ISO Guide 35:2017
Reference materials — Guidance for characterization and assessment of homogeneity and stability
ISO/Guide 35:2017 explains concepts and provides approaches to the following aspects of the production of reference materials:
- the assessment of homogeneity;
- the assessment of stability and the management of the risks associated with possible stability issues related to the properties of interest;
- the characterization and value assignment of properties of a reference material;
- the evaluation of uncertainty for certified values;
- the establishment of the metrological traceability of certified property values.
The guidance given supports the implementation of ISO 17034. Other approaches may also be used as long as the requirements of ISO 17034 are fulfilled.
Brief guidance on the need for commutability assessment (6.11) is given in this document, but no technical details are provided. A brief introduction for the characterization of qualitative properties (9.6 to 9.10) is provided together with brief guidance on sampling such materials for homogeneity tests (Clause 7). However, statistical methods for the assessment of the homogeneity and stability of reference materials for qualitative properties are not covered. This document is also not applicable to multivariate quantities, such as spectral data.
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Foreword
Introduction
1 Scope
2 Normative references
3 Terms and definitions
4 Symbols
5 Conventions
6 An overview of reference material production
6.1 General
6.2 Summary of project design
6.3 Acquisition of starting material
6.4 Feasibility studies
6.5 Reference material processing
6.6 Homogeneity assessment
6.7 Stability assessment
6.8 Choice of measurement procedures
6.9 Metrological traceability
6.10 Characterization and uncertainty evaluation
6.11 Commutability assessment
6.12 Transport issues
6.13 Value assignment
6.14 Stability monitoring
6.15 Reference materials produced in repeated batches
7 Assessment of homogeneity
7.1 Preamble
7.2 Need for an experimental homogeneity study
7.3 Properties to be studied
7.4 Statistically valid sampling schemes
7.4.1 Minimum number of units for a homogeneity study
7.4.2 Use of statistical power analysis
7.4.3 Sampling strategy for a homogeneity study
7.5 Choice and conduct of the measurement procedure for a homogeneity study
7.5.1 Choice of measurement procedure
7.5.2 Conduct of measurements for homogeneity studies
7.6 Homogeneity study designs
7.6.1 Objective of a homogeneity study
7.6.2 The basic homogeneity study design – measurement in a single run
7.6.3 Randomized block design
7.6.4 Balanced nested design
7.6.5 Alternative strategies
7.7 Evaluating a homogeneity study
7.7.1 Initial inspection for measurement trends and outliers
7.7.2 Inspection for processing trends
7.7.3 Evaluation of the between-unit term – basic design
7.7.4 Evaluation of the between-unit term – randomized block design
7.7.5 Evaluation of the between-unit term – balanced nested design
7.7.6 Other homogeneity designs and alternative estimation methods
7.8 Insufficient repeatability of the measurement procedure
7.9 Within-unit homogeneity
7.9.1 Assessing the need for within-unit homogeneity study
7.9.2 Testing for significant within-unit heterogeneity
7.9.3 Assessing minimum sample size
7.10 Check for sufficient homogeneity
7.11 Uncertainty evaluation from homogeneity studies
8 Assessment and monitoring of stability
8.1 Preamble
8.2 Assessment of stability
8.2.1 Requirement for stability assessment
8.2.2 Types of (in)stability
8.2.3 General methods for assessment of stability
8.2.4 Need for experimental study of stability
8.3 Classification of stability studies
8.3.1 General
8.3.2 Classification according to conditions of measurement
8.3.3 Classification according to stability study duration and conditions
8.3.4 Classification by study objective
8.3.5 Designs for different storage and treatment conditions
8.4 General requirements for effective stability studies
8.4.1 Overview of requirements
8.4.2 Selection of units
8.4.3 Suitable measurement procedure(s) for stability studies
8.4.4 Appropriate experimental design
8.5 Evaluation of stability study results
8.5.1 General considerations for stability study data treatment
8.5.2 The basic stability study: multiple points in time at a single storage condition
8.5.3 Isochronous designs
8.5.4 Accelerated stability studies with multiple exposure conditions
8.5.5 Additional sources of random variation in stability studies
8.6 Action on finding of a significant trend in a stability study
8.7 Uncertainty evaluation from stability studies
8.7.1 General considerations for uncertainty evaluation from stability studies
8.7.2 Sources of uncertainty in predicted change over time
8.7.3 Estimation of stability uncertainties in the absence of significant trends
8.7.4 Evaluation of stability uncertainties in the case of a known significant trend
8.8 Estimation of storage lifetime (“shelf life”) from a stability study
8.9 Instructions for use related to management of stability
8.10 Stability monitoring
8.10.1 Requirements for monitoring
8.10.2 Choice of initial monitoring point and monitoring interval(s)
8.10.3 Experimental approaches and evaluation for stability monitoring
9 Characterization of the material
9.1 Preamble
9.2 Establishing metrological traceability
9.2.1 Principle
9.2.2 Metrological references
9.2.3 Types of measurands
9.2.4 Effect of sample preparation or pre-treatment
9.2.5 Verification of traceability
9.3 Characterization using a single reference measurement procedure (as defined in ISO/IEC Guide 99) in a single laboratory
9.3.1 Characterization by a reference measurement procedure without direct comparison with a CRM of the same kind
9.3.2 Characterization by value transfer from a reference material to a closely matched candidate reference material using a single measurement procedure performed by one laboratory
9.3.3 Selection of RM units for single-laboratory characterization
9.3.4 Formulation methods
9.4 Characterization of a non-operationally defined measurand using two or more methods of demonstrable accuracy in one or more competent laboratories
9.4.1 Concept
9.4.2 Study design
9.4.3 Evaluation
9.4.4 Single-laboratory multi-method studies
9.5 Characterization of an operationally defined measurand using a network of competent laboratories
9.5.1 Concept
9.5.2 Study setup
9.5.3 Evaluation
9.6 Purity
9.6.1 General
9.6.2 Direct determination of purity
9.6.3 Indirect determination of purity
9.7 Identity
9.7.1 Materials certified based on provenance
9.7.2 Materials certified for identity based on measurements
9.8 Presence/absence
9.9 Ordinal scales
9.10 Qualitative properties
9.11 Characterization of non-certified values
10 Evaluating measurement uncertainty
10.1 Basis for evaluating the uncertainty of a property value of a CRM
10.2 Basic model for a batch characterization
10.3 Uncertainty sources
10.4 Coverage intervals and factors
Annex A (informative) Design and evaluation of studies for the characterization of a method-independent measurand using two or more methods of demonstrable accuracy in one or more competent laboratories
Annex B (informative) Statistical approaches
Annex C (informative) Examples
Annex D (informative) Measurement uncertainty evaluation
Bibliography
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Foreword
Introduction
1 Scope
2 Normative references
3 Terms and definitions
4 Symbols
5 Conventions
6 An overview of reference material production
6.1 General
6.2 Summary of project design
6.3 Acquisition of starting material
6.4 Feasibility studies
6.5 Reference material processing
6.6 Homogeneity assessment
6.7 Stability assessment
6.8 Choice of measurement procedures
6.9 Metrological traceability
6.10 Characterization and uncertainty evaluation
6.11 Commutability assessment
6.12 Transport issues
6.13 Value assignment
6.14 Stability monitoring
6.15 Reference materials produced in repeated batches
7 Assessment of homogeneity
7.1 Preamble
7.2 Need for an experimental homogeneity study
7.3 Properties to be studied
7.4 Statistically valid sampling schemes
7.4.1 Minimum number of units for a homogeneity study
7.4.2 Use of statistical power analysis
7.4.3 Sampling strategy for a homogeneity study
7.5 Choice and conduct of the measurement procedure for a homogeneity study
7.5.1 Choice of measurement procedure
7.5.2 Conduct of measurements for homogeneity studies
7.6 Homogeneity study designs
7.6.1 Objective of a homogeneity study
7.6.2 The basic homogeneity study design – measurement in a single run
7.6.3 Randomized block design
7.6.4 Balanced nested design
7.6.5 Alternative strategies
7.7 Evaluating a homogeneity study
7.7.1 Initial inspection for measurement trends and outliers
7.7.2 Inspection for processing trends
7.7.3 Evaluation of the between-unit term – basic design
7.7.4 Evaluation of the between-unit term – randomized block design
7.7.5 Evaluation of the between-unit term – balanced nested design
7.7.6 Other homogeneity designs and alternative estimation methods
7.8 Insufficient repeatability of the measurement procedure
7.9 Within-unit homogeneity
7.9.1 Assessing the need for within-unit homogeneity study
7.9.2 Testing for significant within-unit heterogeneity
7.9.3 Assessing minimum sample size
7.10 Check for sufficient homogeneity
7.11 Uncertainty evaluation from homogeneity studies
8 Assessment and monitoring of stability
8.1 Preamble
8.2 Assessment of stability
8.2.1 Requirement for stability assessment
8.2.2 Types of (in)stability
8.2.3 General methods for assessment of stability
8.2.4 Need for experimental study of stability
8.3 Classification of stability studies
8.3.1 General
8.3.2 Classification according to conditions of measurement
8.3.3 Classification according to stability study duration and conditions
8.3.4 Classification by study objective
8.3.5 Designs for different storage and treatment conditions
8.4 General requirements for effective stability studies
8.4.1 Overview of requirements
8.4.2 Selection of units
8.4.3 Suitable measurement procedure(s) for stability studies
8.4.4 Appropriate experimental design
8.5 Evaluation of stability study results
8.5.1 General considerations for stability study data treatment
8.5.2 The basic stability study: multiple points in time at a single storage condition
8.5.3 Isochronous designs
8.5.4 Accelerated stability studies with multiple exposure conditions
8.5.5 Additional sources of random variation in stability studies
8.6 Action on finding of a significant trend in a stability study
8.7 Uncertainty evaluation from stability studies
8.7.1 General considerations for uncertainty evaluation from stability studies
8.7.2 Sources of uncertainty in predicted change over time
8.7.3 Estimation of stability uncertainties in the absence of significant trends
8.7.4 Evaluation of stability uncertainties in the case of a known significant trend
8.8 Estimation of storage lifetime (“shelf life”) from a stability study
8.9 Instructions for use related to management of stability
8.10 Stability monitoring
8.10.1 Requirements for monitoring
8.10.2 Choice of initial monitoring point and monitoring interval(s)
8.10.3 Experimental approaches and evaluation for stability monitoring
9 Characterization of the material
9.1 Preamble
9.2 Establishing metrological traceability
9.2.1 Principle
9.2.2 Metrological references
9.2.3 Types of measurands
9.2.4 Effect of sample preparation or pre-treatment
9.2.5 Verification of traceability
9.3 Characterization using a single reference measurement procedure (as defined in ISO/IEC Guide 99) in a single laboratory
9.3.1 Characterization by a reference measurement procedure without direct comparison with a CRM of the same kind
9.3.2 Characterization by value transfer from a reference material to a closely matched candidate reference material using a single measurement procedure performed by one laboratory
9.3.3 Selection of RM units for single-laboratory characterization
9.3.4 Formulation methods
9.4 Characterization of a non-operationally defined measurand using two or more methods of demonstrable accuracy in one or more competent laboratories
9.4.1 Concept
9.4.2 Study design
9.4.3 Evaluation
9.4.4 Single-laboratory multi-method studies
9.5 Characterization of an operationally defined measurand using a network of competent laboratories
9.5.1 Concept
9.5.2 Study setup
9.5.3 Evaluation
9.6 Purity
9.6.1 General
9.6.2 Direct determination of purity
9.6.3 Indirect determination of purity
9.7 Identity
9.7.1 Materials certified based on provenance
9.7.2 Materials certified for identity based on measurements
9.8 Presence/absence
9.9 Ordinal scales
9.10 Qualitative properties
9.11 Characterization of non-certified values
10 Evaluating measurement uncertainty
10.1 Basis for evaluating the uncertainty of a property value of a CRM
10.2 Basic model for a batch characterization
10.3 Uncertainty sources
10.4 Coverage intervals and factors
Annex A (informative) Design and evaluation of studies for the characterization of a method-independent measurand using two or more methods of demonstrable accuracy in one or more competent laboratories
Annex B (informative) Statistical approaches
Annex C (informative) Examples
Annex D (informative) Measurement uncertainty evaluation
Bibliography