1. Use of Reference Materials in Medical Testing SLAB 10th Anniversary Celebrations Accreditation Conference 10 th November 2015 Dr Deepani Siriwardhana Senior Lecturer in Pathology Faculty of Medicine University of Ruhuna Galle

2. Overview What are customer expectations in medical laboratory testing? How do we conform to customer expectations? What are the requirements regarding accuracy in the ISO 15189 standard? What are medical reference materials? Are there analytes without reference materials?

3. Does the ISO 15189 standard address accuracy of test results? 5.3.1 Equipment 5.3.1.4 Calibration and metrological traceability Metrological traceability shall be to a reference material or reference procedure of higher metrological order available.” “documentation of calibration traceability to a higher order reference material or reference procedure may be provided by an examination system manufacturer.” 3

4. Metrology Definition – science of measurement Measurements are comparisons against known standards

5. Metrological Traceability Metrological Traceability “ property of a measurement result whereby the result can be related to a stated reference, through a documented unbroken chain of calibrations (comparisons),each contributing to the measurement uncertainty.” International Vocabulary of Basic and General Terms in Metrology (VIM)

6. Metrological Traceability Key Features – It is a property of a measurement result – The results are obtained through a series of comparisons to a reference standard – All comparison steps documented – Measurement uncertainty (MU)stated for each comparison step – Preferably results traceable to an SI unit

8. Metrological Traceability for Kg 8

9. What is the significance of traceability? Link measurement results of a patient sample to a commonly accepted reference (certified reference material or reference measurement procedure) Renders measurement results comparable across different – methods and systems – locations – times

10. What is the definition for RM? Material, sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process http://www.nist.gov/srm/definitions.cfm

11. What are the uses of reference materials? Uses – calibration of a measurement system – assessment of a measurement procedure – assigning values to other materials – for quality control purposes What it cannot be used for? – Same RM for both calibration and validation of the same analytical method

12. What are different categories of Reference Materials? Used with a primary reference measurement procedure To produce primary calibrators Primary Reference Materials Used to calibrate secondary reference measurement procedure To produce secondary calibrators Primary Calibrators Used in manufacturer’s method To produce master calibrators Secondary Calibrators

13. Traceability Chain for Serum Calcium Gravimetry SRM 3109a SRM 915b (NIST) Mass Fraction of CaCO3 ID-TIMS SRM 909b SRM 3109a Aqueous CaCO3 Atomic absorption spectrometry Master calibrator (Ca in mmo/L) SRM 909b (human serum)

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15. Do all analytes have primary and secondary Calibrators? No Reason: most analytes are yet inadequately defined for – Physico-chemical characteristics – Molecular weights What are the alternatives for such analytes?

16. Calibration Hierarchies

17. Measurement of Total Haemoglobin International conventional reference measurement procedure with an international conventional calibrator ICSH-endorsed absorptionspectrometry method for measuring haemiglobinocyanide international conventional calibrator (IRMM BCR 522) Bovine blood lysate containing haemiglobinocyanide – certified value & – uncertainty assigned using calibrated spectrophotometers

18. International Conventional Reference Measurement Procedures Catalytic activities of enzymes IFCC reference measurement procedure for – Alanine transaminase

19. International Conventional Calibrators C-reactive protein FSH TSH Produced by WHO

20. Lowest Order Metrological Traceability No international reference measurement procedure or calibrator Only a manufacturer’s method and calibrators Eg. Tumour markers like CA 19-9

21. Information about Reference Materials Joint Committee for Traceability in Laboratory Medicine (JCTLM) National Institute of Science and Technology (NIST) Institute for Reference Materials and Measurements (IRMM) WHO Expert Committee on Biological Standardization (WHO-ECBS) International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) International Council for Standardization in Haematology (ICSH)

23. SRM for Clinical Diagnostics by NIST

24. Take Home Message Request for traceability information from manufacturers. Use methods which are traceable to reference materials/reference methods. Awareness needed regarding analytes lacking highest order metrological traceability.

25. References White G. Metrological Traceability in Clinical Biochemistry. Annals of Clin Biochem 2011; 48: 393-409 Vesper HW, Thienpont LM. Traceability in Laboratory Medicine. Clin Chem 2009; 55: 1067-1075