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PD ISO GUIDE 35:2017

Reference materials - Guidance for characterization and assessment of homogeneity and stability - - -- -- - - --

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PO ISO GUIDE 35:2017

PUBLISHED DOCUMENT

National foreword This Published Document is the UK imple me ntation of ISO GUIDE 35:2017. The UK participation in its preparation was entrusted to Technica l Committee RMI/1, Reference Materials. A lis t of orga nizations represented on this committee can be obta ined on request to its secretary.

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This publication does not purport to include a ll the necessa ry provis ions of a contrac t. Users are responsible for its correct application. © The British Standards In s titution 2017 Published by BSI Standa rds Limited 2017 ISBN 978 0 580 86736 1

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ICS 71.040.30 Compliance with a British Standard cannot confer immunity from legal obligations.

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This Published Docume nt was published unde r the authority of the Sta ndards Pol icy and Strategy Comm ittee on 31 October 2017.

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PD ISO GUIDE 35:2017

GUIDE 35 Fourth edition

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2017-08

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Reference materials - Guidance for characterization and assessment of homogeneity and stability Materiaux de reference- Lignes directrices pour /a caracterisation et !'evaluation de l'homogeneite et de Ia stabilite

Refe re nce number ISO GUIDE 35:20 17(E)

© ISO 2017

PD ISO GUIDE 35:2017

PD ISO GUIDE 35:2017

ISO GUIDE 35:2017(E)

GUIDE

Reference materials - Guidance for characterization and assessment of homogeneity and stability 1 Scope T his document expla ins concepts a nd provides approaches to the following aspects of the production of reference mate ria ls: the assessment of homoge ne ity; the assessment of sta bility and the management of t he risks associated with possible stability issues related to the properties of interest; the characterization a nd va lue assignment of properties of a reference ma te rial; the evaluation of uncerta inty for certified values; the establis hme nt of the metrological traceability of certified property va lues. The g uida nce g ive n supports the implementation of ISO 17034. Othe r a pproach es may also be used as long as the req uirements of ISO 17034 a re fulfill ed . Brief g uidance on the need for commutabi lity assessment (6.11) is given in this document, but no technical details a re provided. A brief introduction for the characterization of qual itative prope rties (2& to 9.10) is provided together with bri ef gu idance on sampling s uch materia ls for h omogeneity tests (Clause 7). However, statistical metho ds for t he assess ment of the homogene ity a nd stability of reference materia ls for qualitative properties are not covered. Th is document is a lso not applicable to multi va riate quantities, s uch as spectral data .

2

Normative references

The following documents a re referre d to in the text in s uch a way that some or all of their content const itutes requirements of this document. For dated references, only the e dition cited a pplies. For undated references, the latest e dition of the referenced document (including any amendments) applies. ISO 3534-2, Statistics- Vocabulruy and symbols - Part 2: Applied statistics ISO 3534-3, Statistics - Vocabulmy and symbols - Part 3: Design of experiments ISO Guide 30, Reference materials - Selected terms and definitions ISO/IEC Guid e 99, lntemational vocabulmy of metrology -

Basic and general concepts and associated

terms {VIM} NOTE

The International vocabulmy of metrology wi ll hereafter be referred to as th e "VIM".

3 Terms and definitions For the purposes of this docume nt, the terms a nd defi nitions given in ISO Guide 30, lSO/ IEC Guide 99, ISO 3534-2, ISO 3534 -3 and the following apply. The definitions in ISO Guide 30 take precedence where more than one definition for t he sa me te rm exis ts. ISO a nd IEC ma inta in terminologica l data bases for use in s tandardizat ion at the follow ing addresses: -

ISO Online browsi ng p latfor m: availa ble a t htt p://vvww. iso.org/obp

© ISO 2017 - All rights reserved

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PD ISO GUIDE 35:2017 ISO GUIDE 35:2017(E)

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IEC Electropedia: available at http: //www.e lectropeclia.org/

3.1 reference material RM material, sufficiently homogeneous and stabl e with respect to one or more spec ified properties, whi ch has been established to be fit for its intended use in a measurement process Note 1 to entry: RM is a generic term. Note 2 to entry: Properties ca n be quantitative or qualitative, e.g. identity of substa nces or s pecies. Note 3 to e ntry: Uses may include the calibration of a meas urement system, assessment of a meas ureme nt procedure, assigning va lues to other mate ria ls, and quality co ntrol. Note 4 to entry: ISO/ IEC Gu ide 99:200713.1 has a n a na logous definition (5.13), but res tri cts the term "measure ment" to apply to quantitative values. ll oweve r~ ISO/ IEC Guide 99:2007, 5.13, Note 3 (VIM), specifically includes qualitative properties, called "nomina l properti es".

[SOURCE: ISO Guide 30:2015, 2.1.1]

3.2 certified reference material CRM reference materi al (RM) characterised by a metrologically v

6.5

Reference material processing

Processing ca n involve a ra nge of processes, including, for example: synthesis, manu fa cture or formulation of a synthetic reference material; drying,lyophilisation, milling, and/or filtration for natural materials; addition of s ta bilizing agents; homogenization prior to packaging. The pa rticula r procedures used depend on the particular material and us ua lly require expert guidance.

6.6 Homogeneity assessment Homoge ne ity is a n important requirement for all RM s a nd includes both within- a nd between-unit homogeneity. Between-unit homogeneity is importa nt to en sure that each RM unit carries the same value for each property; within-unit homoge ne ity is important where s ubsa mples ca n be taken for measurement by users of the material. Clause 7 gives detailed guidance on homoge nei ty assess ment.

6.7 Stability assessment RMs should be s ufficie ntl y s table for their intended use, so that the end us er can rely on the ass igne d value at any point within the period of validity of the certificate. Typically, it is important to consider stability under long-te rm storage condi tions, und er transport conditions and, where applicable, the storage cond ition s at the RM user's laboratory. This can include consideration of stability afte r opening, if re-use is permitted. Cl ause 8 provides detailed guidance on s tability assess me nt.

6.8 Choice of measurement procedures In a reference materia l production project, each step that requires meas urements may use different measurement procedures because, for exa mple, characterization ge nera lly requires minima lly bias ed measurement procedures with low uncertainty; homogene ity studi es primarily requ ire the best

© ISO 201 7 - All rights res erved

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PD ISO GUIDE 35:2017 ISO GUIDE 35:2017(E)

available repeatability; and classical stability studies typically require mea surement procedures that show good precision over time within the same la boratory. The choice of measure ment procedures for homogeneity studies, stability studies and charac terization is considered in Clauses 7. .8. and 2. respectively.

6.9 Metrological traceability Me trological traceability is key to ensuring the comparability of measurement res ults over time and between locations, including those used to characterize reference materials. By definition, CRMs are accompanied by a s tate ment of metrological traceability for each certified prope rty value. The proper choice of the stated references to which metrological traceability of the property values is established is essential for CRMs, because CRMs are primarily used to make measurement results traceable. Establishment of metrological traceability is considered in detail in 9.2.

6.10 Characterization and uncertainty evaluation Characterization refers to the determination of the property values of the r eleva nt properties of an RM, as part of the production process. Characterization of an RM is described in Clause 9. For CRMs, certified values are accompanied by a statement of meas urement uncertainty; the evaluation of uncertainty is considered in Clause 10.

6.11 Commutability assessment

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The commutability of a n RM relates to the a bility of the RM, cha racte ri zed by one measurement proce dure (usually a reference procedure) to ac t as a calibrator or quality control (QC) materia l for a second meas ureme nt or testing procedure applied to routine test materials. This is particularly important where different measure me nt procedures can respond ve ry differently t o different types of test materials. Com mutability assessment is not required for all RMs but is required for some importa nt classes of RM. NOTE

Curre nt ISO/REM CO information o n commutability assess menti2J states that:

"A r efer ence mate ri a l producer should cond uct an assess ment of co mmutability w here a) the inte nded use requires com mutability of ca librati o n or quality cont rol materia ls, a nd b) the refe rence material producer warrants that the mat eri a l is fit for the inte nded use. NOTE 1 De monstration of commutability is us ually required when the intended u se includes calibration or qua lity control in biological measureme nt, a nd is not us ually require d w he n the intend ed use does not include biological measure ment and the procedure is known to be a dequa tely s peci fi c for the measurand in the matrix of the re fe re nce mat eria l and the inte nded routine sa mples. NOTE 2 It is not usu ally necessary to esta blish commutability w he n the re fe rence material and its orig in are obtained from sources a nd handled the sa me as sa mple s that would be t es ted for cus to me rs, for exa mple, ma tri x reference materi a ls.

6.12 Transport issues Nearly all RMs have to be transported to the location of use. The means and conditions of trans port of a n RM after production are relevant to the need for s ta bility studies (see Cla use 8) and it is the re fore useful to conside r tra nsport conditions at a n early s tage in th e project. NOTE 1 Nation a l a nd/or inte rn ationa l tra nsport regulations may limit the options for tra nspo rt, prohibit the tra ns port of some mater ia ls, or re quire s pecific packaging or precaut ion s for sa fety or o ther rea so ns. NOTE 2 T he time taken for officia l procedures s uch as cu sto ms or o ther border control clearance ca n increase shipm ent times for some des tinations.

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© ISO 2017- All rights reserved

PO ISO GUIDE 35:2017

ISO GUIDE 35 :2017(E)

6.13 Value assignment Value assignment is the process of combining the results from the homogeneity a nd s ta bility assessment with the results from the characterization s tudies to de te rmine the assigned values a nd their uncertainties. These va lues are s ubsequently issued on a cert ificate or product in fo rma tion sheet.

6.14 Stability monitoring Most refere nce materials are s tored for exte nde d pe riods at t he RM producer's premises or by distributors. Since stability assessme nt cannot us ually a nticipate all changes t hat may occur, it is usually necessa ry, as a part of ma naging the ri sks associated with possible ins tability, to monitor the property values of ma te rials held for extended periods. Beca use the requirements for moni toring de p{,!nd in pa rt on knmvledge obtained during st a bility as sessment, 1Ll.Q. includes guida nce on s tabili ty monitoring.

6.15 Reference materials produced in repeated batches The need for expe rime ntal s tudy of some cha racte ris tics (par ti cul a rly homogeneity, st ability and com mutability) can be reduced whe re the ma terial is produced in a repeat production run following a n established procedure. Reliance on prior expe rience is reasonable so long as: a)

the process for producing bat ches of the RM has not cha nged in a ny way tha t might adversely a ffect the end use;

b)

the ma terials used in producti on of the RM have not changed in any way t hat might adversely affect the end use;

c)

ma terials previous ly produced by the same process have shown no fa ilures a ttributable t o the production process, eithe r during routine moni toring or by users ; a nd

d)

the requirements for the ma terial a re reviewed regularly, ta king account of the intended use of the material a t the time of the review, to ensure t ha t the production process remains fit for purpose.

Consis tent performance of the production process should be checked, for example by compa ring the property values of samples from successive batches under repea tability condition s.

7 7 .1

Assessment of homogeneity Preamble

Most RM s a re prepared as ba tches of 'units' (e.g. bottles, vials or test pieces). It is imp orta nt th at all dis tributed units are the sa me within the stated uncertainty for each p rope rty value and, unless sold as s ingle-use units, tha t the ma teria l within each unit is uniform . ISO 17034 accordingly requires the assessme nt of the homogeneity of a refe rence ma teria l (RM). Homogeneity ca n refer eit he r to va riation of a prope rty value be t\-veen sepa rate units of t he mate rial, or to varia tion within each unit. It is a lways necessa ry to assess the between-unit varia tion. Whe re t he intended use pe rmits the use of part of a unit- for exa mple, a small porti on of a solid or liquid mate rial, or a sma ll region of the surface - it is also us ually necessary either to assess t he within-unit va ria bili ty of the mate ria l (within-unit he te rogeneity) or to provide in s tructions for use t ha t control the impact of within-unit heteroge neity. These ins tructions ca n include, for exa mple, re mi xing of t he sa mple and, fo r gra nul

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there is sufficiently high statistical correlation between particular property values in the type of material of interest to allow useful prediction of one property value from one or more others, and it can be shown that particular groups of properties are sufficiently closely associated (for example, because of their presence in a particular component of a mixture) that meas ure ment of one property in such a group furni shes ev ide nce of homogeneity for other properties in the same group. It is essential that any subset of properties taken as representing homogeneity for a larger set of properties be appropriately selected on the basis of established chemical or physical relation ships. For example, an inter-ele me nt concomita nce in the mineral phases of an RM would s upport the assumption that the RM also has a s imilar degree of homogeneity for the non-selecte d ele ments . In cases where homogeneity is assessed ex perime ntally by us ing a subset of propert ies of interest, additional evidence should be gained about the homogeneity of properties that are not studied experimentally. The evidence should be sufficient to show that the uncertainty associated with heterogeneity is not underestimated for those properties tha t are not experimenta lly s tudi ed .

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NOTE Such evidence ca n be gai ned, for example, fro m literature releva nt to the materi a l in question, through the stability st udy or the cha racterizatio n of the material.

7.4 Statistically valid sampling schemes 7.4.1 7.4·.1.1

Minimum number of units for a homogeneity study Homogeneity study for quantitative properties

Homogeneity st udies for qua ntitative properties are typically inte nded to provide information on the variance due to heterogeneity and on any (possibly nonlinear) trends arising from processing. To achieve these objectives, the number of items should be s ufficie nt to give a reasonable estimate of the between-unit va ria nce, and sufficie nt items taken to give a clear view of a ny tre nds present. Based on current practice, a n accepta ble estimate of the be tween-unit va ri a nce for the purposes of unce rtainty evaluation ca n be obtained with nine or more degrees of freedom. For a s imple © ISO 201 7 - All rights reserved

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PO ISO GUIDE 35:2017 ISO GUIDE 35:2017(E)

homogeneity s tudy design or a randomized block design (see below), this corresponds to the selection of a minimum of 10 units. Where a nested design is to be used for measurements, in which a subset of units is measured in each of several runs, additional units should be included in the s tudy in order to maintain the required degrees of freedom. 7.6.4 gives further details about the additional number of units required for a nested design.

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Trends arising from processing often appear as an initial trend followed by stable output, as a trend developing late in the process, or as a combination of the two. Where these features occur, it is often possible to provide a homogeneous material by discarding the affected units from the beginning or end of the run. However, examining only 10 units might not provide sufficient information a bout the onset of trends near the ends of a lengthy processing run . Current best practice therefore increases the number of units examined as the total number of units produced, Nprod· increases. Typical recommendations are between ~Nprod and 3x~Nprod [211. Taken together with the degrees of freedom requirement above, this leads to a recommended minimum number of units Nmin for a homogeneity study of materials characterized for a quantitative property given by

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An RM producer prepa res 3 000 units of a candidate RM and intends to undertake a homogeneity

study in a sing le run. Then Nprod = 3 000 and Nmin = max(1o,V3000 ). which is 11,1. This s tudy accordingly req uires 15 units of material for the homogeneity study.

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For reference materials certified for a qu alitative, or "nominal", property, the number of units chosen for the homogeneity study should be set ba sed on sa mpling guidance for inspection by attributes as described in the ISO 2859 series[fi) or s imilar guidance.

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Homogeneity study for qualitative ("nominal") properties

Sampling plans for inspection by attributes lead to very high inspection numbers if low proportions of defective units are to be detected by sampling alone. For exa mple, to detect a 1 % defective rate with high confidence based on one or more observed defectives, about 300 randomly chosen units have to be inspected (thi s number is based on a statistical pmver calculation for 95% test power for 1% defectives, assuming batch size much greater than 300 units) . Thi s is often unreali s tic for typical reference material batch sizes. For qualitative materials, there fore, an experimental homogeneity study is likely to be limited to a check for unexpec ted gross hete rogeneity (for example, greater than 10% defective), w ith other information on origin of material, processing, etc. used to support any stateme nt of homogeneity. If a certified qualitative property is individually verified for every unit of s uch a materia l, it is not necessary to perform a further test of the homogeneity of that property. 7.4.1.3

Small production batches

Some reference materia ls are produced in s mall batches of 50 or fe\•v er units, for exa mple, secondary gas cal ibration sta ndards. For s uch s mall production batches, the minimum number of units specified in 7.4.1.1 usua lly represents a very large frac tion of the avai lable units. Where the batch size is below 100 units, homogeneity shou ld be assessed on the la rger of three units or 10 % of the batch s ize, ra nd omly selected from the batch . Replication s hould be as high as practically feasible to provide the bes t ava ilable tes t powe r for the number of units used. Power a na lys is ( 7.4.2) may be used to assis t in considering desirable replication levels. For example, vvith three units, four observation s per unit g ives 12

© ISO 2017 - All rights reserved

PD ISO GUIDE 35:2017

ISO GUIDE 35:2017(E)

app roxi mately the same power of detecting normally distributed between-unit deviations as observing 10 units in duplicate, though with much lower probability of detecting occasional defective units in an otherw ise homogeneous batch. 7 .4.2

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Use of statistical power analysis

Statistical powe r a na lys is may be used to assist in choosing a su itable number of un its and replicates for the homogeneity study. Power analysis ai ms to control the probability of failing to detect a particular level of heterogeneity given a proposed s tatistical t est for significant hete rogeneity. Power analysis is a specialized topic but is increasingly available in software, some available without charge. The most common example of power analysis in thi s context is the calculation of the numbers of test items and re plicate measurements on the ass umption that one-way analysis of variance (see 7.7.3) is to be used to test for a s ig ni fica nt between-unit e ffect. Although statistica l powe r a na lysis ca n be useful in compari ng different proposed strategies, considerable care should be taken in its use. In particular, the choice of replicate numbers and unit numbers is very strongly dependent on the ass umed distribution of any hypothes ized between-sa mple difference. For exa mple, ass uming a norm al di stribution for the (true) mea ns of different units, a common default in power calculatio n software, leads to a high proposed number of replicates and a sma ll nu mber of units. This is a poor choice if the most likely pattern of heterogeneity is a s mall proportion of discrepant units among a la rgely homogeneous population. In the absence of good information on the likely distribution of different (true) unit means, therefore, power analysis is most useful as an aid in choosing replicate numbe rs after the proposed numbe r of units has been decided. NOTE 1 When us ing power ~

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