Reference Material Commutability: 2 Lab Methods Using IFCC and ISO
Commutability is the property of a reference material that shows whether it behaves like a genuine clinical sample across two or more measurement procedures. If you intend to use a reference material as a calibrator, a trueness control, or an external quality assessment (EQA) sample, we recommend assessing commutability using the established IFCC, NIST, and ISO procedures described below, applying either the difference-in-bias or the prediction-interval approach.
TL;DR:
- Calibrators, trueness controls, and EQA samples need assessment; pure substance materials used only to prepare solutions for one defined procedure usually do not.
- Select clinical samples across relevant concentrations, prequalify procedures for precision and selectivity, and plan sample counts with replicates because both affect uncertainty.
- Use difference in bias for pairwise method comparisons; choose prediction intervals for EQA materials tested across many IVD methods, especially when nonselectivity differences are acceptable.
- Set criterion C using medically relevant differences; a result is indeterminate when the uncertainty interval crosses its boundary, often because the study lacks precision.
- If a material fails for particular procedures, investigate calibration, interference, and handling before rejecting it, then limit its stated use and document the restriction.
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- 1. Formal definitions and when commutability applies
- 2. Why noncommutable materials create real risk
- 3. Standards and guidance documents to consult
- 4. Design parameters to set before you measure
- 5. How the two main statistical approaches work
- 6. A practical workflow for running an assessment
- 7. Interpreting results: commutable, noncommutable, or indeterminate
- 8. Publisher background and further technical resources
- Where labs underestimate the work involved
- Ordering research-grade materials with documentation support
- FAQ
- Sources
1. Formal definitions and when commutability applies
The IUPAC gold book defines commutability through the closeness of agreement between the relationship of results for a reference material and the relationship for routine clinical samples, when both are measured by different procedures. That definition matters because commutability is never a fixed property of a material; it depends on which measurement procedures are being compared and on the calibration hierarchy those procedures sit within.
Not every reference material needs this scrutiny. We find it useful to separate the categories:
- Calibrators and trueness controls that transfer values across methods typically require commutability assessment.
- EQA materials that compare clinical laboratories against each other or against a reference method also require it.
- Pure substance certified reference materials used only to prepare calibration solutions in a single, well-defined procedure often fall outside this requirement.
Producers generally carry the obligation to assess and declare commutability, while laboratories verify it holds for the specific procedures they run.
2. Why noncommutable materials create real risk
A noncommutable material can pass a calibration check on one analyzer and fail silently on another, because its matrix does not respond to the assay the way a patient sample does. That mismatch breaks the calibration hierarchy that ISO 17511 relies on to keep results traceable across instruments and sites.
A reference material is only as useful as its match to patient samples. The IFCC working group recommends judging commutability against medically relevant differences rather than arbitrary statistical thresholds, precisely because the clinical stakes of a mismatch (misclassified EQA performance, disagreeing patient results between methods) are what the assessment is meant to prevent.
When an EQA scheme uses a noncommutable sample, a laboratory can appear biased when its method is actually sound, or vice versa. The error does not stay theoretical: it propagates into decisions about which analyzer to trust for a given patient result.
3. Standards and guidance documents to consult
Several documents work together rather than competing, and each covers a different stage of a commutability study.
- IFCC Part 1 lays out the experimental design essentials: sample selection, replicate structure, and qualifying measurement procedures (MPs).
- IFCC Part 2 supplies the difference-in-bias statistical procedure, defining the commutability measure dRM and its expanded uncertainty U(dRM).
- IFCC Part 3 extends the approach to calibration-based assessments where a reference measurement procedure anchors the comparison.
- NIST provides recommendations for setting a criterion and assessing commutability for EQA materials, favouring prediction-interval criteria that account for nonselectivity differences between in vitro diagnostic (IVD) methods.
- ISO guidance, including the ISO-TC334 position paper, clarifies when ISO 15194 requires an assessment and what producers must document in certificates, tying back to the ISO 17511 traceability framework.
Together, these documents cover design, statistics, and documentation, so a lab rarely needs to look beyond them for a defensible study.
4. Design parameters to set before you measure
A commutability study lives or dies on its design choices, made before any sample touches an analyzer.
- Select clinical samples (CSs) that span the full concentration range relevant to clinical decision points, since a narrow range weakens the conclusions you can draw.
- Prequalify candidate MPs for acceptable precision and selectivity before including them in the comparison.
- Decide on replicate counts and sample numbers together, since both drive the uncertainty of the final estimate.
- Randomize run order and block by day or analyst to reduce systematic bias in the measurements.
A worked allocation from the IFCC supplemental materials illustrates one workable design with a substantial number of clinical samples, replicates, measurement procedures, and candidate reference materials, structured to let investigators separate uncertainty contributions by source.
Pro Tip:Run a small pilot with a handful of clinical samples before committing to the full design; it often reveals a prequalification problem with an MP before you’ve spent replicates on it.
5. How the two main statistical approaches work
Labs generally choose between two approaches, and the choice depends on what the material will be used for.
- The prediction-interval (regression) approach builds a prediction interval from clinical sample data and checks whether the candidate reference material falls inside it; its width depends heavily on MP precision, so a noisy method can mask real noncommutability.
- The difference-in-bias approach (IFCC Part 2) computes dRM, the difference in bias between a candidate MP and a comparator for the reference material relative to clinical samples, along with its expanded uncertainty U(dRM).
The commutability criterion C anchors the judgment either way. A recommended design target is that U(dRM) should stay below half of C, since that margin is what allows a decisive rather than ambiguous conclusion.
The difference-in-bias method tends to suit pairwise MP comparisons well, and it scales reasonably when several MPs need checking against a single reference procedure. The prediction-interval approach, favoured in NIST’s EQA guidance, fits situations where a sample material must satisfy many IVD methods simultaneously and some acceptable nonselectivity difference between them is expected from the outset.
6. A practical workflow for running an assessment
Most studies follow the same sequence, whether they are run by a producer or verified independently by a laboratory.
- Define the intended use of the material and select a commutability criterion C tied to a medically relevant difference, often expressed as a maximum allowable noncommutability bias (MANCB).
- Select and prequalify your clinical samples and candidate measurement procedures.
- Implement the measurement plan with planned replicates, blocking, and randomized run order.
- Compute the biases, the commutability measure dRM, and its expanded uncertainty U(dRM) for each MP pair.
- Compare dRM ± U(dRM) against C for each pairwise or reference-measurement-procedure comparison.
- Document the outcome and, when appropriate, record a commutability statement in the material’s certificate, following the documentation guidance in ISO’s position paper.
A lab evaluating a supplied reference material rather than producing one can shorten this to steps 1, 2, 5, and 6, relying on the producer’s own study data where it is available and sufficiently documented.
7. Interpreting results: commutable, noncommutable, or indeterminate
The decision rule is straightforward once dRM and U(dRM) are in hand.
- If dRM ± U(dRM) falls entirely within ±C, the material is judged commutable for that MP pair.
- If it falls entirely outside ±C, the material is noncommutable for that pair.
- If the interval straddles the boundary, the result is indeterminate, usually because U(dRM) is too wide relative to C.
When U(dRM) exceeds half of C, consider that your design, not necessarily the material, may be the limiting factor. Investigate MP calibration, possible interferences, or sample-handling issues before concluding a material is unsuitable, since noncommutability often traces back to method or design artifacts rather than the material itself. Where a material proves noncommutable for specific MPs, restrict its stated use accordingly and record that limitation plainly in the certificate.
8. Publisher background and further technical resources
We write from a laboratory supply perspective, working alongside researchers who order research-grade reference materials and need batch-specific documentation to support their own qualification work. Our technical posts on reference material traceability and certification cover the documentation practices this article describes, for teams building out their own assessment files.
Where labs underestimate the work involved
The most common pitfall we see is an underpowered design: too few replicates, clinical samples clustered at one concentration, or candidate MPs that were never properly prequalified before the study began. Commutability assessment deserves the most attention for calibrators and EQA materials specifically, and we think producers should include a plain commutability statement whenever a material is marketed for either use, rather than leaving labs to infer it.
— Deek
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If your commutability study needs custom dosage formulations or additional documentation beyond a standard COA, contact us before ordering to discuss your requirements. Browse our research-grade product catalogue to see current tablet and powder options and request the paperwork your study requires.
FAQ
What is an example of a reference material?
A certified pure substance used to prepare calibration solutions, a matrix-based calibrator for an immunoassay, and an external quality assessment sample sent to multiple laboratories are all reference materials. Each serves a different purpose, and only some, such as calibrators and EQA samples, typically require a commutability assessment.
What is commutability?
Commutability is the property of a reference material demonstrated by the closeness of agreement between its measurement results and those of routine clinical samples, when both are tested by different measurement procedures, as defined in the IUPAC gold book. A material can be commutable for some method pairs and noncommutable for others, so the assessment is always specific to the procedures being compared.
What is the difference between an SRM and a CRM in chemistry?
A certified reference material (CRM) is any material with one or more property values certified by a documented, metrologically valid procedure, while a standard reference material (SRM) is a specific brand of CRM issued by NIST. Both carry certified values, but SRM refers to NIST’s particular program rather than a distinct technical category.
What does “reference material” mean?
A reference material is a material sufficiently homogeneous and stable with respect to one or more specified properties, used for calibrating equipment, assessing a measurement method, or assigning values to other materials. Whether it needs a commutability assessment depends on its intended use, particularly if it will serve as a calibrator or an EQA sample.
Sources
- IFCC Working Group recommendations for assessing commutability, Part 2 (PMC5835923)
- NIST recommendations for setting a criterion and assessing commutability of sample materials used in EQA
- IUPAC gold book: commutability of a reference material (08064)
- ISO position paper on commutability of reference materials (ISO-TC334, 2023)
