

6 Beckman

AU680

4.4% 5.6% 3.1% 1.0263

(P=0.0086)

2.8

(P=0.57)

7 Beckman

AU6800

8.6% 8.3% 4.3% 1.0320

(P=0.012)

5.7

(P=0.46)

8 Beckman

AU5800

6.3% 7.4% 5.9% 1.0566

(P=0.0055)

1.5

(P=0.63)

9 Siemens

Advia

-2.3% -2.9% -4.5% 0.9500

(P=0.0049)

2.5

(P=0.41)

10 Roche

Cobas 8000

-5.0% -5.6% -6.8% 0.9275

(P=0.0037)

2.0

(P=0.38)

11 Roche

Cobas 8000

-5.8% -6.8% -8.6% 0.9075

(P=0.0056)

3.0

(P=0.38)

12 Siemens

Vista

-6.1% -1.4% -2.0% 0.9868

(P=0.0054)

1.9

(P=0.54)

13 Abbott

Architect

c16000

2.3% -1.0% -0,6% 0.9895

(P=0.0039)

1.3

(P=0.57)

The ability to meet or not the desirable APS for

bias is clearly dependent on the measuring

system used.

The ability to meet or not the desirable APS for

bias is clearly dependent on the measuring

system used.

Schumann G, et al.

Clin Chem Lab Med 2011;49:1439-46

Schumann G, et al.Schumann G, et al.

ClinClin ChemChem Lab Lab MedMed 2011;49:14392011;49:1439--4646


CompanyCompany PlatformPlatformPrinciple of Principle of

commercial methodcommercial methodCalibratorCalibrator

Declared standard Declared standard


HigherHigher--order reference order reference

employedemployed

Abbott Abbott ArchitectArchitect pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA Molar extinction coefficientMolar extinction coefficient

Beckman Beckman AUAU IFCC (1983)IFCC (1983) System calibratorSystem calibrator 6.00%6.00% Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator

pp--NPP/DEANPP/DEA System calibratorSystem calibrator NANA Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator

SynchronSynchron pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 6.22%6.22% IFCC reference method (2011)IFCC reference method (2011)

Enzyme Enzyme ValidatorValidator level 2level 2 1.86%1.86% IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 3.64%3.64% DGKC standard methodDGKC standard method

Enzyme Enzyme ValidatorValidator level 2level 2 1.27%1.27% DGKC standard methodDGKC standard method

Roche Roche CobasCobas cc IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s.. 0.59%0.59% IFCC reference method (1983)IFCC reference method (1983)

IntegraIntegra IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s 1.22%1.22% IFCC reference method (1983)IFCC reference method (1983)

ModularModular IFCC liquidIFCC liquid C.f.a.sC.f.a.s 1.65%1.65% IFCC reference method (1983)IFCC reference method (1983)

SiemensSiemens Dimension VistaDimension Vista pp--NPP/AMPNPP/AMP ALPI calibratorALPI calibrator 4.51%4.51%cc IFCC reference method (2011)IFCC reference method (2011)

AdviaAdvia pp--NPP/AMPNPP/AMP Chemistry calibrator control 1Chemistry calibrator control 1 3.70%3.70% IFCC reference method (2011)IFCC reference method (2011)

Chemistry calibrator control 2Chemistry calibrator control 2 1.00%1.00% IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/DEANPP/DEA Chemistry calibrator control 1Chemistry calibrator control 1 1.40%1.40%cc Molar extinction coefficientMolar extinction coefficient

Chemistry calibrator control 2Chemistry calibrator control 2 1.30%1.30%cc Molar extinction coefficientMolar extinction coefficient


CompanyCompany PlatformPlatformPrinciple of Principle of

commercial methodcommercial methodCalibratorCalibrator

Declared standard Declared standard


HigherHigher--order reference order reference

employedemployed

Abbott Abbott ArchitectArchitect pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA Molar extinction coefficientMolar extinction coefficient

Beckman Beckman AUAU IFCC (1983)IFCC (1983) System calibratorSystem calibrator 6.00%6.00% Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator

pp--NPP/DEANPP/DEA System calibratorSystem calibrator NANA Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator

SynchronSynchron pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 6.22%6.22% IFCC reference method (2011)IFCC reference method (2011)

Enzyme Enzyme ValidatorValidator level 2level 2 1.86%1.86% IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 3.64%3.64% DGKC standard methodDGKC standard method

Enzyme Enzyme ValidatorValidator level 2level 2 1.27%1.27% DGKC standard methodDGKC standard method

Roche Roche CobasCobas cc IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s.. 0.59%0.59% IFCC reference method (1983)IFCC reference method (1983)

IntegraIntegra IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s 1.22%1.22% IFCC reference method (1983)IFCC reference method (1983)

ModularModular IFCC liquidIFCC liquid C.f.a.sC.f.a.s 1.65%1.65% IFCC reference method (1983)IFCC reference method (1983)

SiemensSiemens Dimension VistaDimension Vista pp--NPP/AMPNPP/AMP ALPI calibratorALPI calibrator 4.51%4.51%cc IFCC reference method (2011)IFCC reference method (2011)

AdviaAdvia pp--NPP/AMPNPP/AMP Chemistry calibrator control 1Chemistry calibrator control 1 3.70%3.70% IFCC reference method (2011)IFCC reference method (2011)

Chemistry calibrator control 2Chemistry calibrator control 2 1.00%1.00% IFCC reference method (2011)IFCC reference method (2011)

pp--NPP/DEANPP/DEA Chemistry calibrator control 1Chemistry calibrator control 1 1.40%1.40%cc Molar extinction coefficientMolar extinction coefficient

Chemistry calibrator control 2Chemistry calibrator control 2 1.30%1.30%cc Molar extinction coefficientMolar extinction coefficient

• The availability of an internationally agreed reference The availability of an internationally agreed reference

measurement system does not automatically mean that measurement system does not automatically mean that

the traceability to it is implemented!the traceability to it is implemented!

•• If a postIf a post--marketing surveillance is lacking alternatives marketing surveillance is lacking alternatives

that do not comply with the EU Directive can remain that do not comply with the EU Directive can remain

undisturbed on the market.undisturbed on the market.

•• Some manufacturers continue to offer assays based on Some manufacturers continue to offer assays based on

different experimental conditions (e.g. use of different experimental conditions (e.g. use of

diethanolaminediethanolamine instead of 2instead of 2--aminoamino--22--methylmethyl--11--propanol propanol

as reaction buffer for ALP) that may significantly influence as reaction buffer for ALP) that may significantly influence

the measurement selectivity and, ultimately, the the measurement selectivity and, ultimately, the

measurandmeasurand definition, one of the indispensable definition, one of the indispensable

prerequisites in the field of enzyme standardization.prerequisites in the field of enzyme standardization.

• The alkaline picrate method is unable to measure solely creatinine

• Endogenous and exogenous substances may significantly interfere

• Interfering substances in serum, particularly proteins, can lead to significant overstimation with various alkaline picrate methods

• Interference from glucose and ketonesparticularly important in diabetics who are at high-risk for CKD

The issue of analytical nonThe issue of analytical non--

selectivity: selectivity:

the case of serum the case of serum creatininecreatinine

Reference System for CreatinineReference System for Creatinine

PanteghiniPanteghini M M etet al., al., ClinClin ChemChem Lab Lab MedMed 2006;44:11872006;44:1187

10,7%

-0,1%-2,0%

-2,8%-1,5%

-2,9%-2,1%

5,3%

-10%

-5%

0%

5%

10%

15%

50 100 150 200 250

Creatinine (µmol/L)

Bia

s b

etw

een o

vera

ll

mean a

nd t

arg

et

valu

e

Picrate Enzymatics

Traceability implementation does not correct for Traceability implementation does not correct for

creatininecreatinine analytical nonanalytical non--selectivity problems!selectivity problems!

Percent bias of overall means for the two method macro-categories based on different

analytic principle in post-standardization years (2010-2011). The dotted and the dashed

line indicate the maximum acceptable bias at desirable (±4.0%) and at minimum quality

level (±6.0%), respectively.

Carobene A et al., Clin Chim Acta 2014;427:100Carobene A et al., Clin Chim Acta 2014;427:100






the random effects



PostPost--marketing


surveillance

Daily surveillance of IVD system traceability Daily surveillance of IVD system traceability

1.1. Verification of the consistency of declared performance Verification of the consistency of declared performance

during routine operations performed in accordance with the during routine operations performed in accordance with the

manufacturermanufacturer’’s instructionss instructions

(checking of system alignment by (checking of system alignment by IQC component IIQC component I))

2.2. Participation to appropriately structured EQASParticipation to appropriately structured EQAS

((““that meet metrological criteriathat meet metrological criteria””))

Braga F & Panteghini M, Braga F & Panteghini M,

Clin Chim Acta 2014;432:55Clin Chim Acta 2014;432:55

IVDIVD

TraceabilityTraceability

SurveillanceSurveillance








Braga F & Panteghini M, Braga F & Panteghini M,

Clin Chim Acta 2014;432:55Clin Chim Acta 2014;432:55

IVDIVD



Analytical quality

of measurement

Check alignment Imprecision

qualify

Reliability of the analytical system

AnalyticalAnalytical QualityQuality Control in the Control in the TraceabilityTraceability EraEra



10-M

ay

25-M

ay

28-J

un

13-Jul

28-J

ul

11-A

ug

27-Aug

11-Sep

26-Sep

13-O

ct

24

+3SD

+2SD

+1SD

19

29

34

Monitoring the reliability of the measuring system through IQC: Monitoring the reliability of the measuring system through IQC:

Component I. Check alignment (Component I. Check alignment (““system traceabilitysystem traceability””))A

cce

pta

ble

Acc

ep

tab

lera

ng

era

ng

eo

f co

ntr

ol

ma

teri

al

of

con

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l m

ate

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l

This program checks whether in the course of an analytical run tThis program checks whether in the course of an analytical run the performance of a he performance of a

measuring system complies with the set goals, represented by themeasuring system complies with the set goals, represented by the acceptable acceptable

ranges of control materials. ranges of control materials.

Clinical laboratories must verify the consistency of declared peClinical laboratories must verify the consistency of declared performance during routine operations rformance during routine operations

performed in accordance with the manufacturerperformed in accordance with the manufacturer’’s instructions, by s instructions, by checking that values of control checking that values of control

materials provided by the manufacturer as component of the measumaterials provided by the manufacturer as component of the measuring system are in the ring system are in the

established control rangeestablished control range, with no clinically significant changes in the assumed traceabl, with no clinically significant changes in the assumed traceable results.e results.

PlatformPlatform

CalibratorsCalibratorsReagentsReagents

Control material(s)Control material(s)

PlatformPlatform


PlatformPlatform


Control material(s)Control material(s)

Acceptance/rejection of

the analytical run in

“real time”

Acceptance/rejection of Acceptance/rejection of

the analytical run in the analytical run in

““real timereal time””

Internal Quality Control

(Component I)

Internal Quality Control Internal Quality Control

(Component I)(Component I)

Testing alignmentTesting alignment

[[““system traceabilitysystem traceability””]]

Any “out of control” signal must be made available with

sufficient time to allow immediate corrective actions

to bring again the situation under control (virtually

“unbiased”) and before reports related to the samples

analyzed in the affected analytical run are issued.

Any Any ““out of controlout of control”” signal must be made available with signal must be made available with

sufficient time to allow immediate corrective actions sufficient time to allow immediate corrective actions

to bring again the situation under control (virtually to bring again the situation under control (virtually

““unbiasedunbiased””) and before reports related to the samples ) and before reports related to the samples

analyzed in the affected analytical run are issued.analyzed in the affected analytical run are issued.








Braga F & Panteghini M, Clin Braga F & Panteghini M, Clin

Chim Acta 2014;432:55Chim Acta 2014;432:55

IVDIVD



Analytical quality

of measurement


qualify





Requirements for the applicability of EQAS results in the Requirements for the applicability of EQAS results in the

evaluation of the performance of participating laboratories evaluation of the performance of participating laboratories

in terms of traceability of their measurementsin terms of traceability of their measurements

FeatureFeature AimAim

EQAS EQAS materialsmaterials valuevalue--assignedassigned

withwith referencereference proceduresprocedures byby

anan accreditedaccredited refref. . laboratorylaboratory

ToTo checkcheck traceabilitytraceability of of

commercial system commercial system toto referencereference

systemsystem

ProvedProved commutabilitycommutability of EQAS of EQAS

materialsmaterials

ToTo allowallow transferabilitytransferability of of

participatingparticipating laboratorylaboratory

performance performance toto the the measurementmeasurement

of of clinicalclinical samplessamples

Definition and use of the Definition and use of the

clinically allowable clinically allowable

measurement errormeasurement error

ToTo verifyverify the the suitabilitysuitability of of

laboratorylaboratory measurementsmeasurements in in

clinicalclinical settingsetting

PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:7 2010;48:7

InfusinoInfusino I I etet al., al., ClinClin ChemChem Lab Lab MedMed 2010;48:3012010;48:301

Braga F & Braga F & PanteghiniPanteghini M. M. ClinClin ChemChem Lab Lab MedMed 2013;51:17192013;51:1719


[Ferraro S, Braga F, Panteghini M. Clin Chem Lab Med 2016;54:523]






the random effects



PostPost--marketing


surveillance

Analytical quality

of measurement


qualify





Internal Quality Control

(Component II)

Internal Quality Control Internal Quality Control

(Component II)(Component II)

Testing the uncertainty Testing the uncertainty

due to the random effectsdue to the random effects

((““imprecisionimprecision””))

System stability at

medium/long term

System stability at System stability at

medium/long termmedium/long term

This program provides, through

mechanisms of retrospective

evaluation, data useful to the

knowledge of variability of

measuring system and of its use by

the individual laboratory.

This program provides, through This program provides, through

mechanisms of retrospective mechanisms of retrospective

evaluation, data useful to the evaluation, data useful to the

knowledge of variability of knowledge of variability of

measuring system and of its use by measuring system and of its use by

the individual laboratory.the individual laboratory.

System

Reagent lots

Laboratory

0,0

2,5

5,0

7,5

10,0

12,5

15,0

august-

09octo

ber-0

9dec

ember-

09febru

ary-10

april-1

0june-10

august-

10octo

ber-1

0dec

ember-

10febru

ary-11

April-11

july-11

septem

ber-1

1Monitoring the reliability of the measuring system through IQC: Monitoring the reliability of the measuring system through IQC:

Component II. Evaluate the system + individual lab imprecisionComponent II. Evaluate the system + individual lab imprecision

System imprecision

System calibration

(combined) uncertainty

Individual lab

performance

(IQC safety margin)

Measurement

uncertainty

budget

[adopted cut[adopted cut--off for myocardial necrosis >15 off for myocardial necrosis >15 ngng/L]/L]Cumulative mean, 17 Cumulative mean, 17 ngng/L/L

CV, %CardiacCardiac troponintroponin T high sensitiveT high sensitive

MonthlyMonthly monitoringmonitoring of of imprecisionimprecision byby IQC materialIQC material

Requirements for IQC material

(Component II)

RequirementsRequirements forfor IQC material IQC material

((ComponentComponent II)II)

RequirementRequirement CommentComment

MatrixedMatrixed material from a thirdmaterial from a third--

party independent source party independent source

should be used (e.g., freshshould be used (e.g., fresh--

frozen pool)frozen pool)

Material must be different from the Material must be different from the

system control material used for system control material used for

checking alignmentchecking alignment

Specimens closely resembling Specimens closely resembling

authentic patient samples authentic patient samples

(commutability)(commutability)

Commercial nonCommercial non--commutable controls commutable controls

may provide a different impression of may provide a different impression of

imprecision performanceimprecision performance

Specimens of concentrations Specimens of concentrations

appropriate to the clinical appropriate to the clinical

application of the application of the analyteanalyte

When clinical decision cutWhen clinical decision cut--points are points are

employed, samples around these employed, samples around these

concentrations should preferentially be concentrations should preferentially be

selected selected

F.F. BragaBraga

http://http://users.unimi.itusers.unimi.it//cirmecirme/home//home/index.phpindex.php

Research Centre for Metrological Traceability in Laboratory Medicine (CIRME),

University of Milan, Milan, Italy

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