FAQ

Our question is related to the interpretation of clause 7.6.3. Measurement Uncertainty, in particular with focus on NOTE 1.
Clause 7.6.3 NOTE 1 states “…where a well-recognized test method specifies limits to the values of the major sources of measurement uncertainty and specifies the form of presentation of the calculated results the laboratory is considered to have satisfied 7.6.3 by following the test method and reporting instructions.”
In Official Medicinal Control Laboratories (OMCL) most of the testing on medicines are carried out to verify the compliance with authorised specifications, laid down in Pharmacopoeias or in the approved Marketing Authorisation dossier of the manufacturer. Such testing is performed using well-established, fully validated test methods for which the uncertainty budget has been evaluated during method validation. Therefore, the method performance including accuracy (confidence interval and bias) and precision (as intermediate precision or reproducibility) is well-known and taken into account for setting the specification limits. The compatibility of the validation data with the proposed limits is assessed by the competent authorities during the approval of the Marketing Authorisation Dossier.
Regarding NOTE 1, compliance testing in OMCLs is performed using well-established test methods, which means compendial methods (elaborated by Group of Experts of the Pharmacopoeias and approved by the European Pharmacopoeia Commission) or methods developed and validated by the manufacturer and subsequently approved by the competent authorities. The test method (compendial method or manufacturer method) specifies all conditions and requirements for used equipment, consumables, reagents, reference standards etc., as well as the limits to the values of the major sources of measurement uncertainty (i.e. system suitability criteria) and the form of presentation of the calculated results. Additionally, the testing result is considered valid only after the repeatability is evaluated against pre-defined acceptance criteria (based on the method validation data).
Considering all the above, in our understanding the ISO/IEC 17025:2017 requirements for evaluation of measurement uncertainty (clause 7.6.3) are fulfilled for compliance testing, if the results are obtained by using well-recognized test methods (compendial method or method given by the manufacturer), provided that the described analytical procedure and reporting instructions are followed, and all uncertainty contributors are under control. This means that testing is performed by qualified personnel using suitable reference standards and calibrated/qualified equipment, system suitability criteria are fulfilled and the repeatability is evaluated against pre-defined acceptance criteria.
Consequently, according to NOTE 1, in case of compliance testing, it is considered that the OMCLs fulfil the clause 7.6.3. and are exempted from any request of evidences of systematic calculation of the measurement uncertainty, on the basis of the following elements:

1. Compliance testing is performed by following the test method and reporting instructions described in well-established methods, which have been validated by the manufacturer and subsequently approved by the competent authorities.
2. The applied test method specifies all conditions and requirements, as well as the limits to the values of the major sources of measurement uncertainty and the form of presentation of the results.
3. The validity of test result and control of uncertainty contributors are ensured by the OMCL via the fulfilment of the system suitability criteria and pre-defined repeatability acceptance criteria.

Glossary:
Compliance testing: tests performed, using well established official or validated analytical procedures to verify that a pharmaceutical substance or medicinal product examined conforms to the specification limits given in the monograph or in the marketing authorisation dossier.
Marketing Authorisation Dossier: the dossier for marketing authorisation (called Marketing Authorisation Application (MAA) in the European Union) contains all data for the registration of the pharmaceutical drug, proving that the candidate drug has quality, efficacy and safety properties suitable for the intended pharmaceutical use. During the Marketing authorisation process the evidence to support a medicinal product, in relation to its marketing, finalised by granting of a licence to be sold are reviewed and assessed. This process is performed within a legal framework defining the requirements necessary for successful application to the regulatory authority, details on the assessment procedure (based on quality, efficacy and safety criteria), and also the circumstances where a marketing authorisation already granted may be withdrawn, suspended or revoked.
System suitability criteria: performance limits designed to ensure the adequate performance of the analytical procedure. These criteria are to be fulfilled before proceeding to the analysis of the sample.

From ISO/IEC 17025:
7.6.3 A laboratory performing testing shall evaluate measurement uncertainty. Where the test method precludes rigorous evaluation of measurement uncertainty, an estimation shall be made based on an understanding of the theoretical principles or practical experience of the performance of the method.
NOTE 1 In those cases where a well-recognized test method specifies limits to the values of the major sources of measurement uncertainty and specifies the form of presentation of the calculated results, the laboratory is considered to have satisfied 7.6.3 by following the test method and reporting instructions.

According to the definition given in ISO/IEC Directives Part 2 §24, the Notes in a standards are used for giving additional information intended to assist the understanding or use of the text of the document; in fact the document shall be usable without the notes. Notes shall not include any requirements (shall) or any information con¬sidered indispensable for the use of the docu-ment, any recommendations (should) or any permissions (may).
Notes cannot overrule any requirement stated in the standard.

The approach explained in Note 1 is already reported in the GUM, focusing the attention on the case where a well-recognized test method is used and sources of uncertainty are minimized (by use e.g., of measuring instruments with maximum permissible errors within specified limits, environmental influences, such as temperature and relative humidity maintained within specified limits, well-documented control of laboratory procedures, and well-documented competency of measurement personnel).
By controlling those sources of variability within prescribed limits, the measurement uncertainty associated with a best estimate of the measurand is assumed to be negligible, is not explicitly evaluated, and plays no role in an accept/reject decision.
The main issue of the Note is then about the significance of MU with respect to decision rules, rather than the MU itself, as reported in the question that relates to compliance testing.

Even where conditions of Note 1 occur, the following shall be fulfilled in any case:

1. Even if it is deemed that the laboratory is not required to evaluate measurement uncertainty systematically (meaning for each measurement result), the laboratory shall in any case ensure that it can properly perform the methods, achieve and maintain the required performances (cl. 7.2.1.5 of ISO/IEC 17025).
2. Even if cl. 7.6.3 is considered satisfied, clause 7.6.1 is still a requirement to be fulfilled: the laboratory shall identify the contributions to measurement uncertainty with respect to its specificity because, although information on MU contributions are available in the test method (which specifies all conditions and requirements, as well as the limits to the values of the major sources of measurement uncertainty and the form of presentation of the results), there can be other sources of uncertainties due to laboratory specificity.
   These contributions, if existing, will need to be identified to demonstrate that the measurement uncertainty of the externally validated method, as applied by the laboratory, remains compatible with the objective of the method and in that case the laboratory cannot be exempted from the obligation to assess its measurement uncertainty.
3. Cl. 7.8.3.1.c of ISO/IEC 17025 is still a requirement to be fulfilled by the laboratory.
   MU shall be evaluated, because it shall be reported in the test report ,when:
   – it is relevant to the validity or application of the test results
   – a customer’s instruction so requires
   – the measurement uncertainty affects conformity to a specification limit.