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Crm chemical measurements

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    Crm   chemical measurements Crm chemical measurements Document Transcript

    • A global view on production of certified reference materials for chemical measurements A global view on production of Topics include: certified reference materials • Use and importance of CRMs for chemical measurements • Definitions • Relevant general normative standards Uma visão geral sobre a produção • Sources of CRMs de materiais de referência certificados • Responsibilities for providers and users of CRMs Reenie M. Parris • Challenges for users Chemical Science and Technology Laboratory National Institute of Standards and Technlology (NIST) – USA • Challenges for providing and maintaining a virtual global system of needed tools to underpin Reenie.Parris@nist.gov (can email me for pdf copy of slides as presented) 100 Bureau Drive, MS 8300, Gaithersburg, MD 20899-8300 USA chemical metrology. If I’m talking too fast – please wave your hands! www.nist.gov19 July 2007 1 2 Mechanisms/Tools for Dissemination to Customers of • Previously here at METROCHEM IV, speakers have well A National Metrology Institute’s (NMI) presented: Calibration and Measurement Capabilities (CMC) – The need for confidence in and acceptance of the for Chemical Measurements results of chemical measurements as published in Appendix C of the CIPM MRA may include: – Impact and importance of this to trade, innovation, quality-of-life, etc. – Reference Methods / Procedures – International strategies/programs established to – Certified Reference Materials / Reference Materials facilitate comparability and demonstration of – Certified Reference Data / Reference Data – Calibration Services calibration and measurement capabilities for chemical – Testing Services / Value-assignment of customer-supplied measurements materials See that CRMs are ONLY ONE of these NMI dissemination tools. 3 4 As example of types and categories:• There are many different providers / sources of CRMs. NIST Standards for Chemical Measurements• Typically, however, these meet the accepted definition of a • High Purity Neat Chemicals CRM. Providers include: • Organic Solution Standards – National Measurement Institute (NMI) or designated institute (DI) • Inorganic Solution Standards responsible for national standards • Gas Mixture Standards – Reference Laboratory as designated by a governmental body, Complex Matrix Standards regulatory body, customer sector group, national or international • Advanced Materials organization, provided for by normative standard requirements, etc. – • Biological Fluids/Tissues may provide CRMs • Foods/Botanicals • Geologicals – Commercial providers of certified reference materials, reference • Metals and Metal Alloys materials and/or proficiency testing • Fuels / Energy Products • Sediments/Soils/Particulates • Cements• There are appropriate roles and needs for these various CRMs in the metrological hierarchy. • Molecular Spectrometry Standards• However, the use of the term “Certified Reference Material” • Electrolytic Conductivity Standards • pH / Ion Activity Standards is not restricted and thus can be misused. 5 Chemical standards constitute over 2/3 of ~1,400 NIST SRM types and ~24,000 of over 31,000 6 NIST SRM Units sold in FY06
    • “VIM 3 (Draft)”: 5.13 (6.13) reference material (continued) Next, a few definitions: *NOTES 1— ‘Reference material’ comprises materials embodying quantities as well as nominal“VIM 2”: International Vocabulary of basic and general standard terms in properties Metrology (VIM), 2nd Edit., ISO, Geneva, Switzerland, 1993 *EXAMPLES OF REFERENCE MATERIALS EMBODYING QUANTITIES b) human serum without an assigned quantity value for the concentration of the inherent cholesterol, used only as a measurement precision control material• Reference Material (RM): c) fish tissue containing a stated mass fraction of a dioxin, used as a calibrator A material or substance one or more of whose property values are *EXAMPLES OF REFERENCE MATERIALS EMBODYING PROPERTIES sufficiently homogeneous and well established to be used for the e) DNA compound containing a specified nucleic acid sequence calibration of an apparatus, the assessment of a measurement method, or f) urine containing androstenedione for assigning values to materials. [ISO VIM: 1993, 6.13] 2— In this definition, “value” covers both quantity value and ‘nominal property value’. 3— Reference materials with or without assigned quantity values can be used for precision control whereas only reference materials with assigned quantity values can be used for“VIM 3 Draft”: International Vocabulary of Metrology – Basic and General calibration or measurement trueness control. Concepts and Associated Terms (VIM), Draft of 2006-08-01 VIM 3rd Edit. 4— Some reference materials have quantities that are metrologically traceable to a measurement unit outside a system of units. Such materials include vaccines to which International Units (IU) have been assigned by the World Health Organization.• 5.13 (6.13) 5— The specifications of a reference material should include its material traceability, indicating reference material its origin and processing. RM 6— In a given measurement, a reference material can only be used for either calibration or material, sufficiently homogeneous and stable regarding one or more quality assurance. properties, used in calibration, in assignment of a value to another material, 7— A reference material is sometimes incorporated into a specially fabricated device. EXAMPLES or in quality assurance b) glass of known optical density in a transmission filter holder 7 c) spheres of uniform particle size mounted on a microscope slide 8 *Typically, only Notes, Examples, etc. that relate to chemical measurements are shown in these slides.“VIM 2”: “VIM 3 Draft”: 5.14 (6.14) certified reference material (continued)• Certified Reference Material (CRM) reference material, accompanied by documentation issued by an authoritative body and referring to valid A reference material, accompanied by a certificate, one or more of whose procedures used to obtain a specified property value with uncertainty and traceability property values are certified by a procedure which establishes its traceability to an accurate realization of the unit in which the property EXAMPLE values are expressed, and for which each certified value is accompanied by human serum with assigned quantity value for the concentration of cholesterol and an uncertainty at a stated level of confidence. [ISO VIM: 1993, 6.14] associated measurement uncertainty stated in an accompanying certificate, used as calibrator or measurement trueness control material NOTES“VIM 3 (Draft)”: 1 — The “documentation” is given in the form of a ‘certificate’, see ISO Guide• 5.14 (6.14) 30:1992. certified reference material 2 — Valid procedures for the production and certification of certified reference CRM materials are given, e.g., in ISO Guides 34 and 35. reference material, accompanied by documentation issued by an 3 — In this definition, “uncertainty” covers both ‘measurement uncertainty’ and authoritative body and referring to valid procedures used to obtain a ‘uncertainty of a nominal property value’, such as for identity and sequence, specified property value with uncertainty and traceability expressed as probabilities. “Traceability” covers both ‘metrological traceability‘ of a quantity value and ‘traceability of a nominal property value. 4 — ‘Certified reference material’ is a specific concept under ‘reference material’ 5 — Specified quantity values in certified reference materials require metrological traceability with associated measurement uncertainty. 9 10 VIM 2 Traceability*: The property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually • The 2nd edition of the International Vocabulary of Basic national or international standards, through an unbroken chain of comparisons, all having stated uncertainties. and General Terms in Metrology was published in 1993. The need to cover measurements in chemistry and VIM 3 DRAFT 2.41 (6.10) laboratory medicine for the first time, as well as to metrological traceability incorporate other additional concepts, such as several property of a measurement result whereby the result can be related to a which relate to metrological traceability, measurement stated reference through a documented unbroken chain of calibrations, uncertainty, and nominal properties (commonly obtained each contributing to the measurement uncertainty by “qualitative measurements”), led to the 3rd edition. Note the difference here between the use of “metrological traceability” and the term relating to traceability of products. Both refer to a “pedigree” but • Furthermore, an attempt has been made to meet one refers to metrology criteria and the other to chain of custody. conceptual needs of measurements in fields such as biochemistry, food science, forensic science, and VIM 2 molecular biology. Uncertainty (of measurement): “A parameter associated with the result of a measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measurand.” 11 12 Applicable ISO/REMCO documents
    • “Accuracy” series”CRMs – General Standards / Guides (there are additional Standards ISO/TR 22971:2005. Accuracy (trueness and precision) of measurement methods and results -applicable for RMs for use in specific customer sectors) - Practical guidance for the use of ISO 5725-2:1994 in designing, implementing and statistically analysing interlaboratory repeatability and reproducibility resultsISO/IEC 17025 – “General requirements for the competence of testing andcalibration laboratories” ISO/TS 21748:2004 Guidance for the use of repeatability, reproducibility and trueness estimates in measurement uncertainty estimationISO Guide 30:1992, Terms and definitions used in connection with referencematerials. ISO 5725-1:1994/Cor 1:1998 Accuracy (trueness and precision) of measurement methods and results -- Part 1: General principles and definitionsISO Guide 31:2000 – “Reference materials -- Contents of certificates and ISO 5725-2:1994/Cor 1:2002 Accuracy (trueness and precision) of measurement methods andlabels” results -- Part 2: Basic method for the determination of repeatability and reproducibility of a standard measurement methodISO Guide 32:1997 – “Calibration in analytical chemistry and use of certifiedreference materials” ISO 5725-3:1994/Cor 1:2001 Accuracy (trueness and precision) of measurement methods and results -- Part 3: Intermediate measures of the precision of a standard measurement methodISO Guide 33:2000 – “Uses of certified reference materials” ISO 5725-4:1994Accuracy (trueness and precision) of measurement methods and results --ISO Guide 34:2000 – “General requirements for the competence of reference Part 4: Basic methods for the determination of the trueness of a standard measurement methodmaterial producers” ISO 5725-5:1998/Cor 1:2005 Accuracy (trueness and precision) of measurement methods andISO Guide 35:2006 – “Certification of reference materials -- General and results -- Part 5: Alternative methods for the determination of the precision of a standardstatistical principles” measurement methodILAC G12:2000 Guidelines for the Requirements for the Competence of 13 ISO 5725-6:1994 Accuracy (trueness and precision) of measurement methods and results -- 14Reference Materials Producers Part 6: Use in practice of accuracy values Critical parameters for provider’s planning and design of a CRM and a user’s choice of an appropriate CRM Certified Reference Materials (CRMs) that are: include: • appropriate for their intended use, and – Intended use of CRM and appropriateness of following for its intended use: • recognized as appropriate by users of these • “measurand” / property as measured / stated materials and users of data resulting from their use • matrix are critical quality assurance components for various • form of CRM as provided aspects such as calibration, method validation, • quantity of CRM available and for which certified value is applicable traceability, etc. of schemes for providing confidence • assigned value and degree of expanded uncertainty and demonstrating comparability of chemical • value assignment mechanism/approach measurements to facilitate their mutual recognition and • traceability linkage; stringancy and appropriateness acceptance of and that may be required by various • homogeneity and stability assessment • uncertainty components and expression of uncertainty regulatory or program needs. • required/needed information for certificate/report 15 16 For measurand: Value-assignment What is the assigned-value meant to provide: From Section 9 of the ISO Guide 35 (2006) for Reference Materials - “There are a number of technically valid approaches to the • “Truth” assignment of property values. – Realization of the SI units: Mole, kilogram, meter • What a standard method should get These include measurement with one or more methods involving one – Method-dependent value or more laboratories. – Realization of operationally defined process • Other??? An appropriate approach can be chosen depending on the type of reference material, its end-use requirements, the qualifications of the laboratories involved, the quality of the “Cadmium” in a soil material as xx mg/kg method or methods, and the ability to estimate the uncertainty associated with the characteristics realistically”. or “Cadmium by US EPA Method yyy” in a soil material or “Cadmium by Brazilian Method zzz” in a soil material or ??? 17 18
    • A number of approaches are used to certify values in CRMs. Responsibilities: These include: : CRM Material Providers: a) Use of Known / Calculated values - with results determined by specific • Provide design/process to assure “quality” of reference or test item formulation (e.g. manufacture or dilution). proficiency test material and its assigned value(s) b) Use of Validated Reference Procedures - as determined by definitive • Provide documentation and information to user to support methods (for quantitative tests). [some refer to definitive methods as primary value-assignment and claim of traceability methods] • Provide information as to intended use and appropriate use c) Use of a specified Measurement Process (method dependent, of material empirical method). • Appropriate use of ISO Guide 30 series and other relevant d) Consensus values from expert laboratories - expert laboratories guides and standards should have demonstrated competence . . . e) Consensus values from participant laboratories Users of material and/or users of resulting analytical data: f) Combinations of these • Assess relevancy and suitability of CRM, including the specified measurand, the measurand assigned value, and its associated uncertainty, for THEIR intended use and program / regulatory / quality system needs 19 20 Challenges associated with chemical • Critical information regarding the scope of usage and use instructions for a specific CRM should be provided in the Certificate accompanying the measurements of “real samples” CRM (see ISO Guides 30-35 series). • The degree to which CRMs are characterized, the detail of information provided to the user including the traceability linkage and components of – tasked with accurately measuring the uncertainty of the certified values are highly variable among various “practically nothing” in the midst of providers. “everything else” without the benefit of • A CRM user is responsible for choosing the most appropriate material for absolute or quantum-based methods a given purpose. – multiplicity of methods being used • General guidelines for choosing appropriate CRMs and RMs as well as their appropriate use are addressed in numerous standards and other – multiplicity of analytes and matrices documents and publications. 21 22 A Context for the Complexity of Chemical ... an example of this complexity Measurements Regulated Classes of Chemicals in Foods Nominal Concentrations of Measurands in Foods • 50 to 60 elemental species of importance 1 g/g proximates dietary fiber minerals • >105 organic species• According to a study released by the Council for Chemical Research, chemistry is core or GMOs in a wide variety of 1 mg/g important to virtually all industrial sectors and trans fatty acids sample types technology areas caffeine – “Measuring Up: Chemical R&D Counts for Everyone”, CCR, 2006 nitrates • covering 12 orders of 1 µg/g vitamins magnitude in allergens• For metrology in chemistry the task is to toxic elements (lead, mercury) concentration. determine the quantity of a specific chemical 1 ng/g pesticides entity and not merely "amount of substance" marine biotoxins (okadaic acid, yessotoxins) 0% Protein 100% Fat veterinary drug residues + mass fraction• Chemical measurements are multidimensional mycotoxins (aflatoxin, ochratoxin) 10 ? rices 1 pg/g <10-12 to 1 – a large number of chemical entities (>105) PAHs 1 – in a broad range of matrices (10?) dioxins and dioxin-like PCBs at + + ++ – and mass fractions ranging from <10-12 to 1 3 fm All of these measurements are impacted by legislation. 2 4 + + #o + + + 5 + 6 + 7 8 9 + + + + 0% Fat + + + 100% Protein # of compounds measured 100% Carbohydrate 0% Carbohydrate >105 23 24
    • Some of the current challenges for CRM users that have been To define terms and criteria for NIST CRMs for chemical measurements - as a CRM Provider, NIST has provided SP 260-136 to the public: 260- expressed include: • describes seven modes NIST Special Publication 260-136 • Availability of materials fit-for-purpose for a specific use currently used at NIST for Standard Reference Materials • Costs value-assigning SRMs and Definitions of Terms and Modes Used • Problems with importing needed CRMs – such as RMs for chemical at NIST for Value-Assignment of Reference Materials for Chemical Measurements clearing customs, shipping times, maintaing needed measurements environmental conditions during shipping, etc. • defines data quality W. May, R. Parris, C. Beck, J. Fassett, R. Greenberg, F. Guenther, G. Kramer, and S. Wise Analytical Chemistry Division Chemical Science and Technology Laboratory • Various terms such as certified value, information value, descriptors used at NIST T. Gills, J. Colbert, R. Gettings, and B. MacDonald Standard Reference Materials Program reference value, non-certified value, etc. are used with for these SRMs and RMs Technology Services – NIST Certified Value National Institute of Standards and Technology no clear explanation of their meaning by some CRM – NIST Reference Value Gaithersburg, MD 20899-8390 providers – NIST Information Value • Varying degrees of provision of information on • links these modes to these Certificates as needed by users. three data quality U.S. DEPARTMENT OF COMMERCE, William M. Daley, Secretary TECHNOLOGY ADMINISTRATION, Dr. Cheryl L. Shavers, Under Secretary for Technology descriptors NATIONAL INSTITUTE OF STANDARDS AND TECHNOLOGY, Raymond G. Kammer, Director Issued January 2000 25 View/download from: http://ts.nist.gov/MeasurementServices/ReferenceMaterials/upload/SP260-136.PDF 26 Terms and definitions for use with NIST Reference Materials NIST Certified Value (for Chemical Composition and Related Properties) NIST Standard Reference Material® (SRM ): Provided on a NIST SRM Certificate - A CRM issued by NIST that also meets additional NIST certification • as a value for which NIST has the highest confidence in its criteria. NIST SRMs are issued with Certificates of Analysis or Certificates that accuracy in that all known or suspected sources of bias have report the results of their characterizations and provide information regarding been fully investigated or accounted for the appropriate use(s) of the material. – requires NIST measurements and oversight of the For RMs for Chemical Measurements, see NIST SP 260-136: 2000: experimental design for the value-assignment process Definitions of Terms and Modes Used at NIST for Value-Assignment of Reference Materials for Chemical Measurements. • with an associated uncertainty that – generally specifies a range within which the true value is expected to lie at a level of confidence of approximately 95% if the sample is homogeneous – generally represents a prediction interval within which the true values of 95% of all samples are expected to lie at a stated level of confidence if significant sample heterogeneity is included 27 28 Terms and definitions for use with NIST Reference Materials Terms and definitions for use with NIST Reference Materials NIST Information Value NIST Reference Value (for Chemical Composition and Related Properties) (for Chemical Composition and Related Properties) Provided on a NIST Certificate/Certificate of Analysis/Report of Provided on a NIST Certificate/Certificate of Analysis/Report of Investigation - Investigation - • as a best estimate of the true value where all known or • as a value that will be of interest and use to the SRM/RM user, suspected sources of bias have not been fully investigated by but insufficient information is available to NIST to assess the NIST uncertainty associated with the value • with an associated uncertainty that may not include all sources • typically,with no reported uncertainty listed of uncertainty and may represent only a measure of the precision of the measurement method(s) 29 30
    • Heterogeneity, Stability, Other Information Value Reference Value Modes Used at NIST for Value-Assignment of Components of Uncertainty of Assigned Value Certified Value Reference Materials for Chemical Measurements Important for provider to include uncertainty component for any significant heterogeneity in the material (typically with defined minimum sample size) in the uncertainty of the assigned value. 1. Certification at NIST Using a Primary Method with Confirmation by • If there is a predictable change in the assigned value over the time Other Method(s) of use of the material, the uncertainty is expanded to include this 2. Certification at NIST Using Two Independent Critically-Evaluated Methods component. 3. Certification/Value-Assignment Using One Method at NIST and Different • Sometimes, the uncertainty of an assigned value is expanded to Methods by Outside Collaborating Laboratories allow for use of the assigned value over a wider range of 4. Value-Assignment Based On Measurements by Two or More Laboratories temperatures. E.g.,. If the assigned value of a formulated solution Using Different Methods in Collaboration with NIST was prepared and value-assigned on a mass/mass basis – the value 5. Value-Assignment Based on a Method-Specific Protocol may to converted to mass/volume basis as well. The uncertainty 6. Value-Assignment Based on NIST Measurements Using a Single Method or would then be expanded to account for uncertainty in determination Measurements by an Outside Collaborating Laboratory Using a Single of density of the solution and to account for change in assigned Method value, say from 20 to 25 degrees C. 7. Value-Assignment Based on Selected Data from Interlaboratory Studies 31 32 As was discussed by Willie May in yesterday’s session: First Step Toward a Solution Stakeholder Workshop with Attendees representing: • IVD Manufacturers • Regulatory Agencies and Notified Bodies • Providers of Proficiency Testing Programs, Laboratory Accreditation, and Measurement Quality assessment Requirement of EC-IVD Directive Annex 1 (3) Materials • Laboratory professionals involved in standardization of “The traceability of values assigned to calibrators and/or control materials laboratory methods must be assured through available reference measurement procedures • International Standards Laboratories and/or available reference materials of a higher order.” Aim of the IVD Directive Next steps based on recommendation from this workshop “to ensure that IVDs do not compromise the health and safety of patients, users and third resulted in the establishment of an international consensus- consensus- parties and attain the performance levels attributed to them by their manufacturer. " based reference system for laboratory medicine. JOINT COMMITTEE on US IVD Manufacturers requested that NIST and other NMIs develop TRACEABILITY in reference materials and measurement procedures to assist them in LABORATORY meeting this new traceability requirement. MEDICINE (JCTLM) 33 34 Additional Applicable ISO Standards required for these “higher order” reference materials and reference Further activities have culminated in JCTLM Database* of measurement procedures for JCTLM databaseReference Materials and Reference Measurement Procedures of “Higher Order” • ISO 17511 In vitro diagnostic medical devices - Measurement of Required for use in qualifying in vitro diagnostic devices quantities in biological samples - Metrological traceability of values for use in numerous countries assigned to calibrators and control materials http://www.bipm.org/en/committees/jc/jctlm/ http://www.bipm.org/en/committees/jc/jctlm/ • ISO 15193 Presentation of reference measurement procedures • Note the difference in intent and content between this and the database comprising Appendix C of the CIPM MRA which lists • ISO 15194 Description of reference materials internationally reviewed and accepted listing of specific NMI / DI Calibration and Measurement CAPABILITIES. • ISO 15195 Reference measurement laboratories • CIPM MRA database entries are only from NMIs or national Officially-designated Institutes • ISO 18153 Metrological traceability of values for catalytic • JCTLM database entries can be accepted for inclusion from any concentration of enzymes assigned to calibrators and control provider IF they are approved by the relevant JCTLM international materials review team as meeting the technical and standards criteria as required in the Quality System and its cited normative standards. 35 36
    • JCTLM Database Comparability Assessment Studies JCTLM α-List: Potassium in Serum CRMs have been proposed for: As first set, NIST performed two independent sets of analyses on all proposed JCTLM α-List Serum Electrolyte CRMs for potassium. The ratio of the NIST measurements to the CRM certified values are shown below:• For Reference Materials and Reference Measurement The error bars represent 95% confidence intervals (k=2) Procedures listed in the JCTLM Database to be assessed for comparability Measured / Certified Value – to assess veracity of the Normative Standards-Based Review 1.01 Process Certificate 95% CI Cam paign 1 – To assess bias that could be introduced by random selection/use 1.00 Cam paign 2 of any of the materials or of the procedures included on these Published Lists of those reviewed and accepted as meeting required stated criteria as “higher order” 0.99 SRM JCCRM SRM SRM JCCRM JCCRM SRM SRM Listed CRMs 0.98 956a Level-3 111-5 L 909 Level-1 956a Level-2 111-5 M 111-5 H 956a Level-1 909 Level-2 are all comparable within current NIST Analyses: ID-ICP-MS needs Calibrant: NIST SRM 918a, Potassium Chloride (Clinical Standard) 37 38 Comparability of Cholesterol in Serum CRMs on JCTLM LIST JCTLM α-List : Potassium in Serum CRMs SRM 1952a l-3 1.01 Measured / Certified Value SRM 909b, l-2 300 6 SRM 956a, l-1 1.010 JCCRM 111-5, H SRM 1951a l-2 1.00 Measured Value, mg/dL Certificate JCCRM M Measured / Certified ValueMeasured Value, mmol/L 1.005 95% CI Cam paign 1 5 Cam paign 2 250 SRM 909b l-2 SRM 1952a l-2 0.99 1.000 JCCRM 111-5, M 4 SRM956a, l-2 JCCRM H 200 0.995 SRM 909b l-1 SRM 909b, l-1 SRM 1951a l-1 0.98 JCCRM 111-5, L 3 SRM 968c l-2 0.990 SRM 1589a 150 SRM 1952a l-1 SRM 968c l-1 Med = 0.9933 JCCRM H JCCRM M SRM 1589a SRM 909b l-1 SRM 909b l-2 SRM 968c l-1 SRM 968c l-2 SRM 1951a l-1 SRM 1951a l-2 SRM 1952a l-1 SRM 1952a l-2 SRM 1952a l-3 2 SRM 956a, l-3 Med = 0.9999 Med:s = 0.0069 SRM 909b, level 1 SRM 909b, level 2 SRM 956a, level 1 SRM 956a, level 2 SRM 956a, level 3 JCCRM 111-5, H JCCRM 111-5, L JCCRM 111-5, M Med:s = 0.0046 150 200 250 300 2 3 4 5 6 U(Med) = 0.0055 U(Med) = 0.0048 Certified Value, mmol/L The measured/certified Ratios for this CRM comparability The measured/certified ratios for this CRM comparability set of CRMs are: independent of set of CRMs are: • ~ normally distributed independent of • normally distributed analyte level • with a standard deviation of ~0.7% • centered on the certified values analyte level • with a standard deviation of <0.5% 39 40 A Global Challenge• Are seeing exponential increase in requests for CRMs – especially in organic and bioscience areas With no quantum methods typically available, – Need an efficient strategy for CRM producers to collectively establish a “virtual system” to provide and maintain a set of CRMs that meet global needs and cover the chemical measurement “space” to meet metrological requirements; with CRMs of “higher order” ….. to CRMs needed for testing laboratories for more routine use. 41 42