Joint Committee for Traceability in Laboratory Medicine

Joint Committee for Traceability in Laboratory Medicine

Bureau International des Poids et Mesures

JCTLM Approach to Higher Order Standards

R.I. Wielgosz, BIPM

www.bipm.org

JOINT COMMITTEE for TRACEABILITYin LABORATORY MEDICINE (JCTLM)

Declaration of co-operation

establishing

A framework for the international recognition of available higher-order reference materials, measurement procedures and

reference measurement laboratories


JOINT COMMITTEE on TRACEABILITY in JOINT COMMITTEE on TRACEABILITY in LABORATORY MEDICINELABORATORY MEDICINE

Established Established in Sevres on 12 June 2002, in Sevres on 12 June 2002, to meet the need for a worldwide platform to promote and give guidance on internationally recognized and accepted equivalence of measurements in Laboratory Medicine and traceability to appropriate measurement standards.

The Declaration of Cooperation betweenThe Declaration of Cooperation between the International Committee of Weights and Measures (CIPMCIPM), the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC),and the International Laboratory Accreditation Cooperation (ILAC(ILAC) for establishment of the JCTLM can be found at http://www.bipm.org/en/committees/jc/jctlm/declaration.html

JCTLM - StructureJCTLM - Structure

JCTLM ExecutiveJCTLM ExecutiveChair: J. Thijssen (IFCC)Executive Secretary: R. Wielgosz (BIPM)

Priority setting Approval of WG’s results

JCTLM Working GroupsJCTLM Working Groups: Task oriented 1. 1. Reference Materials and Reference MethodsReference Materials and Reference Methods

Co-Chairs: W.E. May (NIST), H. Schimmel (IRMM)

2. 2. Reference Laboratories - NetworksReference Laboratories - Networks

Co-Chairs: L. Siekmann (U. Bonn), L. Thienpont (U. Gent)


JCTLM Working Group I on Reference Materials and Reference Measurement Procedures

Charged with:Charged with:

• establishing a process for identifying, and reviewing against agreed upon criteria “higher order” Certified Reference Materials and Reference Measurement Procedures required for IVD industry compliance with the EC IVD Directive regarding in vitro diagnostic medical devices.

• publishing a List of “higher order” Certified Reference Materials and Reference Measurement Procedures required for IVD industry compliance with the EC IVD Directive regarding in vitro diagnostic medical devices.

Co-Chairs: W.E. May (NIST), H. Schimmel (IRMM)

“.... the traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or reference materials of a higher order ...” Annex 1 (3) 2nd para

IVD Manufacturers have requested that NMIs develop internationally recognized

reference methods and CRMs to meet this assist them in meeting this traceability

requirement.


Relevant ISO Standards

ISO 17511 In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values assigned to calibrators and control materials

ISO 15193 Presentation of reference measurement procedures

ISO 15194 Description of reference materials

ISO 15195 Reference Measurement Laboratories

ISO 18153 Metrological traceability of values for catalytic concentration of enzymes assigned to calibrators and control materials

Definitions (International Vocabulary of Basic and General Terms in Metrology –VIM)

(Metrological) traceability property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties

Uncertainty parameter, associated with the result of a measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measurand

Quantity attribute of a phenomenon, body or substance that may be distinguished qualitatively and determined quantitatively


SI traceability - Primary Calibrators (ISO 17511)


Traceability to an international conventional calibrator (ISO 17511)


Traceability to manufacturer’s selected measurement procedure (ISO 17511)


JCTLM WG1 Review Process (ISO 15194)


8

9

J K L M N O P Q R S

Matrix Category

MatrixIdentifier / Number

NameCertifying

Organization

Mode / approach used for value assignment (if

not clearly stated in

certificate)

CommentsIssued by NMI with

Certificate

Certificate from other

RM provider ?

RM listed in BIPM

Database?

Matrix RM

8

9

A B C D E F G H I

Analyte CategoryAnalyte Name

IUPAC/IFCC

Number

List I or II?

Traceable to SI ?

Procedurally-defined

(if so, name/cite procedure)

Traceable to an international

(WHO or other) standard? If so name standard

Unique Nomination

Number

Analyte / Parameter

Date Nomination

Filed

Basis for Traceability


JCTLM Reference Materials Nominations Template (1/3)


8

9

T U V W X Y Z AA AB AC AD AE AF

From To Unit From To UnitLev. of conf. (%)

Physical form of RM matrix

RM fortified with analyte or

naturally incurred

Applicable analyte

characteristics (e.g., isoform(s);

free/bound, total)

Other relevant factors (list)

Citation of specific

publication / reference if

available

Range of Analyte Certified / Assigned

Value and Unit

Range of Expanded Uncertainty for Analyte

Certified/Assigned ValueInformation for Assessing Commutability

Quantity

8

9

AG AH AI AJ AK AL AM

Expression of

Uncertainty

Justification of source

of reference material

Are intended use and

instructions for use

available?

Are dates of

authorization and revision given?

Are safety precautions listed?

Validation report

available?

Congruent with other critical factors in ISO 15194 (list other relevant factors)?

Additional Comments



8

9

AN AO AP AQ AR AS AT AU AV AW AX AY AZ

Hyperlink to Comparability Assessment

Studies Among listed RMs

Other relevant publications

CommentsProducer

nameCountry Website

email address

Phone number

Fax number

Nameemail

addressPhone

number

How to obtain

certificate?

Contact information for publication in the JCTLM DBContact Information for additional

details (for review process)CRM information for publication in the JCTLM DB

7

8

9

BA BB BC BD BE BF BG

FOR REVIEW COMMITTEE USE

Recommended for publication in the JCTLM

DB?

Manufacturer Comment (in

case of delisting)

Review team name

Review Word

Document

Does RM value-assignment

approach meet traceability

requirements of IVDD industry and

regulatory community ?

Additional Reviewer

Comments

Is there a sustainable source

for the material?


Priority Analyte Areas for Cycle I Review Process (Sept 2002 – March 2004)

Review Teams established with worldwide representation from Lab Accreditation Organizations, NMIs, Professional Societies, and IVD Industry in order to facilitate a fair and transparent review process.

Electrolytes EnzymesMetabolites and Substrates ProteinsNucleic Acids DrugsHormones Coagulation FactorsQuality Systems and Implementation Protocols

Additional Priority Areas for Cycle II Review Process (April 2004 - Dec 2004)

Blood Grouping/ Typing Blood Gases Microbial Serology Non-Electrolyte Metals Vitamins and Micronutrients


Initial Provisional Lists of Higher Order Reference Materials and Reference Measurement Procedures

I.I. Certified Reference Materials and Reference Measurement Certified Reference Materials and Reference Measurement ProceduresProcedures for well-defined chemical entities or internationally recognized reference method-defined measurands, such as enzymes. Reference Materials included in this category are those that are traceable to the SI units. [Electrolytes, Drugs, Metabolites and Substrates, Non-Peptide Hormones, Enzymes and some

Proteins]

II.II. Reference MaterialsReference Materials that are value-assigned using an internationally agreed upon protocol e.g., reference materials for Blood Typing, Coagulation Factors, Microbial Serology, Nucleic Acids, and some Proteins. The values of the measurands in the reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedures exist.


Initial Lists of Higher Order Reference Materials and Reference Measurement Procedures published

01 April 2004

Certified Reference Materials and Reference Measurement Certified Reference Materials and Reference Measurement ProceduresProcedures for well-defined chemical entities or internationally recognized reference method-defined measurands, such as enzymes. Reference Materials included in this category are those that are traceable to the SI units. [Electrolytes, Drugs, Metabolites and Substrates, Non-Peptide Hormones, Enzymes and some

Proteins]

approximately 100 Reference Measurement Procedure entries for 58 different health status markers

approximately 150 Reference Material entries for 96 measurands

http://www.bipm.org/en/committees/jc/jctlm/jctlm-db/Bureau International des Poids et Mesures

List updated in January 2005 to include – based on List updated in January 2005 to include – based on Cycle I nominations:Cycle I nominations:

Reference Materials that are value-assigned using an Reference Materials that are value-assigned using an internationally agreed upon protocolinternationally agreed upon protocol e.g., reference materials for e.g., reference materials for Blood Typing, Coagulation Factors, Microbial Serology, Nucleic Blood Typing, Coagulation Factors, Microbial Serology, Nucleic Acids, and some Proteins. The values of the measurands in the Acids, and some Proteins. The values of the measurands in the reference materials on this List are not SI-traceable and/or no reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedures exist. internationally-recognized reference measurement procedures exist.

• 10 CRMs for Coagulation Factors• 7 CRMs for Proteins

Hereafter, Lists I and II to be updated in April of each year



Database of higher-order reference materials and reference measurement procedures

List I : Certified Reference Materials and Reference Measurement Procedures for well-defined chemical entities or internationally recognized reference method-defined measurands.Reference Materials and Measurement Procedures included in this category are those that provide values that are traceable to the SI units; e.g., electrolytes, enzymes, drugs, metabolites and substrates, non-peptide hormones and some proteins.

List II: Reference Materials (e.g. reference materials for blood typing, coagulation factors, microbial serology, nucleic acids, and some proteins) that are value-assigned using an internationally agreed upon protocol. The values of the measurands in the reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedure exist. List II also contains a group of purified substances that due to the absence of reference measurement procedures should not be directly used for calibration unless commutability is established.

Search the database

JCTLM Database: Laboratory medicine and in vitro diagnostics

JCTLM-DB- JCTLM-DB home

- Search form

- Preamble

- Quality manual

- Review Teams

- Nomination forms

- JCTLM

Useful links

- ILAC

- IFCC

- KCDB

- Metrologia

Contact

-JCTLM Secretariat

Home page

Higher-order reference materials

Results of the search

Cholesterol in human serumNational Institute of Standards and Technology (NIST), United States

Name of reference material: SRM 1951a, lipids in frozen human serum

Quantity: Amount-of-substance concentration

Range of analyte certified/assigned value: 4.7109 mmol/l to 7.1554 mmol/l

Range of expanded uncertainty at a 95% level of confidence: 0.0116 mmol/l to 0.0142 mmol/l

Traceability: SI

CRM listing: List IRM

-Create a .PDF file

-Modify your selection

-Refine your search

-RM no longer listed


JCTLM Database: Results of the search


- Search form

- Preamble

- Quality manual

- Review Teams

- Nomination forms

- JCTLM

Useful links

- ILAC

- IFCC

- KCDB

- Metrologia

Contact

-JCTLM Secretariat

RM Producer’s Contact Information

NIST, United StatesWebsite: http://www.nist.gov/srmEmail:[email protected]: (301)975-6776Fax: (301)948-3730

Create a .PDF file

Cholesterol in human serum (lyophilized)National Institute of Standards and Technology (NIST), United States

Name of reference material: SRM 909b, human serum

Quantity: Amount-of-substance concentration

Range of analyte certified/assigned value: 3.787 mmol/l to 6.084 mmol/l

Range of expanded uncertainty at a 95% level of confidence: 0.047 mmol/l to 0.077 mmol/l

Comparability assessment study among listed RMs: See summary of Comparability Assessment for Cholesterol in Human Serum CRMs on JCTLM List I at http://www1.bipm.org/utils/en/pdf/jctlm_preamble.pdf

Other relevant publication(s) : Certification process: Fresenius’ J. Anal. Chem. 361:2 71-80 (1998); Method used for certification: Anal Chem 61, 1718-1723 (1989)

Traceability: SI

CRM listing: List I

RMP

-Create a .PDF file

-Modify your selection

-Refine your search

-RMP no longer listed


JCTLM Database: Results of the search


- Search form

- Preamble

- Quality manual

- Review Teams

- Nomination forms

- JCTLM

Useful links

- ILAC

- IFCC

- KCDB

- Metrologia

Contact

-JCTLM Secretariat

Create a .PDF file

Higher-order reference measurement procedures

Results of the search

CDCAbell-Kendall method for cholesterolCholesterol in blood serumApplicable matrices: human serum; lyophilized, fresh or frozen serumMeasurement principles: SpectrophotometryCitation(s): Clin Chem, 1986, 32, 921-929Comparability assessment studies: Clin Chem, 1990, 36, 370-375

DGKC definitive Method for Serum CholesterolCholesterol in blood serumApplicable matrices: human serum or plasma; lyophilized, fresh or frozenMeasurement principles: ID/GC/MSCitation(s): Z. anal Chem, 1976, 279, 145-146

Comparability assessment studies: See CCQM-P6 results in CCQM-K6 Report

NIST definitive method for serum cholesterolCholesterol in blood serumApplicable matrices: human serum: lyophilized, fresh or frozen serumMeasurement principles: ID/GC/MSCitation(s): Anal Chem, 1989, 61, 1718-1723

Comparability assessment studies: CCQM-K6 Final Report, Clin Chem, 1990, 36, 370-375

All Listed Reference Materials will be assessed for comparability by a reference measurement procedure under repeatability conditions:

• to assess veracity of the Normative Standards-Based Review Process• To establish bias that could be introduced by randomly selecting any material from

the List

Fig 1: The vertical axis reports the ratio between the measured and certified values of each CRM, Xi/Ci. The dark vertical

lines represent the approximate 95% CI about the ratios. The light horizontal lines represent the certified 95% CIs. The dotted line represents the expected ratio for the suite of all materials given the observed identity between the measured and certified values. (CI = Confidence Interval)

Fig 2: The data demonstrate that these CRMs are comparable over a wide concentration range. The horizontal axis reports the certified values, Ci; the vertical reports the average measured values, Xi. Each level of each CRM is

displayed as approximate 95% CIs along both axes. The intersection of these intervals is bounded by an open circle to aid visual inspection.

Example: Potassium in Human Serum CRMs on provisional JCTLM List 1 were assessed for comparability by a single laboratory (NIST) using a reference measurement procedure under repeatability conditions.

Fig 1: Ratio Display Fig 2: Scattergram Display

Lev3956aSRM

Lev2956aSRM

Lev1956aSRM

Lev2909bSRM

Lev1909bSRM

H111-5

JCCRM

M111-5

JCCRM

L111-5

JCCRM0.98

0.99

1.00

1.01

1.02

Mea

sure

d / C

ertif

icat

e

Certified 95% CI Average Ratio Ratio ~95% CI

956a 3

956a 2

956a 1909b 2

909b 1

111-5 H

111-5 M

111-5 L

1

2

3

4

5

6

1 2 3 4 5 6

Certified [Potassium], C i , nmol/L

Mea

sure

d [P

otas

sium

], X

i, n

mol

/L

X i = (0.003 ±0.013) + (0.9993 ±0.0028)×C i

CRM comparability independent of

analyte level

The measured/certified ratios for this set of CRMs are:

• ~ normally distributed• with a standard deviation of ~0.7%

150 200 250 300

150

200

250

300

JCCRM H

JCCRM M

SR

M 9

09

b l-

1

SRM 909b l-2

SRM 968c l-1

SRM 968c l-2

SRM 1589a

SRM 1951a l-1

SRM 1951a l-2

SRM 1952a l-1

SRM 1952a l-2

SRM 1952a l-3

Certificate Value, mg/dL

Me

asu

red

Va

lue

, mg

/dL

Comparability of Cholesterol in Serum CRMs on JCTLM LIST

U(Med) = 0.0055

Med:s = 0.0069Med = 0.9933

1.01

1.00

0.99

0.98

SR

M 1

952a

l-3

SR

M 1

952a

l-2

SR

M 1

952a

l-1

SR

M 1

951a

l-2

SR

M 1

951a

l-1

SR

M 1

589a

SR

M 9

68c

l-2

SR

M 9

68c

l-1

SR

M 9

09b

l-2

SR

M 9

09b

l-1

JCC

RM

M

JCC

RM

H

Me

as

ure

d /

Ce

rtif

ied

Va

lue


Upcoming JCTLM MeetingsUpcoming JCTLM Meetings

• JCTLM WG1+WG2– September 19-20, IRMM, Geel, Belgium

• JCTLM Members meeting – September 21, IRMM

• JCTLM WG2 – July 27, AACC/IFCC meeting, Orlando USA


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Joint Committee for Traceability in Laboratory Medicine

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