1. STANDARDISATION, HARMONISATION AND TRACEABILITY
Dr A A KHINE
DIVISION OF CHEMICAL PATHOLOGY
NHLS TYGERBERG
STELLENBOSCH UNIVERSITY
Laboratory Management workshop 3-6 June 2019

2. Good laboratory practice requires
Error of measurement must be small enough that a result reflects a patient’s biological condition.
Comparable results that are independent of:
Where and when a test was performed
The measurement procedure used

3. Total Error
Calibration bias to an accepted reference ( and also includes bias from calibrator lot-to-lot variability)
Imprecision in a measurement procedure
Sample specific influences
non-specificity for the measurand
interfering substances

4. Why We Need Comparable Results?
If different measurements give different results for the same patient sample:
Clinical practice guidelines become less useful.
Patients may receive incorrect treatment.
Patients may be moving around, thus specimens sent to various labs

5. Three areas of standardization in the clinical laboratory
procedures that are followed before analysis
How sample is analysed (test methods used)
What calibrator is used and how it is traceable

6. Standardisation versus harmonisation
Standardization:
Same method or same instrument used
Using calibrator with a traceability ref number
Results are uniform among measurement procedures
Reporting units are the same
Harmonization:
Different methods are used but results are not uniform but comparable
Reporting units may not be the same originally but conversions help to make comparable (SI units)
No reference measurement procedure and no “pure substance” reference material

7. How To Achieve Comparable Results?
Laboratories using a common traceable calibrator or different calibrators with the same traceability ref number
Performance is monitored and maintained by surveillance using proficiency testing (PT), external quality assessment (EQA), or a certification program.

8. Metrological traceability
True value is not known unless it is attached to a reference so that value can be assigned
is defined as “the property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the measurement uncertainty”.
Traceability is established to SI using a reference calibrator and reference measurement procedure

9. Metrology traceability chain

13. COMMUTABILITY ISSUES
Commutable means that the ref material reacts with the reagents in the ref method and other methods in the same way that analyte in the patient sample would
Thus, values obtained from the calibration material and from native clinical samples have the same relationship across measurement procedures for the same measurand.
Ideally a reference material should be validated for commutability against all field methods and types of samples but it is rarely the case
Poor commutability means there is matrix effect affecting reaction between reagent and measurand

14. When there is no or poor commutability
A manufacturer uses a “master lot of calibrator” that may be traceable to a non-commutable reference material, then the Traceability chain is broken
Even though manufacturers claim traceability, the process fails to provide equivalent results for patient samples when different measurement procedures are used.

16. Calibration Traceability Does Not Ensure Accuracy for an Individual Patient Sample
Measurement procedure may not be specific for the measurand.
Measurand may not be well defined.
Molecular form(s) of clinical interest
Interfering substances present in a patient’s sample may influence the result

17. Use of a Non-commutable Material for Calibration Will Cause
Incorrect value assignment for the manufacturer’s calibrator
Incorrect results for patient samples

21. Calibrators in the routine laboratory
A manufacturer's calibrator is proprietary (patented)- intended for use with a specific measurement procedure.
It cannot be used with a different manufacturer’s measurement procedure
This is because the company has validated its commutability only with their own reagent

22. Change in Practice Needed
In the business of producing and marketing PRM, SRM and TRM, there must be requirement to submit commutability validation against
Reference methods
Manufacturer’s methods and reagents
Routine clinical laboratory procedures and reagents
A guideline for validating commutability is available: CLSI C53-A- Characterization and Qualification of Commutable Reference Materials for Laboratory Medicine (2010)

23. No traceability No reference measurement procedure or
No reference material
Can there be harmonisation?

24. Barriers to Harmonization
Lack of a systematic process to identify and prioritize measurands
Materials labelled as “reference materials” that have not been validated to be commutable for the intended measurement procedures
Inadequate definition of the measurand
Inadequate analytical specificity for the measurand
Lack of systematic procedures to implement harmonization, in particular:
When there is no reference measurement procedure
When there is no reference material

25. Initiatives in establishing S and H
IFCC has been a key leader in developing science in developing PRMs and RMPs.
Many national and international groups are engaged
JCTLM (joint committee for traceability in lab measurements) composed of three organizations:
International Committee of Weights and Measures
International Federation of Clinical Chemistry and Laboratory Medicine
International Laboratory Accreditation Cooperation

26. Functions of JCTLM Maintain the list of reviewed and approved
Reference measurement procedures
Reference laboratories
Reference materials
Commutability requirements are being addressed.

27. Possibilities for consideration:
Traceable to an all methods mean (outliers removed) of a panel of patient samples
Traceable to a designated measurement procedure (arbitrary, but which has good correlation with clinical outcome)

28. References
Mary Lou Gantzer, PhD, FACB. President, CLSI, CEO, BioCore Diagnostics. Laboratory Standardization: Bringing Order to Chaos
Standardization –the theory and practice-Jill Tate, M Panteghini
The JCTML- A global approach to promote standardization of clinical laboratory test results
Traceability, Reference systems and result comparability- Clin Biochem reviews- 28Aug 2007
ISO 17511

29. EXERCISE
What are the analytes in routine chemistry that have been standardized using both ref material and ref method procedure?
What are the analytes that have been standardized through development of primary ref material but not all routine laboratories use the reference method procedure?
What are the analytes that have been standardized through development of primary ref material but lacking method standardization?
What are the analytes that have not been standardized through both development of primary ref material or method standardization?
How has NHLS tried to harmonise the analytes under 2, 3, 4 and 5?