1. 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

2. JOINT COMMITTEE for TRACEABILITY in 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 Bureau International des Poids et Mesures

3. JOINT COMMITTEE on TRACEABILITY in LABORATORY MEDICINE Established in Sevres on 12 June 2002, The Declaration of Cooperation between CIPM (ILAC Established 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 between the International Committee of Weights and Measures (CIPM), the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC),and the International Laboratory Accreditation Cooperation (ILAC) for establishment of the JCTLM can be found at http://www.bipm.org/en/committees/jc/jctlm/declaration.html

4. JCTLM - Structure  JCTLM Executive Chair: J. Thijssen (IFCC) Executive Secretary: R. Wielgosz (BIPM)  Priority setting  Approval of WG’s results  JCTLM Working Groups  JCTLM Working Groups: Task oriented 1. Reference Materials and Reference Methods 1. Reference Materials and Reference Methods Co-Chairs: W.E. May (NIST), H. Schimmel (IRMM) 2. Reference Laboratories - Networks 2. Reference Laboratories - Networks Co-Chairs: L. Siekmann (U. Bonn), L. Thienpont (U. Gent) Bureau International des Poids et Mesures

5. JCTLM Working Group I on Reference Materials and Reference Measurement Procedures 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)

6. “.... 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. Bureau International des Poids et Mesures

7. 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

8. 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 Bureau International des Poids et Mesures

9. SI traceability - Primary Calibrators (ISO 17511) Bureau International des Poids et Mesures

10. Traceability to an international conventional calibrator (ISO 17511) Bureau International des Poids et Mesures

11. Traceability to manufacturer’s selected measurement procedure (ISO 17511) Bureau International des Poids et Mesures

12. JCTLM WG1 Review Process (ISO 15194) Bureau International des Poids et Mesures

13. JCTLM Reference Materials Nominations Template (1/3)

14. JCTLM Reference Materials Nominations Template (2/3) Bureau International des Poids et Mesures

15. JCTLM Reference Materials Nominations Template (3/3) Bureau International des Poids et Mesures

16. 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. ElectrolytesEnzymes Metabolites and SubstratesProteins Nucleic AcidsDrugs HormonesCoagulation Factors Quality 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 Bureau International des Poids et Mesures

17. Initial Provisional Lists of Higher Order Reference Materials and Reference Measurement Procedures I.Certified Reference Materials and Reference Measurement Procedures I.Certified Reference Materials and Reference Measurement Procedures 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.Reference Materials II.Reference 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. Bureau International des Poids et Mesures

18. Initial Lists of Higher Order Reference Materials and Reference Measurement Procedures published 01 April 2004 Certified Reference Materials and Reference Measurement Procedures Certified Reference Materials and Reference Measurement Procedures 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

19. List updated in January 2005 to include – based on Cycle I nominations: Reference 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. 10 CRMs for Coagulation Factors 7 CRMs for Proteins Hereafter, Lists I and II to be updated in April of each year Bureau International des Poids et Mesures

20. 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

21. Higher-order reference materials Results of the search Cholesterol in human serum National 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 I RM -Create a.PDF file -Modify your selection -Refine your search -RM no longer listed Bureau International des Poids et Mesures JCTLM Database: Results of the search JCTLM-DB - JCTLM-DB home - 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 States Website: http://www.nist.gov/srm Email:srminfo@nist.gov Tel: (301)975-6776 Fax: (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

22. RMP -Create a.PDF file -Modify your selection -Refine your search -RMP no longer listed Bureau International des Poids et Mesures JCTLM Database: Results of the search JCTLM-DB - JCTLM-DB home - 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 cholesterol Cholesterol in blood serum Applicable matrices: human serum; lyophilized, fresh or frozen serum Measurement principles: Spectrophotometry Citation(s): Clin Chem, 1986, 32, 921-929 Comparability assessment studies: Clin Chem, 1990, 36, 370-375 DGKC definitive Method for Serum Cholesterol Cholesterol in blood serum Applicable matrices: human serum or plasma; lyophilized, fresh or frozen Measurement principles: ID/GC/MS Citation(s): Z. anal Chem, 1976, 279, 145-146 Comparability assessment studies: See CCQM-P6 results in CCQM-K6 Report NIST definitive method for serum cholesterol Cholesterol in blood serum Applicable matrices: human serum: lyophilized, fresh or frozen serum Measurement principles: ID/GC/MS Citation(s): Anal Chem, 1989, 61, 1718-1723 Comparability assessment studies: CCQM-K6 Final Report, Clin Chem, 1990, 36, 370-375

23. 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, X i /C i. 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, C i ; the vertical reports the average measured values, X i. 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

24.  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% Comparability of Cholesterol in Serum CRMs on JCTLM LIST Bureau International des Poids et Mesures

25. Upcoming 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 Bureau International des Poids et Mesures