ISO/FDIS 33407

ISO/FDIS 33407:2023(E)
ISO/TC 334
Date: 2023-06-23
Secretariat: SABS
Date: 2023-08-22
Guidance for the production of pure organic substance certified
reference materials
Recommandations pour la production des matériaux de référence certifiés pour des substances organiques
pures
FDIS stage
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ISO/FDIS 33407:2023(E)
© ISO 2023
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Published in Switzerland
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ISO/FDIS 33407:2023(E)
Contents
Foreword . v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Technical and production requirements . 2
4.1 General . 2
4.2 Production planning . 2
4.3 Specification of the CRM and its measurand . 2
4.3.1 General . 2
4.3.2 Specification of purpose . 2
4.3.3 Specification of the measurand . 3
4.3.4 Definition of the metrological reference . 3
4.3.5 Fitness for purpose . 3
4.3.6 Safety considerations . 3
4.3.7 Resources and approaches to purity analysis . 4
4.4 Candidate material sourcing and assessment of suitability, including verification of PC identity and
adequate purity . 4
4.4.1 Material sourcing . 4
4.4.2 Verification of PC identity . 4
4.4.3 Material suitability . 5
4.5 Product packaging and specification of conditions for storage and safe handling . 5
4.5.1 General considerations . 5
4.5.2 Selection and treatment of packaging materials . 6
4.5.3 Storage and transportation issues . 6
4.5.4 Label of containers . 7
4.6 Determination of approaches to purity assessment of the CRM . 7
4.7 Development and validation of procedures for characterization, including achieving target
measurement uncertainty . 8
4.7.1 General . 8
4.7.2 Multiple methods for purity determination . 9
4.7.3 Property value boundaries . 9
4.8 Assessment of homogeneity . 9
4.8.1 General . 9
4.8.2 Preliminary assessment of homogeneity . 9
4.8.3 Sampling strategy . 10
4.8.4 Minimum sample size . 10
4.8.5 Experimental method of homogeneity assessment . 10
4.9 Assessment and monitoring of stability . 10
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ISO/FDIS 33407:2023(E)
4.9.1 General . 10
4.9.2 Sources of instability . 10
4.9.3 Repeated use stability . 11
4.9.4 Stability monitoring . 11
4.10 Characterization of the CRM . 11
4.10.1 General . 11
4.10.2 Direct determination . 11
4.10.3 Indirect determination . 12
4.10.4 Characterization for use in multi-component solutions . 12
4.11 Metrological traceability of the certified property value . 12
4.12 Preparation of certificates . 12
Annex A (informative) Examples of structure identification approaches . 14
Annex B (informative) Examples of measurement procedures for assessment of purity . 16
Annex C (informative) Examples of production of pure substance organic certified reference materials
by reference material producers . 20
Bibliography . 40

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ISO/FDIS 33407:2023(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO
collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documentsdocument should be noted. This document was drafted in accordance
with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawnISO draws attention to the possibility that some of the elementsimplementation of this
document may beinvolve the subjectuse of (a) patent(s). ISO takes no position concerning the evidence,
validity or applicability of any claimed patent rights in respect thereof. As of the date of publication of
this document, ISO had not received notice of (a) patent(s) which may be required to implement this
document. However, implementers are cautioned that this may not represent the latest information,
which may be obtained from the patent database available at www.iso.org/patents. ISO shall not be held
responsible for identifying any or all such patent rights. Details of any patent rights identified during the
development of the document will be in the Introduction and/or on the ISO list of patent declarations
received (see ).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the World
Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 334, Reference materials.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
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ISO/FDIS 33407:2023(E)
Introduction
Reference materials (RMs) play an important role in measurement processes and support sound, widely
recognized measurement systems. ISO 17034 specifies general requirements to be met by reference
material producers (RMPs), including for the production of certified reference materials (CRMs). CRMs
play a key role in ensuring that measurements are comparable across time and space and are used by
laboratories to establish metrological traceability of their measurement results to appropriate
references.
This document outlines recommendations, which conform to general requirements of ISO 17034, for
production of pure organic substance CRMs used to calibrate measuring instruments. These materials
primarily comprise organic chemicals of specified, determinable structure. Guidance provided for
characterization of pure organic chemical materials is also appropriate for those used to prepare pure
organic substance solution CRMs. This document provides guidance on key aspects of the production of
such CRMs, including the assessment of homogeneity and stability. Recommended approaches for
characterization and assignment of certified purity values are described.
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ISO/FDIS 33407:2023(E)
Guidance for the production of pure organic substance certified
reference materials
1 Scope
This document notes the requirements of ISO 17034, and provides specific guidance on technical
considerations for the production of pure organic substance certified reference materials (CRMs) that are
used by laboratories to calibrate measurement equipment and procedures and to establish metrological
traceability of the respective results. The guidance is relevant only to CRMs comprising organic
compounds whose structures are specifically defined, where polymeric materials are not included.
In this document, reference to a CRM is limited to pure organic substance certified reference materials,
including candidate materials, unless otherwise noted.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 9000, Quality management systems — Fundamentals and vocabulary
ISO/IEC 17000, Conformity assessment — Vocabulary and general principles
ISO 17034, General requirements for the competence of reference material producers
ISO Guide 30, Reference materials — Selected terms and definitions
ISO/IEC Guide 99, International vocabulary of metrology — Basic and general concepts and associated
terms (VIM)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 9000, ISO/IEC 17000,
ISO Guide 30, and ISO/IEC Guide 99, ISO 9000 and the following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— — ISO Online browsing platform: available at https://www.iso.org/obp
— — IEC Electropedia: available at https://www.electropedia.org/
3.1
primary component
PC
principal chemical species of interest in the certified reference material
Note 1 to entry: A perfectly pure material is only an ideal concept because chemical species other than the PC will
always exist in a material, even in very small amounts.
3.2
purity
quantity ratio of the primary component in the certified reference material
Note 1 to entry: Purity is usually expressed as the mass fraction fof the PC.
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ISO/FDIS 33407:2023(E)
Note 2 to entry: Purity is ideally close to 1, but it can be considerably lower than 1.
4 Technical and production requirements
4.1 General
The production of a CRM requires diligent planning. The requirements can be found in ISO 17034, and
[1 [1]]1
recommendations can be found in ISO 33405. . Central to this effort is clear specification of the
intended uses of the CRM and characterization appropriate for these purposes. The following subclauses
provide an overview of considerations relevant to the production of CRMs.
4.2 Production planning
The production of a CRM includes the following steps:
a) a) specification of the CRM and its measurand;
b) b) candidate material sourcing and assessment of suitability, including verification of PC identity
and adequate purity;
c) c) product packaging and specification of conditions for storage and safe handling;
d) d) determination of approaches to purity assessment of the CRM;
e) e) development and validation of procedures to achieve target measurement uncertainty;
f) f) assessment of homogeneity;
g) g) assessment and monitoring of stability;
h) h) characterization of the CRM;
i) i) consideration of metrological traceability of the certified property value;
j) j) preparation of certificates.
4.3 Specification of the CRM and its measurand
4.3.1 General
The intended use and relevant properties of the CRM should be clearly specified at the outset of the
production process. This can include, but is not limited to, measurement procedures or type of measuring
systems for which it is intended to be used, properties to be characterized, target purity, appropriate
metrological reference of the certified value and target measurement uncertainty. Special attention is
needed for these topics, as described in the following subclauses.
4.3.2 Specification of purpose
It is important to consider the intended use of the CRM because it can affect various aspects of the CRM
production process, including the verification of the suitability of the sourced material. Pure substances
constitute the source of primary measurement standards and higher-order metrological traceability in
most traceability chains in chemistry. The demand for such a CRM is usually recognized through
engagement with the intended user community. The measurement needs that are commonly served
include improved accuracy of relevant measurement procedures, establishment of metrological
traceability and regulatory compliance for chemical testing laboratories.

1
 Under preparation. Stage at the time of publication: ISO/DIS 33405:2023.
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ISO/FDIS 33407:2023(E)
Such CRMs are typically used for the calibration of measuring instruments and measurement systems. An
impurity in a CRM can create interferences in a measurement,; while the presence of such interferences
would not generally invalidate the certified purity value of the CRM, it can render the CRM suboptimal
for some measurement methods. When a CRM is intended to be used for preparing a multiple-component
calibration solution, it should be characterisedcharacterized to account for all relevant chemical entities
because an impurity in the CRM can be the PC of another material intended to be mixed, leading to biases
in certified values derived from the preparation process of the multi-component calibration solution.
Quantities of all compounds of interest in each of these materials, present as either a PC or impurities,
should be evaluated during the purity assessment. The decision on which quantities are significant
depends on the targets for production of the CRM and the producer should define them as part of the
specification for the material. An example of quantities which need to be considered is the amount of
substance that can interfere with the PCs (of the CRMs used to prepare a multiple-component calibration
solution CRM) in a measurement method that is expected to be used.
CRMs can also be used in chemical identification and validation of procedures for elemental analysis.
4.3.3 Specification of the measurand
A clear and unambiguous specification of the measurand is key to the production planning. The certified
purity value of a CRM is usually expressed as the mass fraction, amount-of-substance fraction or amount
content of a structurally specified chemical or set of chemicals within the material. The measurand
requires specification of the organic chemical structure(s), including the assigned stereochemistry, when
applicable, and the relevant units for expressing composition.
4.3.4 Definition of the metrological reference
ISO 17034 requires the metrological traceability of certified values to be established for CRMs such a way
[2 [2]]
that in accordance with ISO/IEC 17025. .
The appropriate metrological reference system is principally dependent upon the purpose of the CRM
and the measurement community it is intended to serve. The SI, a coherent system widely used in
commerce and science, is the most appropriate system of units for most chemical measurements. The
certified purity value of a CRM is ideally obtained by, but not limited to, the practical realization of SI
measurement units.
For certified values of nominal properties, traceability to appropriate chemical references should be
carefully considered for each case. Some CRMs have certified values for chemical identity. Valid evidence
linking this characterization to the chemical structure of the PC should be provided.
4.3.5 Fitness for purpose
Fitness for purpose of a measurement is the extent to which the measurement result meets the stated
requirement for which the measurements are being made. Formal definitions can be found in various
sources, such as Reference [11[11].]. For the CRM to be fit for purpose, the uncertainty in the delivered
certified value should be small enough to be useful. For example, it is not appropriate to use a CRM of
certified purity with 10 % relative standard uncertainty for calibrating procedures that aim to produce
results with 1 % relative standard uncertainty.
NOTE 1 A measured property value without associated uncertainty does not conform to the definition for the
certified value of a CRM specified in ISO 17034.
NOTE 2 Some pure organic substance RMs and their intended use are covered by other standards, e.g.,for
example pharmacopoeia assay standards, and uncertainties in property values are not typically specified. Rather,
they are treated as negligible in relation to the defined limits of the method-specific assays for which they are used.
4.3.6 Safety considerations
In regard to the workplace health and safety considerations, the reference material producer (RMP)
should conduct a risk assessment, which can be replaced by the RMP’s pre-established standard safety
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procedures, to establish that appropriate facilities and safeguards are in place to handle the candidate
material.
4.3.7 Resources and approaches to purity analysis
Considerations for resource requirements are described in ISO 17034. CRM characterization should be
fit for purpose and achievable with available laboratory resources, including labour, packaging materials
and candidate materials. Allocation of these resources and anticipated cost recovery through CRM
distribution are key considerations that govern the practicality of CRM production. Costs largely depend
upon the rigour of analytical methods selected for characterization. For the CRMs, purity determination
can be accomplished through either one or a combination of several basic approaches described in
4.64.6.
The target measurement uncertainty should be considered prior to attempting
[12],[13 [12],[13]]
characterization. . Use of two or more independent methods with different principles can
evaluate possible systematic errors. Analyst expertise and preliminary experiments conducted for
method development can generally inform realistic expectations of measurement uncertainty for specific
measurement techniques and assist with experimental design for CRM characterization using either
approach to purity analysis.
Statistical methods can also be employed to estimate optimal experiment design for a given set of
[14 [14]]
constraints, including the target measurement uncertainty. . This experimental design should take
into account sampling that is required to adequately assess homogeneity across the entire lot of candidate
[1 [1]]
CRM. . As such, the number of units in the production lot should be known prior to development of
methods for CRM characterization.
4.4 Candidate material sourcing and assessment of suitability, including verification of
PC identity and adequate purity
4.4.1 Material sourcing
Candidate materials can be sourced commercially, through custom synthesis or from refinement of
materials. Factors that should be considered in screening such materials include affordability, purity,
homogeneity, and stability.
Impurities can have a significant effect on the long-term stability of the material as well as on the accuracy
of complex purity analyses. The RMP can conduct further purification of the sourced material when a
sufficiently pure material cannot be sourced. The RMP should consider the advantages of purification
against the recovery of PC during the process and any other potential changes to material composition of
the sourced of material during this process.
When the candidate material is sourced as a coarse powder or pellets, the RMP can grind and sieve the
bulk material to produce a fine powder that is more suitable for its intended use, for example one that
should be sufficiently homogenous for a small minimum sample size. Moreover, a more homogeneous
particle size distribution is less prone to spatial stratification during packaging and transportation. When
solid-state properties are relevant for a particular certification study, i.e. when the RMP intends to
characterize the crystalline composition of the material or when these properties substantially affect the
handling of the powder (e.g. hygroscopicity, electrostatic effects, dissolution rate or flow behaviour), the
RMP can carry out preliminary tests with the candidate material to evaluate its suitability. When the RMP
decides to purify the candidate material using processes such as recrystallization or drying, an interval
of time before packaging the candidate batch can be useful to allow the stabilization of the moisture
content of the bulk material and avoid future stability issues with water mass fraction.
4.4.2 Verification of PC identity
The identity of the PC is critical for any chemical CRM. ISO 17034 requires the RMP to address the
verification of the identity of the PC. In addition to verifying chemical bond connectivity between atoms,
knowledge of the geometric arrangement of the PC can be critical for the intended use of the CRM.
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Techniques executed to identify chemical components of the CRM should promote confident distinction
of the PC from other inherent substances, especially those of similar structure.
The identity of the PC can be specified as a single precise organic chemical structure or as a closely related
group of molecular entities. This structural specification should be governed by the intended use of the
CRM to ensure that the measurand comprises only those chemical entities relevant for the intended use.
For example, when only the L arrangement of a chiral compound is biologically active, this quantity in a
CRM should be specifically known, exclusive of the quantity of the compound having the D arrangement.
Conversely, less specificity can define a measurand that includes related entities with slightly different
structures, yet with similar or effectively the same properties, for example when the L and D
arrangements serve the same purpose.
Specification of the measurand can consider the distinction of entities within the following classes of
related chemical structures:
a) a) constitutional isomers – compounds with the same molecular formula, but different chemical
bonding between atoms;
b) b) stereoisomers – compounds with the same molecular formula and bonding between atoms, but
different three-dimensional spatial orientation of atoms within the molecule.
Tautomer and conformer structures of the PC should be considered if they are observed during candidate
material characterization. When appropriate,
...