Introduction

ISO 17034:2016 sections 7.2.3 (k) and 7.14.2 (l) require that reference material producers consider the assessment of commutability “(where appropriate)” in planning the production of reference materials and, (where appropriate), provide information on commutability in RM certificates and information sheets.

This position paper describes the typical circumstances in which commutability assessment by or on behalf of the reference material producer should, or should not, be considered necessary. In doing so the paper recognises that the requirement differs considerably from one sector to another and in particular that commutability is of particular importance for clinical measurement.

In order to establish the necessity for commutability, and therefore of commutability assessment, it is necessary to consider the circumstances in which the reference material will be used, and in particular the characteristics of the relevant measurement procedures and the role of the reference material in the measurement process.

Characteristics of measurement procedures

The response of most analytical instruments and test kits to the quantity of interest is influenced by the nature of the test sample matrix, by interfering compounds present in routine test materials and, particularly in the case of substances with biological functions, by the particular form of the molecular or (sometimes) biological species of interest. The great majority of analytical measurement procedures are therefore developed to reduce this influence to an acceptable level. This is usually achieved by one or more of the following strategies:

isolation of the substance of interest from the test material matrix and from other potentially interfering species prior to the actual measurement process, for example by thorough extraction and clean-up or purification.
on-line separation technologies, usually chromatographic, which isolate the species of interest in the measurement process. Examples include liquid chromatography with on-line detection methods of limited selectivity, or coupled to more selective technologies as for example in the case of LC-MS-MS.
sample pre-treatment – for example, digestion or dissolution – reduces the test material to a simple and well understood form which permits calibration using simple solutions of a certified reference material (CRM).
special calibration strategies, such as the method of standard additions, which may allow the use of a pure material as calibrant in a complex matrix.

Where these strategies have been shown to operate acceptably, commutability is rarely an issue.

These strategies are, however, not always applicable or sufficient. This is particularly common for biological measurement procedures which are, for example, sensitive to conformation, secondary structure, or complexation, or for which aggressive sample treatment is not suitable. In these cases, a key strategy for calibration or quality control is to ensure that the behaviour of the calibrator and the measured samples are consistent between measurement procedures, so that results of one (reference) procedure can reliably be used to calibrate another (usually a transfer procedure or routine test method). This calibration strategy requires assurance of commutability.

Role of the reference material in the measurement procedure

The measurement procedure covers all activities needed to produce a measurement result for a given test sample. This includes extraction and separation steps and the actual measurement process, that is, the signal producing step. Reference materials may be used for calibration of the entire procedure (usually with a matrix CRM), to determine the recovery of extraction or separation steps (usually with a matrix CRM which is not used for calibration of the same procedure), to calibrate the final measurement step (e.g. with a pure substance CRM transformed into a calibration solution) or for quality control of either part of the procedure or the entire procedure.

Assessment of commutability

When should commutability be assessed?

Reference material producers should ensure that a reference material is suited for its intended use. For calibrators and quality control materials this usually includes verification that the raw material selection and processing procedures result in a material with the same behaviour as routine samples in the relevant measurement proced ures. The assessment of commutability is part of the demonstration that such a reference material is fit for the intended use.

In some cases it may be trivial to conclude on commutability. In other cases the assessment should include a dedicated study. Examples of cases for which commutability is relevant are well known in the field of laboratory medicine; for example, solutions of glucose are not commutable for point of care blood testing devices. Commutability may also be relevant in other fields; for example, for X-ray fluorescence measurements can be affected by the composition of the material and close matching of the matrix composition between reference material and test sample is needed for accurate calibration.

Commutability assessment is always required when adherence to a particular documentary standard requires commutability assessment. For example, compliance with ISO 15194 will usually require commutability assessment.

For which methods and samples?

A commutability assessment, if required, should study:

representative (typical and extreme) samples intended to be measured by a procedure (which may be a routine procedure or a “transfer” procedure designed to characterise secondary RMs) and the reference material(s) used to calibrate that procedure,
the response of the reference material(s) and representative test materials to both the routine (or transfer) procedure and the reference method used to assign values to the reference material(s).

The relationship between these sets of responses gives an indication of the commutability of the material.

For which part of the measurement process?

Commutability of reference materials needs to be assessed for the part of the procedure in which the CRM is intended to be used.

If the reference material is only to be used for the calibration of the final measurement step, and not for the extraction, other separation or sample pre-treatment steps, then it is evident that the commutability of the reference material need only be assessed in comparison to the routine samples as they occur after the preliminary steps of the procedures to be assessed, i.e. at the start of the measurement step. It may not be necessary to assess the commutability, if there are good reasons to assume that the calibration solutions prepared from the reference material are behaving analytically equivalent with the samples measured.

In some circumstances, particularly in the case of immunoassay methods, the measurement step is not preceded by and separated from sample pre-treatments or extractions. This is the case if methods are capable of measuring directly in the matrix and are sufficiently robust to cope with matrix variations found in routine samples. In these circumstances the best available calibration strategy may be the use of a suitably matched calibration material containing a known amount of the species of interest, in the particular form to which the proposed routine measurement method responds.

Such matrix reference materials are usually different from routine samples in several aspects (e.g. storage, stabilising agents). Therefore the commutability of such matrix material should be assessed for the methods for which they are intended to be used.

Where the method for the property value assignment of the calibration material differs from the measurement method to be calibrated by the material, it is usually also important to establish that the signals from the proposed routine method and the signals from the value assignment method show at least a consistent (although not always linear) mathematical relationship under changes in the level of the species of interest. Also here a commutability assessment is necessary prior to the use of the material for calibration.

Who should do the assessment?

Formally, the choice of calibration material and the verification that it is suitable for its purpose is the responsibility of the laboratory undertaking a particular measurement. However, where the reference material producer warrants that a reference material is appropriate for a particular intended use which requires a commutable material, the reference material producer is required to undertake an assessment of commutability. This requirement is, amongst others, laid down in ISO 15194.

Exceptions

There are circumstances in which commutability assessment is either unnecessary or impossible.

For example:

For materials certified for a parameter that is fully structurally defined, for example, lead ions in water, it is trivial that the material is commutable for methods that indeed measure the analyte as defined.
It is not possible to assess commutability if only one method exists for the quantity intended to be measured. This is the case if the measurand is defined by an internationally recognised measurement procedure, or if at the current stage only one method exists.
A reference material produced for validation of a wide range of measurement methods may be intentionally poorly matched to provide an extreme challenge, allowing method developers to gain assurance of performance on extreme materials. Such a material should not be used as a calibrator, and commutability studies are not required.
Materials certified for purity do not normally require commutability assessment, though it may be important to show that the analyte is in a particular form (e.g. for proteins). However if calibration solutions are prepared from such a material the user should ascertain that the calibration solutions have the same analytical behaviour as routine sample within the analytical procedure. The evaluation of the commutability of such calibrators may be useful in this regard

Commutability statement

Where commutability information is required the reference material producer must provide sufficient information for the end user to judge whether the material is appropriate for the specified use without further qualification, or whether additional qualification by the end user is required before use. In particular, the certificate or associated documentation must make clear;

whether commutability studies have been carried out,
where a study has been carried out, for which particular measurement methods or classes of measurement methods the material has been shown to be commutable and any for which the material has been shown not to be commutable,
any differences between the reference material and routine test materials which are known to the reference material producer and which might reasonably reduce commutability for other test methods (specifically: any differences in the levels of known metabolites of the species of interest; differences in form or structure of the species of interest; differences in preparation of the reference material, including the presence of stabilisers etc.; differences in accessibility of the species of interest, in particular whether the species of interest is within or outside cell membranes in the reference material and in routine test materials).

This information should be available to the end user prior to purchase.

Summary

1. It is appropriate, as required by ISO 15194, for a reference material producer to conduct an assessment of commutability where;

The intended use requires commutability of calibration or quality control materials and,

the reference material producer warrants that the material is fit for the intended use.

Note: Demonstration of commutability is usually required when the intended use includes calibration or quality control in biological measurement, and is not usually required when the intended use does not include biological measurement and the procedure is known to be adequately specific for the measurand in the matrix of the reference material and the intended routine samples.

2. Where knowledge of commutability is important for the intended use, the producer should inform the purchaser of the material, via a statement on commutability, of any known factors related to commutability which materially affect the suitability of the material for calibration.

Status: March 2023

A copy of this position paper is available here.