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CCQM Strategy Document for Rolling Programme Development Date drafted: 21 February 2017 (Revised 27/06/17, 07/09/17 & 15/01/18) Period covered: 2017-2026 Table of Contents CCQM Strategy Document for Rolling Programme Development..................................................................... 1 1. General Information on Consultative Committee: ....................................................................................... 2 2. Terms of Reference of the CCQM ................................................................................................................. 2 3. Progressing the State of the Art for Chemical and Biological Measurement Science .................................... 5

3.1 A forum for exchange of information on technical activities ....................................................... 5 3.1.1 Activities prior to 2017 .......................................................................................................... 5 3.1.2 Forward Scan 2017-2026....................................................................................................... 6

3.2 Research and Development activities stimulated by comparisons .............................................. 6 3.2.1 Activities prior to 2017 .......................................................................................................... 6

3.3 Documenting comparability of novel measurement capabilities and standards ......................... 8 3.3.1 Forward Scan 2017-2026: New analytes to be investigated ................................................. 8 3.3.2 Forward Scan 2017-2026: Areas to be covered by CCQM pilot studies (Track D comparisons) .................................................................................................................................. 9

3.4 The redefinition of the mole and the other SI units ................................................................... 11 4. Reaching out to new and established stakeholders ................................................................................... 13

4.1 Activities prior to 2017 ............................................................................................................... 13 4.2 Forward Scan 2017-2026 ............................................................................................................ 13

5. Demonstrating the global comparability of chemical and biological measurement standards ................... 15 5.1 CCQM Achievements (2012-2016) ............................................................................................. 15

5.1.1 Related RMO activities since 2012 ...................................................................................... 17 5.2 Changes in needs and issues arising in the period 2012-2016 ................................................... 19

5.2.1 The CIPM MRA review ......................................................................................................... 19 5.2.2 Core comparisons and capabilities and broad scope CMCs ................................................ 20 5.2.3 Addressing new emerging fields/needs .............................................................................. 24 5.2.4 Advising on the BIPM work programme in Metrology in Chemistry .................................. 27

5.3 Future Scan (2017-2026) ............................................................................................................ 28 5.3.1 More efficient and effective underpinning of CMCs ........................................................... 28 5.3.2 Support for NMIs to meet new measurement requirements in sectors ............................ 28 5.3.3 Links with RMO activities .................................................................................................... 30

5.4 Rationale for measurement standard global comparability activities (2017-2026)................... 32 5.4.1 An effective and efficient programme of comparisons to support current capabilities .... 32 5.4.2 Organizational aspects ........................................................................................................ 34

5.5 Required Key comparisons and pilot studies 2017-2026 with indicative repeat frequency ...... 34 5.6 Resource implications for laboratories for piloting comparisons .............................................. 35 5.7 Summary table of comparisons, dates, required resources and the laboratories already having institutional agreement to pilot particular comparisons ................................................................. 37

6. Document Revision Schedule ..................................................................................................................... 37 References ..................................................................................................................................................... 38 Appendix I :BIPM Laboratory activities as part of the CCQM Strategic Plan ................................................... 40 Appendix II: Examples of the impact of CCQM Comparisons and the calibration and measurement capabilities they support (2012-2016) ............................................................................................................ 42

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1. General Information on Consultative Committee: CC Name: CCQM Date Established: 1993 Number of Members: 25 members; 10 Observers; 6 Liaisons Number of Working Groups: 12 Number of Participants at last meeting: 71 Number of Institutes participating in CCQM WGs: 56 Periodicity between Meetings: 1 year Date of last meeting: 21-22 April 2016 CC President: Dr Willie E May, NIST, from 01/01/2013 Number of KCs organized (from 1999 up to and including 2016): 172 Key comparisons Number of Pilot studies organized (from 1999 up to and including 2016): 134 stand-alone pilot studies Number of CMCs published in KCDB supported by CC body activities (up to and including 2016): 6227

2. Terms of Reference of the CCQM The CCQM is responsible for developing, improving and documenting the equivalence of national standards (certified reference materials and reference methods) for chemical and biological measurements. It strives to progress the state of the art of chemical and biological measurement science and to work with global stakeholders to promote and increase the impact of metrology in chemistry and biology. It advises the CIPM on matters related to chemical and biological measurements including advice on the BIPM scientific programme activities. The objectives of the CCQM are:

a. to progress the state of the art of chemical and biological measurement science (including contributing to the establishment of a globally recognized system of national measurement standards, methods and facilities for chemical and biological measurements; and acting as a forum for the exchange of information about the research and measurement service delivery programmes and other technical activities of the CC members and observers, thereby creating new opportunities for collaboration)

b. to reach out to new and established stakeholders (facilitating dialogues between the NMIs and global stakeholders in order to define new possibilities for metrology in chemistry and biology to deliver impact)

c. to demonstrate the global comparability of chemical and biological measurements (through promoting traceability to the SI, and where traceability to the SI is not yet feasible, to other internationally agreed references; contributing to the implementation and maintenance of the CIPM MRA with respect to chemical and biological measurements; reviewing and advising the CIPM on the uncertainties of the BIPM's calibration and measurement services as published on the BIPM website)

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CCQM Working group Date

Established Technical area covered

Organic Analysis Working Group (OAWG)

1997 "higher order" measurement procedures for well-defined organic molecular entities for which the SI traceable amount of substance is to be determined (“Organic molecular entities” are taken to exclude gaseous compounds, organometallic compounds, and large bio-molecules); also covering high-priority method-dependent analyses/measures, on a selective basis.

Gas Analysis Working Group (GAWG)

1997 gas composition (including binary and multicomponent mixtures); gas/liquid mixture composition; nanoparticle and aerosol concentration; isotope ratio measurement; concentration of dissolved gases in liquid or solid matrices; also covering dynamic dilution techniques for unstable gases, as well as spectroscopic techniques with the potential to be used as primary methods.

Inorganic Analysis Working Group (IAWG)

1997 amount of substance fraction or mass fraction measurements of the elements, their isotopes and isotope ratios (absolute or relative), cations and anions, inorganic compounds and organo-metallic compounds in matrices which include pure materials, calibration solutions and complex samples such as those used for matrix reference materials.

Electrochemical and Classical Analysis Methods Working Group (EAWG)

2017 (1998)

pH, electrolytic conductivity measurements, coulometry and classical measurement methods

Key Comparison and CMC quality Working Group (KCWG)

2000 As described in the section 10 of the CIPM document “Calibration and Measurement Capabilities (CMCs) in the context of the MRA” (CIPM MRA-D-04). Responsibilities for overseeing the review of CMCs, defining specific technical review criteria, coordinating the inter-regional review process, providing guidance on the range of CMCs supported by specific comparisons, identifying where comparisons are needed and coordinating the review of existing CMCs in the context of new information.

Surface Analysis Working Group (SAWG)

2004 Spatially resolved chemical surface measurements at the micro and nanoscale

Nucleic Acid Analysis Working Group (NAWG)

2015 Nucleic acid analysis: Including, but not limited to, chromosomes, DNA, nucleotides, oligonucleotides, modified DNA (e.g. DNA methylation and other epigenetic modifications), mRNA, miRNA (and other short non-coding RNAs) in a biological measurement context; NA measurement includes, but is not limited to, the identification and quantification of nucleic acids in complex matrices (such as those derived from plant, animal and microbial origins)

Protein Analysis Working Group (PAWG)

2015 Proteins and Peptides

Cell Analysis Working Group (CAWG)

2015 Includes, but is not limited to, the identification and quantification of intact cells and cell properties indicative of function as a result of emergent behavior in complex matrices and mixtures.

Ad hoc Working Group on the Mole

2007 Responsibilities: (1) to draft a set of "mise-en-pratiques" for the realization of the mole; (2) to create awareness with respect to a possible redefinition of the mole, explain reasons and prepare opinions for discussion in the CCQM. (3) to interact with and respond to CCU in matters related to the definition of units (4) to interact with and respond to external stakeholders such as IUPAC on matters related to the redefinition of the mole

Strategic Planning Working Group (SPWG)

2012 Chaired by the CCQM President with membership composed of the CCQM WG Chairs, RMO Metrology in Chemistry Technical Committee Chairs and the CCQM Executive Secretary, responsibilities are: (1) to draft and update the CCQM Strategic Planning Document , with input from the CCQM WGs and RMO TCs in Metrology in Chemistry, for review, comment and approval by the CCQM; (2) to develop and advisory opinion on the BIPM programme in Metrology in Chemistry for comment, review by the CCQM.

Ad hoc WG on KCDB 2.0 2016 Responsibilities are to: 1) Propose the data fields that an NMI/DI shall be required to complete in submitting a CMC claim via the KCDB 2. 0 web platform 2) Propose what information/document/tools shall be provided to reviewers via the KCDB 2.0 web platform 3) Propose the format and content of CMC information that should be available to customers via the KCDB 2.0 website

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Table 1: Description of technical areas covered/responsibilities of the CCQM WGs In order to carry out its responsibilities, the CCQM has currently ten standing working groups and two ad-hoc working groups. The standing working groups (with the exception of the KCWG and the SPWG) all have the following common responsibilities:

a) To carry out Key Comparisons, and where necessary pilot studies, to critically evaluate and benchmark NMI/DI competences for measurement standards and capabilities in their technical area; providing demonstrable evidence of the validity and international equivalence of NMI/DI measurement services offered to customers.

b) To identify and carry out inter-laboratory work and pilot studies required to underpin the development of reference measurement systems in their technical field, of the highest possible metrological order with traceability to the SI, where feasible, or to other internationally agreed units, to support NMI/DI measurement services being developed in response to customer needs.

c) To act as a forum for the exchange of information about the research and measurement service delivery programmes and other technical activities of the WG members and thereby creating new opportunities for collaboration.

d) to provide input into the development of a CCQM strategic plan and develop and maintain a work plan consistent with the strategic plan adopted by the CCQM;

e) to interface with other CCQM WGs and international stakeholder organizations working on measurement issues related to those covered by the working group;

f) to support the RMOs in the critical evaluation of calibration and measurement capabilities of NMIs to be entered into Appendix C of the CIPM-MRA.

Table 1 lists the technical areas and responsibilities of the various CCQM Working Groups.

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3. Progressing the State of the Art for Chemical and Biological Measurement Science Regular review and revision of the scope of activities of the CCQM has permitted the Committee to address novel and state of the art Chemical and Biological Measurement Science issues. Recent changes in the working group structure, both in terms of Working Groups and Task Groups, of the CCQM have been focused on measurements science issues in: Protein, Nucleic Acid and Cell Analysis (since 2015); Isotope ratio measurements and standards (since 2017); Carbon Black, particulate and ozone measurements (since 2015); Electrochemical and Classical Chemical Measurements (since 2017).

3.1 A forum for exchange of information on technical activities

3.1.1 Activities prior to 2017 In the last four year period the CCQM WGs have organized sixteen workshops with the goal of exchanging information on research and development activities in chemical and biological measurement science and standards being undertaken by NMIs across a range of sectors. These are summarized in Table 2. In addition to this, a number of CCQM WGs regularly devote parts of their biannual meetings for NMIs to make technical presentations on research and development activities going on in their laboratories, with activities that have been either been prioritized at national or regional levels.

Year Technical Activity Addressed Organizing WG(s) 2012 Challenges in Food Safety and Biopharmaceutical testing OAWG/BAWG 2012 SI traceable elemental calibration IAWG 2012 Mass Spectrometry and Molecular Structure Research for

Reference Material Development OAWG/BAWG

2013 Carbon dioxide and methane isotope ratio gas standards GAWG 2013 Biochemical Measurement Research: Challenges and New

Developments OAWG/BAWG

2014 New measurement challenges in gas analysis GAWG 2014 Impact of Chemical Analysis and Reference Materials in Food IAWG/OAWG/BAWG 2015 Particulates in air GAWG 2015 Protein Purity BAWG/OAWG 2015 Bioimaging IAWG 2016 Standards and Measurements for Clean Air GAWG 2016 Cutting edge research for Gas Metrology GAWG 2016 Organic purity measurement uncertainties OAWG 2016 Emerging Measurement Technologies for certification of

Reference Materials IAWG

2017 Techniques for measurement of nanoparticle number concentration in colloidal suspensions

SAWG/IAWG

2017 Cell Quantitation – Emerging Methods and Comparison for Microbial Systems

CAWG

Table 2: Information exchange forums organized by CCQM

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3.1.2 Forward Scan 2017-2026 CCQM will continue to provide a forum for information exchange on leading edge measurement research activities. Mechanisms for achieving this include: a) Technical presentations as part of the CCQM WG activities b) Focused workshops on cutting edge measurement science research within the CCQM WGs c) Sector specific workshops organized by the CCQM d) Support of workshops with RMOs, NMIs and Stakeholders (e.g. Protein and Peptide Therapeutics and Diagnostics PPTD-2018, organized with BIPM, NIM and JCTLM)

3.2 Research and Development activities stimulated by comparisons

3.2.1 Activities prior to 2017 Research and development activities have been stimulated by comparisons either in the preparation phase, frequently by the coordinating laboratory in developing and characterizing appropriate samples to demonstrate the compatibility of measurement capabilities, or subsequent to comparisons where methods and capabilities have been developed to reduce measurement uncertainties. Examples from the 2012-2016 period include: CCQM-K129 (Copper Indium Gallium (di)Selenide (CIGS) thin layer composition) , with publications (Metrologia [1], 2012) describing novel methods for quantifying quaternary thin film composition by secondary ion mass spectrometry using a total number counting method. BIPM.QM-K1 (Ozone), with publications (in Atmospheric Measurement Techniques [2], 2015 and Analytical Chemistry [3], 2016) providing new measurements of ozone absorption cross sections in the UV by independent methods and with the smallest reported uncertainties to date for accurate measurements of ozone in the atmosphere. CCQM-K120.a,b (Carbon dioxide in air) , with publications (in Analytical Chemistry [4], 2017) describing novel calibration methods and standards for carbon and oxygen isotope ratio measurements of CO2 in air, and enabling accurate corrections to CO2 in air concentration measurements with laser based instrumentation. CCQM-K115 series (Peptide primary reference material purity), with publications on methods for characterization of ever more complex peptides with high resolution mass spectrometry (in Rapid Comm. Mass Spectrom.[5], 2015) and ion mobility mass spectrometry (in Anal. Bioanal. Chem. [6], 2017) CCQM-K55 series (Organic small molecule primary reference material purity), with publications on mass balance methods for reference material value assignment (in Analytical Chemistry [7], 2013 and in Talanta [8], 2014) CCQM-K101 (Oxygen in nitrogen) addressing Ar impurity problems in oxygen mesaurements, with publications (in Metrologia [9], 2017) to support the CCT thermal study by providing the argon-in-oxygen primary mixtures to reduce uncertainty by the effect of argon impurity on the triple point of oxygen. CCQM-K83 (halocarbons in air at ambient levels), with publications (in Elementa: Science of the Anthropocene [10], 2015) describing agreement among four independent calibration scales from institutes related to WMO global atmosphere watch.

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CCQM-K67 with its parallel Pilot Study CCQM-P108 on the composition of binary alloy thin films a new method for energy dispersive electron probe microanalysis (ED-EPMA) for a traceable determination of elemental composition and thickness of Fe-Ni alloy films was developed. (Surface and Interface Analysis [11], 2012) CCQM-P37.2 (International Comparison on Ag/AgCl electrodes for pH Measurement) studied factors that influence Ag-AgCl electrode performance and repeatability and provided insights on variability of the electrode potentials (in Measurement [12], 2015) CCQM-P142 (Equivalence of conductance ratio measurement results of seawater) and CCQM-K105 (Electrolytic conductivity at 5.3 S·m-1) provided background information contributing to the review paper dealing with definition and measurement of salinity, which is a key variable in the modelling and observation of ocean circulation and ocean-atmosphere fluxes of heat and water. (in Metrologia [13], 2016) CCQM-P154 (Absolute quantification of DNA) with publications identifying the major sources of measurement uncertainty for digital PCR and establishment of this technology as a primary method for DNA quantification (in Analytical Chemistry [14], 2016)

CCQM-K98 and CCQM-K122; with a publication describing the characterization of a new candidate isotopic reference material for natural Pb using primary measurement method (in Anal. Chim. Acta, [15], 2017)

CCQM-K140; with a publication on the determination of stable carbon absolute isotope ratios in a glycine candidate reference material by elemental analyser-isotope ratio mass spectrometry (in Anal Bioanal Chem,[16] 2015) Dunn P., Malinovsky D. and Goenaga-Infante H., Anal Bioanal Chem, 2015, 407, 3169-3180.

CCQM-P160; with publications on accurate determination of the isotopic composition and molar mass of a new Avogadro-crystal to enable the determination of NA in support of the redefinition of the SI units (in Metrologia [17], 2017)

CCQM-K72; with publications on the use of glow discharge mass spectrometry as a potentially primary method for the assignment of purity to primary metal calibrants (in Metrologia [18], 2014), and the use of Instrumental Neutron Activation Analysis to investigate the distribution of trace elements among subsamples of solid materials (in Metrologia [19], 2014); G D'Agostino, L Bergamaschi, L Giordani, M Oddone, H Kipphardt and S Richter; (2014) Metrologia, 51, 48-53).

CCQM-K103; with a publication on the determination of the purity of avermectins by High Performance Liquid Chromatography - Quantitative Nuclear Magnetic Resonance (HPLC-qNMR) (in Analytical Methods, [20] 2016 and Talanta, [21] 2017 CCQM-K126; with a publication on the simple and accurate measurement of carbamazepine in surface water by use of porous membrane-protected micro-solid-phase extraction coupled with isotope dilution mass spectrometry in Analytica Chimica Acta, [22] 2016 CCQM-K95.1; with a publication on optimisation of extraction methods and quantification of benzo[a]pyrene and benz[a]anthracene in yerba maté tea by isotope dilution mass spectrometry in Analytical and Bioanalytical Chemistry, [23]

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CCQM-K119 (liquefied Petroleum Gas), with a publication (in Analytical Chemistry [24], 2017) describing a novel leak-free constant pressure cylinder for primary reference materials of liquid hydrocarbon mixtures and with reducing uncertainties in primary (or certified) reference materials. CCQM-K94 (dimethyl sulfide), with a publication (in Talanta [25], 2016) providing a new dynamic dilution method to generate SI-traceable dimethyl sulfide at ambient levels (down to sub nmol/mol) and with the reported uncertainties much less than WMO-GAW DQO.

3.3 Documenting comparability of novel measurement capabilities and standards

3.3.1 Forward Scan 2017-2026: New analytes to be investigated The range and complexity of analytes covered by the CCQM is expected to expand, and this will require technological developments including:

a) Metrological traceability for measurements of new and more complex analytes

The development of SI traceable reference systems, including primary calibrators where applicable, was highlighted by many institutes as a priority for organic and inorganic analysis and bio-analysis.

Many groups within NMIs/DIs are also working on larger molecules of biological significance, including whole cells and complex cell systems, and this will lead to more closely coordinated activities amongst a number of WGs.

Primary calibrator materials, including isotopic reference materials, be they of organic, inorganic or biological nature, are crucial for the traceability of routine measurement results. Therefore, they are a priority area; however only a limited number of NMIs currently have programmes in this area.

b) Continued development of an international metrological infrastructure for 'biological' measurements

A lack of higher order reference methods and materials is a major hindrance for deriving traceability and comparability in biomeasurement, and this impacts upon accreditation and regulatory compliance. The need to underpin higher order measurement capabilities is a central driver for the activities of the NAWG, PAWG and CAWG.

Areas which are expected to develop and lead to measurement services from NMIs which will be compared in the future CCQM programme will include:

• Synthetic biology relevant biological components • miRNA and other short /non-coding nucleic acid measurement • Quantification of nucleic acid, including DNA and RNA (for gene expression • GMO determination, gene expression and quantitation of mutation, including single

nucleotide variants. • Nucleic acid sequencing including high throughput next generation sequencing

(NGS) • Quantification of post-translational modification / epigenetics, particularly

methylation

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• Regulation of gene editing (CRISPR) requiring measurement of very low copy number ratios for mutations or variants in relation to wild-type sequence, down to 10-8 or 10-9 for clinical and other applications.

• Quantification of microbial and mammalian cells in complex matrices (including 3D matrix materials),

• Quantitation of cells as a function of behavior in complex biological systems (e.g. microbiome and the immune system),

• Regenerative medicine and associated gene editing for therapeutic cell line production,

• Enhanced requirements for protein and cell / interactional and structural analysis; • Development of analytical approaches for the characterization of more complex

proteins and DNA modifications, the properties of which are not easily expressed in SI units, but which still involve metrological principles;

• Support for the validation of highly multiplexed measurements, including the provision of traceability for ‘horizontal’ (performance) standards;

• Increasingly multivariate nature of diagnostics – key comparisons to support ‘panel’ biomarker measurements, also comparisons which bring together different biomolecular measurements (e.g. DNA/protein protein/cell markers);

• Cell counting and quantitation, including identification and counting of cells in particular states (e.g. viability, toxicity, proliferation, apoptosis) and function;

• Assessing and meeting comparability where requirements for eukaryotic cell line reference materials which may include quantification of blood cells (erythrocytes, leukocytes, thrombocytes) in a blood matrix;

• Assessing and meeting comparability where requirements for prokaryotic reference materials are identified to underpin services for water and food safety;

• Cell viability and toxicology measurements • Nano particle interaction with cells • Discoveries from proteomics and requirements for characterized peptides and

proteins. • Measurement capability for low level proteins in complex matrices • Detection of novel trace level protein biomarkers in serum • Characterization of biological drugs including monoclonal antibodies and biosimilars

and other cell-based therapeutics, • Antibody drugs have become the major success in the domain of biological drugs. • Sophisticated protein analysis in food sector related to food adulteration and

authenticity

3.3.2 Forward Scan 2017-2026: Areas to be covered by CCQM pilot studies (Track D comparisons) CCQM pilot studies (also referred to as Track D comparisons in a number of CCQM WGs) are coordinated for activities such as the development of metrology in new application areas, investigation of emerging techniques, and to facilitate collaboration with other expert laboratories outside the CIPM-MRA. The largest number of pilot studies relative to key comparisons is foreseen in areas where the further development of a metrological infrastructure is required, notably for SAWG, NAWG, CAWG and PAWG. In the area of surface chemical analysis at the nano and micro scale, studies to develop the traceability and comparability of quantitative data will be required for:

• methods of surface chemical analysis at the micro scale (e.g. EPMA, EDS, WDS, AES)

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• measurements of amount of matter in a shell for a core-shell engineered nanoparticle (e.g. by XPS, AES, TEM)

• measurements of the amount of matter in a buried organic layer (e.g. by SIMS, XPS, XRR, NR, ellipsometry)

• measurements of composition and spatial distribution of matter for functionalized nanomaterials (e.g. by DLS, XPS, SPM, TEM).

• measurements of composition and spatial distribution of matter for thin film systems (e.g. by XPS, EPMA, XRD, XRR, CRM, AEM)

• determining the accuracy and comparability of nanoscale 3D chemical imaging methods (e.g. SIMS, tomographic methods using X-rays or atom probe techniques)

• quantification of both inorganic and organic contaminants on silicon surfaces measurement of concentrations of active proteins at surfaces (e.g. by SIMS, fluorescence microscopy, non-linear optical microscopy).

• Quantitative measurements with 3D Raman Microscopy Studies required in the gas metrology field will follow the research and development activities carried out by various NMI’s, including

• Particle and aerosol measurements • Quantification of black carbon • Spectroscopic methods for trace gas quantification • Quantification of isotopolgues in the gas phase

Key areas of inorganic metrology that will require further development will include:

• Providing key comparisons to underpin metrological services at ultra-low analyte levels, which present major technical challenges, not least storage and transport of reference materials and comparison samples;

• Determination of more complex and/or labile inorganic or organo-metallic species, which will require further extensive development of hyphenated methods, coupling separation science with spectroscopic or other measurement techniques;

• Matrix specific isotope ratio measurement standards or reference materials, particularly for application areas such as geology, forensics, food adulteration or origin and environmental studies. This will require programmes in the area of Delta values (C, H, O, N) and for absolute metal or other non-metal isotope ratios determined by techniques such as TIMS or ICP-MS.

• Developing techniques such as LC-ICP-MS for quantitation of metal- and heteroatom-containing proteins, including P-, S- or Fe-based protein quantification.

• Characterization and amount of substance measurements of nanoparticles, including single particle counting and number concentration.

• Solid sampling for quantitative analysis and/or quantitative elemental imaging including techniques such as GD-MS and laser ablation ICP-MS.

Key areas of cell analysis metrology that will require further development will include: • Providing pilot and key comparisons to underpin metrological services including calibration

using flow cytometry to quantify cells and cell biomarker expression. • Underpinning current reference value assignments for both prokaryotic and eukaryotic cell

quantitation such as complete blood count, adherent cells on 2D supports, concentration of biomarker expression in therapeutic relevant cell lines, antimicrobial susceptibility, yeast and bacterial reference materials.

• Identification of higher order measurements to underpin eukaryotic reference material production capabilities including viable count on 2D and 3D extracellular matrices, concentration of blood cells in a matrix, concentration of blood cells in blood matrix, concentration of cell surface properties.

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• Identification of higher order measurements to underpin prokaryotic reference material production capabilities including viable count on 2D and 3D extracellular matrices, pathogens in water and food matrices, biodegradation/biocorrosion potential of complex microbial communities.

• Exploration of appropriate cell analogs to be used as calibrants and for instrument performance evaluation (e.g. peptide or lipid micro-shells and microspheres).

Once the foundation of higher order measurement capabilities and reference methods are established, more metrology to underpin more complex systems can be developed. These systems include cell-cell interactions, emergent behavior and cell functional behavior as a result of environmental conditions. In the organic analysis field, Track D comparisons will be used in new and emerging areas where further investigation of specific techniques/methods is warranted. For instance, quantitative NMR is a technique which is being implemented in an ever-growing number of laboratories as a high-accuracy reference measurement procedure. The OAWG envisage coordinating only a limited number of these types of comparisons. In the field of electrochemical analysis future studies will be required for the investigation of measurement standards and reference methods for:

• mixed solvent/low conductivity and pH measurement standards; • measurement standards relevant for sea water salinity and pH • characterization of Li-ion batteries

3.4 The redefinition of the mole and the other SI units The CCQM activities related to the redefinition of the SI units, have been led by the CCQM ad hoc WG on the mole, that has drafted a mise-en-pratique for the mole. A CCQM workshop on the redefinition of the mole and the draft mise-en-pratique was held on 20 April 2014, including presentations from the IUPAC Analytical Division and CIAAW, including the announcement of an IUPAC Project: ‘A critical review of the proposed definitions of fundamental chemical quantities and their impact on chemical communities’. A symposium on the mole was held as part of the ACS meeting in Boston in August 2015, in order to further publicise the changes being proposed. In 2016 the results of a survey, with national science and chemistry academies, that constituted part of the IUPAC project became available. Unfortunately, no clear pattern had emerged from the survey. Equal numbers of responders had either liked or did not like the old definition of the mole. The same was true for the new definition. The IUPAC Technical Report which has undergone a scientific review process was published in Pure and Applied Chemistry (DOI:10.1515/pac-2016-0808) in February 2017. The Technical Report presents an overall positive appreciation of the redefinition of the mole, based on a specified number of entities (typically atoms or molecules) that will not depend on the unit of mass, the kilogram. Proposals on the exact wording of the redefinition have been submitted by IUPAC to the CCQM, which has incorporated these in its recommendation to the CCU. The activities of CCQM, including the extended consultation with the international chemical community, are expected to lead to a definition of the mole, and by consequence the quantity of amount of substance, that will be better understood by the scientific community at large, whilst ensuring that the accuracy of chemical measurements are maintained and no step function change in measurement will occur as a result of redefinition. The CCQM has contributed to the CCU WG on Angles and dimensionless quantities in the SI, due the increasing importance of counting methods (enumeration) especially in biological measurements,

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and specifically how to deal with the unit 1 for counting within the SI. As a result, the draft 9th edition of the SI brochure includes additional text on how to deal with such issues, notably:

• ‘There are also quantities that cannot be described in terms of the seven base quantities of the SI at all, but have the nature of a count. Examples are a number of molecules, a number of cellular or biomolecular entities (e.g. copies of a particular nucleic acid sequence), or degeneracy in quantum mechanics. Counting quantities are also quantities with the associated unit one’.

• ‘The unit one is the neutral element of any system of units – necessarily and present automatically. There is no requirement to introduce it formally by decision. Therefore, a formal traceability to the SI can be established through appropriate, validated measurement procedures’.

• ‘It is especially important to have a clear description of any quantity with unit one that is expressed as a ratio of quantities of the same kind (length ratios, amount fractions, etc.) or as a count (number of photons, decays, etc.)’.

• ‘Quantities that are ratios of quantities of the same kind (length ratios, amount fractions, etc.) have the option to be expressed with units (m/m, mol/mol) to aid the understanding of the quantity being expressed and also allow the use of SI prefixes, if this is desirable (μm/m, nmol/mol). Quantities relating to counting do not have this option, they are just numbers’.

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4. Reaching out to new and established stakeholders

4.1 Activities prior to 2017 The CCQM has a long history in the organization of workshops with stakeholder and sectorial groups in order to understand their requirement for accurate and traceable measurement results and guide the work of the CCQM working groups (including the fostering of new working groups as appropriate). Since 2004, 10 CCQM Stakeholder Workshops have been organized:

• CCQM Workshop on the Re-definition of the Mole (April 2012 and 2014) • CCQM Workshop on the Role for Reliable Traceable Microbiological Measurements to

Ensure Food Quality and Safety (6-7 April 2011) • CCQM Workshop on Forensics (12 April 2010) • CCQM Workshop on the Frontiers of Traceability in Chem/Bio Measurement (22 April 2009) • CCQM Pharma & Bio-pharma Workshop (4-5 December 2008) • CCQM Workshop on Gas metrology to support measurements of the atmosphere and of

ambient air quality (26 October 2007) • International Symposium on Certified Reference Materials for Quality of Life (1 November

2006) • CCQM Workshop on higher-order measurement methods for physiologically significant

molecules (13 April 2005) • Reference Measurement Systems for Food Analysis – CCQM Focus Group Meeting (13

September 2004) In addition, several BIPM organized workshops have provide further contact with stakeholders important to CCQM, notably:

• BIPM-IAEA Workshop on Carbon Dioxide and Methane Stable Isotope Gas Standards, June 2013

• BIPM Workshop on Global to Urban Scale Carbon Measurements, 30 June-1 July 2015 • BIPM-NIM workshop on Protein and Peptide Therapeutics and Diagnostics, 1-3 June 2016 • BIPM-WADA Symposium on Standards and Metrology in support of Anti-Doping, 28-29

September 2016

4.2 Forward Scan 2017-2026 For CCQM activities, the NMIs have the primary link to stakeholders as these are at the national level, and are responsible for influencing the development on national metrology programmes. Examples of these stakeholders are:

• National government departments or agencies, responsible for Environment, Justice and Forensics, Drugs and medical devices

• Transnational policy bodies such as the European Commission with its Metrology Research Programme, EMPIR, managed by EURAMET

• National and international standardisation and accreditation bodies such as ISO and ILAC • National and international trade or inspection organizations such as APEC • Industries across sectors such as food, environmental, energy, clinical, forensic and

pharmaceutical, semiconductor and nanotechnology

• National and international professional organisations such as IUPAC and IFCC • Field laboratories which are the ultimate end-users of the services such as microbiological

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testing laboratories and harmonization organizations that support them e.g. AOAC International

International stakeholders will continue to be invited to specialist workshops and when further collaboration is required, and invited to participate in meetings of the CCQM WGs (e.g., IAEA, WMO, WHO/NIBSC, national and regional Pharmacopeias, such as USP and EDQM) or the CCQM (e.g., IUPAC, WMO, WADA, Codex Alimentarius, WHO, IFCC, ENFSI, ISO/REMCO, ILAC, VAMAS). The Laboratory Medicine community is expected to remain a major stakeholder for the activities of NMIs and the CCQM, where the requirements for metrological traceability and their impact on consistency of diagnostic test results are well understood. The regulatory requirements within the field have continued to evolve (within the EU the IVD directive is being replaced a Regulation, requiring mandatory adoption within Member States) responding increased focus on risk management of IVD devices, and with continued requirements to demonstrate metrological traceability. The Joint Committee for Traceability in Laboratory Medicine continues to be well supported by NMIs, both in nominating reference materials and methods for publication in the JCTLM database, as well as scientists participating in review teams and evaluating nominations of reference material, methods and services. As of December 2016, the JCTLM Database contained: - 293 certified reference materials (CRMs) (The majority provided by NMIs/DIs active in the CIPM MRA) - 180 reference measurement methods covering 80 analytes, and - 146 reference measurement services covering 39 analytes. These services were delivered by 15 reference laboratories accredited for compliance against ISO 15195 and IEC/ISO 17025 as Calibration laboratories and by two National Metrology Institutes (NMIs).

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5. Demonstrating the global comparability of chemical and biological measurement standards

5.1 CCQM Achievements (2012-2016) At the end of the period 2012-2016, the NMIs participating in the CCQM have published 6227 calibration and measurement capabilities (CMCs) in the BIPM KCDB, an increase of 867 from the last reporting period of December 2012 (compared to the increase of 1286 CMCs in the 2008-2012 period). Figure 1 shows how the total number of published chemical and biological CMCs has evolved over the period 2000-2016. The decreased rate of growth in CMCs seems explainable by two effects: a moderate decrease in the number of new CMCs being claimed; a considerable decrease in the total number of CMCs held by a small number of major CMC holders. The change in the number of Chem-Bio CMCs published by different countries in the KCDB over the last 4-year period is illustrated in Figure 2.

Figure 1. Evolution of the total number of published Chemical and Biological CMCs in the BIPM KCDB (2000-2016) In order to underpin CMCs the CCQM has coordinated 43 Key comparisons and 14 stand-alone pilot studies over this period. The CCQM comparison programme has been supported by the BIPM Chemistry Department comparison coordination activities, which have been formulated and prioritized with the advice of the CCQM. During this period, the BIPM has coordinated 6 of these key comparisons, with 100 NMI participations in these.

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The number of comparisons run by the CCQM is less than estimated for this period in 2013, with 10% less key comparisons and 50% less pilot studies organized. This will be discussed further in section 5.5. The information for each one of the 15 Chemical and Biological CMC categories is summarized in Table 3. The numbers of countries providing CMCs for a specific CMC category ranges from 4 (for Surfaces, films and engineered nanomaterials) to 25 (for Food) to 32 (for Gases) as of December 2016. The largest increase in new countries claiming CMCs in the last 4 years has occurred in the following categories: Food (6); Metal and Metal Alloys (6); and Inorganic Solutions (5). The total number of NMIs/DIs providing Chemical and Biological CMCs is 61 (50 in 2012) from 48 different countries (39 in 2012).

Figure 2. Change in number of number of published Chemical and Biological CMCs in the BIPM KCDB (2013-2016) (For countries/economies that have published Chem-Bio CMCs) The development of reference measurement systems and CMCs for the Chemical and Biological fields has been driven by the increasing need for data of known quality for making decisions on high impact areas and sectors, such as Health, the Environment and Climate, Energy, Advanced Materials and the Food Safety.

Category

Number of CMCs published in the

KCDB in December 2008

Number of CMCs published in the

KCDB in December 2012

Number of CMCs published in the

KCDB in December 2016

Number of countries having declared CMCs in December 2008

Number of countries having declared CMCs in December 2012

Number of countries having declared CMCs in December 2016

1: High purity chemicals 263 445 656 11 15 172: Inorganic solutions 324 361 409 11 14 193: Organic solutions 351 473 498 12 14 164: Gases 1500 2039 2340 22 28 325: Water 132 160 224 13 17 206: pH 89 79 92 15 19 217: Electrolytic conductivity 27 38 45 11 14 158: Metal and metal alloys 276 194 226 6 7 139: Advanced materials 56 113 144 5 12 1410: Biological fluids and materials 316 382 399 12 15 1811: Food 241 426 502 14 19 2512: Fuels 47 54 61 5 6 1013: Sediments, soils, ores, and particulates 418 558 562 12 16 1614: Other materials 34 34 61 2 2 1115: Surfaces, films, and engineered nanomaterials 0 4 8 0 3 4Total CMCs: 4074 5360 6227 Table 3: Numbers of CMCs and Countries providing services for each of the CMC Categories as of 2016 (31/01/17), and comparison with 2012 and 2008.

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As user needs for internationally equivalent and accurate measurements in various sectors have developed, the CCQM has reacted by creating appropriate working groups to coordinate comparisons and studies to address these issues. Following the creation of four working groups in 1997/8 (covering Organic, Inorganic, Gas, and Electrochemical Analysis), working groups covering Bioanalysis (established 2002) and subsequently subdivided in 2015 to WGs on Nucleic Acid Analysis, Protein Analysis and Cell Analysis, and also Surface Analysis (established 2004) have developed active programmes in coordinating key comparisons and studies to meet stakeholder needs. Examples of the impact of CCQM Comparisons and the calibration and measurement capabilities they support in a number of key sectors are given in Appendix II, and cover the areas of health care, environment and climate change, food safety, energy, advanced manufacturing, and the redefinition of SI units. The number of countries and institutes participating in the CCQM WGs has generally increased over the period, with WG participation described in Table 4. Activities in newly formed working groups often start with pilot studies and develop onto key comparisons supporting CMC claims. This is true of the CAWG, where pilot study activities are on-going, and key comparisons and CMC are expected as the activities of the group develop.

CCQM Working Group

Number of NMIs/DIs listed with a WG contact person

Estimated Number of CMCs underpinned by

WG activities as of 31/01/17

IAWG 43 2057 GAWG 34 2340 EAWG 30 141 OAWG 29 1650 PAWG 25 3 NAWG 22 10 CAWG 20 0 SAWG 17 26

Table 4: Number of NMI/DIs participating in each of the CCQM WGs, and the estimated number of CMCs covered by WG activities.

5.1.1 Related RMO activities since 2012 There have been significant levels of activity within the RMOs during the 2013-2016 period, including the coordination of regional comparisons. The activity in each RMO is listed below:

• AFRIMETS has organized 1 Key Comparison in the organic analysis field. • APMP has organized 2 APMP Key Comparisons, 9 Supplementary Comparisons and 6 APMP

Pilot Studies. • COOMET has organized 1 COOMET Key Comparison, 3 Supplementary Comparisons and 16

COOMET comparisons. • SIM has organized 4 SIM Key Comparisons and 4 Supplementary Comparisons. • EURAMET has organized 5 Supplementary Comparisons, 18 EURAMET pilot Comparisons.

In addition within EURAMET, the European metrology research and innovation programmes (EMRP and EMPIR) have led to the development of new capabilities in chemistry and biology in the region and capacity building at emerging European NMIs/DIs. The comparisons of newly developed capabilities were organized within the first instance as regional comparisons and this has later fed into the work programme of CCQM (e.g. particle metrology or speciation analysis).

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Within APMP, focus groups, such as the food safety focus group and the climate change focus group, have been established, and this has and is leading to the development of new measurement capabilities for chemical and biological measurements. In addition, APMP TCQM has cooperated with APLAC in organizing joint Proficiency Tests (PTs) among testing laborites within the Asia Pacific region. NMIs/DIs have coordinated the PTs and provided homogeneous and stable samples with certified reference values, using capabilities described in published CMCs. The requirement to demonstrate the international equivalence of such capabilities has been a driver in shaping the programme of key comparisons developed within the CCQM. The AFRIMETS TCQM VISION is to ““Promote metrology in chemistry and related activities in Africa with the view of facilitating intra–African and international trade and to ensure the safety, health, and protection of its citizens and the environment”. Of the 54 countries in Africa, 18 were identified to be active in scientific and industrial metrology in chemistry or be equipped with chemical testing facilities. The most abundant chemistry areas are organic and inorganic analysis, however, with only a few laboratories currently involved in metrology in chemical measurements. There is significant activity in the microbiology field within the region, although little to no activity in bio-analysis metrology (apart from NMISA). Inter-laboratory comparisons organized in the 2012-2016 period within AFRIMETS have covered:

• Ethanol in Aqueous solution: AFRIMETS.QM-K27, including a repeat at commodities/methanol adulteration level; • Ambient air quality/ Emissions monitoring: SO2 in N2 • Heavy metal; IAEA –RAF/0/027, Consumer safety and Trade Development through

Competent Nuclear testing and Metrology Laboratories (AFRA IV-13) • Microbiology -Total plate counts for Coliform bacteria (E.coli) • Edible (Table) salt, • Edible vegetable oil, • Wheat Flour, KEBS • Pesticides; aqueous solution, simple matrix, complex or low level

The metrology in chemistry activities in AFRIMETS are predominantly focused on issues related to food security and food safety for the purposes of consumer protection and exports, as well as health and environmental protection. During 2015/16 NMISA launched The African Food and Feed Reference Material Programme (AFFRMP) to specifically address analytical challenges testing laboratories face, through the provision of food and feed reference materials that more accessible, affordable and relevant to Africa. This was also the driver for the establishment of the Mycotoxin Metrology Capacity Building and Knowledge Transfer programme at the BIPM, started in 2016. Within SIM, the metrology in chemistry activities in the last years were focused on issues related to implementation of electrochemistry and gas analysis facilities (automobile emission and natural gas) that originate from the developing NMIs. A considerable amount of effort was put on the aspects of preparing and reviewing CMC claims. Short training courses implemented in the last two SIM Chemical Metrology Working Group meetings resulted in an improvement of quality and efficiency of the SIM CMC claim submissions and reviews. Additional activities were also recently included in SIM discussions, including training courses in clinical chemistry and food metrology and safety, important areas for ensuring quality of exports, and health and environmental protection. Two NMIs (INTI and INMETRO) are participating of the Mycotoxin Metrology Capacity Building and Knowledge Transfer programme at the BIPM, which started in 2016. The objective is to expand this program for other NMIs that are building their facilities in this emerging metrology field.

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5.2 Changes in needs and issues arising in the period 2012-2016

5.2.1 The CIPM MRA review Resolution 5 of the 25th CGPM (2014), whilst considering the appreciation and support expressed by all interested parties for the CIPM MRA since its entry into force more than fifteen years ago, invited the Consultative Committees to continue their ongoing efforts to streamline operations within the existing framework, and the CIPM to establish a working group to conduct a review of the implementation and operation of the CIPM MRA. The recommendations from the working group were published on 23 August 2016. Seventeen key points were agreed including: a) The MRA should continue to maintain its high levels of quality and integrity so as not to undermine the effort invested over 15 years; b) The total effort required to operate all aspects of the MRA should not rise above the present levels and should be reduced where possible. Steps should be taken to spread the load more widely. c) There is a need to upgrade the KCDB and the JCRB databases using new modern IT tools. The working group were also posed nine questions which were considered to be central to the future implementation and operation of the MRA, including: a) How can the level of participation in KCs be managed more effectively? b) How can the proliferation of CMCs be constrained? c) Should new scopes and processes be developed for CMCs in chemistry? Should new areas such as biology and emerging technologies also be considered? The working group formulated nine recommendations with 28 sub-recommendations to these questions, including: a) The strategy documents of the CCs must clearly define the long-term timetable for KCs (including the repeat cycle). The RMO TCs should also plan regional KCs and SCs strategically, to reflect the needs of the RMO. b) The use of CMCs to cover as many services as is technically justified should be encouraged, so that CMCs become representative rather than comprehensive. It should be emphasized that the goal is for NMIs to develop services and that CMCs are tools for describing the capabilities maintained to underpin the delivery of those services. The NMI QSs should document the relationship between services and CMCs. c) NMIs should be advised to use the percentage of coverage of their services by CMCs as a metric of success rather than the number of CMCs (the number of CMCs alone should not be considered a metric of the success of an NMI). d) The BIPM should investigate the feasibility of a web-based tool for the complete CMC submission and review giving full tracking of the CMC review process, for example as part of the KCDB 2.0. e) The CCQM should review and revise the templates, if needed, for Chemistry and Biology CMCs to ensure they are appropriate. In response to a number of these recommendations the CCQM established and ad hoc WG on KCDB 2.0 after its meeting in April 2016. The ad hoc WG produced the following recommendations for consideration by the CCQM: 1. The CMC template can be simplified by suppressing the nine columns that describe CRMs. This information can just as well be included in the ‘disseminated capability’ columns (with ranges and uncertainties adjusted accordingly if necessary). The recommendation was not supported by the CCQM in its April 2017 meeting, where a number of NMIs requested the columns were retained , as the information they contained was used by the NMI and its customers.

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2. The current measurement service categories for the ‘Amount of Substance’ need to be reviewed, taking into account what these categories are being used for. This may also mean that the CMC template allows listing of a disseminated capability for a number of service categories. 3. The WG noted that a common request from the Bio group had been that their description of the measurand may need to be quite lengthy, and a future template/data entry field should not limit this. 4. Further discussion would be needed on how broad scope CMC claims would be introduced into the KCDB. Whilst the template did not appear in any way to limit broad scope claims being made, there were questions on what practical use broad scope claims would be for users? In bio area – broad base claims thought to be more use for customers e.g. NA quantification in specific range/measurement space. Studies should be designed to support broader claims to better support the range of measurement services being provided by NMI/DIs. 5. The WG agreed on the proposal to keep the field “Analyte Group” in the current template for now, as it might find use for linking the CMC claim to a HFTLS statement (e.g. stating MW and pKow for the analyte). 6. The WG supported the proposal to produce a CCQM best practice guide on preferred units to use for expressing CMCs in the KCDB, noting that the choice of units would still be driven by customer requirements, but in other cases it would be possible to harmonize (e.g. to decide whether to use g/g or kg/kg for expressing mole fractions as an example). 7. The WG supported the approach being currently investigated by the BIPM on the feasibility of a web-based tool for the CMC submission and review, giving full tracking of the CMC review process, for example as part of the KCDB 2.0. The possible web-based tool for making and tracking comments on each CMC during the intra- and/or inter-RMO review process as well as the option for uploading the QS evidence attached with a CMC submission were welcomed, as well as the ability to export CMCs, and print out or save the comments generated from the active review process (to demonstrate and track the review process). Standard reviewing web software tools could potentially be employed.

5.2.2 Core comparisons and capabilities and broad scope CMCs The CCQM has continued its efforts to streamline operations with respect to key comparisons and CMCs within the existing framework, as already described in the 2012-2023 CCQM strategy document. With respect to core comparisons and capabilities, a number of important advances have occurred: a) The Gas Analysis WG has adopted the nomenclature for its comparisons developed in the Organic WG referring to these as track A, B, C and D comparisons. Track A comparisons are designed to test the core skills and competencies required in gravimetric preparation, analytical certification and purity analysis of the gas mixtures covering nine analytes and mole fractions over five orders of magnitude, where a number of NMIs/DIs have consistently demonstrated equivalence since the GAWG was established. Track A key comparisons are intended to assess the basic capabilities of NMIs active in gas analysis. Track B comparisons are designed to support CMC claims for components which present an analytical challenge and are prepared and analysed using competencies beyond those required for track A. Track B key comparisons address issues such as

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unstable and reactive gas mixtures. Examples are CH4 at an amount-of-substance fraction below 10 µmol/mol (e.g. CCQM-K82 with CH4 in air at 1.8 µmol/mol), nitrogen dioxide, ammonia and ethanol. Track C comparisons are for an emerging area of global interest and innovation. The aim of track C key comparisons is to underpin future CMCs. Track D includes all other studies (stand-alone studies and studies run in parallel to key comparisons). These studies are not intended to lead to CMCs or to support CMC claims in the KCDB. In addition, the GAWG has developed a model for extrapolating performance in key comparisons to claimable uncertainties for CMCs covering seven orders of magnitude in mole fraction (see Figure 3). It has been estimated that if the model is adopted and used to describe CMCs for gas metrology, the number of CMCs in this field could be reduced by as much as 50%.

Figure 3. GAWG model for extrpolating performance in a key comparison to claimable CMCs over seven orders of magnitude of amount fraction. b) In the organic analysis working group models have been developed to plan a finite number of comparisons to cover capabilities both for primary calibrators as well as complex matrix reference measurements. This results in a model with 20 Track A key comparisons which would be sufficient to underpin CMCs across the core organic measurement capabilities. The WG decided to rationalize the high-purity organics measurement space (Figure 4) and define X (low polarity, small size), Y (high polarity, small size) and Z (all polarities, large size) spaces leading to a new “3-sector” organic purity model which maps the organic purity space up to MW 1000 into three sectors:

• X : MW < 500, pKOW < -2 • Y : MW < 500, pKOW > -2 • Z : MW > 500

This will be the basis of future purity campaigns, and reduce the number of comparisons required to cover these capabilities.

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Figure 4: Revised Model for future OAWG purity comparisons based on areas representing different measurement challenges For Track A core competency comparisons a proposed model has been developed for calibration solutions and matrix comparisons, which divides the OAWG measurement space into a series of classes of types of matrices. Dealing with different matrix effects is typically the greatest challenge in organic analysis. Sitting under this the mass fraction of the analyte is deemed to be the next level of measurement challenge. The polarity of the analyte is then considered as the third level of competency as it often determines the type of analysis techniques that can be employed. Rather than developing an objective ‘scale’ for matrix type, which is rather difficult, the approach divides the matrices into four classes– calibration solution/low interference liquid, clinical, food and abiotic matrices and then into a total of eleven subcategories within these classes. Overall the four main categories and eleven sub-categories define a range of organic matrix material types sufficient to support current and emerging CMC claims. These categories can then be used to define a set of comparisons to demonstrate the different types of competencies needed. For food matrices, four separate sub categories have been identified. The focus on this area is justified by the high strategic priority given by NMIs to the demonstration of competency and equivalence for the assessment of levels of contaminants and nutrients in a range of foodstuffs and primary produce. The proposed four matrix classes, divided in eleven sub-classes, are:

o Calibration solutions and low interference liquid matrices organic solvent calibration solutions aqueous solvent calibration solutions waters, beverages etc.

o Clinical materials Serum/plasma other

o Food > 60% fat* [AOAC Food Triangle Categories 1,3] > 60% protein* [AOAC Food Triangle Categories 8,9] > 60% carbohydrate* [AOAC Food Triangle Categories 5,6] mixed matrix* (no component present > 60 %, AOAC Food Triangle

Categories 2,4,7]

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(* % of combined fat, protein and carbohydrate content. Does not take into account other components (water, fibre, etc))

o Abiotic soil, sediment and particulate other (plastics, etc)

As described above, sitting under each of these four categories of matrices the next level of measurement challenge is deemed to be mass fraction of analyte and this model considers four main ranges. This can be defined as: Analyte Mass fraction (w) - four sectors

I. 1 g/kg < w < 1 kg/kg II. 1 mg/kg < w < 1 g/kg

III. 1 μg/kg < w < 1 mg/kg IV. w < 1 μg/kg

A further sub-division is the polarity of the analyte defined as: polar (P) (pKow > -2) or non-polar (NP) (pKow < -2) In all cases for this proposed Track A model only analytes of molecular weight below 500 are considered.

Figure 5: Clinical KCs carried out to date and their log(KCRV) plotted versus polarity to demonstrate the model for defining key comparisons based on matrix type, analyte mass fraction and polarity acting as surrogates for the core capabilities required to deliver measurement services In practice, not all concentration ranges are relevant for the different matrix classes, and the analytes of interest for a particular matrix are often limited to one polarity category (e.g. non-polar analytes in abiotic or high fat food matrices, polar analytes in aqueous calibration solutions). This reduces the effective number of comparisons needed to cover the competencies for the delivery of existing and anticipated CMC claims to the end of the next planning period to about twenty. c) The IAWG has recently begun a comprehensive review of the core capability approach. In particular:

• The new requirement is for a simpler summary of proven capabilities which can be quickly assessed by a review panel using the minimum amount of supporting documentation.

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• It is proposed to reduce the large numbers of CMCs by allowing implementation of fewer broader scope CMCs. This concept needs to be developed in parallel with the revision of the methodology for supporting the capabilities.

The revised core capability approach is based on tables with less detail for techniques but indicating how far a key comparison can support broad scope claims for each technique that was used. Tables are structured by (i) analytical approach and calibration methodologies and (ii) matrix and analyte groups which exhibit a similar degree of complexity for the corresponding analytical approach. The tables also indicate the analyte concentration range over which a capability has been demonstrated. Such tables will become part of the key comparison report together with the traditional “how far does the light shine statement”. These tables and the NMI record card used previously will serve as evidence when submitting broader scope CMC claims, avoiding the need for institutes to prepare additional core capability tables. The revised approach will facilitate the use of broader scope CMCs whilst reducing the workload of those submitting and reviewing CMCs. d) The focus on core competence measurement claims in the Nucleic Acid WG have followed on from those initiated in the Bioanalysis WG, and the CMC’s supported by NAWG activities have progressively (1-3) supported broader claims with the careful design of recent Pilots studies and Key comparisons to support as broad a measurement claim as possible, to allow capabilities demonstrated with a particular NA target / matrix combination to support scientifically equivalent measurements eg:

1. MON810 (5) – specific genetic modification in specific matrix 2. Copy number ratio of specified intact sequence fragments of 70 to 150 nucleotides length in a single genomic DNA extract in a specified matrix group 3. Quantification of linearised plasmid DNA (4.4 ± 1) kbp

The issue of broad claim CMCs, was addressed by a CCQM workshop held in April 2016, as a response to find a way of registering capabilities more broadly to reduce the workload associated with the CMC process. The concept of broad scope CMC claims will be developed further in the next years. Currently, there are few such claims, with purity of organic reference materials by qNMR classified by molecular weight and polarity of the analyte being one example. These CMCs have highlighted one concern with this approach, which is how to appropriately deal with underperformance in key comparisons. The CCQM will be examining how to deal with these issues, including in relation to expectations in the quality systems within NMIs.

5.2.3 Addressing new emerging fields/needs Following the 2013 CIPM decision to change the name of the CCQM to include specific reference to Metrology in Biology, the CCQM was reorganized in 2015 with the sub-division of the working group on bioanalysis, into discipline-based Working Groups (WGs), namely: a Nucleic Acid WG, a Protein Analysis WG and a Cell Analysis WG. The activities of the ad hoc Steering Group on Microbial Measurements (MBSG) have subsequently been integrated into the three new standing working groups. All three WGs have developed strategy documents and planned comparisons to develop emerging measurement services in the fields covered by the WGs. The activities of the Nucleic Acid WG have followed on from those initiated in the Bioanalysis WG, more specifically informed by a participant survey to prioritise NA measurement study areas required to support services. The NAWG strategy prioritises:

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• Quantification of nucleic acid, including DNA and RNA (for gene expression). Specific measurands included absolute copy number concentration and ratios, within and between different samples. Applications included GMO determination, gene expression and quantitation of mutation, including single nucleotide variants.

• Nucleic acid sequencing (high throughput next generation sequencing (NGS), from the perspective of a drive for standardization in this area, identity “measurements”, metagenomics and use of sequencing for sequence purity applications, including determination of purity of calibration materials.

• Quantification of post-translational modification / epigenetics, particularly methylation NMI services currently provided and expected to be supported by CCQM NAWG comparisons in the field include;

• CRM production/value assignment (ranging from DNA SNV and other mutations and pathogen quantification to microbial metagenome sequencing)

• Digital PCR calibration services for PT, NA RM and EQA material value assignment • GMO detection and quantification

In the short to medium term it is expected that these services will be extended, with an emerging trend towards the use of nucleic acid sequencing. The Protein Analysis WG has established two focus groups for developing future activities. The first is focusing on peptide and protein calibrators, and has completed its first key comparison on pure C-peptide, a diabetes diagnostic marker, and a strategy for underpinning peptide/protein calibrators of ever increasing complexity (See Figure 6). The second focus group has concentrated on developing a comparison programme for proteins in complex matrices, starting with a pilot study of human growth hormone in serum.

Figure 6: Model for the classification of peptides for primary structure purity comparisons

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The strategy of the Cell Analysis working group, builds upon prior studies under the direction of the Bioanalysis working group: • P102 Quantification of cells expressing CD4 in presence of nonexpressing PBMC [Completed] • P123 Number and geometric property of cells adhered to a solid substrate • P165 Quantification of CD34+ cell counts As well as the two pilot studies organized by the Microbiology Steering Group including quantifying bacteria (Listeria monocytogenes in bioball format) by colony forming units on solid media (traditional microbiology techniques) based on ISO standard method common in industry. The CAWG is working to outline follow-on studies, with immediate focus on comparisons that underpin existing measurement services including quantification of CD4+ and CD34+ cell surface properties, and quantification of bacteria in a food and water matrix. Other measurement services include underpinning reference value assignments for complete blood count, adherent cells on 2D supports, antimicrobial susceptibility, cell viability and cell count on a range of cell types and sizes (microbial, yeast and mammalian). The other CCQM WGs have continued to react to changing and expanding numbers of stakeholders and sectors with measurement traceability needs. Some examples from the Working Groups are given below: In the last four (4) years, the following new developments in the GAWG programme have occurred:

• The formation of 3 task groups to deal with emerging issues: - Strategy for Particulate Comparisons to plan the first key comparison on particle number

and charge concentration. - Black Carbon to identify key issues for making measurements of black carbon and elemental

carbon comparable and traceable, and to set out a way forward, in the form of a roadmap. - Ozone cross section with the task of recommending a value and uncertainty for the ozone

cross section at 253.65 nm to be used in ozone reference photometers and for comparisons of these standards in BIPM.QM-K1.

• Expansion of the gas metrology scope of activities to include the determination of isotope ratios of components in the gaseous state, in particular for greenhouse gases;

• Development of measurement capabilities for composition and quality assurance of emerging fuels, notably hydrogen and biogas and liquefied energy gases

• The need to react to more stringent rand emerging requirements for air quality, including nitrogen dioxide, hydrogen chloride and ammonia.

In the Organic analysis field, a diverse range of types of residues in food (melamine, pesticides, PAHs, antibiotics) have been examined over the last 4 years. For abiotic environmental samples a class of flame retardants, PBDEs, formed the subject of a challenging comparison. For clinical markers in serum cholesterol, glucose, creatinine, urea, uric acid and Vitamin D have been examined. These have all been selected to cover a representative range of current measurement challenges in these fields. Whilst, the Clinical Sector currently remains the focus of the highest level of activity, programmes in food matrices have also seen significant increases, driven by world-wide food safety priorities and by national food labeling regulations, and underpinning measurement services related to food safety have been identified as the highest common priority amongst NMIs. In addition, recent trends have been on developing measurements services on natural toxins in food and more sophisticated clinical biomarkers. A comparison for aflatoxins in food was commenced in 2016. Comparisons of calibration material and solution value assignment capabilities remain an active field, with the BIPM and NIST taking the lead on providing support for this series of comparisons, and the high purity material CMC category representing the largest growth in the last period. Recent comparisons have seen an increasing number of NMIs implementing quantitative NMR (qNMR) for

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their primary reference material/purity assessments, with improved consistency between this and more traditional mass balance methods being demonstrated. In response to more and more users wanting certified reference materials for calibration provided as solutions, comparisons of calibration solutions will increase in importance. Future priority areas for the organic analysis working group are likely to include areas such as: algal toxins; mycotoxins; veterinary drugs; cannabinoids and high MW biomarkers. Within the Inorganic Analysis WG good progress has been made in providing SI traceability for inorganic elemental analysis with respect to the use of pure metals as calibrants. This has involved an extensive practical assessment and the preparation of guidance in the form of a “purity assessment roadmap”. Plans are now in place to extend the work to preparation and SI traceable certification of salts as elemental calibrants. The situation with regard to SI traceability of isotopic materials is much less satisfactory, with those NMIs and DIs active in this field continuing to provide relative isotope ratio measurements (Delta values) based on internationally accepted scales implemented with very limited NMI involvement. Several institutes have started to address the issue, and collaboration with other WGs, having similar needs (e.g. the GAWG for atmospheric measurements; the IAWG for stable carbon isotope ratios in food matrices (CCQM-K140 with measurements in honey) is anticipated. Within the Electrochemical Analysis Working Group, links to the oceanographic community have been established to support the development of traceability concepts for pH and salinity measurements in seawater, including a pilot study and a key comparison on conductivity measurements in seawater. Also a few NMIs are extending their electrochemical activities to the characterization of Li-ion batteries and the development of adequate traceability concepts using electrochemical impedance spectroscopy The scope of the Surface Analysis Working Group was extended to include comparable measurements of specific adsorption, specific surface area (BET), specific volume and pore diameter in solid nanoporous substances in 2014 and to traceable quantitative micro analysis with Raman microscopy in 2015. Further needs for comparisons are foreseen for:

• quantitative data for the amount of matter in a shell of a core-shell engineered nanoparticle (XPS, AES, TEM);

• quantitative data for the amount of matter in a buried organic layer (SIMS, XPS, XRR, NR, Ellipsometry);

• Accuracy and comparability of micro to nanoscale 2D/3D chemical imaging methods.

5.2.4 Advising on the BIPM work programme in Metrology in Chemistry The CCQM has been highly active in advising the CIPM on BIPM Scientific Programme Activities in Metrology in Chemistry, and requires annual reports from the BIPM on progress with its Metrology in Chemistry Programme. The CCQM Strategic Planning Working Group’s terms of reference include it providing advice on the BIPM work programme so that it meets strategic needs defined within the CCQM Strategy (see Annex I for details).

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5.3 Future Scan (2017-2026)

5.3.1 More efficient and effective underpinning of CMCs CCQM WGs are continuing to implement a 'core capability' approach to the organization of Key comparisons, which are expected to lead to the gradual implementation of rolling programmes with more efficient and effective support of calibration and measurement capabilities (CMCs). The expected benefit of adopting a "core capability" approach is to maintain the number of required key comparisons at manageable levels. The stabilization in the number of key comparisons required to underpin increasing numbers of CMCs, suggests that this approach is leading to the desired result. This approach is not without its difficulties, where in some areas it is more common now to develop comparisons for current or emergent measurement areas to underpin a wider range of CMCs. This presents a significant challenge, in particular for institutes that may have never worked in the specific measurement area, but would participate in order to demonstrate the breadth of their capabilities. Nevertheless, overall it is expected that the additional resource required to develop capabilities for the new measurand is significantly less than would be required to maintain a 1:1 correspondence between key comparisons and CMCs. Traditional key comparisons with well developed ‘how far the light shines’ statements will be maintained for areas where the reported uncertainties are critical to the capability, or where very specific measurands need to be studied to underpin stakeholder needs in a particular application/sector (e.g. greenhouse gases, where the compatibility and uncertainties demonstrated for each of the major greenhouse gases are reuired by the user community) More broad-claim CMCs are expected to increase in number for the Chem-Bio area. This is already evident in some of the technical areas, and has the potential to decrease the number of current CMCs by over 50% for some measurement categories (notably in the field of gas metrology). On the other hand, concerns on whether broad claim CMCs will be useful to outside customers have been raised, and will require further guidance on what is expected in the KCDB.

5.3.2 Support for NMIs to meet new measurement requirements in sectors A number of key sectors will require the development of traceable measurement results and the demonstration of their international equivalence, and amongst these several NMIs have indicated that the healthcare, food safety and nutrition, energy and environment, and advanced materials and manufacturing sectors will be of particular focus for future activities. Specific examples of important issues and trends in various sectors that are likely to drive the development of NMI services are given below. Future CCQM comparisons would then be selected to establish the international equivalence of these measurement standards and services:

a) Health care • Requirements to develop Reference Measurement Systems for Diagnostics driven by

regulatory requirements, e.g. the EU IVD Directive/Regulation and the US FDA • Requirements for underpinning work to assure the traceability of quantitative

measurements of nucleic acids, cells, proteins and metal containing proteins, polysaccharides and cells to the SI, including high accuracy purity assessments.

• Support of electronic health records • Systems biology support (e.g. combined ‘omic’ approaches lipid/cell/gene/protein…) –

including interactions in immune systems • Measurements of immunosuppressants • Medical gases

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• Regenerative medicine therapeutics • Predictive medicine requirements for trace level circulating biomarker measurement • Metrology support for development of point of care in vitro diagnostic devices • Measurement to support bio/pharmaceutical quality, safety and efficacy • Metrology support for nanoparticles used for diagnostics and drug delivery • Measurement of contamination of surfaces of medical devices

b) Food safety and nutrition • Residues including new types of antibiotics, hormones, veterinary drugs and pesticides • Contaminants including mycotoxins and seafood • Microbial pathogen identification and quantification • Enhanced food constituent labeling requirements • Food provenance, fraud and adulteration • Migration of contaminants from packaging materials

c) Environment • Long-term global, direct and remote monitoring of carbon dioxide and other greenhouse

gases • Long-term monitoring of the oceans, including pH and salinity • Development of emission controls on toxic and reactive gases from industrial activities to

atmosphere and workplace • More stringent and emerging requirements for air quality • Particulates and nanoparticles in indoor and urban air • Semi-volatile organic compounds in indoor air • Emerging contaminants with respect to environmental monitoring, including perfluorinated

compounds and emerging water contaminants • Isotope ratio measurements for sensitive environmental studies • Water quality, e.g. requirements from the EU Water Framework Directive • Management of waste streams (reduction, treatment, and recycling of solid, liquid, gaseous

or radioactive waste substances) • Real time analysis of complex particulate composition (for instance metals and PAH content)

d) Energy • Emerging hydrogen economy (e.g. measurements of impurities in hydrogen) and hydrogen

induced degradation of infrastructure (measurements of hydrogen in steel microstructure) • Diversification in the supply of energy gases (e.g. biogas, coal mine methane, shale gas,

liquefied energy gases) • Dissolved gas in water (e.g. methane and methane hydrates) • Usable energy from bio waste, which may require biological as well as calorific value

measurements. • Industrial biotechnology (harnessing sustainable microbial energy) • Chemico-physical properties of biofuels • Alternative technologies in organic and inorganic thin film photovoltaic systems • State of health and of charge of energy storage systems (e.g. batteries in the automotive

sector) • Injection of non-conventional gases into existing gas grids

e) Manufacturing • Ultra-low levels of water vapour and water vapour permeation, as well as

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• Zero gas ammonia and hydrogen chloride for air monitoring and cleanrooms • On-line chemical sensors providing intelligent feedback for process control • Organic and inorganic thin film technologies for electronic devices including displays, sensors

and photo-catalytically active surfaces • Bio-manufacturing materials

f) Advanced materials • Development of metrologically underpinned characterization tools and protocols for analysis

of nano-structured surfaces, nano-particles nano-electronics, nano-magnetic and nano-electro-mechanical systems and nano-materials.

• Research towards traceability of toxicity measurements with a focus on chemical and biological characterization of nano-particles.

• Development of new materials with functional surfaces including, biomaterials, meta materials, and hybrid materials

• Electrochemical sensors to monitor and feedback on the performance of smart materials • Embedded chemical sensors in intelligent buildings • Nanoporous materials for applications as adsorbent materials, catalysts and gas cleaning in

gas industry.

5.3.3 Links with RMO activities The continuing growth of capabilities among NMIs/DIs has led to the RMOs to start to more formally address the strategic planning of regional key and supplementary comparisons. In particular, promoting the participation of NMIs/DIs from outside the region to avoid unnecessary duplication will be encouraged, particularly in mature areas such as gas, organic and inorganic analysis. The initiation of metrology research programmes within the RMOs, notably the European Metrology Research Programme (EMRP) within EURAMET, has and is leading to the development of new measurement capabilities for chemical and biological measurements. The requirement to demonstrate the international equivalence of such capabilities has and is shaping the programme of key comparisons developed within the CCQM, in addition to the activities in the RMOs. Regional key comparisons are carried out when the corresponding CC cannot accommodate all NMIs/DIs interested to participate. They should thus be carried out as close in time as possible with CC key comparisons. Thus, on the RMO level only supplementary comparison can be strategically planned. Within EURAMET a strategic planning instrument for supplementary comparisons is under development. The guiding principles are that supplementary comparisons are based on a gap analysis of published CMCs within the region and their coverage with key comparisons as well as a risk and complexity assessment of the concerned CMCs. Prioritisation is given to supplementary comparisons with broad CMC coverage and maximal impact for the region. All Technical Committee (also EURAMET TC-MC) are going to establish a strategic plan which will be regularly reviewed by the EURAMET BoD. Applicability for EURAMET TC-MC strongly depends on the strategy and CMC coverage of future CCQM / RMO KCs. Pilot comparisons will be organised to address specific needs and validate newly developed capabilities. Within APMP, future comparisons will be designed: – to develop new capabilities of NMIs/DIs in chemical and biological measurements to support

their CMCs; – to provide supplementary comparisons for compliance to Asia Pacific legislation, especially for

regional and international social and economic development and free trade (e.g. food safety, climate change, clean water, industrial products, consumption goods…);

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– to encourage exchange of comparison plans between RMOs, encouraging participation in other RMOs’ KCs and/or SCs, so as to raise efficiency and promote cooperation between members from different RMOs;

– to reduce the number of APMP KCs, SCs, and encourage APMP members to participate in CCQM comparisons and/or pilot study directly;

Date Activity

2017-2021 Five year Seasonal Pesticides in fruit/vegetable PT scheme (one per quarter), pilot, NMISA

Early 2018 Mycotoxin in maize PT, pilot by NMISA (in collaboration with NIM China) Propose AFRIMETS Supplementary comparison

March 2018 Training Workshop: Mycotoxin metrology workshop: NMISA, South Africa

Late 2018

Aflatoxin in peanut PT, pilot by NMISA (in conjunction with IAEA-AFRA 5078 food safety network project) Propose AFRIMETS Supplementary comparison

2018/19

Training secondments at NMISA on mycotoxin analysis in maize/nuts Secondments will be 3 months in duration (May-July; Sept-Nov) accommodating 2 visiting scientists per year

2018/19

Seasonal Pesticides in fruit/vegetable PT scheme, pilot, NMISA Propose AFRIMETS Supplementary comparison

Early 2019

Antibiotic residue in meat/tissue PT, pilot by NMISA (in conjunction with IAEA-AFRA 5078 food safety network project) Propose AFRIMETS Supplementary comparison

2019/20

Training secondments at NMISA on mycotoxin analysis in maize/nuts Secondments will be 3 months in duration (May-July; Sept-Nov) accommodating 2 visiting scientists per year

Table 5: Plans for future pilot studies and key comparisons and activities for AFRIMETS Within the COOMET region in the period 2017-2020, regional comparisons are planned to cover: - С3-С5 components in mixtures of liquefied hydro-carbons; - measurements of moisture mass fraction in wood material; - Ethanol in aqueous solution; - Activity of Na ions in aqueous solution (рNa); - Determination of polychlorinated terphenyls in sediments; - Purity of tributyltin; - Natural gas; - Ammonia in Nitrogen in the range 10-30 ppm; - Dissolved gases in transformer oil; - Determination of Hg in natural gas; - Components C1-C40 in gas-condensate media. A major focus of the AFRIMETS programme will be measurement support for safe food and feed.

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Plans for future pilot studies and key comparisons for AFRIMETS (Table 5) will focus on the comparability of nutritional content and regulated toxic compounds in indigenous food products, such as wheat, white maize, cassava, etc. More work on the establishment of measurement equivalence between national metrology institutes in Africa in the field of water testing is foreseen. In addition, a few NMIs in Africa have already started to establish a capability in the field of gas metrology and future RMO comparisons in this field are planned. The three-year plan for SIM is to strength the activities in food safety and gas metrology (specifically, automobile emissions and GHG measurements). A Supplementary regional comparison for automobile emissions is planned for 2017, as is complementary training in GHG measurements and gravimetric preparation of gas standards relevant for developing NMIs. A Workshop on Protein CRMs is planned for 2017, as part of the SIM project entitled “Strengthening National Metrology Institutes in the Hemisphere, in support of emerging technologies”, and funded by the Interamerican Development Bank (IADB). In addition, an associated workshop to determine the variation in measurements for glycated hemoglobin (HbA1c) in blood and provide training in protein primary method development across SIM countries was also proposed to IADB. Another submitted proposal is the project on “Development of Metrology in Chemistry at the Nanoscale”. A submission to NIST (IAAO/NIST-SIM Engagement) is under discussion and would cover a training in Chemical Metrology for Food Safety and Nutrition-Prominent Issues. These projects are designed specifically to provide the SIM community at large with the opportunity to strength the cooperation among SIM NMIs in joint research projects relevant for health care, environment and food safety applications. The Chem-Bio activities within GULFMET are just beginning, further interaction between GULFMET and the other RMOs is expected in the upcoming period. The CCQM will need to work closely with the RMOs to ensure that: a) unnecessary duplication is avoided; b) results of supplementary comparisons are accepted outside of the region; c) comparisons of novel measurement methods and standards are carried out with the broadest international participation.

5.4 Rationale for measurement standard global comparability activities (2017-2026)

5.4.1 An effective and efficient programme of comparisons to support current capabilities The CCQM programme of comparisons is being designed to:

• meet NMI/DI needs in the most efficient and effective manner through the use of a ‘core capabilities’ approach

• continue to use conventional key comparisons (with ‘how far does the light shine?’ statements) where there are specific and critical reasons to do so, or where very specific measurands need to be studied to underpin stakeholder needs in a particular application/sector.

Repeat frequencies of comparisons shall be determined based upon a consideration of:

• The scope of the comparison, i.e. comparisons covering a wider range of capabilities will have many participants and will be repeated more frequently (than comparisons with narrow scope and few participants)

• Number of existing and new CMCs in a category addressed by the comparison • Performance of participants: if good then the repeat frequency may be longer

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• Technological change requiring new comparisons • Need to cover staff turnover and other organisational changes • Need to cover new entrants

The consideration of the above points has led to the following recommendations for the organization and periodicity of key comparisons in the various CCQM working groups:

• NMIs using the broad claims strategy in Gas Analysis, must take part in one Track A comparison (such as CO, CO2, SO2, NO etc.) every three years when avaialable (GAWG).

• Ozone key comparison (BIPM-QM.K1): each NMI should participate at least once every eight years, and generally not more often than once every four years (GAWG-based on performance in key comparisons).

• Continuation of key comparisons with ‘how far the light shines’ statements (GAWG), including for greenhouse gas and air quality measurement standards where the uncertainty of the demonstrated measurement capability is critical to the application of the measurement standards. These comparisons are included in the activities of the GAWG, which has advised that they should be coordinated within the BIPM laboratory programme, to ensure a uniform worldwide metrological system for the long term accurate global monitoring of these species.

• Natural gas comparisons will be repeated once every six years (GAWG) • In the field of organic analysis, a set of 20 ‘Track A’ Key Comparisons shall be selected to test

core competencies covering most of the CMCs in the organic analysis area, with two studies to be initiated per year, one in primary calibration reference services and one in accuracy control services (OAWG). Specific classes within the framework may only be repeated every 5-10 years due to the breadth of areas to be covered.

• Continuation of the OAWG programme of organic purity comparisons, coordinated by the BIPM, based on a set of three comparisons covering all organics with a molecular weight of less than 1000 gmol-1 in a period of 10 years.

• The IAWG has proposed the following policy on frequency of participation: o Each NMI/DI with current CMCs should participate at least once every two years in a

key comparison relevant to its field of application. o Each NMI/DI with current CMCs should participate at least once every four years in a

comparison which provides a ‘1:1’ KC:CMC check. o Every two to three years the IAWG will declare an appropriate comparison to be a

‘benchmarking exercise’ for all active participants in order to obtain a direct assessment of performance across the entire IAWG.

• In order to allow flexibility regarding frequency of participation in specific comparisons, the IAWG has also proposed that each NMI/DI should maintain a ‘record of participation’ in an agreed tabular format in order to demonstrate its overall KC performance during the preceding 7 years.

• Closer links will be established between the comparison schedule and the CRM production plans of NMIs and DIs. This principle will greatly reduce costs by facilitating use of the same materials for both purposes. In order to facilitate this approach, the IAWG has established a rolling forward programme of ‘slots’ for comparisons and pilot studies based primarily on matrix type and maintains a database of future CRM production plans of its participants.

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5.4.2 Organizational aspects The CCQM Working Groups have been organized on the basis of assembling in the most efficient and effective way the best globally available expertise, knowledge and competence in the different fields of metrology. The Working Groups all operate under the umbrella of the CCQM and report jointly and when required have periodic inter-disciplinary sessions. In this way the CCQM has also been able to organize almost yearly one or more workshops or symposia with major stakeholders, to bring in views and expertise not yet available within the NMI/DI community, to address in an open and transparent way the metrological needs of the stakeholders, and to set the necessary priorities. Further inter-disciplinary cooperation is expected in the future. Another important aspect for CCQM remains the close relationship between organisation of comparisons and production of certified reference materials, and the expansion in the production of CRMs by NMIs active in the CCQM. This relationship has developed because of the added information that a comparison can bring in the characterization of a reference material, and secondly the high financial cost of developing suitable materials for CCQM comparisons, which can only be justified within national programmes if the materials are primarily intended to be developed as CRMs.

5.5 Required Key comparisons and pilot studies 2017-2026 with indicative repeat frequency The number of key comparisons and stand-alone pilot studies per year foreseen for the period 2017-2026 for each of the CCQM working groups is given in Table 6, and is compared to the data available for the period 2013-2016. The approximate number of CMCs currently underpinned by the activities of each of the WGs is also given in the table. The total number of key comparisons and stand-alone pilot studies that will be coordinated (115 to 120 KCs and 42 to 47 pilot studies) in the ten-year period 2017-2026 is comparable in terms of key comparisons to the previous ten-year period, but a significant decrease in terms of pilot studies. The figures below indicate that at the CCQM level, the number of comparisons required to maintain the CIPM-MRA have not increased. In particular, the number of pilot studies in the future are expected to proceed at the level seen over the last few years (which was much reduced to that originally predicted). The running of stand-alone pilot studies was historically an activity that resulted in the number of pilot studies being run being equivalent to the number of key comparisons up to around 2012. In the last period, the total number of stand-alone pilot studies run has decreased, and the reduced number of pilot studies is expected for the following ten-year period. This can be explained by several effects: a) The proportion of the methods and capabilities in NMIs that are at a mature level in a number of the WGs has increased, noting that developments into new analytes and technologies are still taking place, with the preference being for the coordination of key comparisons. b) More recently created WGs have not proceeded with the number of pilot studies initially predicted, and have proceeded with a lower and more sustainable number. c) The core comparison models developed within the CCQM have provided a framework that allows a limited set of comparisons to underpin a growing set of capabilities.

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CCQM Working group Number* of Key

comparisons 2013-2016

Number* of (standalone) Pilot Studies 2013-2016

Approximate Number of

CMCs underpinned

by WG activities at the end of

2016

Estimated Number of

Key comparisons

for 2017-2026

Estimated Number of

(standalone) Pilot Studies

for 2017-2026

Gas Analysis Working Group (GAWG)

9 0 2340 27 3

Organic Analysis Working Group (OAWG)

12 1 1650 20 to 25a 0 to 5b

Inorganic Analysis Working Group (IAWG)

13 3 2057 30 8c

Electrochemical analysis (EAWG)

4 3 141 15d 5d

Surface Analysis Working Group (SAWG)

2 1 26 5d 7d

Nucleic acid Analysis Working Group (NAWG)

2 2 10 10e 10e

Protein Analysis WG (PAWG)

1 1 3 6f 6f

Cell Analysis Working Group (CAWG)

0 1 0 2 3

Total number of CCQM comparisons (2013-2016)

43 12 - - -

Average number of CCQM comparisons per year (2013-2016)

11 3 - - -

Estimated total number of CCQM comparisons (2017-2026)

- - - 115 to 120 42 to 47

Estimated average number of CCQM comparisons per year (2017-2026)

- - - 12 4 to 5

Table 6: Estimations of the number of key comparisons and stand-alone pilot studies that are foreseen to be run each year during the period 2017-2026 by each of the current CCQM WGs, and data from 2013-2016. a Assumes up to 5 track B and C comparisons organized in period b Assumes up to 5 track D comparisons (pilot studies) organized in period c Based on number organized in 2013-2016 period d Extrapolated to whole period e Based on statement of maximum of 1 to 2 comparisons per year f Twelve comparisons identified in WG strategy currently assumed 50:50 split between KCs and PSs

5.6 Resource implications for laboratories for piloting comparisons For CCQM comparisons, NMIs piloting key comparisons must allocate resources for two distinct activities, notably:

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a) Preparation and characterization of the measurement standard or sample material to be used in the comparison, including the value assignment of the measurement standard or sample material;

b) Organizing, conducting and reporting the comparison. CCQM Working group

Minimum resources for

Sample Preparation

in Person Months (PM)

Maximum resources for

Sample Preparation in

Person Months (PM)

Minimum resources for Comparison

Coordination in Person

Months (PM)

Maximum resources for Comparison

Coordination in Person

Months (PM)

Minimum resources for Comparison

PARTICIPATION in Person

Months (PM)

Maximum resources for Comparison

PARTICIPATION in Person

Months (PM) Gas Analysis Working Group (GAWG)

2 12 3 6

Organic Analysis Working Group (OAWG)

2 20 6 12 1 12

Inorganic Analysis Working Group (IAWG)

12 18 6 1

Electrochemical analysis (EAWG)

1 3 2 6 1 2

Surface Analysis Working Group (SAWG)

2 12 5 10 1 6

Nucleic acid Working Group (NAWG)

12 36 1 12

Protein Analysis Working Group (PAWG)

24 48 24 48 6 12

Cell Analysis Working Group (CAWG)

6 18 6 12 1 12

Table 7: Resource estimates in Person Months (PM) required for: a pilot laboratory to a) prepare and characterize samples for comparisons and b) to coordinate the comparison; and resources required for a laboratory to participate in a comparison. Samples prepared for key comparisons must be of sufficiently high quality to meet the requirements of the comparison, which in reality means that the preparation and characterization of these samples must follow the processes used for certified references materials (CRMs). Related costs can be far greater than those required to coordinate the comparison, and for this reason a large number of CCQM comparisons are being run on candidate reference material samples, where the cost of material preparation is borne by the CRM production activity, and not considered as part of the comparison costs. Nevertheless, the resources to prepare appropriate materials for comparisons is partially included in Table 7, as this can be a limitation in having materials available. However, once a material is available there is added value for the NMI proposing its candidate CRM as a comparison sample as further information and measurement results on the material will be obtained.

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The resources required to coordinate a comparison vary depending on the type and difficulty of the measurement and the stability of the measurement standard/ material. A break down on the range of costs/resources required to pilot a comparison for the various CCQM WGs is given in Table 7.

5.7 Summary table of comparisons, dates, required resources and the laboratories already having institutional agreement to pilot particular comparisons Information by Working Group is contained on the BIPM website at http://www.bipm.org/utils/en/xls/CCQM_PKC.xls .

6. Document Revision Schedule 1 year for exceptions 2 year updating of all lists 4 year major revision with extension of period covered by rolling programme

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References [1] Jang, Jong Shik; Hwang, Hye Hyen; Kang, Hee Jae; Jung Ki Suh, Hyung Sik Min, Myung Sub Han, Kyung Haeng Cho, Yong-Duck Chung, Dae-Hyung Cho, Jeha Kim, Quantitative analysis of Cu(In,Ga)Se-2 thin films by secondary ion mass spectrometry using a total number counting method, METROLOGIA 2012, 49 522-529 [2] Viallon J., Lee S., Moussay P., Tworek K., Petersen M., Wielgosz R.I., Accurate measurements of ozone absorption cross-sections in the Hartley band, Atmos. Meas. Tech., 2015, 8, 1245-1257 [3] Viallon J., Moussay P., Flores E. and Wielgosz R.I., Ozone cross-section measurement by gas phase titration, Analytical Chemistry, 2016, [4] Flores E., Viallon J., Moussay P., Griffith D.W.T., Wielgosz R.I., Calibration strategies for FT-IR and other isotope ratio infrared spectrometer instruments for accurate δ13C and δ18O measurements of CO2 in air, Anal. Chem., 2017, 89(6), 3648-3655 [5] Stoppacher N., Josephs R.D., Daireaux A., Choteau T., Westwood S.W., Wielgosz R.I., Accurate quantification of impurities in pure peptide material – angiotensin I: Comparison of calibration requirements and method performance characteristics of liquid chromatography coupled to hybrid tandem mass spectrometry and linear ion trap-high resolution mass spectrometry, Rapid Comm. Mass Spectrom., 2015, 29, 1651-1660 [6] Bros P., Josephs R.D., Stoppacher N., Cazals G., Lehmann S., Hirtz C., Wielgosz R.I., Delatour V., Impurity determination for hepcidin by liquid chromatography - high resolution and ion mobility mass spectrometry for the value assignment of candidate primary calibrators, Anal. Bioanal. Chem., 2017, 409(10), 2559-2567 [7] Westwood S., Choteau T., Daireaux A., Josephs R.D., Wielgosz R.I., Mass balance method for the SI value assignment of the purity of organic compounds, Anal. Chem., 2013, 85, 3118-3126 [8] Precise measurement for the purity of amino acid and peptide using quantitative nuclear magnetic resonance, Ting Huang, Wei Zhang, Xinhua Dai, Xiaoguang Zhang, Can Quan, Hongmei Li and Yi Yang Talanta, 2014, 125, 94-101 [9] Yang I., Lee J.B., Moon D.M., Kim J.S., Preparation of primary reference material of argon in oxygen by the gravimetric method for application to thermometry, Metrologia, 2017, 54, 184-192 [10] Rhoderick G.C., Hall B.D., Harth C.M., Kim J.S., Lee J., Montzka S.A., Mühle J., Reimann S., Vollmer M.K., Weiss R.F., Elementa: Science of the Anthropocene, 2015, 3, 000075,doi: 10.12952 [11] Hodoroaba, Vasile-Dan; Kim, Kyung Joong; Unger, Wolfgang E. S., Energy dispersive electron probe microanalysis (ED-EPMA) of elemental composition and thickness of Fe-Ni alloy films, SURFACE AND INTERFACE ANALYSIS 2012, 44 1459-1461 [12] Brewer P.J., Panagoulia D., Brown R.J.C., Tromans A., Reyes A., Arce M., Vospelova A., Roziková M., Pratt K.W., Asakai T., Jakobsen P.T., Camões M.F., Oliveira C.S., Godinho I., Spitzer P., Sander B., Máriássy M., Vyskočil L., Fisicaro P., Stoica D., Uysal E., International comparison on Ag|AgCl electrodes for pH measurement, MEASUREMENT 2015, 66, 131-138 [13] Pawlowicz, R.; Feistel, R.; McDougall, T. J.; et al., Metrological challenges for measurements of key climatological observables Part 2: Oceanic salinity METROLOGIA 2016, 53, R12-R25 [14] H.-B. Yoo et al.: "International Comparison of Enumeration-Based Quantification of DNA Copy- Concentration Using Flow Cytometric Counting and Digital Polymerase Chain Reaction, Anal. Chem. 88 (2016) 12169-12176 [15] Naoko Nonose, Toshihiro Suzuki, Ki-Cheol Shin, Tsutomu Miura, Akiharu Hioki, Characterization of a new candidate isotopic reference material for natural Pb using primary measurement method, Analytica Chimica Acta, Volume 974, 2017, Pages 27-42 [16] Philip J. H., Dmitry Malinovsky & Heidi Goenaga-Infante, Analytical and Bioanalytical Chemistry, April 2015, Volume 407, Issue 11, pp 3169–3180, Calibration strategies for the determination of

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stable carbon absolute isotope ratios in a glycine candidate reference material by elemental analyser-isotope ratio mass spectrometry [17] Pramann A, Narukawa T, Rienitz O, Metrologia , Volume 54, Number 5,2017; Determination of the isotopic composition and molar mass of a new 'Avogadro' crystal: homogeneity and enrichment-related uncertainty reduction - https://doi.org/10.1088/1681-7575/aa7bf3 [18] Assignment of purity to primary metal calibrants using pin-cell VG 9000 glow discharge mass spectrometry: a primary method with direct traceability to the SI international system of units? Sturgeon R.E., Methven B., Willie S.N., Grinberg P., Metrologia, 2014, 51, 410-422 [19] Use of Instrumental Neutron Activation Analysis to investigate the distribution of trace elements among subsamples of solid materials; D'Agostino G., Bergamaschi L., Giordani L., Oddone M., Kipphardt H., Richter S3, Metrologia, February 2014, 51(1):48-53 [20] Ting Huang, Wei Zhang, Xinhua Dai, Liang Huang, Can Quan, Hongmei Li and Yi Yang Analytical Methods, 2016, 8, 4482-4486 [21] Wei Zhang, Ting Huang and Hongmei Li Talanta, 2017, 172, 78–85) [22] Hui Ling Teo, Lingkai Wong, Qinde Liu, Tang Lin Teo, Tong Kooi Lee, Hian Kee Lee, Analytica Chimica Acta, 912, 2016, 49-57). [23] Ee Mei Gui, Ting Lu, Tang Lin Teo, Pui Sze Cheow, Tong Kooi Lee Analytical and Bioanalytical Chemistry, 409, 2017, 6069-6080 [24] Doo Kim, Yong & Hwan Kang, Ji & Kil Bae, Hyun & Kang, Namgoo & Hyub Oh, Sang & Lee, Jin-Hong & Chun Woo, Jin & Lee, Sangil. (2017). Development of a Novel Leak-Free Constant-Pressure Cylinder for Certified Reference Materials of Liquid Hydrocarbon Mixtures. Analytical Chemistry. 89 10.1021/acs.analchem.7b03858. [25] Eon Kim, Mi & Doo Kim, Yong & Hwan Kang, Ji & Heo, Gwi & Lee, Dong & Lee, Sangil. (2016). Development of traceable precision dynamic dilution method to generate dimethyl sulphide gas mixtures at sub-nanomole per mole levels for ambient measurement. Talanta. 150. 516-524. 10.1016/j.talanta.2015.12.063.

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Appendix 1 :BIPM Laboratory activities as part of the CCQM Strategic Plan CCQM Strategy document references to laboratory activity at the BIPM

The BIPM Chemistry Department coordinates key comparisons and pilot studies prioritized by the CCQM in response to NMI needs (6 key comparisons were coordinated in the period 2013-2016, with over 100 NMI participations in these comparisons). The BIPM activities have been strategically focused to meet CCQM comparison needs for:

a) greenhouse and air quality gases, for which the uncertainty of standards is critical, to ensure the long term accurate global monitoring of these species, including BIPM.QM-K1 for surface ozone; b) the purity assessment of pure organic calibrators for both small and large organic molecules. Coordination of an on-going series of 3 comparisons covering small organic molecule based CMCs, and comparisons for large organic molecules, with current focus on peptide calibrators.

The BIPM Chemistry Department provides the Secretariat for the Joint Committee for Traceability in Laboratory Medicine (JCTLM), as well as running capacity building and knowledge transfer laboratory activities related to calibrators relevant to the fields of Metrology for Safe Food and Feed and Clean Air.

BIPM Laboratory Activities to meet future CCQM Strategic Plans

The future CCQM strategic plan relies on a range of comparisons underpinning a broad range of NMI capabilities through core capability comparisons in addition to specifc analyte-matrix comparisons which are required when uncertainties are challenging and critical to the application of the capability.

In consequence, CCQM comparisons vary amongst:

a) irregular/’one off ‘ comparisons to comparisons with regular repeat periodicities to closely monitor long term performance of capabilities;

b) comparisons which underpin fundamental and more stable capabilities (e.g. primary reference materials/calibrators) versus comparisons that underpin applied and changing capabilities (e.g. complex matrix reference materials)

BIPM laboratory activities enable a long-term commitment to comparison coordination, which is best adapted to periodic comparisons, underpinning fundamental capabilities, and allowing close monitoring of their performance. The CCQM strategy document foresees BIPM coordinated CCQM comparisons for a) primary calibrators for prioritized green-house gases and air quality gases, and b) purity assessment capabilities for primary reference materials for small and large organic molecules The on-going requirement for these comparisons can be best met through BIPM laboratory coordination of the comparisons, since:

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a) the comparisons are fundamental to a broad range of NMI services and require a long-term commitment to their coordination that can be met by the BIPM; b) comparability at the smallest levels of uncertainty need to be demonstrated for high impact measurands on a continued basis; this is bet met with a long-term comparison programme, as established and demonstrated at the BIPM. The CCQM tables of future comparisons for 2017-2026 have been developed with input from all WGs, and the BIPM has already been identified as the comparison coordinator for the comparisons in the tables below, developed from the Gas, Organic and Protein Analysis WGs. Required Key comparisons and pilot studies 2017-2026 with indicative repeat frequency from CCQM (WG) Planned comparisons

Sub Area Reference No. DescriptionPilot (Coordinating) Laboratory

Expected Start date Rational for Key Comparison

GAWG BIPM.QM-K1 KC (Ozone at ambient level) BIPM2007 - ongoing Atmospheric and air quality

OAWG CCQM-K78.a Mass Fraction of Organic Calibration Solutions (low MW, high polarity, multi-component) - mixed amino acid solution

BIPM 2017 Track A comparison

GAWG CCQM-K137 Track A KC (NO in Nitrogen, 30-70 μmol/mol) BIPM 2017

Atmospheric and air qualityRepeat of CCQM-P73track A for 70 μmol/mol, not for 30

OAWG CCQM-K148.a Purity assessment of high purity organic materials: MW 100-500, non-polar analyte, Bisphenol A

BIPM 2018 Track A comparison

GAWG CCQM-K74.2018 KC (NO2 in Nitrogen, 10 μmol/mol) BIPM 2018Atmospheric and air qualityRepeat KC of CCQM-K74 in 2018

GAWG CCQM-P172PS (NO2 in Nitrogen, 10 μmol/mol, Spectroscopic impurity study by FTIR) BIPM 2018

Spectroscopic study of HNO3, NO, etc. as impurities in NO2/Nitrogen

PAWG CCQM-K155.b Oxytocin purity BIPM 2018 Protein measurement - underpinning capability

GAWG CCQM-K68.2019 KC (Ambient N2O) BIPM with KRISS 2019Atmospheric and air quality, Automotive exhaust gases

PAWGCCQM-K155.c HbA1C hexapeptide purity BIPM/HSA/NIM 2019

Protein measurement - clinical requirementOAWG CCQM-K78.b Mass Fraction of Organic Calibration Solutions:

Non-polar multi-componentBIPM 2020 Track A comparison

GAWG CCQM-PXX PS (Carbon/Oxygen isotope ratios in CO2 ) BIPM with IAEA 2020 Atmospheric and air qualityOAWG CCQM-K148.b Purity assessment of high purity organic

materials: MW 100-500, polar analyte BIPM 2021 Track A comparison

PAWG CCQM-K155.d Peptide calibrator purity: Straight chain, MW 5-10 kDa BIPM 2021 Protein measurement - underpinning capability

GAWG BIPM.QM-K2 KC (Ambient CO2) BIPM 2022On-going comparison for CO2 standards, based on PVT facility at the BIPM

OAWG CCQM-K148.c Purity assessment of high purity organic materials: Large MW (500 Da to 1000 Da)

BIPM 2023 Track A comparison

GAWG CCQM-KXX CO2 isotope BIPM with IAEA 2023 Atmospheric and air quality

GAWG CCQM-K82.2023KC (Ambient methane) and pilot study on isotope ratios BIPM 2023 Atmospheric and air quality

PAWG CCQM-K155.e Peptide calibrator purity: Cross-linked, MW 5-10 kDa BIPM 2024 Protein measurement - underpinning capability

PAWG CCQM-K155.f Peptide calibrator purity: Multiple Cross-links, MW < 5kDa BIPM 2024 Protein measurement - underpinning capability

GAWG CCQM-K120.2026 KC (Ambient CO2) BIPM 2026Atmospheric and air qualityAmbient lebel GHG, CO2 in a matrix of air

GAWG CCQM-K90.2026 KC (Formaldehyde 1 μmol/mol in nitrogen) BIPM 2026 Atmospheric and air qualityGAWG CCQM-K137.2027 Track A KC (NO in Nitrogen, 30-70 μmol/mol) BIPM 2027 Track AGAWG CCQM-K68.2027 KC (Ambient N2O) BIPM 2027 Atmospheric and air quality

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Appendix II: Examples of the impact of CCQM Comparisons and the calibration and measurement capabilities they support (2012-2016)

A) Impact of CCQM Activities in the Healthcare Area Case Study 1: International Equivalence of Vitamin D in Serum Measurements Vitamin D has been described as the “Vitamin of the decade” with a growing list of adverse health outcomes linked to its deficiency. There has been an associated significant increase into research to provide better understanding of vitamin D metabolism and function and a complex range of roles of this steroid hormone have emerged. Vitamin D is being studied for its possible connections to conditions such as diabetes, hypertension, autoimmune diseases, bone disorders and some types of cancer. High levels of Vitamin D can also be toxic and lead to a range of symptoms with excess vitamin D reported to lead to damage to the kidneys. A wide range of platforms are used within the clinical community for the measurement of serum levels of vitamin D such as radioimmunoassay, enzyme immunoassay, chemiluminescent immunoassay and high pressure liquid chromatography mass spectrometry (LC-MS/MS). Across these different platforms significant differences have been observed in measured vitamin D levels and even within platforms across different manufacturers there have also been differences observed. This has led to numerous reports of concerns over “considerable inter-assay variability” in the literature and in the press. Over the last decade there has been a world-wide increase in the level of vitamin D testing. In Australia, for example, an almost 4,000 per cent jump in the number of patients having their vitamin D levels checked has occurred and this has prompted many countries to place restrictions on rebates to attempt to control the level of testing which is occurring. This increase has not only been linked to the growing awareness of the importance of vitamin D but also the lack of trust in the quality of measurements prompting regular repeat testing requests. The international acceptance of the importance of vitamin D and the issues associated with the comparability of measurements prompted the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) to establish the Vitamin D Standardization Program (VDSP) in 2010. The goal of the VDSP is to improve the detection, evaluation, and treatment of vitamin D deficiency by promoting the standardized laboratory measurement of serum total 25-hydroxyvitamin D [25(OH)D] to improve clinical and public health practice worldwide. Several metrology institutes are involved in the VDSP and are working on programs to provide appropriate certified reference materials for both calibration and validation of vitamin D metabolite testing. CCQM have coordinated a large number of key comparisons examining important clinical analytes to support the demonstration of the equivalence of higher order measurement services being provided by metrology institutes in this crucial area of clinical chemsitry. Vitamin D is a fat soluble vitamin that is obtained from sun exposure, food, and supplements, however it is biologically inert and must undergo hydroxylation within the body for activation. This occurs in both the liver and kidneys to produce the two main 25-hydroxyvitamin D metabolites.

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These metabolites are present in combination with other minor forms of vitamin D making the accurate detection of this vitamin challenging, particularly in platforms such as immunoassays. In addition, the concentration of these metabolites in serum are very low. The international importance of vitamin D within the clinical community, combined with its specific measurement challenges prompted CCQM to coordinate a dedicated key comparison examining the measurement of the two major metabolites of vitamin D in serum. This study extended the mass fraction capability range to 105 to 106 times lower than that demonstrated in previous CCQM key comparisons for similar types of clinical analytes, e.g. cholesterol. In CCQM-K132 metrology institutes demonstrated their capabilities for the measurement of vitamin D metabolites in two different serum pools. All participants demonstrated the capability of determining the main metabolite, 25(OH)D3, at levels ~25 ng/g with a CV of 3%. This comparison underpins critical programs covering the production of certified reference materials and the complementary provision of reference values for External Quality Assurance Schemes. It supports the VDSP and the broader international programs aimed at working towards improved comparability of this important clinical analyte. Case Study 2: International Equivalence, Accuracy and Traceability for Measurement of Clinical Enzymatic Activity α-amylase is a protein enzyme EC 3.2.1.1 that hydrolyses alpha bonds of large, alpha-linked polysaccharides, such as starch and glycogen, yielding glucose and maltose [1]. Serum α-amylase is produced mostly by the pancreas and saliva glands. Abnormally high amounts of the enzyme may indicate a pancreatic condition such as cancer or necrosis. Conditions affecting the kidneys or liver may also result in high serum α-amylase levels. The serum α-amylase test is generally used to help diagnose and monitor acute pancreatitis. It is often ordered along with a lipase test. It may also be used to diagnose and monitor other disorders that may involve the pancreas. Therefore, in order to make accurate diagnosis of pancreas related diseases, it is important to obtain the accurate measurement results of serum α-amylase and make them comparable across various clinical laboratories and platforms. ISO 18153, In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values for catalytic concentration of enzymes assigned to calibrators and control materials, describes the traceability of enzyme assays. The IFCC has established reference measurement procedures to standardize the measurement of enzyme catalytic concentrations and the serum α-amylase is also included [2]. Different from common organic compound quantitation, though the measurement result of the enzyme activity can be traced to the SI unit of katal, it is defined by the reference measurement procedures. Therefore, in order to measure the accurate serum α-amylase activity, all measurement conditions specified in the reference measurement procedures must be strictly controlled and maintained. Successful participation in the study of serum α-amylase activity measurement requires not only the measurement capability of serum α-amylase, but also the measurement and control capability for each key parameters specified in the reference measurement procedure. The CCQM-P137 study coordinated by NIM China allowed 6 NMIs to demonstrate their capabilities for the catalytic concentration measurement of serum α-amylase, which can be used for the value assignment of related certified reference materials and allows NMIs to establish calibration hierarchies for serum α-amylase measurements. Similar measurement procedures have been

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adopted by other clinical enzymes, such as alkaline phosphatase, alanine aminotransferase, Gamma-glutamyl transferase. Currently, the majority of biological measurements in area of health care cannot be made traceable to SI units and they measurement results are often method-dependent. This study has highlighted how method-dependent measurements can benefit from the establishment of calibration hierarchies. Maureen Barlow Pugh, ed. (2000). Stedman's Medical Dictionary (27th ed.). Baltimore, Maryland, USA: Lippincott Williams & Wilkins. p. 65. ISBN 978-0-683-40007-6 International Federation of Clinical Chemistry and Laboratory Medicine, IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 °C, Clin Chem Lab Med 2006;44(9):1146–1155. Case Study 3: International Equivalence, Accuracy and Traceability for Measurement of Protein Diagnostic Markers Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Both the number of cases and the prevalence of diabetes have been progressively increasing over the past few decades. Globally, an estimated 422 million adults were living with diabetes in 2014. The worldwide prevalence of diabetes has nearly doubled since 1980, rising from 4.7 % to 8.5 % in the adult population. It has been estimated that the direct annual cost of diabetes to the world is more than EUR 700 billion. [1]. The improvement of diagnosis and management of diabetes in primary health care are key factors to reduce the impact of diabetes. Improved measurements of human C-peptide could lead to benefits for people with diabetes. In diabetes patients, a measurement of C-peptide blood serum levels can be used to distinguish between certain diseases with similar clinical features. As C-peptide is secreted in equal amounts to insulin but is eliminated much more slowly from the body, measuring it helps to determine the level of natural insulin a person is producing, even if they receive insulin injections. Reliable measurements of C-peptide can be used to assist classification and management of insulin-treated patients. It is therefore important that C-peptide measurements be harmonized to a common reference to compare and interpret results across various clinical trials and other research studies. A special report recently published by clinical chemists in collaboration with National Metrology Institutes (NMIs), including the BIPM, emphasizes the importance of calibration hierarchies in harmonizing C-peptide measurements to a common reference to enable comparison of results using different assay methods. The special report highlights the advantages of a new reference measurement system for C-peptide and identifies further requirements to ensure the successful implementation and sustainability of the system. It also provides an overview of the general process of harmonization and standardization and the challenges encountered with implementing a new reference measurement system [2,3]. The reference measurement system described in the report is supported by the CCQM-K115 key comparison coordinated by the BIPM together with NIM China, which allowed nine NMIs to compare their capabilities for value assigning peptide primary reference materials such as C-peptide [4]. The parallel CCQM-P55.2 pilot study permitted six NMIs to assess alternative methods for value assigning peptide primary reference materials [5]. A concept has been elaborated by the Focus Group I on peptide/protein purity for the strategic planning of ongoing PAWG key comparisons [6,7]. The C-peptide comparison was the first study of the CCQM-K115/P55.2 comparison series on assignment of the mass fraction content of high purity peptide/protein materials to directly support NMI services and certified reference materials currently being provided by NMIs.

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The production of reference materials, the development of reference measurement procedures, and the provision of reference measurement services often occur in different laboratories, making it essential for these organizations to work together to ensure consistency of results within the traceability chain. With the implementation of the European Union Regulation on in vitro diagnostic (IVD) devices [8], the metrological traceability of calibration and control materials for IVD became mandatory. Although an EU Regulation, this created a worldwide effect on clinical laboratory measurements as these devices are found on global markets. Following the work carried out by the Joint Committee for Traceability in Laboratory Medicine (JCTLM) a database exists to help industry meet regulations, by identifying available reference materials, methods and services that can be used to comply with metrological traceability requirements. Both higher-order reference materials and reference measurement methods/procedures are listed for C-peptide. WHO Global Report on Diabetes, World Health Organization, Geneva, 2016. Little RR et al., Implementing a Reference Measurement System for C-peptide: Successes and Lessons Learned. Clin Chem. 2017; 63(9):1447-1456. Little RR et al., Implementing a Reference Measurement System for C-Peptide: An Addendum. Letters to the Editor. Clin Chem. 2017; 63(12) in press. Josephs RD et al. Final Report on key comparison CCQM-K115: Peptide Purity - Synthetic Human C-Peptide. Metrologia. 2017;54: Tech. Suppl., 1A, 08007. Josephs RD et al. Concept Paper on SI Value Assignment of Purity - Model for the Classification of Peptide/Protein Purity Determinations. J Chem Metr. 2017; 11(1):1-8. Josephs RD et al., State-of-the-art and Trends for the SI Traceable Value Assignment of the Purity of Peptides Using the Model Compound Angiotensin I. Trends Anal Chem. 2017; in press. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017, Official Journal of the European Union, 2017, L 117/176.

B) Impact of CCQM Activities in the Environmental and Climate Change Monitoring Area Case Study 4: Underpinning Effective Environmental Contamination Monitoring Technical mixtures of polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants (i.e., to reduce the inflammability) in many combustible commercial and household products, such as polymers, electrical and electronic equipment, textiles, furniture, building and packaging materials. PBDEs are additive type brominated flame retardants, meaning that they are not chemically bound but only physically mixed/dissolved in the material. Due to the lack of covalent bonds between PBDEs and the material, the release of these compounds into the environment can occur not only when they are manufactured but also when products that contain them are used and disposed of. Environmental contamination by PBDEs has attracted public attention and concern in recent years due to their large scale use, high persistence, bioaccumulation and toxicity. Thus presenting a potential threat to wildlife and human health. The presence of PBDEs has been reported in a range of environmental media and biota including fish, sediment, treated sewage sludge and household dust. PBDEs are a class of chemical compounds and a number of the individual chemicals, PBDEs #28, 47, 99, 100, 153 and 154, are listed as Priority Substances under the EU Water Framework Directive (WFD) and they are also considered of primary interest for the environment in US and Canada (e.g., EPA Method 1614). The production and usage of PBDE technical mixtures began to be regulated in the early 2000s with the European Union banning Penta-BDE and Octa-BDE in 2004 and prohibiting the use of PBDEs (and polybrominated biphenyls) in electric and electronic devices in 2006. Despite the introduction of regulations around the world covering these chemicals, contamination from their use is still a

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significant environmental issue. The analysis of these chemicals is also challenging due to their toxicity at low levels and their presence as complex mixtures. The CCQM selected PBDEs in sediment as a model system for the core comparison CCQM-K102. The comparison selected three important PBDE congeners, PBDE-47, PBDE-99 and PBDE-153, as the target analytes, each representing a subtly different measurement challenge. The comparison was aimed at demonstrating the capabilities of institutes to measure complex non-polar environmental contaminants in abiotic sample types. Successful participation in the comparison allowed the bench marking of capabilities for those institutes providing reference materials or reference values in this important area. Case Study 5: International Equivalence, Accuracy and Traceability for Sea Salinity Measurements and Climate Change The 2002 IUPAC recommendation (Buck 2002) on pH in dilute aqueous solutions provides also a guideline for extending “definitions, standards, and procedures” to other important environments of both theoretical and practical relevance, e.g. non-aqueous and aqueous–organic mixed solvents. The prominent importance of this topic lies not only in the infinite number of different solvents (in principle, a slightly different amount of water in a binary water–organic co-solvent mixture constitutes a different solvent), but also in the huge field of applications (from industrial to analytical, from biological to environmental (Rondinini 2002). Much of the previous work was done on pH of potassium hydrogen phthalate (KHP) as the “reference standard” (Rondinini 1987) in different solvents. The CCQM P152 comparison was organised as a feasibility study to ensure metrological traceability of pH measurements in aqueous-alcoholic mixtures. The potassium hydrogen phthalate (KHPh) solution was studied as a possible primary buffer in water-ethanol mixture (mass fraction 50 %). The results of the study CCQM-P152 (Pilot study on pH of an unknown phthalate buffer in water-ethanol mixture (mass fraction 50 %)) clearly show that although such measurements are possible, the solutions in a water-alcohol mixture are inherently not stable and do not satisfy the primary buffer requirements. As an extension, any standardisation in alcohol-water mixtures has to be done using buffer systems that do not undergo esterification in the given medium. Buck, R.P et al., Measurement of pH. Definition, standards, and procedures (IUPAC Recommendations 2002), Pure Appl. Chem., 2002, 74, 2169-2200 Rondinini S., pH measurements in non-aqueous and aqueous–organic solvents – definition of standard procedures, Anal Bioanal Chem 2002, 374, 813-816 Rondinini S., Mussini P.R., Mussini T., Reference value standards and primary standards for pH measurements in organic solvents and water + organic solvent mixtures of moderate to high permittivities, Pure AppI. Chem., 1987, 59, 1549-1560 Case Study 6: Underpinning Effective Water Quality Chemical pollution from pharmaceutical residues in water supplies poses a threat to the aquatic environment and human health, and this phenomenon has become one of the major emerging environmental issues in recent decades. In Europe, the European Water Framework Directive (Directive 2000/60/EC) committed to achieve good qualitative and quantitative status of all water bodies within Europe by 2015. The framework laid down a strategy which involved the identification of priority substances that pose a significant risk to the aquatic environment and establishment of environmental quality standard (EQS) for the priority substances at union level. Accurate assessment methods for measuring hazardous substances in surface waters were highlighted as indispensable tools to safeguard the environment and the public health.

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This issue has become a priority area across the globe and in response to the importance of this issue internationally CCQM coordinated a key comparison CCQM-K126 for pharmaceuticals in surface water. The target analyte was a typical low-polarity pharmaceutical, carbamazepine. The carbamazepine in the comparison sample was at the ng/kg level to test the ability of NMIs and DIs to provide reference measurement services at levels relevant to regulatory limits. The comparison allowed the assessment of a wide range of analytical approaches to these measurements and showed very good comparability for the majority of the eight institutes who participated. With increasing water reuse and recycling the assessment of levels of compounds like pharmaceuticals in water will continue to be a high priority. Institutes that successfully demonstrated their capabilities in this comparison will have an international benchmark to underpin services they are able to offer across the broader classes of similar types of contaminants in water supplies. Case Study 7: New Generation standards for Greenhouse Gas Monitoring In the spring of 2015, the World Meteorological Organization (WMO) reported that the global average mole fraction of carbon dioxide (CO2) crossed the 400 µmol mol-1 threshold. The study of isotopic composition of CO2 in the atmosphere permits the identification of sources and sinks of carbon at local, regional, and global scale, and contributes to the understanding of their relative impacts on atmospheric concentrations.

Over recent years the introduction of Isotope Ratio Infrared Spectroscopy (IRIS), based on various spectroscopic techniques, has revolutionized stable isotope analysis in the atmosphere, allowing in-situ field measurements of the isotope ratio of CO2 in air, performed in real time directly on the air sample without separation of CO2 from air. Techniques that can be used include tunable diode laser absorption spectroscopy (TDLAS), quantum cascade laser absorption spectroscopy (QCLAS), cavity ring down spectroscopy (CRDS), off-axis integrated cavity output spectroscopy (OA-ICOS) and Fourier transform infrared spectroscopy (FTIR). At the same time the techniques are also used to measure CO2 mole fractions, and for the most accurate measurements calibration gases need to have their isotope ratios of the CO2 value assigned, either by sourcing air from natural sources [1,2] or by blending CO2 gases from different sources to achieve close to atmospheric ratios [3].

The equivalence of the next generation of CO2 in air standards that meet these requirements was addressed in the CCQM-K120.a and b comparisons, during which 46 standards were compared.

As part of the preparation for the comparison, methods to accurately calibrate optically based instruments for δ13C and δ18O measurements were developed and their performance validated [4]. In particular it was demonstrated that using only two mixtures with the same delta values and different mole fractions, bracketing the mole fractions to be measured, δ13C and δ18O values can be measured with uncertainties of 0.1 ‰ and 1.0 ‰ respectively. The comparison supports the development of the next generation of greenhouse gas standards, which will be valued assigned for CO2 mole fraction and isotope ratio and matrix matched to atmospheric compositions, providing instrument manufacturers and atmospheric scientists with the standards required to monitor CO2 mole fractions and isotope ratios accurately in real time. The activities have improved the state of the art in measurement science, benchmarked comparability and supported NMIs in working towards addressing the needs of stakeholders.

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[1] Rhoderick, G. C.; M. E. Kelley; W. R. Miller; G. Brailsford; A. Possolo. Analytical and Bioanalytical Chemistry 2015, 408(4): 1159-1169. [2] Rhoderick, G. C.; D. R. Kitzis; M. E. Kelley; W. R. Miller; B. D. Hall; E. J. Dlugokencky; P. P. Tans; A. Possolo; J. Carney. Analytical Chemistry 2016, 88(6): 3376-3385 [3] Brewer, P. J.; R. J. C. Brown; M. N. Miller; M. D. Miñarro; A. Murugan; M. J. T. Milton; G. C. Rhoderick. Analytical Chemistry 2014, 86(3): 1887-1893. [4] Flores E., Viallon J., Moussay P., Griffith D.W.T., Wielgosz R.I., Calibration strategies for FT-IR and other isotope ratio infrared spectrometer instruments for accurate δ13C and δ18O measurements of CO2 in air, Anal. Chem., 2017, 89(6), 3648-3655 C) Impact of CCQM Activities in the Food Area Case Study 8: Underpinning Food Fraud Detection Food fraud has become a growing concern with estimates that the global food industry loses over $US10 billion per year through food substitutions, dilutions and fake labels. Food fraud is defined as the deliberate and intentional substitution, addition, tampering, or misrepresentation of food, ingredients or packaging; or false or misleading statements made about a food, for economic gain. Food fraud incidents have also involved high profile cases where food consumers have been put at considerable risk and the need to protect consumers by strengthening the ability to detect fraud across supply chains has been an agreed priority within the food industry and analytical chemistry communities. A particular case of this involved the chemical melamine (1, 3, 5-triazine-2, 4, 6-triamine) that was first synthesized in 1834 and later found to have extensive uses in the industry. With high nitrogen content, the chemical can be unethically added to food products in order to increase the apparent protein content. The melamine incidents that occurred as a result of tainted pet food in the United States in 2007 and tainted milk powder in China in 2008 caused significant impact. After these crises, the analysis of melamine in food has become one of the important routine measurements for food testing laboratories. CCQM coordinated a specific key comparison CCQM-K103 “Melamine in Milk Powder” to demonstrate the capability of NMIs/DIs to analyse for traces of melamine in milk and milk powder. The key comparison assisted in ensuring the comparability of reference measurement procedures being used internationally to produce certified reference materials for food laboratories. In addition, several NMIs/DIs have been coordinating proficiency testing (PT) schemes for melamine in milk products and assigning reference values to the samples to provide participants with an independent benchmark to assess their accuracy. Melamine can be a challenging chemical to detect and quantify and tools such as matrix reference materials and PT schemes are essential in ensuring the quality of these measurements. Melamine continues to be a contaminant that is monitored in an ongoing way by the food industry and CCQM’s activities have helped ensure there is an effective internationally recognized metrology infrastructure to support this. D) Impact of CCQM Activities in the Energy Area Case Study 9: Diversification of the gas supply

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As worldwide natural gas resources are declining, there is a growing interest in exploiting alternatives to the use of conventional natural gas. Some of these alternatives do not only contribute to the availability of natural gas and its substitutes, but also to a reduction of greenhouse gas emissions. Examples of the latter include biogas, biomethane and liquefied biogas (LBG).

In the Gas Analysis Working Group (GAWG), several projects have been initiated to address the need of assessing the comparability of novel measurement standards and calibration methods. The projects so far (CCQM-K1efg, CCQM-K16, and CCQM-K23) were all focussed on natural gas. The values and uncertainties for the amount-of-substance fractions of the components as obtained from gravimetric gas mixture preparation were used as key comparison reference values. The key comparison CCQM-K77 aimed at assessing the comparability of measurement results for the composition of refinery gases. These gases are a by-product in the processing of crude oil and rich of hydrocarbons. The measurements are generally more challenging than those for natural gas, for these gases contain also unsaturated hydrocarbons, which are not saturated on gas chromatographs configurations designed for natural gas.

A second project addressing a natural gas substitute is CCQM-K112 Biogas. Biogas is very rich in carbon dioxide and nitrogen, and usually contains 0.3 % -- 0.6 % oxygen and approximately 1 % hydrogen. The results of the key comparison underlined the challenges with measuring the amount-of-substance fraction oxygen in energy gases. The comparison is operated using key comparison reference values from analysis, thus permitting to use transfer standards prepared by a third party. This design has been explored to see whether it leads to a reduction of the costs associated with the coordination and operation of a key comparison.

The forthcoming CCQM-K118 on natural gas is operated with a similar design as the biogas key comparison. It addresses, apart from the equivalence of natural gas measurement standards and calibration methods, two topics related to the diversification of the natural gas supply: (1) elevated levels of hydrogen and (2) very low levels (200 µmol mol-1) carbon dioxide. The elevated levels of hydrogen are relevant in those regions where hydrogen, produced from excess electricity from wind farms is converted into hydrogen and injected into the natural gas grid. The very low levels of carbon dioxide occur in LNG (liquefied natural gas).

Brown A.S., Jones D.N., Milton M.J.T., Downey M.L., Vargha G.M., Van der Veen A.M.H., Ent H., Arrhenius K., Tuma D., “Towards an European infrastructure for the characterisation of energy gases”, Proc. 2nd IMEKO TC 11 International Symposium Metrological Infrastructure, 2011 Van der Veen A.M.H., Ziel P.R., Li J., ”Validation of ISO 6974 for the measurement of the composition of hydrogen-enriched natural gas”, International Journal of Hydrogen Energy 40(46) (2015), pp. 15877-15884

E) Impact of CCQM Activities in Advanced Manufacturing Case Study 10: International Equivalence, Accuracy and Traceability for the Reliable Metrology for Advanced Thin Film Technologies Next generation electronic devices in the advanced industries, such as, semiconductors, displays, solar cells and light emitting devices are developed from various fabrication processes using thin films. Therefore, measurements of thickness, relative composition and chemical state of the films are important analytical issues and the development of traceable, repeatable and reproducible measurement methods for these measurands are required for a successful implementation of the technology.

In the Surface Analysis Working Group (SAWG) the amount of substance expressed as a film thickness and the chemical composition of thin films were measured by surface analysis methods, such as, Secondary Ion Mass Spectrometry (SIMS), Auger Electron Spectroscopy (AES) and X-ray Photoelectron Spectroscopy (XPS). These are the key metrologies and related to the SI units of length and amount of substance, respectively. In the past CCQM-K32 and -K67 were launched by the

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SAWG for the thickness measurement of nm SiO2 films on Si wafer and the chemical composition of nanoscaled binary FeNi alloy films, respectively. Recently relevant industries require also precise metrologies for the analysis of multi-element alloy thin films.

A Cu(In,Ga)Se2 (CIGS) film is a promising material for next-generation solar cells. Recently, a power conversion efficiency of 22.6% was achieved using CIGS based solar cells. The market size of thin film solar cells is anticipated to hit USD 30 billion by 2024. However, the analysis of CIGS film is very difficult because it is a multi-element alloy film with non-uniform in-depth distribution of the constituents.

A pilot study, CCQM-P140, was performed to address this problem and a variety of analytical approaches utilizing a total number counting (TNC) method to determine integrated signal intensities of the constituent elements. Relative sensitivity factors of Cu, In, Ga and Se were determined from the mole fractions of a CIGS CRM certified by isotope dilution ICP-MS.

The subsequent CCQM-K129 key comparison showed that a degree of equivalence can be for Cu small as 0.0228 mol/mol. The result of CCQM-K129 was that the quantification of multi-element alloy films is possible by depth profiling analysis using the TNC method. The calibration and measurement capabilities reached at NMIs and proved by the Key Comparison can be achieved for thin film analysis of a variety of multi-element alloy films used in various advanced industries. F) Impact of CCQM Activities on the redefinition of the units Case Study 11: Application of isotope ratio measurements to fundamental metrology

The ongoing international effort to redefine the kilogram and the mole in terms of the fundamental constants is now well known. The kilogram will be defined in terms of an exact, fixed value of the Planck constant (h) which is being determined by two quite different, independent techniques. One technique uses a watt balance to determine h directly. The other approach, called the x-ray crystal density (XRCD) method, determines h indirectly by measuring the Avogadro constant NA and converting it to the Planck contant via the molar Planck constant (NAh). This is achieved by measuring the number of silicon atoms in a kilogram of silicon. The practical realisation of this measurement requires highly pure and polished single crystal Si spheres made from isotopically enriched Si (x(28Si) > 0.999 96 mol/mol). The Avogadro constant NA can then be determined from measurements of the mass, volume, crystal lattice parameter and molar mass of the sphere. A key requirement for the molar mass determination is measuring the absolute isotopic composition of the silicon. The molar mass is calculated by multiplying the amount-of-substance fractions by the relative atomic masses of the three naturally occurring silicon isotopes (28Si, 29Si, 30Si). The Si isotopic measurements have presented a demanding experimental challenge which has been met by members of the Inorganic Analysis WG of the CCQM.

The Inorganic Analysis WG has metrological experience of isotopic measurements dating back 20 years having established isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS) as the reference method of choice for a wide range of inorganic measurement applications. Recent results for isotopic composition obtained by INRIM and ANSTO in the framework of the Avogadro measurements demonstrated that Instrumental Neutron Activation Analysis (INAA) can be used as a complementary method. The WG has validated a range of isotopic composition measurements through a number of key comparisons and pilot studies, including: CCQM-K98 (isotopic composition of Pb in solution and in bronze), CCQM-K122 ( including isotopic compositions and molar mass of Pb), CCQM K140 (carbon stable isotope ratio delta values in honey), CCQM-P48 (Uranium Isotope Ratio in Synthetic Saline Matrix), CCQM-P75 (stable isotope delta values in methionine), CCQM-P105 (Sr isotopic ratio measurements) and CCQM-P160 (isotope ratios / molar mass measurements of Si isotopes in isotopically enriched silicon).

Notwithstanding the previous experience of the WG members, measurement of the silicon sphere molar mass with sufficiently small uncertainty to meet the needs of the redefinition project required

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major advances in isotopic composition determination by the six NMIs (KRISS, NIM, NIST, NMIJ, NRC and PTB) all of whom contributed to this work. Particular issues which had to be addressed included: selection of an optimum solvent for dissolution of the silicon and for the ICP-MS measurements; the enormous disparity in amount between 28Si and the other two isotopes; overcoming instrumental interferences when determining the very low levels of 29Si and 30Si; correcting for instrumental mass bias (K-factor calibration) between the three isotopes; methodology for processing the ICP-MS data to achieve a relative uncertainty of the molar mass of the silicon crystal of less than 1 × 10−8. CCQM-P160 has facilitated a collaborative investigation of some of these issues.

The most recent work on this task has been the determination of NA with two independently grown 28Si -enriched crystals with an agreement at the level of a few parts in 108. It has also been possible to compare the XRCD results with the most accurate results of the watt balance by calculating a value of NA from the Planck constant, again using the molar Planck constant for the conversion. The difference is again just a few parts in 108, confirming that the XRCD method is a robust and unbiased method for the realization of the new definition of the kilogram.

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