ERMCRM Web site - Technical guidelines for the production and acceptance of a European Reference Material

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Technical guidelines for the production and acceptance of a European Reference Material

Every European Reference Material project must be executed in accordance with internationally accepted guidelines such as ISO-Guides 30-35 (and more particularly ISO Guide 34, specifying the general requirements for the competence of reference material producers), WHO Guidelines (for clinical reference materials), the ISO-Guide to the Expression of Uncertainty in Measurement (GUM), etc.

Details of the European Reference Material project planning related to selection of base material, technical aspects of the production process of the candidate material and its subsequent storage, homogeneity control, short- and long-term stability testing, characterisation of the batch, long-term storage and monitoring are described in a project planning form, to be submitted to and approved by the European Reference Materials panel within 6 weeks after receiving the complete documentation.


	European Reference Materials samples

European Reference Materials samples (bottles, vials, ampoules, etc.) must be tight and contain not less than the stated amount of material
Samples must have appropriate homogeneity and stability.
Whenever relevant (e.g., in case of clinical ERM-CRMs), the commutability of the European Reference Material has to be assured.
Packaging must be appropriate for the purpose.
Labelling must be clear and of good quality.

Usually, between bottle homogeneity must be examined. Exceptions can be made, when previous experience has shown that CRMs are prepared with negligible heterogeneity, such as for some solutions. However, even in such cases homogeneity testing is advisable to check for possible heterogeneity due to contamination.

Any possible between-bottle heterogeneity must be accounted for in the overall estimated CRM uncertainty. This requirement applies even when no statistically significant between-bottle variation is present. In this case the method variation or the actual calculated between-bottle variation (whichever is larger) should be included in the overall uncertainty.

Whenever relevant, long-term stability must be positively demonstrated by appropriate statistical extrapolation for the certified European Reference Material's shelf-life to be within the certified uncertainty; the uncertainty related to this demonstration is normally part of the estimated CRM uncertainty.
Exceptions can be made, when previous experience has shown that the uncertainty of stability is negligible. In such cases the uncertainty contribution of long-term stability is set zero. In all other cases this parameter is determined from regression analysis of the results of the long-term stability study.
Whenever possible, stability studies should be carried out using isochronous measurements.

When a quantity that is not method dependant is certified, batch characterisation can be carried out

on hand of a primary method of measurement by a primary/definitive method of measurement
or by laboratory intercomparison, using, whenever possible, two or more independent analytical methods.

When a method dependant quantity is certified by laboratory intercomparison, all laboratories must strictly comply with the imposed standard operating procedure.

have the required competence for the execution of the task in the European Reference Material project,
be able to achieve traceability to the required stated references,
be able to estimate its measurement uncertainty in accordance with GUM,
have in place a sufficient and appropriate quality assurance system.

Whenever possible, standard uncertainties of bacth-characterisation (uchar) by both primary methods of measurement or laboratory intercomparisons should be based on the combination of detailed uncertainty budgets of the contributing values.
If insufficient information is available for values based on laboratory intercomparisons, uchar can, in the absence of uncertainties common to all participants (e.g., common standard), also be approximated by the standard deviation of the mean of laboratory means.
be able to estimate its measurement uncertainty in accordance with GUM,
If such common uncertainties are present, they have to be added to the uncertainty of the mean of laboratory means.


	Establishment of a certificate

The European Reference Material-Project Manager establishes a draft certificate (possibly complemented by a certification report) in accordance with ISO Guide 30, containing all information relevant to and needed by the user.
Certified values must be traceable to stated references and be accompanied by a GUM-compatible expanded uncertainty statement valid for the entire shelf-life of the European Reference Material.
After approval by the European Reference Materials panel, the certificate and report are made available, both on the European Reference Materials-web site and in printed form, and the European Reference Material is put on sale.


	Transfer of samples to final storage place

To avoid degradation after certification, all samples are best transported to the location which offers the conditions designated for the final storage of the European Reference Material before measurements are started.
Otherwise, they must be transported from door to door keeping them at all times under such storage conditions for which it has been demonstrated that there is no influence on the certified values.