1. 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.gov
19 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

2. “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

3. “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 results
ISO/IEC 17025 – “General requirements for the competence of testing and
calibration laboratories” ISO/TS 21748:2004 Guidance for the use of repeatability, reproducibility and trueness estimates
in measurement uncertainty estimation
ISO Guide 30:1992, Terms and definitions used in connection with reference
materials. ISO 5725-1:1994/Cor 1:1998 Accuracy (trueness and precision) of measurement methods and
results -- Part 1: General principles and definitions
ISO Guide 31:2000 – “Reference materials -- Contents of certificates and
ISO 5725-2:1994/Cor 1:2002 Accuracy (trueness and precision) of measurement methods and
labels”
results -- Part 2: Basic method for the determination of repeatability and reproducibility of a
standard measurement method
ISO Guide 32:1997 – “Calibration in analytical chemistry and use of certified
reference 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 method
ISO 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 method
material producers”
ISO 5725-5:1998/Cor 1:2005 Accuracy (trueness and precision) of measurement methods and
ISO Guide 35:2006 – “Certification of reference materials -- General and results -- Part 5: Alternative methods for the determination of the precision of a standard
statistical principles” measurement method
ILAC G12:2000 Guidelines for the Requirements for the Competence of 13
ISO 5725-6:1994 Accuracy (trueness and precision) of measurement methods and results --
14
Reference 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

4. 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

5. 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

6. 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 database
Reference 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