1

Establishing Traceability and Comparability of

measurement results by a limited number of

well-chosen Certified Reference Materials

Robert Kaarls

Secretary CIPM, President CCQM

The Future of Reference Materials – Science and Innovation

November 23-25, 2010, JRC IRMM Geel, Belgium

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Contents

• Comparability and traceability

• Primary methods, primary calibrators and purity analysis

• Criteria for NMIs

• An efficient and effective approach: testing core capabilities

and competencies

• Well choosen primary calibrators

“Once measured, everywhere accepted” requires Comparability through Traceability

Metrological traceability

Property of a measurement result whereby the result can be related to a reference through an unbroken chain of calibrations, each contributing to the measurement uncertainty

JCGM 200:2008 (VIM 3)

Traceability to the SI, or if not (yet) possible to another internationally agreed reference (hardness, pH, WHO International Units)

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Traceability

Traceability to the mole or other SI units

�Amount of substance : mol

�Amount fraction : mol/mol

�Amount concentration : mol/m3

�Mass concentration : kg/m3

�Amount content : mol/kg

�Mass fraction : kg/kg

(or expressed in multiples or sub-multiples)

and

� Identification of the entity (measurand/analyte)4

Traceability

Method dependence

�Measurand

�Defined by the method/procedure

� Influence quantities fixed

�Nevertheless in general still SI traceable

�Biological measurands often defined in terms of WHO reference standards and measured in terms of WHO International Units (IU)

�WHO reference standards defined by “what it does”, instead of “what it is”

�WHO and other “consensus” reference standards not really reproducible; thus large(r) measurement uncertainty

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Traceability

Potential primary methods

�Gravimetry

�Titrimetry

�Coulometry

�Calorimetry (differential scanning calorimetry)

�Cavity Ring Down Spectrometry

� Isotope Dilution Mass Spectrometry

� Instrumental Neutron Activation Analysis

Only when the procedure is completely understood and precisely followed and staff is competent and experienced to carry out the measurement/analysis process

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Traceability primary methods and primary calibrators

Purity analysis » often (100% - impurities)

Impurity analysis: measurement uncertainty less critical, but add uncertainty component for unknown impurities

�Calibration solutions

�Calibrators, pure compounds

�Certified Reference Materials

�Matrix CRMs

�Recovery factor (if correction applied, part of calibration)

�Method validation

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Chemical measurement standards, CRMs and procedures

�Organic, inorganic, gas, electro-chemical, surface and bio analysis

- complex molecules in a complex matrix environment

- in a number of cases measurand defined on basis of “what it

does” and not on basis of “what it is”; what is the “conversion

factor”?

- definition of measurand/analyte often not understood

- measurement method/procedure dependent measurand/results

- from measurement dependent prescription to performance

criteria

- commutability

- method validation

- sample preparation often largest source of measurement

uncertainty

Traceability and measurement uncertainty

Major uncertainty components

� Sampling (normally not taken into account)

� Sample preparation (dilution, extraction, clean up, contamination, separation, etc., etc.)

� Homogeneity (bulk, with-in bottle and between-bottle)

� Stability

� Sample size

� Recovery (matrix CRM when used for calibration)

� Commutability

Most uncertainty components are type B

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10

Primary Calibrators (ISO 17511)

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NMI

DIs

Accredited

Calibration

labs & CRM

prod.

Products and services

Testing and

industrial/field

laboratories

The National Metrological Infrastructure

Dissemination

of traceability to

the SI

Traceability to

the SI

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Traceability requirements for NMIs ultimate source of traceability (CIPM MRA)

� only by own primary realisation or from another recognized NMI/DI

� traceability can not come from a non-NMI/DI(accredited or not-accredited)

� traceability can not come from CRMs delivered by non-NMIs/DIs

� traceability is not realized by the result in a comparison or PT scheme

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Traceability

� NMI/DI may carry out purity analysis on “commercial”bought CRMs and, if CRM quality is in conformity with fit-for-purpose requirement, use these (in that case traceability comes from the NMI itself)

� Sub-contracting (ISO/IEC 17025)/Collaboration (ISO Guide 34) only in addition to own measurement capabilities as extra check (e.g. expensive NMR facility or a reactor for NAA)

�NMI responsible for assuring QS (ISO/IEC 17025)

�Can not lead to smaller measurement uncertainty claims than can be achieved with own capabilities

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Traceability

� In general not to be realized by taking a “consensus”value obtained from a collaborative trial (a weak, costly and time consuming, and in general wrong, way of establishing traceability)

� Like in physics, also in chemistry the NMI should be able to establish traceability by applying one or two techniques/methods/procedures

� NMI has to demonstrate its competence and capabilities to assign measurement values and to deliver traceability through CRMs by participation in a limited number of well selected international comparisons

� The big question: How far does the light shine?

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The CIPM Mutual Recognition Arrangement

• Published are the Calibration and Measurement Capabilities (CMCs), that are the services of the NMIs and other designated institutes, which are normally delivered to the customers

* Analysing/measurement/calibration/value assignment capabilities for “in-house RMs”, and/or

* CRM’s delivered/sold to customers

* Delivering assigned reference values for PT schemes

• Some 23 200 CMCs of which 4700 chemical, 3800 ionizing radiation, 14700 physical (Appendix C)

• Some 450 CMCs greyed out

• Data Base – KCDB on www.bipm.org/kcdb

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CCQM Approach to increase efficiency and effectiveness of demonstrating NMI capabilities and competences

� CCQM IAWG, OAWG and GAWG are now trying out and implementing new approach to demonstrating the validity of claimed CMCs:

� Key Comparisons testing core competencies

� Key Comparisons of deliverables, like CRMs

� Key Comparisons of challenging components and matrices

� Pilot Study Comparisons (bench marking, research, try out, newcomers, etc.)

� “A System to Interpret the Results of Key Comparisons to Support CMCs Based on Demonstrations of Core Capabilities”(Greg Turk, NIST)

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OAWG Core Competencies • Purity Assessment/value assignment of Primary

References: Mass fraction and associated uncertainty– Identify verification– Molecular weight– Polarity– Level of purity

• Value-assignment (including verification) of single and multi-component formulated solutions: Mass fraction and associated uncertainty

– Identify of components– Molecular weight– Polarity– Volatility– Multicomponent effects– Solution matrix– Selectivity of analytes of interest (verification)

• Extraction of analytes of interest from matrix

• Cleanup – separation of analytes of interest from other undesirable/interfering matrix/extract components … as needed

• Transformation: Hydrolysis or derivatization or … as needed

• Analytical separation/specificity

• Value-Assignment of Analytes in Complex Mixtures: Mass fraction and uncertainty

For the delivery of Measurement Services to Customers

Providing

Primary

Calibration

Reference

ServicesProviding

Accuracy

Control

Reference

Services

By courtesy of Willie May and Reenie Parris - NIST

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Core Capabilities for Inorganic Analysis

• Contamination control and correction

• Sample dissolution and preparation

• ICP-MS

• ICP-OES

• Graphite furnace AA

• Flame AA

• Ion Chromatography

• X-ray Fluorescence

• Neutron Activation Analysis

By courtesy of G. Turk – NIST and M. Sargent - LGC

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Sub-Capabilities Inorganic Analysis

• Contamination control and correction

– Clean room operation

– High purity water and acid

– Blank correction procedures

• Sample dissolution and preparation

– Routine organic matrices

– Routine inorganic matrices

– Refractory matrices

– Flammable matrices

– Non-reactive matrices (i.e. plastics)

– Volatile element containment

– Pre-concentration

– Matrix separation

– Species separation

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CCQM Gas Analysis WG approach to testing NMI’s claimed capabilities and competences

� Retrospective approach based on results of prior comparisons and tabled CMCs � Identified sets of core species as good predictors of competence to perform measurements of non-reactive species� NMIs have to participate in a number of KCs before CMC claims can be considered� Based on good results, a broader range of analytes and concentrations can become accepted� More time will be devoted to challenging reactive species

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1.Preparation and certification of Reference Materials

The CMQ has prepared and certified 86Reference Materials such as:

Metals and anions in aqueous matrixes

Heavy metals in wines.

Under development processes, there are Reference Materials of Quinolones in Salmon and Pork and heavy metals in sea-food.

Several Reference samples have been prepared for Proficiency Tests in Salmon, wines and organic solutions.

By courtesy of CMQ - Chile

FIELDS OF ACTIVITIES

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CRMs for Nutrients and Contaminants in Food

• Most food analysis labs provide analyses for a similar set of analytes but in a wide range of food types (matrices)

• Matrix differences and concentration differences are the primary measurement challenges.

• By providing SRMs certified for these common food analytes in each of the major sections of the “food triangle”, NIST covers most of the field of CRMs needed for the validation of these measurements of foods.

Examples of Food-matrix Standard Reference Materials by Sector

Every food can be placed in

one of these 9 sub-triangles

according to its % protein,

% fat, and % carbohydrate

coordinates.

By courtesy of NIST

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Impact: A model for Primary Calibrator Comparisonsestablishing, demonstrating and delivering traceability

0

250

500

750

1000

-8,0 -6,0 -4,0 -2,0 0,0 2,0 4,0

- Log KOW

( Polarity )

Mo

lec

ula

r W

eig

ht

(Str

uc

tura

l C

om

ple

xit

y

)

CMC Analytes

CCQM-P20

CCQM-K55a,b

PCBs

PAHs VOCs

OCs

Nonachlor Folic Acid

Creatinine

Ethanol

“HFTLS” for CCQM-K55a

“HFTLS” for CCQM-K55c

“HFTLS” for CCQM-K55b

Aldrin

Atrazine

Estradiol

Chlorpyrifos

Oxytetracycline

Digoxin

Theophylline

Xylene

■

CCQM-P20.f (2007/2008)

CCQM-P20.e (2006/2007)

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Characterization of CCQM-P20.e Study Materials

Pilot study results

Ralf Josephs, Steven Westwood, Robert Wielgosz, Adeline Daireaux

Bureau International des Poids et Mesures

Organic Analysis Programme - April 2007

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CCQM-P20.e

Gravimetric Reference Value = 983.1 ± 1.5 mg/g

Mean = 984.7 mg/g (SE = 0.66 mg/g)

Weighted Mean = 984.1 mg/g (weighted SE = 0.35 mg/g)

Theophylline content of CCQM-P20.e.2

975

980

985

990

995

1000Q

NM

R (in

it.)

CS

IRQ

NM

R (co

rr.)

NIS

TU

SP

(R

el.)

NM

IA

LG

C

BIP

M

CE

NA

MU

SP

(A

ssay

)

NIM

DM

Sc

NM

IT

BA

M

NM

IJ

Ma

ss

fra

cti

on

(m

g/g

)

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0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

-8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0

-K(ow)

Re

lati

ve

Mo

lec

ula

r M

as

s

Reference Measurement Systems for Peptides and Proteins

Theophylline

Angiotensin

Insulin

IGF-1

Blood pressure regulation

Biological Activity (IU) and Amount (SI)

Therapeutic: Carbohydrate Metabolism Control

1st International Standard 26 IU/mg

Diagnostic: Growth hormone deficiency

International Reference Reagent 3.1 µg/ampoule

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CIPM-MRA

Technical basis for:

-Determination of the degree of

equivalence of measurement

standards

-Mutual recognition of

calibration and measurement

certificates

BIPM and the Mutual Recognition Arrangement

By courtesy of the BIPM

BIPM and the Mutual Recognition Arrangement

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Calibration and Measurement

Capabilities

Key Comparisons

Mechanisms for measurement service delivery: CRMs

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Contact Information

Analyte Matrix

Material Name

and/or ID #

Estimated *

Availability

(months, as of

Jan 2004)

- Producer

- Country

- Website

- Email Address

- Phone Number

- Fax Number

Commutability Study Information and/or

Citations

cholesterol cholesterol GBW09203b 60

NRCCRM, China

Tel: 086-10-64221811

Fax: 086-10-64213149

Email: crmservice@nrccrm.com.cn

Primary calibrator for higher order reference

methods

cholesterol cholesterol SRM 911b 21

NIST, USA

http://ts.nist.gov/ts/htdocs/230/232/232.htm

Email:srminfo@nist.gov

Tel:(301)975-6776

Fax: (301)948-3730

Primary calibrator for higher order reference

methods

cholesterol human serum JCCRM 211 12

HECTEF, Japan

http://www.in8.co.jp/hectef/starte.htm

Tel: 81-44-813-0055

Fax: 81-44-813-0224

cholesterolhuman serum

(frozen)SRM 1951b 60

NIST , USA

http://ts.nist.gov/ts/htdocs/230/232/232.htm

Email:srminfo@nist.gov

Tel:(301)975-6776

Fax: (301)948-3730

Material prepared following NCCLS Document

C37-A

"Preparation and Validation of Commutable

Frozen Human Serum Pools as Secondary

Reference Materials for Cholesterol

Measurement Procedures; Approved

Guideline"

Method used for certification: Anal Chem 61,

1718-1723 (1989)

cholesterolhuman serum

(lyophilized)SRM 1952a 60

NIST, USA

http://ts.nist.gov/ts/htdocs/230/232/232.htm

Email:srminfo@nist.gov

Tel:(301)975-6776

Fax: (301)948-3730

cholesterolhuman serum

(lyophilized)SRM 968c 38

NIST , USA

http://ts.nist.gov/ts/htdocs/230/232/232.htm

Email:srminfo@nist.gov

Tel:(301)975-6776

Fax: (301)948-3730

cholesterolhuman serum

(lyophilized)SRM909b 60

NIST,USA

http://ts.nist.gov/ts/htdocs/230/232/232.htm

Email:srminfo@nist.gov

Tel:(301)975-6776

Fax: (301)948-3730

Information about Material

Reference Materials

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SRM

956a

Level-3

JCCRM

111-5

L

SRM

909

Level-1

SRM

956a

Level-2

JCCRM

111-5

M

JCCRM

111-5

H

SRM

956a

Level-1

SRM

909

Level-20.98

0.99

1.00

1.01

Me

asu

red

/ C

ert

ifie

d V

alu

e

Comparability Assessment for Potassium in Human Serum CRMs

on JCTLM List I: Ratio Display

Certificate

Campaign 1

Campaign 2

95% CI

Potassium in Human Serum CRMs on provisional JCTLM List 1 were assessed for comparability

by a single laboratory using a reference measurement procedure under repeatability conditions.

The horizontal axis reports the CRMs evaluated. The vertical axis reports the ratio between the

measured and certified values of each CRM, Xi/Ci.

� Listed CRMs

are all comparable

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CRM comparability studies

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Market needs for CRMs

- essential for realizing global comparability through traceability- need for primary calibration solutions and primary pure materials, calibrators- shortage of variety of CRMs ( different analytes in different matrix with different concentrations)- lack on demonstrated metrological traceability (accredited CRM producers in compliance with ISO/IEC 17025 and ISO Guide 34)- necessity for international cooperation in CRM production and certification

- better traceability ↔ faster and cheaper CRMproduction

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Conclusion- Global comparability requires metrological traceability

- Reliable, traceable calibration solutions, primary calibrators and CRMs are essential

- NMIs capabilities have to be demonstrated in an efficient and effective way

- Delivering traceability has to be done in an efficient and effective way

- Comparability and traceability of CRMs has to be demonstrated by comparisons

- International recognition is essential (BIPM - Inter-Governmental Treaty Organisation; CIPM MRA)

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Thank you

www.bipm.org