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A n L G C p u b l i c a t i o n i n s u p p o r t o f t h e N a t i o n a l M e a s u r e m e n t S y s t e m I s s u e N º 2 8 S p r i n g 2 0 0 3

VAM BULLETIN

Traceability for in-vitro diagnostic medical devices

Process Analytical Technology – a new initiative within pharmaceutical development and manufacture

Assessing the performance of indoor and in-car air monitoring devices

Isotope-Dilution Mass Spectrometry – A ‘quantum’ method for chemistry?

VAM 2003–2006 formulation update FUNDED BY THE DTI

Contents

2 V A M B U L L E T I N

C O N T E N T S

Photography by Andrew Brookes

Guest column

Traceability for in vitro diagnostic medical devices..........................................................3

Contributed articles

VAM 2003–2006 Programme Formulation Update ........................................................7

Assessment of the performance of low-cost indoor and in-car air monitoring devices ......10

Process Analytical Technology – a new initiative within pharmaceutical development and manufacture: Implications for the development and validation of methodology .......13

Isotope-Dilution Mass Spectrometry – a ‘quantum’ method for chemistry? ....................16

Case study

Meeting the needs of regulation and trade: determining low levels of sulfur in fuel .........18

VAM in education

Decline in skills ...........................................................................................................23

VAM news

European Trial of Airborne Particle Measuring Instruments comes to NPL...................24

UKAS appoints Lord Lindsay as Chairman..................................................................25

RSC to produce perfect cup of tea ...............................................................................25

Challenging the Limits Of Detection ............................................................................26

ROMIL launches fully SI-traceable CRMs for trace element calibration ........................27

MCERTS – Performance standard for laboratories undertaking chemical testing of soil ..............................................................................27

UK Analytical Partnership

Science & Hazard Regulation – claim or blame?............................................................28

Product and process competitiveness............................................................................30

Chemical nomenclature

Introduction to polymers .............................................................................................30

Proficiency testing update

Accreditation of PT schemes puts UK in ‘First Division’ ..............................................32

COEPT to examine the comparability of PT schemes...................................................32

EEE Working Group discusses measurement uncertainty in PT ....................................33

Reference materials update

A network for users of reference materials.....................................................................34

New products

VAM publishes guides for measurement in the laboratory .............................................35

New method validation software under development ....................................................36

Forthcoming events........................................................................................................37

Contact points ................................................................................................................40

Keith MarshallEditor020 8943 7614

General enquiries about VAM to:VAM Helpdesk 020 8943 [email protected]

LGC’s address:LGC, Queens RoadTEDDINGTONMiddlesex TW11 0LY.

ISSN 0957 1914

The DTI VAMprogramme:The DTI’s programme on Valid AnalyticalMeasurement (VAM) is an integral part ofthe UK National Measurement System. TheVAM programme aims to help analyticallaboratories demonstrate the validity of theirdata and to facilitate mutual recognition ofthe results of analytical measurements.

The VAM programme sets out the followingsix principles of good analytical practice,backed up by technical support andmanagement guidance, to enable laboratoriesto deliver reliable results consistently andthereby improve performance.1. Analytical measurements should be

made to satisfy an agreed requirement.2. Analytical measurements should be

made using methods and equipment,which have been tested to ensure theyare fit for their purpose.

3. Staff making analytical measurementsshould be both qualified and competentto undertake the task.

4. There should be a regular independentassessment of the technical performanceof a laboratory.

5. Analytical measurements made in onelocation should be consistent withthose elsewhere.

6. Organisations making analyticalmeasurements should have welldefined quality control and qualityassurance procedures.

The VAM Bulletin is produced by LGCunder contract with the UK Department ofTrade and Industry as part of the NationalMeasurement System Valid AnalyticalMeasurement Programme. No liability isaccepted for the accuracy of informationpublished and the views expressed are notnecessarily those of the Editor, LGC or DTI.

The quest for metrological traceability in laboratory medicine


G U E S T C O L U M N

René DybkaerH:S FrederiksbergHospital, Denmark

Introduction

Effective globalisation of information andknowledge necessitates mutual trust in

the reliability and comparability of data overspace and time. Resources are saved ifprimary measurement results are acceptedwithout need of confirmation. Thecredibility is obtained by reference to aninternational infrastructure for metrology1.Its top elements are the Metre Convention,the General Conference on Weights andMeasures (CGPM) defining the Inter-national System of Units (S1), the executiveInternational Committee for Weights andMeasures (CIPM), and the InternationalBureau of Weights and Measures (BIPM) atSèvres, France. The CIPM is advised invarious fields of metrology by consultativecommittees (CCs) of which a ten-year oldnewcomer is the Consultative Committee forAmount of Substance: Metrology inChemistry (CCQM). An important task ofthe CCs is to identify primary measurementmethods and provide the material under-

pinning of the CIPM Mutual RecognitionArrangement (MRA) in the form of KeyComparisons leading to the Calibration andMeasurement Capabilities of the NationalMetrology Institutes (NMIs). The next levelis the associated Regional MetrologyOrganisations (RMOs) with their keycomparisons, followed by the ReferenceMeasurement Laboratories.

Resources are saved ifprimary measurement

results are accepted withoutneed of confirmation.

Metrological Traceability

This global complex structure provides

dissemination of the SI2 and the upper

stretches of metrological traceability:

currently defined by the International

vocabulary of basic and general terms in

metrology3 as being the “property of the result

of a measurement or the value of a measurement

standard whereby it can be related to stated

references, usually national or international

measurement standards, through an unbroken

chain of comparisons all having stated

uncertainties”. The salient concepts here are

“stated references” and “uncertainties”.

Laboratory Medicine

There is no long-standing tradition for

stating global metrological traceability in

laboratory medicine, including clinical

chemistry, clinical immunology, and

haematology. Each medical laboratory has

had its own measurement procedures and

biological reference intervals. For several

reasons, this is now changing:

• Clinical specialisation

Patients are increasingly being transferred

from one service to another within a

hospital, between hospitals, and even

between countries.

There is no long-standingtradition for stating globalmetrological traceability in

laboratory medicine.

• Laboratory specialisation

A referral laboratory may serve several

hospitals and private practices, but its

results should mesh with those from the

originating sites.

• Accreditation according to the standards

ISO 170254 or EN ISO 151895 is now being

favoured as a competitive advantage,

and the standards require metrological

traceability of measurement results;

• Production of reliable, biological

reference intervals often requires collab-

oration between several laboratories with

common stated references to allow

pooling of data.

In vitro diagnostic medicaldevices (IVD MDs)

A major impetus of the recent flurry ofactivities towards creating and organising themetrological wherewithal of traceability isundoubtedly the EU Directive 98/79/EC onIVD MDs6, which requires that “Thetraceability of values assigned to calibratorsand/or control materials must be assured throughavailable reference measurement proceduresand/or available reference materials of a higherorder”. The directive has to be implementedby manufacturers in December of this year.The very general statements in a modern EU directive are explained and specified in harmonised European Standards (ENs) from the European Committee forStandardization (CEN). Thus, the aboverequirement has occasioned five suchstandards produced by Technical Committee(TC) 140 “In vitro diagnostic medicaldevices” over the last fifteen years andadopted by the International Organizationfor Standardization (ISO) through its

TC 212 “Clinical laboratory testing and invitro diagnostic test systems”.

• Presentation of reference measurementprocedures; EN 12286:1998 +12286/A1:2000 = ISO 15193:2002

• Description of reference materials; EN12287:1999 = ISO 15194:2002

• Laboratory medicine - Requirements forreference measurement laboratories; ENISO 15195:2003

• Metrological traceability of valuesassigned to calibrators and controlmaterials; EN ISO 17511:2003

• Metrological traceability of values forcatalytic concentration of enzymesassigned to calibrators and controlmaterials; EN ISO 18153:2003

Chemical calibration hierarchy

The first three standards mentioned may be

seen as detailing important elements in the

chemical calibration hierarchies specified in

the last two documents.

In principle, a calibration hierarchy requires

the use of a sequence of documents,

measuring systems, calibrators, and events,

in the form of calibrations and value

assignments. A comprehensive chemical

calibration hierarchy may look as follows:

Definition of SI unit by CGPM, e.g. mole

per litre

(Level 1.) Primary reference measurement

procedure specified by BIPM or an NMI,

(e.g. isotope dilution – mass spectrometry)

with a completely described measurement

equation in terms of SI units, governing a…

(Level 2.) …mass spectrometer operated byan analyst assigning a quantity value andmeasurement uncertainty to a…

(Level 3.) …primary calibrator issued withcertificate by BIPM or an NMI and specifiedin a…

(Level 4.) …secondary reference measurement

procedure (e.g. based on atomic absorption),

described by an NMI or accredited reference

measurement laboratory (ARML) and

governing an…

(Level 5.) …atomic absorption spectrometer

assigning a quantity value and larger

measurement uncertainty to a secondary

calibrator which is acquired for a…

(Level 6.) …manufacturer’s selectedmeasurement procedure (perhaps based onflame emission), governing the…

A calibration hierarchyrequires the use of a sequence

of documents, measuringsystems, calibrators, and events,

in the form of calibrationsand value assignments.

(Level 7.)….manufacturer’s flame emissionspectrometer assigning value and uncertaintyto the…

(Level 8.) …manufacturer’s workingcalibrator used in the…

(Level 9.) …manufacturer’s standing

measurement procedure, perhaps with a

measurement principle close to that of the

end-user’s measurement, e.g. titration,

governing the…

(Level 10.) …manufacturer’s standing

measuring system assigning value and

uncertainty to the…

(Level 11.) …manufacturer’s product

calibrator utilised according to an…

(Level 12.) …end-user’s routine measure-

ment procedure for his…

(Level 13.) …routine measuring system

assigning to a…

(Level 14.) …routine sample a…

routine result, i.e. quantity value and final

(largest) measurement uncertainty.





Variation in hierarchical structure

This quite extensive structure of acalibration hierarchy may be modifiedaccording to available elements and purpose.

It is always possible to excise one or twosegments each comprising procedure-measuring system-calibrator or calibrator-measuring system-procedure. This simplifi-cation should reduce the measurement

uncertainty, but may not be economical,such as applying primary measurementprocedure with measuring system directly onroutine samples.

The EN ISO 17571 also outlines the lessfortunate situations where no SI unitis applicable.

One possibility is for an internationalscientific organisation or the World HealthOrganization to specify an…

(Level 1.) International conventional

reference measurement procedure (ICRMP)governing a…

(Level 2.) …measuring system, assigningquantity value and measurement uncertaintyto an…

(Level 3.) …international conventionalcalibrator, which is offered to themanufacturers.

Sometimes, the ICRMP with measuringsystem operates directly on the manu-facturer’sworking calibrator. Or, with no ICRMP havingbeen agreed, an international protocol for valueassignment with varying measuring systemsfurnishes the value and uncertainty of theinternational conventional calibrator.

Finally, any laboratory may specify ameasurement procedure without precedingcalibration hierarchy, but the ensuing results from the measuring system are notdirectly comparable with those obtained by other means.

Prerequisites of a calibration hierarchy

Prior to choosing a calibration hierarchy,that which is to be measured, i.e. themeasurand, must first be defined with regardto system, component, and kind-of-quantity.Such requirements are described inpublications from the International Union ofPure and Applied Chemistry (IUPAC) andthe International Federation of ClinicalChemistry and Laboratory Medicine(IFCC).7,8 The measurand must be of thesame type throughout the hierarchy.

Then, the allowed maximum measurementuncertainty should be specified in view of theclinical requirements and finally obtained bythe principles presented in ‘Guide to theexpression of uncertainty in measurement’9,based on a measurement function.

If several measurement procedures areinvolved in a hierarchy, as is usually the case,they must have the same analyticalspecificity and analytical selectivity.

A calibrator must have sufficientcommutability, i.e. the same behaviourtowards preceding and following measure-ment procedure as routine samples.

The calibration hierarchies describedhitherto are all single-stranded betweenstated reference and measurement result.

In principle, however, each input quantity ofa (final) measurement function must have itsown more or less complicated subsidiarycalibration hierarchy, together yielding apluri-stranded hierarchy. For example, if ameasurement result for a mass concentrationis obtained by separate weighing of componentand determination of volume of system, theirhierarchies start from the definitions of thekilogram and meter respectively.

It should be added that it is possible todefine a measurand with the specificationthat a certain measurement procedure beused. In this way the stated reference may bean SI unit, but the results cannot beexpected to equate those of an otherwiselook-alike measurand with another specifiedmeasurement procedure.

Metrological traceabilityrevisited

Having established a suitable calibration

hierarchy a priori, connecting “stated

reference” to “measurement result”, the latter

can now be claimed a posteriori to be

metrologically traceable to the former. In

physics, the retrograde series of elements

from measurement result to stated reference

is classically just seen as consecutive

comparisons between measurement

standards, where the quantity value of a lower

standard is compared to that of the next

higher standard. The unbroken series of

comparisons is designated ‘traceability chain’.

In chemistry, the ‘comparisons’ are effected

after calibration, measurement procedure,

measuring system, and assignment of quantity

value and measurement uncertainty from the

higher calibrator to the next lower one.

The challenge

The end-user’s task of establishing a calibration

hierarchy for a given type of quantity from, e.g.,

the definition of an SI unit to measurements

results, usually requires involvement of BIPM,

NMI, ARML, manufacturer, and end-user.

None of these stations can provide the

hierarchy by itself. Any lower station has to plug

in at a higher station, even if some level may be

bypassed. The connection is usually achieved

by acquiring a calibrator, often a reference

material, preferably a certified reference

material, embodying the higher hierarchical

levels for the measurand.

As laboratory medicine is concerned withthousands of types of quantities, the creationof the upper levels of all the individualhierarchies is an enormous challenge andbeyond the capacity of a single institution oreven a single country. Still, themanufacturers of IVD MDs in view of theEU Directive’s requirement of metrologicaltraceability are clamouring for assistance.

The Joint Committee onTraceability in Laboratory

Medicine (JCTLM)

During the last few years, representatives of

the responsible bodies have discussed the

problems and finally, at a meeting in BIPM

last year, the stakeholders agreed to create an

organising Joint Committee on Traceability

in Laboratory Medicine. Its general mission

is ‘to support world-wide comparability,

reliability and equivalence of measurement

results in Laboratory Medicine, for the

purpose of improving health care’.

Specific means include promoting

traceability, networks of NMIs and RMLs,

and reference measurement systems.

The four principal promoters andstakeholders are the CIPM/BIPM, IFCC,International Laboratory AccreditationCooperation (ILAC), and the World HealthOrganization (WHO). Other importantstakeholders include professional scientificorganisations, CRM producers, IVD MDindustry, written standards developers,external quality assessment organisers,networks of RMLs, and regulatory bodies.

The second meeting of JCTLM is planned

for this summer.

Actual work will be done in Working Group

1 on “Reference materials and reference

procedures”, formulating criteria for

inclusion of such items in recommended

lists, and Working Group 2 on “Reference

laboratories” setting criteria for accreditation

of reference laboratories and promoting

networks. Progress reports should appear

towards this year’s end.

A salient function of JCTLM is to identify

and prioritise the major measurement

problems requiring development of primary

and secondary measurement procedures and

calibrators. The CCQM should be advised

on the selection of measurands in laboratory

medicine needing CIPM key comparisons to

complement the few already completed ones

on amount-of-substance concentration in

serum of cholesterol, creatinine, and glucose.

The choice should be influenced by the

expectation that the metrological knowledge

gained from a given exercise may help in

creating calibration hierarchies for similar

measurands. As the saying goes, the question

to ask is ‘How far does the light shine?’

Conclusion

With the description of various calibrationhierarchies and the creation of JCTLM, thestakeholders in the provision of reliable andglobally comparable medical laboratoryresults have fashioned an importantinfrastructure for adequate and economicallaboratory examinations in healthcare.

REFERENCES

1. Wielgosz, R., VAM Bulletin (2001) 25, pp

3–7.

2. Quinn, T.J., Metrologia, 1994/95, 31, pp

515–527

3. BIPM, IEC, IFCC, ISO, IUPAC, and

OIML, International vocabulary of basic

and general terms in metrology, 2nd ed.,

Geneva, ISO, 1993

4. ISO/IEC 17025:1999 General require-

ments for the competence of testing

and calibration laboratories

5. ISO 15189:2003 Medical laboratories.

Particular requirements for quality and

competence.

6. EU Directive 98/79/EC on in vitro

diagnostic medical devices, Off J Eur

Comm, 1998. L 332/1–37.

7. Rigg, J.C., Brown, S.S., Dybkaer, R., and

Olesen, H., Compendium of terminology

and nomenclature of properties in

clinical laboratory sciences, IUPAC/IFCC

Recommendations 1995, Oxford,

Blackwell Science Ltd, 1995.

8. http://dior.imt/liu.se/cnpu

9. BIPM, IEC, IFCC, ISO, IUPAC, and

OIML, Guide to the expression of

uncertainty in measurement, Geneva,

ISO, 1993 and 1995




C O N T R I B U T E D A R T I C L E S

Martin MiltonNPL John MarriottLGC

In the last issue of the VAM Bulletin1 weannounced plans for the formulation of

the next VAM Programmes, which are dueto start at the beginning of October 2003,subject to approval within the DTI. Sincethen, significant progress has been madeand, following extensive consultation, theinitial drafts of the new ‘Physical’ and‘Chemical’ VAM Programmes have beendrawn up. These have been published forpublic comment and can be viewed on theDTI’s website www.dti.gov.uk/nms

The Physical and Chemical VAM Programmes(which are being formulated by NPL andLGC respectively) have been developedagainst a background of significanttechnological change and continuedglobalisation of trade. Here we review themain elements of the two programmes.

The Physical VAM Programme

NPL has carried out a substantial consultationexercise to establish the requirements for thePhysical VAM Programme. In addition to on-going contacts made through the knowledgetransfer activities of the VAM 2000–2003Programme, the following special events havebeen held:

• A one-day focus group attended by invitedrepresentatives of industry and tradebodies with expertise in different industrialsectors and international standards bodies.The discussion was based on responses toa questionnaire to establish requirementsfor gas and particulate analysis circulatedamongst a wider group.

• A one-day focus group of representativesfrom different industrial sectors, serviceproviders and academics supported by aquestionnaire to establish requirements forsurface and nano-analysis measurements.

• A one-day focus group held withregulators from the Environment Agencyto establish future regulatory drivers forVAM-Physical.

• A questionnaire circulated amongstparticipants at the RSC Electro-analyticalGroup meeting sponsored by VAM.

• A meeting of the Trace Gas FocusGroup in order to develop requirementsfor trace gas measurements.

The Physical and ChemicalVAM Programmes have been developed against abackground of significanttechnological change andcontinued globalisation

of trade.

The consultations have established fourbroad-based drivers for physical analyticalmeasurements which support the objectivesof the Physical Programme:

Industrial competitiveness and trade:Industrial production and innovationdepends on the capability to measure thespecifications of outputs and to controlefficiency in manufacture. This is onlypossible when access is available to a uniformand comparable basis for measurements.Innovative new technologies poserequirements that are at the cutting edge ofmeasurement capability. The optimisation ofprocess performance depends on the abilityto monitor control parameters on a stablebasis. Import and export of manufacturedgoods depends on the acceptance of auniform basis for measurements.

Regulation: Regulations developed at bothEU and UK level act to ensure that emissionsfrom industry are controlled within agreedlimits. Such regulations are most effectivewhen they define performance levels that areboth achievable by industry with availabletechnology and operate at levels that provideadequate protection for society. In caseswhere protection is required that goes beyond

that which can be achieved with availabletechnology, regulation can act to stimulateinnovation in the development of improvedtechnology. The imposition of such regulationon a basis that is fair to regulated industry andsociety requires an infrastructure for traceablemeasurements at a level of uncertaintyappropriate for the application.

Representing the UK Internationally:The effective achievement of theprogramme’s objectives requires input to bemade into representing the UK’s interests invarious international fora whereinternational documentary standards aredeveloped and where the validity of theUK’s national measurement standards mustbe demonstrated. Activities of this type havebecome more intense as a result of the driveto provide a single set of standards across theEU and to provide a measurementinfrastructure that can support global trade.

Environmental Protection and Qualityof Life: The protection of human health andthe environment depends on the capabilityto monitor and reduce the concentrations ofcertain species in the environment and tomeasure whether sources of the mostdamaging species are below accepted levels.These objectives can only be achieved ifboth regulators and regulated industry haveaccess to measurement standards that arevalid at the very low levels appropriate forenvironmental protection.

The four main themes of the Physical VAMProgramme are as follows:

1. Gas and Particulate Analysis:Measurements of gases and particulatesare fundamental to the control ofemissions, the quality of ambient andindoor air, and to many aspects ofindustrial process control. Thesemeasurements are applicable across a widerange of industrial sectors including powergeneration, chemicals/petrochemicals, oiland other fuels, aerospace, vehicles,electronics, water, waste incineration andlandfill, public health, analyticalinstrumentation (including sensors), metaland non-metal processing, andpharmaceuticals. The VAM PhysicalTheme on Gases and Particulates enables

VAM 2003–2006 ProgrammeFormulation Update

industry to demonstrate compliance withregulations and statutes in a fair and cost-effective manner, it ensures theacceptability of results by regulatorsaccreditation bodies and the public, andprovides support to regulators to enablethem to enforce legislation in a technicallysound and impartial way.

2. Electrochemical Analysis: Electro-chemistry represents an increasinglyimportant area of quantitative analyticalchemistry. In particular, the deter-mination of pH is the most commonlymade analytical measurement throughoutthe world. The majority of thesemeasurements are made to fulfil QA/QCrequirements where traceability isincreasingly being required. The VAMProgramme has supported thedevelopment of the UK’s primarystandard pH facility, which is usedprincipally to provide experimental datato support the UK’s position ininternational negotiations at CCQM andCEN. This has enabled the UK to makea major input into the redefinition of theIUPAC pH Scale which was publishedin November 2002. The next VAMProgramme will meet the requirement tomaintain standards and calibrationfacilities for pH and electrolyticconductivity, together with exploitingresearch established under the NMSQuantum Metrology Programme intothe optimisation of electrochemicalmethods for use in quantitative sensing.

3. Surface and Nano-analysis: Surfaceanalysis and nano-analysis are essentialtools for today’s high technology andinnovative industries. Interactions ofsurfaces with the surrounding environ-ment are key to durability, compatibilityand enhanced product quality. This is ofprime importance for aerospace,chemicals, pharmaceuticals, health,personal care, packaging, electronics and ITequipment, oil and petroleum products,polymers, sensors, and transport. Fornanotechnology applications, the spatialresolution is now critical. Issues formeasurement by both lateral and normalforces in the AFM (Atomic ForceMicroscopy) as well as chemical imagingto work close to the molecular level will beresolved and protocols and traceablecalibration systems developed andpromulgated. Methods will also bedeveloped for improving the spatialresolution for valid analysis in Secondaryand Gentle Secondary Ionisation Mass

Spectrometry (SIMS). This will includemethods to address the identification ofdifferent compounds where the phase sizeis less than the probe size.

4. Knowledge Transfer: The requirementfor cross-programme knowledge transferhas increased in recent years as the keystakeholder communities have becomemore aware of the outputs anddeliverables. The key knowledge transferobjectives for the Physical VAMProgramme will address the requirementto maximise the impact and increase usageof the outputs from the Programme. Thiswill involve promotion and awarenessraising through a range of knowledgetransfer activities, services and productstailored to target audience groups.

The Chemical VAM Programme

Chemical measurement is a complex andcritical process. The results can informdecisions whose economic value are manyorders of magnitude higher than the cost of theanalysis, or that are critical to quality of lifedecisions, particularly in healthcare. Theseconsiderations were high in our minds as LGCformulated the Chemical VAM Programme,which has a basic aim to improve the qualityand comparability of measurements made inthe UK, in order to improve our compet-itiveness and support regulatory need.

In formulating the Chemical VAMProgramme, we have also taken into accountthe key trends and issues influencing chemicaland biochemical measurement. These werehighlighted in LGC’s independent survey intothe analytical sector, which targeted keydecision-makers. They confirmed that thespending on analysis was continuing to growand they indicated that the main qualities thatthey looked for from analytical suppliers werelaboratory accreditation and the cost andspeed of the analysis.

Chemical measurement is acomplex and critical process.

Heading the major issues facing analysis overthe next few years were:

• Difficulties in resourcing trained analysts

• Increasing legislation

• Cost of analysis

• Implementing New Technology

The acute shortage of analytical skills andresources has been a consistent messagecoming from the consultation process.Clearly there is a danger that if staff carryingout analysis lack the basic understanding ofhow to make valid measurements, this couldhave serious implications for the reliability ofthe results and the consequential decisions.

Other factors that have been taken into accountin developing the new Programme include thecontinued globalisation of trade, whichincreases the need to have results that are validand comparable on an international scale. Thechemical measurement infrastructure beingdeveloped through the International Weights &Measures Organisation, the BIPM, is making akey contribution to this. We have now reachedthe point where the UK analyst can start tobenefit directly from these efforts.

Thus, the new Programme seeks to help theUK analyst consistently achieve valid results,which are globally acceptable and toembrace new analytical technologies. Themain mechanisms through which theProgramme seeks to achieve this are by:

• Providing UK analytical laboratories witha ‘total analytical package’ to help themproduce valid, globally acceptable results.Key to this is the provision of referencevalues and tools to help analystsimplement the ‘six VAM principles’ forgood measurement practice

• Anchoring the UK measurement systemto the emerging global system, throughparticipation in the key internationalintercomparisons

• Developing and maintaining a highaccuracy analytical capability to providevalues for reference materials ofimportance to the UK, which arerecognised globally

• Evaluating new technology, addressingthe associated measurement issues andproviding the tools that enable analyststo use these with confidence

The proposals build on the considerablecapabilities in chemical and biochemicalmeasurements, which have been establishedin previous programmes, particularly thoserelating to high accuracy mass spectrometrymeasurements for the assignment ofreference values and in DNA quantificationand highly multiplexed analysis. In addition,we have introduced a new theme relating tonew analytical technologies.

The five main themes of the Chemical VAMProgramme are:




1. Chemical Metrology: This is anintegrated work programme at the heartof the Chemical VAM Programme,which will deliver reference materials,reference values and validated highaccuracy methods. It is aimed atimproving measurement reliabilitywithin a framework which relates theaccuracy of the measurements tonational and international standards.The work will be focused on workingwith UK industry, regulators andlaboratories in key areas of regulation,trade, health and the environment.Following consultations with UKexperts, UK and European bodies andin a specially convened workshop on theuse of reference materials we haveidentified a wide range of measurementissues to be addressed. These have beenhighlighted in the individual projects.Also included is work on selectedinternational comparisons of the UK’schemical measurement capabilities withthose of other countries. This is vital fordemonstrating the accuracy andinternational uniformity of our methodsand the global acceptance of ourstandards and reference materials.

2. New Analytical Technologies: A newtheme for VAM, introduced in responseto the significant impact of newtechnology. During the consultation,input and feedback was sought fromover 50 UK experts in a variety ofsectors, which indicated that the UK waslagging in the uptake of new analyticaltechnology. The work is aimed atcorrecting this by addressing the needfor validation and awareness of the newtechnologies. In particular it focuses onthe development of an infrastructure tohelp UK industry implement newtechnology with confidence. It coverssupport for the adoption of newtechnology for characterising complexsystems and the quality infrastructureneeded to apply new technology to out-of-laboratory measurements.

3. Nucleic Acid Measurements: Therapid advances in the technology and theintroduction of highly multiplexedmeasurements raise some critical issuesrelated to the validity and comparabilityof results. The proposals have beendesigned to strike a balance betweenbuilding on the substantial outputs fromthe current programme and addressingnew areas of technology. Included are

the provision of techniques andstandards for quantitative DNA analysis,quality assurance for array-basedmeasurements and work to address themeasurement issues associated with keyemerging technologies.

We have introduced a new theme relating to new

analytical technologies.

4. Tools for Analytical Quality: Theproposed work is focused on deliveringpractical help to analysts in the form ofsoftware and on-line tools for keystatistical applications, includingsampling, method validation andmeasurement uncertainty. It will provideimproved access to method validationusing web-based tools and address theneed for ready access to information onsampling plans and for software toevaluate the results.

5. Knowledge Transfer: The trainingwork package is aimed at addressing oneof the key issues highlighted in theconsultation process, namely theshortage of skilled analysts, by focusingon support for the professional analystthrough sector-based training networksand ‘training the trainer’. The work wasproposed following direct contacts withstakeholders from the public and privatesectors and academe, to determinewhere the focus of the VAM workshould be. Also included are activities tosupport the effective dissemination ofthe outputs of the Programme throughthe VAM website, the ‘VAM Bulletin’and technology transfer events.

International Comparabilitythrough Traceability

A common continuing objective for both thePhysical and Chemical VAM Programmes isto provide UK users with direct access to thereference methods and measurementstandards that are needed for traceablequantitative measurements of chemical andbiochemical species and the determination ofthe composition of materials and compounds.

Much of the demand for traceablemeasurements is to support fair internationaltrade and the free movement of productsand services. Measurement traceabilityensures that the results of measurements can

be accepted around the world without theneed for additional testing of products andcommodities.

It is this driver that provides the principaljustification for the UK’s involvement in theinternational measurement system beingdeveloped under the auspices of theInternational Bureau of Weights and Measures,the BIPM. As a signatory to the MutualRecognition Arrangement2 (which involves 41nations from around the world) the UK iscommitted to the development of measurementtraceability to the international system of units(SI) demonstrated through internationalcomparisons, termed Key Comparisons.

For many analytical laboratories, the conceptof measurement traceability is relatively new.However, the concept, requirement andbenefit of measurement traceability is gainingincreasing recognition, particularly followingthe adoption of ISO 17025, theinternationally-accepted standard for test andcalibration laboratories, which requires thatlaboratories make use of traceablemeasurement standards where available.

This can only be met by ensuring thatmeasurements made in the Key Comparisonsare made on a basis that is transparent andrecognised internationally, and by ensuringthat the results of routine measurements andtests can be linked to the internationally-agreed reference values established throughKey Comparisons. Whilst it is not possible toprovide traceable measurement standards forevery analytical quantity that is measured, thePhysical and Chemical VAM Programmeswill continue to support the development ofstandards and reference materials to underpinkey measurements in trade, health andconsumer and environmental protection.

Further information

Further information on proposals for the new ‘Physical’ and ‘Chemical’ VAM Programmes is available in theprogramme drafts which have beenpublished for public review on the DTI’swebsite www.dti.gov.uk/nms

REFERENCES

1. VAM Bulletin (2002) 28: 3–7.

2. Mutual recognition of national measure-

ment standards and of calibration and

measurement certificates issued by

national metrology institutes, Paris,

October 1999.


1 0 V A M B U L L E T I N

Lesley HannaSira Ltd

Introduction

Indoor and in-car air quality have alreadybeen recognised as significant measure-

ment topics in recent years. It has beenestimated that people in developed countriescan spend as much as 90% of their timeindoors1. In addition, the most vulnerablepeople in society, the very young, the infirmand the very old, are the most likely to spenda higher proportion of their time inside.

Problems generated by indoor pollution havealready been identified and have beenlabelled ‘Sick Building Syndrome’ or‘Building Related Illness’ by the public. Poorquality air has even been linked to reducedproductivity and lost time in industry. Manyof these problems arise in the context of awide variety of pollutants being present innew buildings from construction materialsand new furnishings. Other potentially

hazardous materials may be present due tocombustion, air exchange with the outdoorenvironment and other human activities.

The air quality inside cars also raises

questions since new cars can contain a high

proportion of materials which can emit

volatile organic compounds (VOCs) such as

plastics, fabric, carpet, paint and leather.

Concerns about the effects of poor quality

in-car air has raised the possibility of

regulations to limit the import of vehicles

that do not meet air quality testing limits.

Project objectives

As a result of the consequences of exposure

to poor air quality, guidelines have been

formulated to control indoor air and for this

strategy to be effective it must be possible to

measure air quality definitively and

accurately. A summary of CEN and ISO

standards applying to measurement of

indoor pollutants is shown in Table 1. In

recognition of the importance of indoor air

chemistry this VAM project was formulated

to look at the influence of reactive air

chemistry on the accuracy and stability of

low-cost devices used to monitor indoor air.

A consortium of organisations was

assembled to carry out the work. The lead

organisation was Sira Ltd, the leading

independent RTO specialising in instru-

mentation and intelligent systems. The

National Physical Laboratory (NPL), with

great expertise in the development and

application of measurement techniques, and

BRE, a world-class centre of capability in

building research, joined Sira in the test

programme. The University of York

Environment Department provided a

modelling facility and Optimat Ltd, an

independent strategy consultancy, carried

out a survey of the issues and requirements

underlying the topics.

Species of interest

There are a large number of materials thatcan contribute to indoor pollution, frominorganic gases, such as nitrogen oxides,


Table 1: Standards on measurement of indoor pollutants.2

CEN standards

ENV 13419-1:1999 Building products. Determination of the emission of volatile organic compounds. Part 1: Emission test chamber method

ENV 13419-2:1999 Building products. Determination of the emission of volatile organic compounds. Part 2: Emission test cell method

ENV 13419-3:1999 Building products. Determination of the emission of volatile organic compounds. Part 3: Procedure for sampling storage of samples and preparation of test specimens

pr EN 13528-4 Indoor air quality – Diffusive samplers for the determination of gases and vapours – Requirements and test methods – Part 4: Guide for selection use and maintenance

BS EN ISO 16017-1:2001 Air quality – sampling and analysis of volatile organic compounds in ambient air, indoor air and workplaceair by sorbent tube/thermal desorption/capillary gas chromatography – Part 1: Pumped sampling

pr EN ISO 16017-2:1999 Air quality – sampling and analysis of volatile organic compounds in ambient air, indoor air and workplaceair by sorbent tube/thermal desorption/capillary gas chromatography – Part 2: Diffusive sampling

ISO standards

ISO/DIS 16000-1 Indoor air – Part 1: General aspects of sampling strategy

ISO/DIS 16000-2 Indoor air – Part 2: Sampling strategy for formaldehyde

ISO/DIS 16000-3 Indoor air – Part 3: Determination of formaldehyde and other carbonyls – Active sampling method

ISO/DIS 16000-4 Indoor air – Part 4: Determination of formaldehyde – Diffusive sampling method

ISO/DIS 16000-6 Indoor air – Part 6: Determination of volatile organic compounds in indoor and chamber air by activesampling on Tenax TA sorbent, thermal desorption and gas chromatography using MS/FID.

Assessment of the performance of low-cost indoor and in-car air monitoring devices

through volatile organic compounds, such assolvents, to particles, bacteria and fungalspores. The major species of interest in thiswork were VOCs. VOCs can arise from manysources: building materials, soft furnishings,paint, solvents, personal care products andcleaning materials to name but a few.

Measurement of air quality

Current methods of sampling air quality areprimarily centred around off-line samplingmethods such as diffusion or adsorptiontubes. These devices contain a packingmaterial that adsorbs VOCs from the air.Subsequent analysis of the tubes will enableidentification of the substances present. Twosampling strategies exist: active and passive.Active sampling involves drawing air throughthe tube and is suited to applications wheretime is limited or the concentrations are low.Passive sampling requires a long samplingtime and is best when long-term exposure isto be assessed. Once the sampling iscomplete, the VOCs must be transferred tosome kind of analytical instrument such as agas chromatograph or mass spectrometer.This analysis will give details of thecompounds present.

Although commonly used and verystraightforward, use of sampling tubes

requires access to expensive equipment andtrained operators for analysis, and this mustalso occur off-line. As interest in air qualityincreases there will be a greater requirementfor lower cost and real-time analysis. Movingto a real-time measurement may alsonecessitate moving away from the ability todistinguish between individual compoundsto a measurement giving an indication of thetotal amount of VOCs present in the air.

As interest in air qualityincreases there will

be a greater requirement for lower cost and real-time analysis.

This approach has the disadvantage that themeasurement does not reflect the fact thatsome VOCs present a greater hazard thanothers, and in addition does not reflect theabsolute VOC concentration, beingexpressed in terms of equivalence to acalibration compound. However a real-timetotal VOC (TVOC) measurement is asignificant advantage in identifying theoptimal sampling location and period, wherehigh VOC concentrations occur inter-mittently, where ventilation or the effect of

outdoor concentrations are beinginvestigated or where the rate of decay ofemissions is to be investigated3.

Instruments such as electronic noses,

photoacoustic spectrometers, flame

ionisation detectors (FIDs) and photo-

ionisation detectors (PIDs) can all be used

to make real-time measurements. Each

technique has strengths and weaknesses,

however, and PIDs were selected as the

most appropriate devices, along with the

more conventional sampling tubes for

evaluation within this study.

Test facilities

Controlled and characterised environments

are required for the validity of measurements

to be assessed within them. The needs of the

project required the ability to provide both a

constant environment and to simulate

indoor air under controlled conditions but

permitting chemical reactions to occur.

For a constant environment, NPL madeavailable their Controlled Atmosphere TestFacility (CATFAC). The CATFAC, shownbelow, allows a multi-component mixture tobe maintained at a constant concentration withtemperature and humidity also controlledand measured to a high degree of accuracy.



NPL CATFAC. (Photo courtesy of NPL.)



The atmosphere generated is then circulatedat a predetermined velocity. The CATFACis therefore ideal for exposure of measuringdevices over a long period, in this casepassive diffusive sampling.

To simulate reactive indoor air chemistry a test

facility was designed and built at Sira as part of

the project (see photo above). This facility

allowed a known environment to be created,

after which reactions could occur and be

measured both with the instruments under test

and equipment designed to monitor the

environment. The test atmosphere was

contained within a chamber made from

fluoropolymer and stainless steel.

Fluoropolymer was chosen since it is not only

chemically inert but also has good transmission

of ultraviolet and visible light, which is required

to initiate photochemical reactions. The

stainless steel plates were provided with ports

for gas inlets, instrumentation mounting and

analytical measurements. This facility was ideal

for shorter-term measurements using the PID

devices described earlier.

A mixture of typical VOCs were selected forthe test programme, with seven compoundsselected, representing the major functionalgroups commonly found in indoor air(aromatic and aliphatic hydrocarbons andoxygenated compounds). The accuracy ofmeasurement of sampling tubes and PIDswere evaluated using these compounds in

the presence and absence of ozone gas.Ozone is highly reactive and the project teamwanted to find out what effect the presenceof ozone had on both the species present inindoor air and the measurements carried outby the instruments themselves.

Modelling of reactions

In the presence of reactive species such ashydroxyl radicals, nitrogen oxides andozone, oxidation of VOCs will occur,resulting ultimately in the formation ofozone and other secondary pollutants suchas carbonyl compounds and particulates.Some change is therefore seen in thecompounds present. In order to give anapproximation of the course of the reactionsarising, models have been designed whichwill calculate the expected reaction pathsand products formed. The model used bythe University of York could calculate theatmospheric degradation of 125 VOCs andwas specially modified for use in this project.Use of the model increased theunderstanding of the reactions occurringduring the reaction chamber test programmeand complemented the work carried outusing reactive systems.

Results and conclusions

The field of indoor air chemistry is a hugesubject and there are many methods of

measuring the species present in indoor air. Itis also clear that accurate measurements ofindoor air quality are of great importance.The course of the project has shown thatsignificant reactions can be expected in atypical indoor environment where VOCs arepresent in a reactive atmosphere, and that thiswill change the composition of theatmosphere. Limitations of the measurementtechniques used have been encounteredduring the project: choice of the sorbant foranalysis is important and ozone was shown tohave some effect on the results of analysis.The PID instruments used showedunexpectedly large variations even in theabsence of ozone and further work is requiredto understand the source of these errors.

Further information is available from:Lesley HannaSira LtdTel: 020 8467 2636Email: [email protected]

REFERENCES

1. Dimitropolou et. al., Atmos. Env., 35,

269–279, 2001

2. D. Crump, BRE, personal communication

3. L.E.Ekberg, ‘Real Time Monitoring of

Organic Compounds’, ‘Organic Indoor

Air Pollutants’, ed. T.Salthammer, Wiley-

VCH, 1999

Sira test chamber.

David RuddGlaxoSmithKline

Introduction

There is a potential revolution in the airin the field of pharmaceutical

development and manufacture.

After many years of threatening to follow the

lead taken by other manufacturing sectors,

the pharmaceutical industry now seems

closer than ever to adopting Parametric

Release and ‘Quality by Design’ concepts in

order to improve its manufacturing

capability and enhance profitability in an

increasingly competitive commercial world.

This article describes what is meant by the

terms Parametric Release and ‘Quality by

Design’ and discusses why these concepts

are now receiving so much attention within

the pharmaceutical sector – despite having

been around for several decades. In turn, the

impact of these approaches on analytical

method development is considered,

suggesting that a step-change in method

validation philosophy is also required.

The need for improveddevelopment and

manufacturing concepts

What do we mean by Parametric Release

and ‘Quality by Design’ and what has

brought about the need for change?

First, it should be said that the term‘Parametric Release’ is a dangerous one touse. It has been around for so long withinthe industry, without ever really beingemployed in earnest, that it has come tomean all things to all men. However, for thepurposes of this article (and without

choosing to show preference for any of themultiplicity of definitions which alreadyexists), the author takes the term to mean a:‘system of quality assurance based on well-understood and well-characterised manu-facturing processes which allows product qualityto be established and demonstrated during themanufacturing process itself.’

A natural corollary of this definition is thatthe demonstration of product quality byend-product testing becomes irrelevant. Andit is this aspect, rather than the objective ofguaranteed product quality based on robustmanufacturing processes, well-characterisedraw materials etc, which many people havecome to associate with the term ‘ParametricRelease’. Nevertheless, whether thecommercial driver is to reduce the volume

and expense of end-product testing orsimply to improve manufacturing efficiency,the concepts embraced by ParametricRelease remain laudable and highly-prized.

In many ways, the principles of ‘Quality byDesign’ are no different to those describedabove, although the emphasis of thismanufacturing strategy is much moreclearly associated with ensuring finishedproduct quality rather than the removal ofend-product testing. A ‘Quality by Design’approach clearly sets out to providefinished product of a guaranteed standard,similarly based on well-understood and well-characterised manufacturingprocesses, but perhaps with more emphasison control and regulation of such processeswithin pre-determined operating limits.


Process Analytical Technology – a new initiative within pharmaceuticaldevelopment and manufactureImplications for the development and validation of methodology




Thus, if finished product quality is likely tobe affected by variation in input raw materialproperties, for example, then a ‘Quality byDesign’ approach might allow slight, butcontrolled variations in manufacturingconditions to achieve finished product of theappropriate quality.

Both Parametric Release and ‘Quality by

Design’ concepts are well-established in other

manufacturing sectors, but are still fairly

peripheral within pharmaceutical development

and manufacture. Of course, there are

examples of certain unit processes or partial

manufacturing steps which incorporate such

philosophies (some antibiotic production, for

example, and most sterilisation procedures)

but, in general, the implementation of such

approaches as part of an integrated develop-

ment and manufacturing strategy is yet to be

widely achieved. In the author’s opinion, this is

largely attributable to two main reasons:

Regulatory authorities have commented thatthe quality of pharmaceutical development isoften determined by ‘time to market’. Keydates generally need to be met during theproduct development phase (for example,when developing products for seasonal marketssuch as rhinitis or influenza) and this willinevitably affect the extent to which full processunderstanding and characterisation can beachieved. Thus, at the point of registration, thelevel of product and process understanding willnot necessarily be complete. While this ishardly surprising (and while attempts atachieving ‘perfection’ in this respect are notnecessarily to be encouraged, due to theirinevitable delaying influence in productavailability), the consequence is that there maybe aspects of routine product manufacturewhich eventually require modification orimprovement in terms of robustness and/oroverall efficiency of operation.

Regulatory authorities havecommented that the quality

of pharmaceuticaldevelopment is often determined

by ‘time to market’.

Generally pharmaceutical manufacturingefficiency has been measured and bench-marked within the industry sector. And, asmost major pharmaceutical manufacturers

seem to be operating to similar principlesand to similar levels of capability, the overallimpression is that the industry remainscompetitive and reasonably efficient. It isonly when comparison is made across othermanufacturing sectors (motor, aircraft, food and beverage etc) that the relativeinefficiency of pharmaceutical manufacturebecomes apparent. The recent infatuation ofthe pharmaceutical industry with LeanManufacturing and Six Sigma concepts isevidence enough that there are significantlessons to be learned from the experiences ofother manufacturing sectors.

However, the relative conservatism whichhas existed within the pharmaceutical sectoris now being subjected to considerablescrutiny, both from within (as manu-facturing groups try to maximise theirproductivity and efficiency in an increasinglycompetitive commercial climate) andexternally (as regulatory agencies recognisethe opportunities for improved pharma-ceutical development and manufacturecoupled with a more science-based agencyinspection and review process1).

And, while these commercial and regulatory

‘agents for change’ are arguably both of

equal significance, it is the regulatory

perspective which is presently having the

greater impact on the way in which

pharmaceutical development and manu-

facture need to evolve.

The Food and DrugAdministration (FDA) Process Analytical

Technology (PAT) initiative

In response to the perceived opportunity for

improved pharmaceutical development and

manufacture, FDA have announced their

‘science and risk-based approach to product

quality regulation incorporating an

integrated quality systems approach’1. This

reflects an increasing concern regarding

instances of product recalls, batch failures

and manufacturing inefficiencies, coupled

with a need to balance an already over-

stretched inspection and review programme

with limited agency resources. In this

context, it is interesting to note that, in

2002, FDA approved a mere sixteen drugs

for use in the US2 – the lowest for more than

a decade – and this despite the investment of

more than £30 billion in pharmaceutical

research and development worldwide.



As part of this new risk-based initiative, it is

recognised that improved product

development and greater manufacturing

efficiency can be achieved using, for

example, the ‘Quality by Design’ concepts

described previously. To this end, it is

appreciated that enhanced approaches to

process monitoring and control – as opposed

to the traditional reliance on end-product

testing – are necessary. As a result, the FDA

Process Analytical Technology (PAT)

initiative has been established and developed

during the last 12 to 18 months.

Broadly PAT describes the type of analytical

monitoring technology which allows

measurements to be made on the

pharmaceutical manufacturing process itself,

rather than on the material (the finished

product or end-product) which results from

such a process. In this respect, PAT may be

considered as in-line or at-line monitoring

(that is, at point of manufacture) rather than

off-line or laboratory-based measurement.

This has the huge advantage that, with

measurements being made in real-time

(rather than after the event), decisions can

be made based on the real-time monitoring

data and actions taken themselves in real-

time. This allows process modifications to

be made via feedback control systems;

thus ensuring that process operating

conditions remain in control at all times.

As part of this new risk-based initiative,it is recognised that improved product

development and greatermanufacturing efficiency

can be achieved.

PAT is seen as part of the toolbox which willallow real-time monitoring (and, hence, real-time control) of pharmaceuticalmanufacturing processes both duringdevelopment and routine application. Theuse of a wide range of diverse measurementtechniques (chemical, physical, spectroscopic,acoustic etc) during product and processdevelopment, allows true process under-standing to be achieved and enables therelationship between critical process

parameters (for example, those which affectpowder blend uniformity during mixing) andend-product quality attributes (in this case,tablet content uniformity) to be established.

In addition, PAT monitoring techniques canbe used during routine manufacture toensure that the process operating conditions(or ‘process specification’ as establishedduring process and product development)remain ‘in control’. As a consequence ofthis, finished product of the desired standardis routinely produced despite any minorvariations in input material quality orprocessing conditions: the ‘Quality byDesign’ concept at its most effective level.

Implications for analyticalmethod validation

Although there are many sources of guidanceregarding analytical method validation (someof which have gained a high level ofregulatory acceptance3,4), the re-location ofanalytical assessment from the laboratory tothe manufacturing process results in anumber of significant implications whenconsidering the development and validationof such technologies.

Many process analytical technologies aresensor-based. As a non-sampling technique,it becomes important to consider how manysensors need to be used, where such sensorsare to be positioned and the reproducibilityof sensitivity from one sensor to another.

Technologies such as acoustic monitoring,which are well-established in other industrysectors, but which are relatively new in termsof pharmaceutical application, requiresophisticated data interpretation method-ologies. The reliability, principles ofoperation and general effectiveness of such algorithms need to be established and demonstrated.

Spectroscopic techniques (such as nearinfra-red) depend on the chemometrictreatment of data and the development ofcalibration models from well-understoodtraining sets of data. The authenticity andreliability of such models need to beestablished and demonstrated.

Suitable reference standards need to bedeveloped for some process-basedmonitoring technologies (for example,acoustic monitoring).

The importance of existing validationparameters (for example, linearity orrepeatability) may need to be questionedwhen considering process-based applications.For example, most processes are dynamic andit may therefore be impossible to demonstraterepeatability of measurement when the‘sample’ itself is changing with time. Indeed,many process-based measure-menttechniques are themselves simply concernedwith change, rather than with any absolutequantitative measurement: for example, nearinfra-red spectroscopy for powder blendmonitoring during mixing processes. So thesemay simply require demonstration ofdiscrimination at an appropriate level ofsensitivity, rather than assessment of any trulyquantitative performance.

Conclusions

A significant opportunity presents itself interms of further development of existingguidance for analytical method validationand performance assessment when appliedto process-based applications.

The FDA ‘science and risk-based’ approachis undeniably with us already and is likely tohave significant impact on product andprocess development in the pharmaceuticalindustry within a very short time-frame. As aresult, it is incumbent upon the analyticalcommunity within the pharmaceutical sectorto recognise the impact of this initiative andto address the issues (and others) raised inthis article regarding development andvalidation of process analytical methodology.

REFERENCES

1. Pharmaceutical cGMPs for 21st century:

A risk-based approach, FDA, August 2002,

ht tp: / /www.fda.gov/oc/guidance/

gmp.html

2. The Financial Mail, 5/1/03, Simon Watkins.

3. ICH Q2A: Text on validation of analytical

procedures, http://www.fda.gov/cder/

guidance/ichq2a.pdf

4. ICH Q2B: Validation of analytical procedures:

methodology, http://www.fda.gov/cder/

guidance/1320fnl.pdf

All views and opinions expressed in this

article are solely those of the author,

Dr David Rudd, and are not necessarily

endorsed by GSK.


Martin Milton& Jian WangNational PhysicalLaboratory

Introduction

One of the features of most high-accuracy analytical methods is their

dependence on Certified ReferenceMaterials (CRMs) to give them well-definedtraceability to stated references. In manycases, suitable CRMs are not available tocover the required range of analytes, andwhen they are available, they are often veryexpensive. The limitations on the availabilityof such CRMs is often considered to be theprincipal difficulty in bringing traceability toa wider range of chemical measurements.Consequently, there is substantial interest inthe development of methods that operatewithout the need for external “references”.In the area of physical measurements suchmethods are known as “quantum methods”since they are ultimately anchored torealisations of fundamental atomicproperties and therefore do not requireaccess to reference standards from externallaboratories. A project at NPL has theobjective of developing an analytical methodfor use in chemical measurement that hasanalogous properties to the “quantummethods” used in physical measurement.This can be achieved by makingmeasurements using a method that providesa link to the most basic components ofchemistry – atoms and molecules.

Isotope Dilution

One of the most fundamental principles usedin chemical analysis is “isotope dilution”. Itrelies on the fact that different isotopes of thesame element have extremely similar chemicalbehaviour. When combined with analysis bymass spectrometry, isotope dilution forms the

basis of a powerful analytical method calledIsotope Dilution Mass Spectrometry (IDMS).Despite its potential to give results that areindependent of both the matrix and theanalyte, most IDMS methods require the useof isotopic reference materials to overcomeinherent limitations in their accuracy. Box 1explains the operation of the two most widelyused IDMS methods. It shows how the directmethod requires an enriched spike materialwith a certified isotope ratio and knownpurity. Additionally, reference materials withcertified isotope ratios are required for thehighest accuracy applications in order tocalibrate the isotope ratio scale of the massspectrometer. The two-step method does notrequire any independent certification of thepurity of the spike, but still requiresindependent certification of its isotope ratio.

NMS Quantum MetrologyProgramme

A research project being carried out under

the National Measurement System’s

“Quantum Metrology Programme”

(www.npl.co.uk/quantum) aims to show

how some of these limitations of the IDMS

method can be overcome. The research uses

well-characterised gases as model systems

for investigating the operation of IDMS and

takes advantage of highly accurate

mass spectrometers available for gas

measurements. Additionally, the results can

be validated against “state of the art” gas

measurements based on gravimetrically

prepared primary gas standards that have

been demonstrated to be traceable to the SI.

The principles being developed in the

project have the potential for application to

other areas where IDMS is used, including

organic and inorganic analysis as well

as the analysis of trace amounts of

radioactive contamination.

Isotope-Dilution Curve Method

The major innovation resulting from the

project is a new IDMS method – known as

the “isotope-dilution curve method” (Box

2)1. The principal of the method is that the

isotope ratio of any blend made from a

given spike and a given unknown must lie

on a mathematical curve – known as the

isotope dilution curve. It is then clear

that when two blends are prepared

gravimetrically, with known ratios of the

spike to unknown, the measurements of the

corresponding isotope ratios will define the

parameters of the isotope-dilution curve.

When the unknown is blended with the

spike, a measurement of its isotope ratio

enables the corresponding ratio of material

blended to be calculated using the

equations given in Box 3. The absolute

mass of analyte in the unknown can then

be calculated by multiplying by the mass

of blend added.


Isotope-Dilution Mass Spectrometry –a ‘quantum’ method for chemistry?

Box 1: The basic equation governingIDMS for a single blend is

where x is the ratio of the mass of theunknown to the mass of an enriched spike.Rsp , Rs and R are the isotope ratios of thespike, unknown and blend respectively. Q isa parameter that involves a summation overall other isotopes in each sample.

The use of this equation without furthermodification is usually referred to as“direct” or “one-step” IDMS. This methodhas the advantage of simplicity. Thedisadvantage, however, is that independentmeasurements of the purity of the spike andof its isotope ratio are required to determineQ. A development of the ‘direct’ methodinvolves the use of a ‘reverse’ step in whichthe spike is blended with a pure sample ofthe same material as the analyte. This ‘two-step’ or ‘reverse’ IDMS method has theadvantage that it is not necessary to haveindependent information about the purityof the spike or Q, but it is still necessary tohave an independent value for Rsp.



Validation of the Isotope-Dilution Curve Method

Laboratory work is underway at NPL tovalidate the isotope-dilution curve methodand to demonstrate its application to themeasurement of primary standard gasmixtures of carbon dioxide. This uses acustom-built mass spectrometer with anarray of detectors configured to measure the

isotopes of carbon dioxide. The most

important feature of the instrument is that it

has four independent gas sample inputs, each

of which can be precisely controlled using a

bellows valve driven by a stepper-motor. This

enables the samples to be changed without

any change in the inlet conditions.

Initial experiments using isotopically

depleted carbon dioxide diluted in natural

carbon dioxide have demonstrated the

principal of operation of the method. These

have shown agreement to better than 100

parts-per-million (relative to the stated

value). The validity of this result is further

assured by observations that the results of

Box 2: The isotope dilution curve method has been validated using gravimetrically preparedblends (mixtures of natural abundance and spike carbon dioxide). The mass ratio of the naturalcarbon dioxide to the spike is determined by gravimetry during its preparation and is then used asthe reference to be compared with the IDMS result. Figure 1 shows the quadruple input massspectrometer used at NPL and Figure 2 shows a typical set of results from five repeat analyses.

Box 3: The basic equation for isotopedilution is given in Box 1. The principleof the isotope-dilution curve method isthat this equation is re-written in a formthat can be plotted as a single curve on agraph of the isotope ratio of the blendversus the amount ratio of blend tounknown. This curve is shown in Figure 3where the isotope ratio of the blend isplotted relative to the isotope ratio of thepure reference material. Each point onthis curve corresponds to a particularblend prepared from the given spike andthe unknown sample. The curve can beuniquely defined through the measurementof any two blends that are known to lieon it. When the curve has been defined, themeasurement of the isotope ratio for anyblend enables the corresponding value x1

to be read from the curve, which can thenbe used to calculate the unknown amountof analyte in the blend using:

where D is a function of the isotope ratiosfor the measured blends, and x2 and x3

are the amount fractions in the two“reference” blends.

Since it is only the relative position ofpoints on the isotope dilution curve that isimportant, the method is relativelyinsensitive to systematic errors arisingfrom either the mass spectrometer or theprocedure used to implement the method.

Figure 1: The four-channel stable gas mass spectrometer used at NPL for isotope dilution studies.

Figure 2: Results of five analyses using the IDMS curve method. The solid line indicates the reference value from gravimetry and the dotted lines indicate its uncertainty (k=2).

Figure 3: The isotope dilution curve – for ablend of a natural isotope blended with aspike that is depleted in the natural isotope.



the measurement are largely independent of

the drift of the instrument. This property of

the isotope-dilution curve method will

enable its application to instruments with

substantially poorer performance than the

one used at NPL.

Recent experiments at NPL have substantiallyincreased the scope of application of themethod by including a GC pre-separationstage which enables the measurements to bemade in the presence of a matrix which isseparated before the sample is introduced intothe mass spectrometer. In the experimentscarried out at NPL, the matrix has beennitrogen and the results of the method havebeen validated against the value of NPL’sinternationally recognised primary standardgas mixtures. The values have been shown to

be comparable to 0.3% (relative to value) andare now largely limited by the repeatability ofthe GC separation process. Further work isaimed at improving this performance and anumber of publications have been producedto give analysts working on the Physical andChemical themes of the VAM Programmethe opportunity to exploit the technique.

Although it seemed unlikely before theinception of this project, it now appearspossible that there are some primary methodsused for chemical analysis, that have some ofthe benefits of the quantum methods exploitedso successfully for high-accuracy measurementsof time, length and electricity. In particular,the isotope-dilution curve method developedat NPL can enable IDMS measurements to becarried out without reference to externallycertified reference materials.

REFERENCES

1. Milton, M. J. T., Wang, J., International

Journal of Mass Spectrometry, 218

(2002), 63–73.

BIBLIOGRAPHY

1. Milton, M. J. T., Wielgosz, R. I., Rapid

Communications in Mass Spectrometry,

16 (2002), 2201–2204.

2. Milton, M. J. T., Wang, J., Harris, P. M.,

“Implementation of isotope dilution

mass spectrometry with one, two and

three reverse steps”, NPL Report COAM

7 (2002).

3. Milton, M. J. T., Wielgosz, R. I.,

Metrologia 37 (2000) 199–206.

Jim Crighton& Harry ReadBP plc

Mike SargentLGC

Introduction

The European commitment to a cleanerenvironment has resulted in fuel

regulations that require a steadily decreasingsulfur content for road transport fuels (seeTable 1). In addition, sulfur free fuels (< 10mg kg-1 sulfur) are becoming increasinglyavailable in EU member states and should beavailable in all member states by 2005. It isanticipated that the 10 mg kg-1 maximumsulfur concentration for road transport fuelswill become mandatory in the EU from2009. With such a significant reduction in

sulfur concentrations, many existing methodsof analysis have had to be adapted to dealwith these new requirements and need to bevalidated at the lower levels of sulfur. Animportant issue for the oil industry has beenthe lack of CRMs or reference methods ableto provide reference values of sufficientlysmall uncertainty for reliable verification ofmethods at the new, low levels.

LGC have recently1 developed a novelreference method for S in fuel based onisotope dilution-mass spectrometry (IDMS)using microwave digestion of samplesfollowed by inductively-coupled plasma massspectrometry (ICP-MS) for the isotope ratiomeasurement. This methodology has itself

been verified by comparison of results withoverseas national measurement instituteswhich provide reference values based onIDMS using well-established thermalionisation mass spectrometry (TIMS)techniques. The latter methods are, however,less well-suited to very low levels of sulfurdue to problems of reagent contamination.

LGC reference values obtained with the new

ICP-MS method have contributed (in

association with BP plc), to the development

of CEN/ISO methods appropriate to the new

regulatory requirements and to validation of

these methods at the new limits required by

the EN228 and EN590 fuel specifications.

The methodology has also been used for

certifying new reference materials for diesel

fuel at levels embracing the new lower limits

required for the EN fuel specifications.

Existing methodology

Following many national workshopsconsidering the implications of the proposedmandatory limits on sulfur concentrations in

C A S E S T U D Y

Meeting the needs of regulation and trade:determining low levels of sulfur in fuel

Table 1: European regulatoryrequirements.

Year Sulfur Content (mg kg-1) EC Directive

1993 2000 93/12/EEC

2000 350 (diesel) 98/70/EC150 (petrol)

2005 50 98/70/EC


road transport fuels, it became clear thatexisting analytical methods quoted in ENfuel specifications were not suitable forsulfur measurements at the proposed newlower levels. As a result, at the plenarymeeting of CEN Technical Committee 19held in Madrid in June 1997, a resolutionwas passed creating a European WorkingGroup (WG27) which would be “concernedwith the comparison of sulfur contentdetermination methods for sulfur levels notgreater than 0.1 % m/m”.

The working group consisted of nationalexperts in sulfur analysis from a number ofEuropean community states and wascharged (in collaboration with nationalstandardisation bodies), with developing aconsensus view on which methods should bereferenced in the revised EN228 and EN590fuel specifications.

The working group considered and rankedmethods on the basis of a number of criteria,which included:

• Sensitivity/limit of quantitation

• Precision

• Availability

• Cost and maintenance

• Robustness/ease of use (including use by shift/less skilled staff)

• Existing methods quoted in EN228 and EN590

Based on these criteria, the following analyticalmethods were short-listed:

• Wavelength Dispersive X-rayfluorescence (WDXRF)

• Energy Dispersive X-ray Fluorescence(EDXRF)

• Wickbold Combustion

• Microcoulometry

• Combustion/Ultra-violet Fluorescence(UVF)

A European wide round robin was carriedout in 1998–92 involving 69 laboratoriesfrom 9 countries in which the precision(repeatability and reproducibility)Φ of theabove analytical methods was tested using

15 fuel samples (8 petrol and 7 diesel)covering sulfur concentrations in the range 5to 500 mg kg-1.

According to EN ISO 4295, for a method tobe acceptable for inclusion in specifications,the reproducibility R should be less than halfof the maximum concentration specified. Onthis basis, it was found that the EDXRFmethod specified in EN228 and EN 590(EN ISO 8754 : 1995) was not suitable foruse at the sulfur concentrations proposed inthe 2000 specifications. However, a newEDXRF method (ISO/DIS 20847)developed by the working group was foundto be suitable for measurement of sulfurconcentrations down to 50 mg kg-1 (i.e. 2005specifications) and it was proposed that thismethod replaced EN ISO 4295 in EN 228and EN590 specifications.

The working group consisted of national experts

in sulfur analysis from a number of European

community states.

WDXRF (EN ISO 14596) and a new UVFmethod (ISO/DIS 20846), developed by theworking group were found to be suitable forinclusion in both the 2000 and the proposed2005 specifications. However, only the UVFmethod was found to have adequatereproducibility for measurement of sulfur atthe 10 mg kg-1 level (i.e. “sulfur free” fuel).

The performance (reproducibility) of themethods at levels below 50 mg kg-1 wasfound to be very disappointing and did notreflect the inherent limits of detection whichmost of the techniques are capable ofachieving. In particular, the reproducibilitiesfor the Wickbold and microcoulometrymethods (EN 24260 and ISO/CD 16591)calculated from the round-robin data werefound to be considerably worse than thosequoted in the methods. In the case of theWickbold method, this was considered to bedue to the loss of skilled operators, as moreand more laboratories are replacing thistechnique with alternatives (particularly on

safety grounds!). For this reason, it wasproposed that the Wickbold technique wasdropped from the EN229 and EN590specifications (and replaced with UVF).

The deterioration in performance of the

microcoulometry method however, was more

worrying. This, together with the relatively

poor performance of the other analytical

techniques at low sulfur concentrations, was

thought to be due to problems associated

with the inexperience of many laboratories in

working at these new, lower levels and

possibly due to problems associated with

standards and instrument calibration.

It was therefore recommended that a further

round-robin study be carried out, concen-

trating on sulfur concentrations lower than

50 mg kg-1. It was also felt that inclusion of

some reference materials of appropriate

matrix and sulfur concentration could

perhaps minimise some of the problems

experienced in the first round-robin and

allow the reproducibilities to better reflect

the inherent sensitivities of the techniques.

The availability of these reference materials

would also allow any biases between the

methods to be evaluated.

Provision of reference valuesusing high accuracy IDMS

The IDMS method used to obtain referencevalues is based on a closed vessel microwavedigestion followed by measurement with asector-field ICP-MS in medium resolutionmode (R=4000). Medium resolution isrequired in order to resolve the sulfurisotope peaks from oxygen polyatomicinterferences. The advantages of this methodover existing IDMS methods based onthermal ionisation mass spectrometry(TIMS) are that it is quicker, there is lessrisk of contamination of low level samplesand it has the potential to achieve lowerdetection limits. The method is applicable tothe quantitative determination of sulfur in fuel samples at concentrations up to ca 1000 mg kg-1 in all fuel types but particularcare must be taken when handling volatilesample types such as petrol. Sample aliquotsare weighed into the microwave digestion

C A S E S T U D Y

Φrepeatability, r – the difference between two test results obtained by the same operator with the same apparatus under constant conditions on identical test material would in the long run, in the normal and correct operation of the test method, exceed this value in only one case in twenty.Reproducibility, R – the difference between two single and independent test results obtained by different operators working in different laboratories on identical test material would in the long run, in the normal and correct operation of the test method, exceed this value in only one case in twenty.

vessel and weighed aliquots of a solution ofisotopically enriched sulfur (34S= 94.2%) areadded to each such that the ratio of 32S/34S is1. The blended sample/spike mixture isdigested with HNO3 and H2O2 in themicrowave for 40 minutes then diluted byweight to the optimum sulfur concentrationfor ICP-MS measurement of the isotoperatio. A spiked solution of a natural sulfurcalibration standard is also prepared andmeasured with the samples; i.e. themeasurements are traceable to a naturalsulfur standard and do not rely on theaccurate characterisation of the isotopicallyenriched spike material.

The methodology incorporates two keydevelopments, which simplify the IDMSmeasurements and reduce the likelihood oferrors. First, the isotope dilution techniqueused for this work is an ‘exact matching’procedure in which the isotopically enrichedmaterial is added to the sample and thenatural calibration standard such that theratio and intensity of the isotopes in eachmeasurement solution is the same. In thecase of this sulfur analysis, the solutions wereblended to give a 32S/34S ratio close to unity.This method, which has been described indetail elsewhere4, has the advantage that iteliminates the effects of instrumental massbias, detector deadtime and linearity since all

samples and calibration standard solutionsare affected to the same degree. The seconddevelopment addresses the problem thatisotope ratios of sulfur are known to vary innature due to biogenic and thermalfractionation and it cannot be assumed thatthe isotope ratios in samples and standardsare identical. Therefore, all test samples mustbe measured for natural isotope ratios beforeIDMS analysis. Accurate measurement ofthis ratio by ICP-MS has been achievedthrough use of silicon to correct forinstrumental mass bias. Silicon has beenfound to be suitable for this purpose sincethe 30Si/28Si ratio (29.88) is similar to that of the 32S/34S ratio (22.0) with the samemass/charge difference in the isotope pairs.Silicon has been found to have minimalnatural variations in isotope ratio.

The methodology incorporatestwo key developments,

which simplify the IDMSmeasurements and reduce the likelihood of errors.

The full method for this procedure has alsobeen described previously1. The precisionand accuracy of the method at higher sulfur

concentrations is demonstrated in Figure 1which shows results for six replicate analysesof a NIST reference material.

Development and validation ofrevised CEN/ISO methodology

Following on from experiences gained in thefirst round-robin, CEN TC19 WorkingGroup 27 decided in 2000 to carry out asecond round-robin3 concentrating on therange 1 to 60 mg kg-1 sulfur. Thisconcentration range was selected in order toobtain robust precision statements for theanalytical methods at levels consistent withcurrent and future sulfur specification limits.

Five analytical methods were included in thestudy, including three new methods(ISO/DIS 20846, ISO/DIS 20847 andISO/DIS 20884) developed by the workinggroup. The methods included were:

• EN ISO 14596 WDXRF (with internal standard)

• ISO/CD 20846 UVF

• ISO/CD 20847 EDXRF

• ISO/CD 20884 WDXRF (withoutinternal standard)

• ISO/DIS 16591 Oxidativemicrocoulometry


CASE STUDY

Figure 1: Results of analysis of NIST SRM2724b by IDMS. Error bars represent ± 95% expandeduncertainty (k=2) for each aliquot. Horizontal lines represent certified value and expanded uncertainty.


CASE STUDY

All of these methods were essentially thesame as those included in the 1998-9 round-robin, with the exception of ISO/CD 20884,which differs from EN ISO 14596 in that itdoes not require use of an internal standard(and is therefore much faster and moreconvenient to use).

Seven petrol samples and seven dieselsamples covering the range 1 to 60 mg kg-1

sulfur were included in the round robin. Inaddition, one of the diesel samples wasblended with 5% FAME (fatty acid methylester) from two different sources to producetwo additional samples for inclusion in theround robin, in order to test the applicabilityof the methods for these products (allowedunder EN590 specifications).

In order to try to minimise any potentialdegradation in reproducibility caused bycalibration issues, two quality controlsamples (one petrol and one diesel) wereincluded in the round-robin. These twomaterials (labelled QCP and QCG) werecertified by LGC using high accuracy IDMSas described above. The reference valueswere provided to the laboratoriesparticipating in the round-robin study sothat they could check performance/calibration of their instruments prior toanalysing the round-robin samples.

A total of 92 laboratories from 10 Europeancountries participated in the round-robin.Table 2 shows the reproducibilities of thevarious methods calculated from the round-robin data for three critical sulfurconcentrations (corresponding to low sulfur(< 50 mg kg-1), ultra low sulfur (< 30 mg kg-1)and “sulfur free” fuel (< 10 mg kg-1)).

In order to try to minimiseany potential degradation in

reproducibility caused bycalibration issues, two quality

control samples were included in the round-robin.

In order to check potential methods forinclusion in the EN228 and EN590specifications for any potential bias, themean results obtained from the round-robinwere compared with results obtained byLGC using high accuracy IDMS. Theresults are shown in Table 3.

In all cases, the differences in concentrationsbetween the method mean values and theIDMS reference values are small relative to therepeatabilities of the methods, indicating thatany biases are insignificant from a practical

point of view. Comparison of the resultsobtained for the diesel fuel with and withoutthe addition of 5% FAME also showed nosignificant differences indicating that themethods are also applicable to these products.

Based on the ISO “2R” rule, it can be seenthat all of the analytical methods included inthe round-robin study are suitable formeasuring sulfur in road transport fuelsdown to and including 30 mg kg-1 S (i.e.ultra low sulfur fuel). Both WDXRF andUVF were found to be suitable for measuringsulfur in “sulfur free” fuels (i.e. < 10 mg kg-1

S), although it was found that some WDXRFinstruments utilising lower power X-raytubes (1 kW and less) could not achieveadequate precision (reproducibility) at thislevel. EDXRF (ISO/CD 20847) was foundnot to be suitable for measuring sulfur infuels at concentrations below 30 mg kg-1.Although, it was found that a new generationof EDXRF instruments utilising polarised X-ray sources gave significantly better precisionfigures for low sulfur concentrations thanthose for conventional EDXRF instrumentsand may be suitable for measuring sulfur infuels at concentrations below 10 mg kg-1 S.

From the above, it is clear the all threemethods developed by CEN TC19 WorkingGroup 27 are suitable for use at the 350,

* All products, X-ray tube power > 1 kW

Method TechniqueSulfur Concentration (mg kg-1)

10 30 50

EN ISO 14596 * WDXRF (internal standard) 3.4 4.7 6.0

ISO/CD 20846 – Petrol Combustion/UVF 2.7 6.2 9.7

ISO/CD 20846 – Diesel Combustion/UVF 2.2 4.5 6.7

ISO/CD 20847 – Petrol EDXRF 11.1 14.3 16.6

ISO/CD 20847 – Diesel EDXRF 12.1 12.5 12.8

ISO/CD 20884 * WDXRF (no internal standard) 3.1 5.5 7.9

ISO/DIS 16591 – Petrol Oxidative microcoulometry 3.6 7.2 10.8

ISO/DIS 16591 – Diesel Oxidative microcoulometry 3.3 4.6 5.9

r = repeatability; |∆| = absolute difference between mean value and IDMS reference value

Petrol Diesel

Sulfur, (mg kg-1) r |∆| Sulfur, (mg kg-1) r |∆|

IDMS 20.10 ± 0.52 32.33 ± 0.65

EN ISO 14596 21.22 2.6 1.12 32.78 3.2 0.45

ISO/CD 20846 20.14 2.2 0.04 32.80 2.9 0.47

ISO/CD 20847 20.74 3.4 0.64 31.92 7.6 0.41

ISO/CD 20884 20.65 2.5 0.55 31.48 1.9 0.85

ISO/DIS 16591 19.55 1.9 0.55 31.82 2.5 0.51

Table 2: Comparison of the reproducibilities obtained in the round robin.

Table 3: Comparison of Method Mean Concentrations with Reference Values provided by IDMS.

150, 50 and 30 mg kg-1 sulfur specificationlevels. ISO/CD 20846 (UVF) and ISO/CD20884 (WDXRF, no internal standard) aresuitable for use at sulfur concentrations of10 mg kg-1. EN ISO 14596 (WDXRF, withinternal standard) was also found to besuitable for measuring sulfur at this level,but since ISO/CD 20884 is faster and easierto use, the working group recommendedthat the former technique was replaced bythe latter in EN228 and EN590.

In general, the precision obtained from the

2001 round-robin was significantly better

than that achieved in the 1998-9 round-

robin Whilst this may be partly explained by

the greater experience which laboratories

had gained in measuring low sulfur

products, the availability of the two quality

control samples with reference sulfur

concentrations certified using high accuracy

IDMS, was undoubtedly a major

contributing factor. The availability of these

reference samples also permitted the

methods to be validated in terms of freedom

from bias.

Production of low sulfur CRMs

Six diesel samples have been collected andbottled for certification as reference materials forsulfur in fuel. These materials represent the rangeof analyses currently required and the lowestlegislative limits that may expected in Europewithin the next 10 years. Preliminary analysis ofthe six materials indicate the concentration levelsdetailed in Table 4. Experimental work for thecertification of the 50 mg kg-1 material has been

completed and indicates a sulfur content of 52.4mg kg-1 with an expanded (95% confidence)uncertainty of 1.3 mg kg-1 (2.4%). Certificationof the other materials is expected to follow in duecourse, with priority being given to the 30 and 10mg kg-1 levels.

Conclusions

International agreement on methodology forthe determination of S in fuel is of majorcommercial importance as well as being anessential requirement to facilitate trade in theface of ever more demanding regulatoryrequirements. Development of a highaccuracy method of analysis within VAM,together with its verification throughinternational collaboration between LGCand other national measurement institutes,has allowed determination of reference valueswith small uncertainties at low sulfur levels.The application of these reference values hasbeen demonstrated for the development ofCEN/ISO methods, for validation ofmethods used by UK industry, and forcertification of new reference materials.

CASE STUDY


© BP plc (2002)

Table 4: Preliminary Analysesof 6 LGC sulfur in fuelreference materials.

Reference Estimated S amountMaterial content (mg kg-1)

LGC3020 1

LGC3021 10

LGC3022 30

LGC3023 50

LGC3024 100

LGC3035 450


CASE STUDY

Acknowledgements

The round-robin studies referred to in this article were carried out under the direction of CEN TC19 Working Group 27, comprising the following national representatives:

Certification data for the LGC referencematerials has been provided by Peter Evansand Ruth Hearn, with the assistance ofCeline Wolff Briche for estimation ofuncertainty. The authors are also verygrateful to all the laboratories whoparticipated in the round-robin studiesthrough the various national standardisationbodies. The work on development of theIDMS method described in this paper andthe preparation of the CRMs is supported by

the Department of Trade and Industry (UK)as part of the National Measurement SystemValid Analytical Measurement Programme.

REFERENCES

1. Evans, P., Wolff-Briche, C., Fairman, B.E.,

J. Anal. At. Spectrom., 2001, 16, 964– 969.

2. “Sulfur Methods for EN 228 and EN 590

Fuel Specifications”, CEN TC19 WG27

Round Robin report 1999.

3. “Test Methods for the Determination of

Sulfur Content”, CEN TC19 WG27

Round Robin report 2001.

4. Guidelines for achieving high accuracy

in isotope dilution mass spectrometry

(IDMS), Edited by M. Sargent, C.

Harrrington, R. Harte, The Royal Society

of Chemistry, Cambridge, UK, 2002.

ISBN 0-85404-418-3.

Paolo Tittarelli, Convenor Stazione Sperimentale Combustibili San Donato Italy

Harry Read, Former Convenor BP plc Sunbury UK

Jim Crighton, Secretary BP plc Sunbury UK

Franck Baco IFP CEDI Vernaison France

Sophie Collet TotalFinaElf CReS Solaize France

Paul Crezee Nerefco Rozenburg The Netherlands

Claudia Do Marco TotalFinaElf CReG Harfleur France

Francoise Douce TotalFinaElf CReS Solaize France

Bo Edroth Preem Raffinaderi Goteborg Sweden

Ralph Hensel Shell Global Solutions – Deutschland Hamburg Germany

Charles-Philippe Lienemann IFP CEDI Vernaison France

Jose Gomez-Martinench CEPSA Research Centre Madrid Spain

Patrizia Ruggieri AgipPetroli CREA San Donato Italy

Mario Van Driessche ChevronTexaco Technology Ghent Gent Belgium

Antoni Marchut, Observer Instytut Technologii Nafty Kraków Poland

V A M I N E D U C A T I O N

Decline in skills

During the last few months we havebeen busy formulat ing the next

VAM programme. Part of this process is tosolicit the views of instrument manu-facturers, analytical staff in a range ofcompanies, regulators and those involvedin education. Most sectors of industry areconcerned about the lack of basic laboratoryski l l s of those graduat ing from UKuniversities and those leaving school. Thereason for this decline is frequently givenas reduced budgets for consumables andincreased safety regulations in schools,colleges and universities. The effect of safety

regulat ions is probably a perceivedproblem rather than a real one. We areaware that the whole of the educationsector is under extreme pressure, but ifUK industry is unable to recruit from withinthe UK it will go elsewhere and there aresigns that is already happening. What hasthis to do with VAM? For the last tenyears the VAM programme has workedwith schools, universities and industry toboth assess the level of competence oflaboratory staff and to provide trainingtools and courses to supplement materialsprovided by instrument manufacturers and

academia. Just this last month, f ivetraining guides have been published by theRoyal Society of Chemistry (RSC) as partof the VAM product portfolio. The guidescover mass, volume, pH, HPLC and GC.These were developed with SANG (theChemical Industr ies Associat ionSpecialised Organic Chemicals SectorAnalytical Networking Group) and havebeen in use by their organisations for thelast few years. As part of the pack there are2 CD-ROMs that deal with the basicpractical skills required by staff who workin analytical laboratories.


V A M I N E D U C A T I O N

V A M N E W S

Airborne particulate matter (PM) is

strongly implicated as being the worst

air pollutant in the UK. The effects of

such material on human health can be worse

than airborne gases such as ozone or

nitrogen dioxide.

Measuring particulate matter is complicated.

Firstly, larger particles are less likely to enter

human lungs and cause medical problems.

There is therefore a desire to exclude these

particles from measurement results.

These larger particles can also have a

disproportional effect on results. Secondly,

measurement is further complicated by there

being no self-evident attribute of the

particles, i.e. size or composition, which is

most relevant for monitoring purposes.

Current air quality standards define the

amount of particulate material in terms of

the mass below a certain aerodynamic

diameter, in a given volume of air. In

principle, such measurements are simply a

matter of weighing suitable filters before and

after a known volume of air is pumped

through them via a size-selective inlet. In

practice, inconsistencies can arise due to a

number of factors such as semi-volatile

matter leaving the filter after sampling,

and the absorption of water by the filter

or particles.

NPL is taking part in a major European trial

to improve the measurements of airborne

particulate matter less than 2.5 microns in

diameter (known as PM2.5). The trial will

involve running 20 separate instruments in

parallel in order to compare results and

ultimately help choose a reference method.

The work will involve comparing different

filter materials and quantifying sources of

measurement uncertainty. NPL is one of the

eight participating sites chosen across

Europe. The trial is jointly funded by the

VAM programme and the EC and is

expected to run until May 2003.

Further information about the trial

is available from:

Paul Quincey

National Physical Laboratory

Tel: 020 8943 6788

Email: [email protected]

Web: www.npl.co.uk/analytical

We continue to work with schools, colleges,

universities and those professionals who are

required to make measurements. One of the

hot topics at the Association for Science

Edcation (ASE) conference in Birmingham

in January was the introduction of applied

courses, but there is a concern that schools

do not have the equipment to deliver the

practical work required and teachers lack

confidence to teach the practical aspects.

Most sectors of industry are concerned about

the lack of basic laboratoryskills of those graduatingfrom UK universities and

those leaving school.

We are working with the RSC, 4 Science

and Dstl to develop INSET training for

teachers to support these courses. The

concept of reliable measurements and words

such as precision, accuracy and bias are

sprinkled through course specifications.

At the ASE we had a workshop session, on

measurement, for teachers and technicians.

It was clear that there was confusion about

the exact meaning of the terms and they

were appreciative of some of the simple tasks

we used to illustrate what they believed to be

complicated issues. The Qualification and

Curriculum Authority (QCA) are interested

to talk with us about help with terminology.

Centres taking part in the PT competitions

appear to have a better understanding of

measurement issues after participation in a

few rounds. We are awaiting the results from

the centres that have taken part in 2003.

Universities have not been neglected.

We are still able to supply lectures on

VAM issues and implementation of best

practice to undergraduates and post-

graduates. Workshops for postgraduates

are also planned.

The three self-help sector-based training

networks supported under VAM are

progressing well. Each of the networks has

had a hot topic that has implications on

measurement performance. The environ-

mental analysis group (EMTN) has been

discussing the Environment Agency’s

monitoring certification scheme MCERTS,

“Performance standard for laboratories

undertaking chemical testing of soils”.

Clinical Governance is having an impact on

point of care testing and this has been on the

agenda of POCT meetings, along with the

possible changes to the accreditation

standard. SANG, the specialised organic

chemicals network, is working on ways to

improve efficiency through better

measurement procedures.

If UK industry is unable to recruit from within

the UK it will go elsewhere.

Further information can be obtained from

the VAM Helpdesk.

European Trial of Airborne ParticleMeasuring Instruments comes to NPL


V A M N E W S

Former Scottish Office Minister, Lord

Lindsay has been appointed as the new

chairman of the United Kingdom

Accreditation Service (UKAS). His

appointment was approved at the

organisation’s Board Meeting, following the

AGM on 8 October 2002.

Commenting on his appointment, LordLindsay said: “As the sole body recognisedby government to accredit organisationsproviding testing, certification, inspectionand calibration services, UKAS plays a vitalrole in maintaining confidence in standards

throughout the British public and privatesectors, enabling markets to function moreefficiently. I look forward to helping UKASto build on its achievements since it wasformed in 1995.”

Welcoming UKAS’ new chairman, Chief

Executive, Linda Campbell, said: “Jamie

brings broad experience of industry,

environmental issues and government policy.

His work in the food sector and the

environment means he has first hand

knowledge of the importance of technical

standards in minimising risk. He will play a

valuable part in providing UKAS with

strategic guidance while acting as a first class

ambassador for the company.”

Lord Lindsay replaces UKAS’ former

chairman, Dr Bryan Smith, who has retired

after seven years in the post.

UKAS appoints Lord Lindsay as chairman

T o honour George Orwell on thecentenary of his birth, the Royal

Society of Chemistry is to decree thedefinitive method by which the perfect cupof tea should be made and served.

The RSC will also try to persuade cookerybook publishers to include the recipe infuture publications, thereby fulfill ingOrwell’s published wish that the step-by-steppreparation of the national drink be properly defined.

Orwell, best known for his books Animal

Farm and Nineteen Eighty Four, wrote the

celebrated essay A Nice Cup of Tea three

years before his death. In the essay, which

stands alongside masterpieces such as

A Hanging and Shooting an Elephant, Orwell

expresses surprise and concern that the

extremely serious matter of tea brewing is

not featured in cookery books, a situation

that has not changed.

Orwell says: “This is curious, not only because

tea is one of the mainstays of civilisation in this

country…but because the best manner of making

it is the subject of violent disputes.”

Now, to celebrate his 100th birthday, the

RSC is to remedy the oversight. The effort

to define what exactly makes the best cup of

tea is also the RSC’s way of saying that it

does not bear ill will for Orwell’s negative

opinions of scientists, and of chemists in

particular, as portrayed in his essay, Science.

The RSC is to consult its own drinks and

flavour specialists in order to identify ways to

prepare and to serve the unbeatable cup of

tea. The RSC will also be seeking the tea-

making views of the general public through

its local branches around the UK.

Orwell defines in his essay the way to make aperfect cup of tea, saying: “I find no fewerthan eleven outstanding points. On perhaps two or three of them there would be prettygeneral agreement but at least four others areacutely controversial.”

He asserts that Indian or Ceylonese teasmust be used, dismissing China tea as havingno stimulation. “One does not feel wiser,braver or more optimistic after drinking it.”

The novelists insists that the tea should bestrong, claiming that six heaped teaspoonsare required for a quart pot. No strainers ortea bags (muslin at that time) should be usedand it is perfectly right that leaves shouldreach the cup and for them to be eaten inconsiderable quantities. He also insists that acylindrical breakfast cup must be used, not aflat-based cup. He is adamant that the teashould be poured before the milk, claimingthat it is the only way by which to regulatethe amount of milk.

His last point is that sugar should never betaken. “How can you call yourself a true tea-lover if you destroy the flavour of your tea byputting sugar in it? It would be equallyreasonable to put in pepper or salt. Tea is meantto be bitter just as beer is meant to be bitter.”

RSC to produce the perfect cup of tea


V A M N E W S

Current trends in bio-analytical methods

show an increased interest in detection

of trace levels of DNA. Such sensitive

detection methods are central to regulatory,

public health, medical, environmental, and

quality control sectors. One such technique,

which is used for a wide range of

applications, is fluorogenic quantitative real-

time PCR, as it provides a route to semi-

quantitative DNA analysis, and sensitivity is

increased compared to conventional

amplification-based methods.

Introduction of robust quantitative PCR

analysis for applications such as the detection

of genetically modified organisms in

foodstuffs, or pathogens in food and

environmental samples requires that the

performance characteristics of the method be

accurately assessed in method validation.

The sensitivity of a method is associated with

the lower limit of applicability of that

method. Derived from this, the performance

characteristic of the limit of detection (LOD)

can be defined as the smallest concentration

of a target analyte that can be detected and

distinguished from a zero result with a given

probability. The evaluation of the LOD of an

assay is critical for trace detection methods,

especially where the result will be used for

regulatory or public health applications.

Introduction of robustquantitative PCR analysis

requires that the performancecharacteristics of the method

be accurately assessed inmethod validation.

Formal derivations concerning LOD do nottake into account atypical data sets that aregenerated from real-time PCR techniques.Fluorogenic real-time PCR measures theaccumulation of relative f luorescenceduring the course of the reaction, which ateach cycle is proportional to the amount ofPCR product formed (Figure 1). Resultsare not always normally distributed, andanalyses using parametric statistics are thusnot valid. Furthermore, negative controlsdo not give a zero measurand result, as atrue negative reaction would give a samplevalue of infinity.

An approach is being developed to determinethis LOD. It uses a data set characteristic oftypical non-normally distributed resultsproduced from real-time PCR, using anexperimental design representative of usuallaboratory conditions. A computer simulationcalculates the probabilities of detecting PCR products from the data set, using bootstrapping techniques. Bothexperimentally and theoretically determinedLODs are produced, and provide an estimatefor the sensitivity of the method, based on thereal laboratory performance of the technique.By using the data analysis approach, theprobability of detecting an analyte at aspecific concentration can be determined,based on the known sensitivity of the method.Such information facilitates the design ofrobust analytical strategies, and thus enablesreliable practical application of real-time PCRanalysis. The wide applicability of thisbootstrapping and data modelling approachshould be of general interest to laboratoriesinvolved in trace-level detection.

For further information, please contact:Malcolm Burns LGC Email: [email protected]

Challenging the Limits Of Detection

Figure 1: Generation, processing, and interpretation of real-time PCR data for limits of detection.Figure 1 illustrates a typical real-time PCR amplification plot where sample values are generated according to the cycle number at which point asample copy number crosses a predetermined noise threshold. These sample values are then used in a simulation to generate a plot of theprobability of detecting a PCR product dependent upon initial copy number.

Relativefluorescence

Threshold

Sample valuesPCR Cycle number

Copy Number108 106 104

Dataprocessing

Probability ofdetecting

target analyte

100%

0%

Log (copy number)


V A M N E W S

ROMIL Limited (Cambridge, UK) has

been accredited to ISO 17025, as a

Calibration Laboratory, for the production

of elemental Certified Reference Materials

(CRMs), enabling ROMIL to certify

reference materials and to market ROMIL

PrimAg CRMs bearing the UKAS (United

Kingdom Accreditation Service) Logo.

The ROMIL PrimAg CRMs provide

analysts with a ready supply of fully SI-traceable CRMs for trace elementcalibration. ROMIL PrimAg CRMs requireno further analyt ical val idation todemonstrate traceability to the SI and meetal l the requirements of laboratoriesworking to ISO 17025. ROMIL isextending and developing the concept tooffer fully traceable analytical reagents foruse in other applications.

Further information:ROMIL LtdThe Source, Convent DriveWaterbeach, Cambridge CB5 9QTTel: +44 (0)1223 863 873Fax: +44 (0)1223 862 700Email: [email protected]: www.romil.com

ROMIL launches fully SI-traceableCRMs for trace element calibration

The Environment Agency has re-launched

its MCERTS scheme for the chemical

testing of soils with publication of Version 2 of

the MCERTS performance standard.

MCERTS provides assurance to all

stakeholders (e.g. laboratories, Local

Authorities, consultants, members of the

public) of the reliability of data from such tests.

Chemical test data on soils is used by the

Agency to support its regulatory activities

under a number of regimes, such as Part IIA

of EPA 1990, Pollution, Prevention and

Control (England and Wales Regulations)

2000 and Waste Management Licensing

Regulations 1994.

For the chemical testing of soil where results

are to be submitted to the Agency for

regulatory purposes, the Agency requires a

laboratory to be accredited to the European

and international standard, BS EN ISO/IEC

17025:2000. Accreditation is undertaken by

an appropriate national organisation, which

in the United Kingdom is the United

Kingdom Accreditation Service (UKAS).

The MCERTS performance standard for

laboratories undertaking the chemical testing

of soil provides an application of BS EN

ISO/IEC 17025:2000 specifically for the

chemical testing of soil and covers:

• the selection and validation of methods;

• sampling pre-treatment and preparation;

• the estimation of measurement

uncertainty;

• participation in proficiency testing

schemes; and

• the reporting of results and information.

To allow laboratories to bring their soil testing

methods up to the MCERTSstandard, the Agency will

be implementing the schemeover an 18-month period,

starting from March 2003.

The Agency is aware that it will take time for

laboratories to gain approval through the

appropriate accreditation process. To

allow laboratories to bring their soil

testing methods up to the MCERTS

standard, the Agency will be implementing

the scheme over an 18-month period,

starting from March 2003. In this

period laboratories reporting data to the

Agency have as a minimum to be accredited

to BS EN ISO/IEC 17025:2000 for the

test methods, and test reports should

include a brief method description and

bias and precision estimates. From

September 2004, only data from labo-

ratories that have been accredited to BS EN

ISO/IEC 17025:2000 for MCERTS will

be accepted.

For further information contact:

Mike Healy

Environment Agency

Tel: 0173 337 1811

Email: mike.healy@environment-

agency.gov.uk

Copies of the standard can be obtained from

the Agency’s website:

www.environment-agency.gov.uk/business/mcerts

MCERTS – Performance standard for laboratories undertaking chemicaltesting of soil


Peter Frier &Kevin ThurlowLGC

There is a special relationship betweenscience, technology and regulation.

Recent years have seen an increase in publicawareness and concern for health andenvironmental issues. New technology andimprovements in analytical techniques haveincreased our capability to detect potentialrisks, but technical uncertainties leaveconsiderable leeway for interpretation ofresults. Scientific disputes often arisebecause different interest groups exploitthese uncertainties to promote their point of

view. Sometimes it is ill-informed scare-mongering. Some years ago, it wasannounced that drinking instant coffeedoubled the consumer’s chance of getting aparticular form of cancer. This dramaticheadline was undermined somewhat whenthe text actually reported that the chance ofgetting that form of cancer increased fromone chance in a million, to two chances in amillion. Instant coffee drinkers, who readthat far, breathed a sigh of relief. Of course,some people only read the headlines.

Thus a climate of claim and counter claim

can arise which ‘muddies’ the interface

between science and policy, with the effect

that judgements made about regulatory

policy (e.g. commands and controls) and

science policy (e.g. prioritising research and

surveillance) may be misdirected. The extent

to which this occurs depends on other

variables, such as public awareness/concern,

media attention, legal and political pressure

and scientific consensus.

Scientific disputes often arise because different interest groups exploit

uncertainties to promote their point of view.

These factors are clearly evident when

perceived hazards or risks are associated with

a particular chemical or process. Science is

then a tool to assess the potential harm,

U K A N A L Y T I C A L P A R T N E R S H I P

Science & Hazard Regulation – claim or blame?



forming part of the quantitative risk

assessment. Hazard identification is

conventionally regarded as the first stage in

assessing risk. It is defined as the

identification of a risk source capable of

causing adverse effects, to people or the

environment, together with a qualitative

description of those effects. In practice, there

is often an overlap between hazard

identification and exposure assessment.

Exposure assessment is concerned with the

likely actual levels and duration of exposure

to the risk source. The availability of

appropriate test methodology to identify

potential hazards and estimate exposure is

essential to risk assessment. However,

increasingly analytical results alone are being

used by some to make qualitative

judgements about risk, or to misrepresent

situations, influence public opinion, create

political pressures, and fuel policy action.

Research is planned by UKAP GRC (United

Kingdom Analytical Partnership Good

Regulation and Competitiveness) and LGC

to investigate the influence of measurements,

measurement techniques, and standards

on issue raising, all the way through to the

effect of chemical evidence on policy

decisions and regulation.

Science is a tool to assess the potential harm.

Problems for the authorities are made more

difficult by a regulatory regime which

attempts to anchor decisions to some

preconceived model of harm, but which is

still subject to the influence of new (and

sometimes conflicting) scientific claims. The

situation is exacerbated at the cutting edge

between science and policy where the

hazards associated with a particular

situation may be indeterminate (e.g.

because monitoring techniques are not able

to detect potential risks). The dilemma then

for policy makers is deciding a course of

action in the absence of complete

knowledge. In other words, how to set

regulatory policy which reflects current

uncertainty (science providing early

warnings) and which is responsive to new

evidence and technical development, which

may reveal hazards not currently known.

There was an example in the UK a few

years ago, when irradiated food was banned,

despite the fact that methods were not

yet available to detect it. Regulations

were introduced to respond to the

understandable concerns that had been

voiced, in case there was a problem.

This precautionary approach is occurring

more frequently now, in an attempt to

prevent harm before it occurs, particularly

where scientific knowledge is limited. There

are dangers that either science is adapted to

fit the mismatched realities of a situation, or

technical and social situations are shaped to

validate the science1.

If the media attentionprevents another

‘thalidomide’, it is obviously worthwhile.

The research will consider how such issues

evolve, gain credence, and influence

chemical policy identifying situational

factors (e.g. technical and social uncertainty)

which potentially combine to create

indeterminacy, addressing:

• how scientific claims about hazard build

and influence policy and regulation;

• how conflicting claims are resolved or

validated to avoid controversy;

• how policy and regulation is eventually

adapted to new evidence and technical

progress;

• how misinformation can lead to

misdirected science policy and regulation.

These aspects need to be understood better.

The aim of the research will be to determine

how regulation and science are influenced,

and what needs to be done to prevent

indeterminacy.

The history of chemical hazard regulation is

littered with examples where agents or

activities that were once stated as safe by

governments have been proven to be

harmful, as new evidence emerges2. This is

in part due to the way in which hazard

regimes are tied to some preconceived model

of harm with deterministic end-points to

detect, quantify and characterise hazards.

But are deterministic end-points wholly

appropriate where subtle, or indeterminate,

changes are being observed or suspected?

The research will be particularly concerned

with how these factors and other variables

combine to create false ‘negatives’ (agents or

activities wrongly thought to be harmless) or

false ‘positives’ (where action to limit hazard

is taken wrongly). You cannot expect a

sound policy decision if scientific

information is uncertain or misleading.

Unfortunately, media ‘hype’ has a

significant role to play. Reports on potential

problems tend to emphasise the worst case

scenario. There are at least nine different

climate models, which predict global

warming of between 1-6 °C by the end of

the century, but media speculation focuses

on the most extreme rise. Controversies

over BSE, Foot and Mouth, GM foods, and

cloning, have led to some highly speculative

(in some cases, just plain wrong) statements

being published as fact. However, if the

media attention prevents another

‘thalidomide’, it is obviously worthwhile.

Scientists do not always help their own case.

If they declare that a contaminant was ‘not

detected’, many people regard that as

meaning that the answer was ‘zero’, whereas

an answer of ‘less than 1 mg kg-1, (assuming

that is the limit of detection), would be

more useful. Also, there is a tendency for

scientists to be unwilling to explain their

activities, as they believe that others will not

understand what they are told. It is not

surprising that policy makers and the public

get confused.

The research should alleviate some of these

problems.

More information on UKAP is available at

www.ukap.org

REFERENCES

1) Wayne, B., ‘Uncertainty and Environ-

mental Learning: Preconceiving Science

and Policy in the Preventative

Paradigm’, Conference Paper on the

Principles of Clean Production,

Lancaster University Centre for Science

Studies and Science Policy, 1992

2) ‘Late Lessons From Early Warning: the

Precautionary Principle 1826-2000’,

Environment Issue Report No 22,

European Environment Agency, 2001.



Kevin ThurlowLGC

The United Kingdom AnalyticalPartnership (UKAP) was formed in

2000 to create an unique alliance ofstakeholders and individuals with an interestin the future of analytical science in the UK.The alliance includes representatives ofgovernment, industry, academia, researchcouncils, learned societies and otherorganisations, all sharing the vision of makinganalysis in the UK ‘world class’. Thesecretariat is run by LGC, with support fromRoyal Society of Chemistry (RSC) and DTI.The intention is to make significantimprovements in the analytical sector, forexample in regulation, supply of skilledpeople, research funding and innovation.UKAP is encouraging collaboration withothers, sharing resources, building networksand establishing joint initiatives to enhance theimpact of analytical science on the economy.

As part of these activities, UKAP organised aconference, entitled ‘Product and ProcessCompetitiveness: The Impact of Analysis’, inLondon last October. There were speakers

from a variety of backgrounds. A commontheme was the importance of high quality on-line measurements during manufacturingprocesses. One company had been making arhodium catalyst for some thirty years andthen instituted modern on-line monitoring.Using ‘React-IR’ to follow the carbonylbands revealed that a previously unknownintermediate formed during the reaction.Furthermore, an unwanted by-productformed about two hours into the process,which was related to the intermediate. It wasimmediately clear that there was no pointcarrying on the reaction beyond this point ifall it achieved was formation of unwanted by-products. This is a simple example of how ananalytical tool can be used to betterunderstand processes. The success of thisapproach encouraged use of high throughputmachinery, maybe with a dozen small-scalereaction vessels, to test reactions. By carryingout multiple analyses concurrently, it ispossible to get a really good picture of themanufacturing process. Several variables maybe changed at the same time and the bestreaction conditions predicted from theavailable trends. The benefits of doing small-scale testing and then building up to the fullmanufacturing process are obvious.

Increasingly companies are using on-line,

off-line and at-line analysis to gain

immediate knowledge of the manufacturing

processes as they happen. With this real-time

analysis it is even more important to do it

correctly the first time. Of course

improvements in scientific equipment have

made a big difference. Gone are the days

where samples had to be sent away for NMR

or mass spectrometry analysis; now

benchtop models are available and such

analyses are almost commonplace.

Spectroscopic techniques are even easier to

use on an on-line or at-line testing basis.

These techniques have been used in such

diverse areas as production of oil, pharma-

ceuticals and titanium dioxide. High quality

analysis coupled with on-line process

control has allowed companies to develop

very efficient manufacturing techniques.

This leads to reduced costs through shorter

process times, and use of smaller amounts

of raw materials. This in turn reduces the

amount of processing required to deal with

waste materials. Increased competitiveness

means savings may be passed on to the

customer. So good planning and good

analysis benefits everybody.

Product and process competitiveness

C H E M I C A L N O M E N C L A T U R E

Kevin ThurlowLGC

Polymers have been with us for a longtime – in fact natural polymers like

proteins, DNA and cellulose were here whenlife began. Even the most primitive dinosaurand its food were stuffed with polymers.Both natural and synthetic polymers tend tobe rather complicated and present specialdifficulties in producing systematic names.Natural polymers are generally named usinga shorthand system to make life easier.

Peptide linkages would be a nightmare toname fully systematically, so it is normal touse the three-letter abbreviations, like ‘ala’for alanine. A simple example might beFigure 1, where the NH2 signifies a terminalamide-group, as it is attached to a ‘carbonyl’.

Nucleic acid sequences are generally named,

using the letters ‘GATC’. However, systems

like this do not usually work for synthetic

polymers. The earliest synthetic polymers

were derived from natural polymers;

cellulose nitrate, was produced from a

cotton extract in the 19th Century. This was

used as gun cotton, and as a replacement for

ivory snooker balls. The latter use was

beneficial to elephants, but not always the

players, as a particularly firm shot could be

punished by a violent explosion. Develop-

ment of synthetic polymers has continued

ever since, and the work of Baekeland and

Introduction to Polymers

Figure 1: Peptide linkage.

His-Phe-Arg-Lys-Pro-Val-NH2



Carothers is rightly regarded as of the

utmost importance1,2. Baekeland called his

first synthetic polymer ‘Bakelite’, which is

considerably easier than its systematic name.

Carothers produced nylon in the late 20s.

Nobody seems to know why the name nylonwas chosen. One theory was that it referredto New York and London, because of atrade exhibition, and another that Carotherstook the initial letters of the wives of histeam. More prosaically, the company’s ownstatement was that it sounded nice. The‘6,6’ shows the number of carbons eitherside of the ‘N’s in the structure. So there aredifferent types of nylon, depending on whichpolyamide is formed. This is quite a nicetrivial name, as it is actually gives someinformation. So if you make nylon frompentamethylenediamine and sebacic acid(decanedioic acid) you get ‘nylon-5,10’. Theamine part is mentioned first, and Figure 2is drawn to reflect this.

At much the same time, PVC came onto thescene and PTFE followed in the late 30s.Since then there has been an enormousproliferation of plastics production. Salesrocketed by a factor of over 100 between theend of World War II and the end of the

century. All these plastics need names. PVCand PTFE are very familiar abbreviations,and are listed amongst others in ISO1043,‘Plastics – Symbols and abbreviated terms’.However, systematic names are still requiredto describe the structures of polymers, andIUPAC rules allow two different ways ofnaming macromolecules. PVC (Figure 3)means poly(vinyl chloride), and this is a‘source-based’ name. In other words, it tellsyou it is a polymer of vinyl chloride. Notethat the brackets are essential for a polymerwhere there are two or more words, to avoidambiguity. Polyvinyl chloride could be takento mean there are many vinyl groups andonly one chloride.

The other (more systematic) way of namingpolymers is to use a ‘structure-based’ name.So PVC becomes poly(1-chloroethylene).This gives more structural information, buteven with this simple molecule, the name isstarting to get a bit unwieldy. The conventionfor a ‘structure-based’ name is that thestructure is named left to right, so the bracketsare drawn where appropriate.

Figure 4 shows the ‘constitutional repeatingunits’ (CRU), and for ‘structure-based’names, you identify the CRU and put ‘poly’in front of it. It is clear that the bracketscould be drawn round the first two carbons(as Figure 3) or round the second and third,but this would put the chlorine on thesecond carbon. This would either requireyou to name the structure right to left, or tocall it poly(2-chloroethylene). However,lower numbers are preferred. This may notseem to matter in such an easy example, butthe convention is more useful with morecomplicated structures.

PTFE is also frequently known by the Du Pont trade name ‘teflon’. A legend builtup that non-stick frying pans arrivedcourtesy of space missions, but PTFE hasbeen around a lot longer than that. PTFE isshort for polytetrafluoroethylene, which wasalso a ‘source-based’ name. Again it getsconfusing, because ethylene nowadaysmeans -CH2-CH2-, but it used also to meanCH2=CH2. Ethene is the preferred name forthe second structure now.

The ‘structure-based’ name for PTFE wouldbe poly(difluoromethylene), as you alwaysuse brackets in ‘structure-based’ names. SeeFigure 5.

It is quite clear here that the CRU is ‘-CF2’.

IUPAC is moving towards recommending

‘structure-based’ names, as they give more

structural information. PVC and PTFE do

not cause any problems, but as examples

become more complicated, the IUPAC

reasoning is explained. See Figure 6.

Figure 2: Nylon-6,6 Poly(iminoadipoyliminohexamethylene) – ‘structure-based’ name.

Figure 3: PVC.

vinyl chloride poly(vinyl chloride)poly(1-chloroethylene)

Figure 4: PVC – selection of CRU.

Figure 5: PTFE.

-(CF2-CF2)-n



Obviously the first name is easier to use, butdoes not give useful structural information.

The second name is not really one you wantto use in general conversation, (see also the‘structure-based’ name for nylon in Figure2), but does permit the structure to bededuced quite easily. The rathercomplicated character of the ‘structure-based’ names does encourage use of either‘source-based’ names or suitable abbre-viations, as long as your audience knowswhat you mean.

These examples are relatively straight-forward, but once you start looking atinorganic polymers, or copolymers, that canbe an entirely different story. But we willhave to leave that for another time.

REFERENCES

1. Time 100: The most important people

of the 20th century.

http://www.time.com/time/time100

2. A Science Odyssey: People and Discoveries.

http://www.pbs.org/wgbn/aso/databank

For advice on ChemicalNomenclature, please contact:Kevin Thurlow, CNAS, LGCQueens Road, TeddingtonMiddlesex TW11 0LY UKTel: +44 (0)20-8943-7424Fax: +44 (0)20-8943-7554 E-mail: [email protected]

Figure 6: Poly(vinyl butyral) –‘source-based’. Poly[(2-propyl-1,3-dioxane-4,6-diyl)methylene]– ‘structure-based’.

P R O F I C I E N C Y T E S T I N G

Accreditation of PT schemes puts UK in ‘First Division’

In July last year, the United Kingdom

Accreditation Service (UKAS) held a

presentation ceremony at London Zoo,

Regent’s Park, for the eight proficiency

testing (PT) providers in the UK who have

successfully become accredited to the

ISO/IEC Guide 43 Part 11 standard. Many

of these provider have since had their first

annual surveillance visit, and more

organisations have started to apply

for accreditation.

This puts the UK firmly in the first division

of European countries in terms of

accredited PT providers, joining the

Netherlands, where this has been

This puts the UK firmly in the first division

of European countries in terms of accredited

PT providers.

established for some years. Other European

countries have also started to accredit PT

providers, and momentum is growing in

this area both in Europe and in other parts

of the World. It is estimated that

accreditation bodies in between 15 and 20

countries are now offering accreditation of

PT providers as a service.

But why is this important, and how does it

raise quality? PT providers, like any other

organisation providing a service to help

laboratories monitor and improve the quality

of their measurements, must themselves

offer a service of excellent quality. The

accreditation of PT providers gives a

significantly increased level of confidence for

laboratories in these PT providers, the PT

schemes on offer are of demonstrably higher

quality, which plays a part in improving the

quality of everyday measurements made in

participating laboratories.

REFERENCES

1. VAM Bulletin 27, pp. 23

COEPT to examine the comparability of PT schemes

The accreditation of PT providers is seen

by many as a major step forward.

However, all those involved in proficiency

testing recognise the fact that there is no single

correct way to organise a PT scheme. There is

no single statistical protocol that covers every

scheme. This leads to a multiplicity of

approaches – which will all be valid for

accredited schemes – for the operation of PT

schemes and the evaluation of PT results.

This situation has been recognised by the

development of an EU-funded project aimed


P R O F I C I E N C Y T E S T I N G

to study the differences and similarities in the

operation of PT schemes in the analytical

chemistry sector, and compare their outputs

(evaluation and reports) in the light of this.

This project “The Comparison of the

Operating Protocols of European Proficiency

Testing Schemes” – known as COEPT for

short – was officially launched with a kick-off

meeting held at LGC in January.

The project is co-ordinated by LGC, with 16

partners from across Europe, many of whom

will be playing very important roles within the

project. The COEPT project will include two

series of intercomparisons of PT schemes.

The first will be a data evaluation exercise,

and the second a full intercomparison using

highly-characterised test samples. These

intercomparisons will take place in 4

measurement areas:

• Drinking water

(trace metal determination)

• Contaminated soil

(organic pollutant determination)

• Milk powder

(fat, lactose, moisture and protein)

• Occupational Hygiene

(trace metals on filters)

The COEPT project will include two series of intercomparisons

of PT schemes.

A total of 30 PT schemes provided by

27 di f ferent organisat ions f rom

across Europe wi l l be involved in

these intercomparisons. A major part

of the project will be the organisation

of three workshops to p lan, d iscuss

and rev iew these intercompar isons.

These workshops will involve the project

team plus the collaborating PT providers,

but wi l l be open to anyone with an

interest in the subject. The first of these

workshops will be held at BAM in Berlin

on 15 April 2003.

There will be many benefits arising from the

COEPT project.

• Laboratories will be able to obtain more

detailed information about the

statistical evaluation protocols of PT

schemes across Europe, enabling them

to make more informed decisions about

which is the appropriate scheme in

which to participate.

• Accreditation bodies, Government

Agencies and other bodies mandating

participation in specific PT schemes will

be able to compare PT schemes directly.

This will enable them to accept

participation in equivalent schemes,

which will free up the market for PT

scheme providers in many areas.

• PT providers will gain information on

the var ious stat is t ical evaluat ion

protocols used in their sectors,

together with ideas for “best practice”

in the operation of PT schemes. This

wil l al low them to make informed

decis ions about modify ing their

protocols which could bring about

harmonisation of the operation of PT

schemes in a voluntary manner.

EEE Working Group discussesmeasurement uncertainty in PT

Anumber of issues relating to

proficiency testing were discussed

at the last meeting of the

EURACHEM/Eurolab/EA Working on

Proficiency Testing in Accreditation

Procedures (EEE-PTWG) held in Vienna in

November. The one issue that is, perhaps, of

most significance, and of wider interest,

concerns measurement uncertainty. With

laboratories accredited to the ISO/IEC

17025 standard now being required, where

appropriate, to report measurement

uncertainty values in reports, it is clear that

this may have an impact on PT providers.

Although PTs in the field of calibration have

been incorporating measurement uncertainty

for many years, this has been far from

commonplace in the field of testing.

The main talking point is whether PT

providers should be REACTIVE or

PROACTIVE. The debate is quite complex.

For example, how does a PT provider

handle a mix of participants who wish to

report uncertainties and those who do not

(and are not accredited and so may be

ignorant of the concept)? Also, if a PT

provider wants to incorporate uncertainty,

how should they do it?

The discussion of this raised a number of

points of consenus:

• PT providers should be REACTIVE,

and incorporate measurement uncertainty

when asked

• Accreditation bodies will not ask PT

providers to incorporate measurement

uncertainty, and will not ask for this for

a provider to be accredited to ISO/IEC

Guide 43

• PT providers should show they are

willing to embrace measurement

uncertainty by starting to introduce the

uncertainty of assigned values (both

reference and consensus).

• Any PT provider wishing to include

measurement uncertainty in a scheme

should start by quoting participants’

uncertainties, before moving to a

position where they can be included in

the evaluation protocol.

• Evaluation of results with their associated

uncertainties should follow the approach

given in ISO 13528 Voting Draft.


R E F E R E N C E M A T E R I A L S U P D A T E

A network for users of reference materials

Figure 1: Framework for collaborative exchange.

Measurementservices andmetrologicalquality assurance

Collaborative projectpartnerships

Partnershipactivities

Exchangeactivities

RM requirements:information andprioritisation

Virtual networksfor education andtechnical support

KEY

Paul Hibbert Optimat Ltd

Richard LawnLGC

In previous VAM programmes LGCsought user views on reference materials

largely through surveys and questionnaires.Although this provided some usefulinformation, the need for a more structuredand interactive dialogue with the usercommunity has become increasinglyapparent. In particular, there is a need toensure that the limited resource available forthe production of reference materials iseffectively directed and that the potentialbenefits of using reference materials are fullyrealised. The development of referencematerial user groups or networks is thereforean important objective within the currentVAM programme.

User network models are being prototypedto investigate methods of collaboration thatare of mutual benefit to end users and theaims of the VAM programme. A workshop,facilitated by Paul Hibbert of OptimatLimited, was held at LGC to kick off the

process of user network development. Theworkshop was attended by representativesfrom the food/agriculture, environment,clinical/medical and industrial measurementsectors, as well as by a representative fromUKAS and a number of LGC staff involvedin the production, certification andmarketing of reference materials.

Practical issues for user groups werediscussed at the workshop and a rationale forsuch groups was developed. A clearrationale, in terms of shared objectives andthe potential for collaborative exchange,established that there were many goodreasons for user groups to be developed.These are summarised in the Figure 1.

The discussions covered the membership ofthe user groups. For the groups to be fullyeffective it was concluded that memberswould include informed and experiencedanalytical scientists, representatives fromsuch parties as accreditation, regulatory andstandards bodies, PT scheme providers,instrument manufacturers and ultimate end-users of analytical data.

The workshop team also considered whetherthere should be a single user network ordiscrete sectoral groups. Whilst theframework given in the diagram was thoughtto be applicable to all users, there wereenough differences in the detailed

requirements of each sector to make separateuser groups a preferred option. Thisapproach to user networking is thereforebeing developed for a pilot sector -organisations with an interest inenvironmental analysis.

Further discussions with users in theenvironmental sector have helped to validateand develop the pilot model for usernetworking and identify a number ofdetailed practical considerations. Theinterest in the concept has beenencouraging, especially:

• a willingness to contribute to sharedactivities in a number of ways, includingtime, expertise and funding;

• an interest in working collaboratively toaddress the requirements for newreference materials in the sector;

• a wish to exploit a combination ofelectronic media and traditionalapproaches to networking.

Further consultations and the initial meetingof the environmental group are planned forearly 2003.

For further information pleasecontact:Paul HibbertOptimat Ltd Email: [email protected]


V A M P R O D U C T S

LGC, as part of the VAM Programme,has produced a series of practical

training guides on a range of basicmeasurement skills and techniques.

Published by the Royal Society of Chemistry(RSC) on behalf of the VAM Programme,‘Practical Laboratory Skills Training Guides’look at the principles and terminology ofeach technique, including the choice ofequipment, and follows this up with step-by-step instructions and some practicalexercises. Titles available as part of thispackage are ‘Measurement of Mass’,‘Measurement of Volume’, ‘Measurement ofpH’, ‘High Performance Liquid Chroma-tography’ and ‘Gas Chromatography’.

‘Practical Laboratory Skills Training Guides’are intended for inexperienced staff inindustry, students at university or anyoneneeding a clear, concise and reliable guide toanalytical procedures. The guides are also auseful refresher for experienced staff whohave been absent from the laboratory for aperiod of time.

Graham Atkinson, Laboratory ServicesManager at Croda Chemicals in Goole, EastYorkshire, said: “We have been using theguides as part of our laboratory trainingprogramme and have integrated them into alaboratory quality assurance system. The

guides have been particularly useful formembers of staff new to analytical chemistry.Using the guides enables them to carry outcompetent analysis more quickly than beforethey were available. Having read the guides,new staff complete simple exercises and thedata are recorded. If new staff meet the setanalytical criteria they are allowed to progressto actual factory analysis.”

The guides include a minimal amount oftheory, as their main function is to guide inbest practice and not teach the subject indepth. There are also practical exercises tohelp to establish whether a trainee hasaccomplished a particular level ofcompetence. The chromatography guidesalso contain trouble-shooting information.

Denis Walker, Director of the DTI’sNational Measurement System Directorate,said: “DTI recognises the essential role ofmeasurement in underpinning the UK’scompetitiveness and quality of life. Throughthe VAM Programme we are helping toensure that the UK has the necessaryinfrastructure and tools to make validanalytical measurements. It is particularlypleasing that the ‘Practical Laboratory SkillsTraining Guides’ developed by LGC arebeing so well received by industry.”

The guides were written by staff at LGC in

collaboration with members of the SOCSA(Specialised Organic Chemical SectorAssociation) Analytical Network Group,which itself is part of the ChemicalIndustries Association.

Each title in this series is sold separately or aspart of a package that also includes the fiveguides and two CD-ROMs. The CD-ROMsgive clear practical instructions on bestpractice. One CD covers the basic skillsrequired by all analysts, as well as others whoregularly make measurements in chemical orsimilar laboratories. The second CD coversadditional skills including drying and ashing,solvent extraction and rotary evaporation.

‘Practical Laboratory Skills TrainingGuides’ can be purchased from:VAM Sales, LGCTel: 020 8943 8441Email: [email protected]

Sales and Customer Care DepartmentRoyal Society of ChemistryThomas Graham HouseScience Park, Milton RoadCambridge CB4 0NWTel: +44 (0)1223 432360Email: [email protected]: www.rsc.org/shop

The guides can also be purchased online atthe VAM web site.

VAM publishes training guides formeasurement in the laboratory

New method validation software under development

LGC, as part of the VAM programme,has teamed up with Tessella Support

Services plc to develop a software packagefor method validation.

Known as ‘mVal’, the package will assistlaboratories in the planning andimplementation of in-house methodvalidation studies. The software is speciallydesigned to allow greater flexibility inspecifying the set of experiments necessary formethod validation. This allows the use ofdifferent validation protocols to suit the needs

of the user and the differing requirements oftheir clients. The package will cover a rangeof methods for assessing all the commonmethod performance characteristics, whichinclude accuracy, linearity, precision,detection capability and ruggedness. Acomprehensive set of statistical dataprocessing options, including all the commonrequirements and a range of options for, forexample, outlier testing, is also incorporated.In order to demonstrate conformance torequirements, the software will also includeprovide for objective comparison of results

with preset validation requirements.

Modern analytical laboratories need to showthat the results they report are obtainedusing valid methods and validation studiesare vital to providing this evidence. ‘mVal’will be an essential tool to make in-housemethod validation more cost effective.

‘mVal’ will be available in summer 2003.

To register an advanced interest in thisproduct, contact the VAM Helpdesk.


F O R T H C O M I N G E V E N T S

ISO/IEC 17025implementation

October 8, 2003 Teddington

The ISO/IEC 17025 standard, “Generalrequirements for the competence of testing andcalibration laboratories”, is the standard thataccreditation bodies such as UKAS in theUK are using as a basis for theiraccreditation. Aimed at quality managers,laboratory managers and those inlaboratories seeking accreditation for someor all of their activities, this course isdesigned to help testing laboratories meetthe requirements of ISO/IEC 17025.

Quality systems in testing laboratories

June 25, 2003 Teddington

December 3, 2003 Teddington

This course provides an introduction toquality systems appropriate for use in atesting laboratory. The main standards inuse, GLP, ISO/IEC 17025 and ISO 9001,will be described and their selection andimplementation discussed. Their similaritiesand differences will be highlighted. Thecourse is aimed at laboratory staff at alllevels. It is appropriate for quality managers,or those about to take on this role, inlaboratories that carry out measurements inthe chemical, biochemical or biotechnologysectors. In addition the material will be ofbenefit to users of results from theselaboratories, who will gain an insight into thefactors that help achieve reliablemeasurement results.

Statistics for analyticalchemists

September 17, 2003 Teddington

The quality of analytical data is a vital aspectof the work of an analytical chemist. Theapplication of statistics is central to theassessment of data quality and anunderstanding of statistics is essential to theinterpretation of analytical results. Theapplication of statistics is required formethod validation and measurementuncertainty calculations, and is thus essentialfor meeting ISO/IEC 17025 accreditationrequirements. This computer-based courseprovides an introduction to the basicstatistical tools that analytical chemists needfor their work. The course starts fromlooking at data and then explains the mostcommon statistical parameters and how tocalculate them.

Analytical quality is of paramount importance to anyone making chemical measurements and to those making decisions based on theresults from such measurements. There are increasing burdens on companies to meet regulatory, trade and quality requirements and this

has resulted in greater emphasis on method validation, measurement uncertainty and traceability. This is endorsed by the internationalaccreditation standard ISO/IEC 17025, used in the UK by UKAS as a basis for laboratory accreditation. The standard contains detailedrequirements for these topics. Evidence of training and competence in the topics mentioned is a requirement of the standard and of customersof analytical results.

The range of courses offered under LGC’s analytical training programme is designed to meet the increasing need for laboratory managersand analysts to demonstrate competence and to keep abreast with quality assurance issues and practises. A number of new courses have beenadded for 2003, to ensure that the training programme continues to meet the needs of the analytical community.

All the courses consist of lectures and workshop sessions, providing opportunities for group discussions and to practise the newly acquiredknowledge. To ensure maximum benefit from each course, delegates work in small groups for the workshop sessions, with a tutor present foreach group.

LGC’s analytical training programme for 2003



Further statistical tools foranalytical chemists

April 29, 2003 Teddington


The ever-increasing amounts of datagenerated in the course of analyticalmeasurements means there is a greaterneed to use statistical tools to assess thequality of the data and to assist with itsinterpretation. Appropriate use of thesetools improves the chances of makingcorrect decisions. The course builds on thematerial in the ‘Statistics for analyticalchemists’ course and is ideal for analyticalchemists who are required to planinvestigations/studies and to make decisionsbased on one or more sets of data.

Principles and practice ofmeasurement uncertainty inchemical testing laboratories

June 17–18, 2003 Teddington

November 18–19, 2003 Teddington

The ability to estimate measurementuncertainty is now a requirement of testinglaboratories accredited to ISO/IEC 17025.The first day introduces the principles ofevaluating uncertainty and the second daygoes on to provide the tools for identifyinguncertainties and using validation data. Thelectures and workshops take delegatesthrough the process of evaluatinguncertainty. Completion of this courseshould provide sufficient training to enableanalysts to carry out an uncertaintyevaluation for their own laboratory methods.This course is in line with ISO principlesand with the EURACHEM/CITAC guide‘Quantifying Uncertainty in AnalyticalMeasurement’. The course is aimed atanalytical chemists who have limitedknowledge of measurement uncertainty andneed to evaluate the measurementuncertainty of a range of analytical methods.

Method validation

July 8–10, 2003 Teddington

December 9–11, 2003 Teddington

Method validation is the process thatprovides evidence that a given analyticalmethod, when correctly applied, producesresults that are fit for purpose. No matterhow well a method performs elsewhere,analysts need to confirm that the method isvalid when applied in their laboratory. Thereis now a much greater emphasis on methodvalidation in the ISO/IEC 17025accreditation standard. Through a numberof workshops, delegates build a validationprotocol for a method of their choice. Thiscourse is designed for analytical chemistsand potential or existing laboratorymanagers who are involved in methoddevelopment and method validation.

Using reference materials inanalytical measurements

May 15, 2003 Teddington


The use of reference materials is an essentialcomponent of a laboratory’s quality systemand is one of the cornerstones for theverification of the accuracy of analyticalmeasurements. Given the greater emphasison method validation, traceability andmeasurement uncertainty in the ISO/IEC17025 accreditation standard, the need forthe effective use of reference materials hassignificantly increased. Attending the coursewill help delegates:

• understand the varied role of referencematerials and the different types available

• select the appropriate material and plan how to use it

• meet the traceability and method validationrequirements of ISO/IEC 17025

• interpret the results from the measurementsyou make on reference materials

• develop in-house standards for use ininternal quality control

Using proficiency testing inthe analytical laboratory

May 1, 2003 Teddington

September 30, 2003 Runcorn

November 27, 2003 Teddington

Participation in a recognised PT scheme isstrongly recommended by accreditationbodies for laboratories accredited toISO/IEC 17025. It gives laboratories anobjective, independent measure of thequality of their output, and is therefore ahighly effective diagnostic tool for alaboratory’s quality system. It is thereforeimportant for analytical laboratories toobtain the optimum benefit fromparticipation in proficiency testing. Thiscourse is designed for laboratory staff(chemists and microbiologists) who haveresponsibility for deciding which PTschemes are appropriate, and for qualitymanagers or others who use and interpretPT results. It is also suitable for customersand auditors who use PT schemeperformance as a tool in monitoringlaboratories’ external quality.

These training courses will be run mainlyat LGC’s facilities at Teddington inSouth-West London and Runcorn,Cheshire. However, they can becustomised to suit the needs of anindividual company that require in-housetraining for a group of staff.

For further information on LGC’sAnalytical Quality Training Programmeplease contact:

Lorraine DidinalLGCTel: 020 8943 7631Fax: 020 8943 7314Email: [email protected]

Or visit the VAM (www.vam.org.uk)or LGC (www.lgc.co.uk) web sites,where on-line booking is available.



APACT 2003 – Advances in Process Analytics andControl Technology –Conference and Exhibition

28 –30 April, 2003Le Meridien Conference Centre,York, UK

Further information:Email: [email protected] Web: www.cpact.com

ACHEMA 2003 – 27th International Exhibition-Congress on ChemicalEngineering, EnvironmentalProtection and Biotechnology

May 19-24, 2003Frankfurt, Germany

For the first time ever, ACHEMA willcombine a dedicated biotechnologyexhibition with a first class biotechnologyconference programme. This offers theunique opportunity to attend an outstandingbiotech event while at the same timeenjoying the vibrant atmosphere of theworld’s largest exhibition conference forchemical engineering, environmentalprotection and biotechnology.

Further information:DECHEMA e.V.P.O.B. 15 01 0460061 Frankfurt am MainGermanyTel: +49 69 7564-0 Fax: +49 69 7564-201Email: [email protected]: www.achema.de/achemaworldwide/wwmain.htm

QA/QC in the field of emissionand air quality measurements:harmonisation, standardisation& accreditation

May 21–24, 2003 National House Smichov, Prague, Czech Republic

The conference will present the latestlegislation relating to ambient air andemission monitoring, different componentsof quality control and quality assurance andexperiences with the implementation ofquality systems. The conference is targetedat air pollution laboratory managers andtechnical personnel who are alreadyacquainted with the technologies, orinterested in their further implementation.

Further information:Web:www.ies.jrc.cec.eu.int/Units/eh/events/EAQH/

ICASS 2003 – The 49thInternational Conference on Analytical Sciences and Spectroscopy

June 1–4, 2003Carleton University, Ottawa, Canada

This conference will cover variousdisciplines of analytical science, with theintent to address specific challenges asexperienced by analytical scientists in today’sworkplace. As part of an exciting technicalprogram, the Laboratory and ScientificDirectorate of the Canada Customs andRevenue Agency will be hosting an‘International Workshop on BeverageAlcohol Analysis.’

Further information:Nimal De SilvaDepartment of ChemistryCarleton University, OTTAWAOntario K1S 4B6 CANADATel: +1 613 520 2600 ext 2338 Fax: +1 613 520 3749 / +1 613 520 2569 Email: [email protected]:www.carleton.ca/~ndesilva/icass2003/Conference%20details2.htm

1st International Forum –Analytics and Analysts

June 2–6, 2003Voronezh, Russia

The conference aims to present fundamentaland applied investigations in analyticalchemistry and its applications, as well asdiscuss new ideas and projects ineducational and computer technologies,perspectives, and general trends. Theconference is aimed at: Chairpersons,teachers, and research associates ofuniversities, colleges and technical andsecondary schools; Managers and employeesof research institutes, enterprises andcompanies; Post-doctorate and postgraduate students.

Further information:Yakov I Korenman Voronezh State TechnologicalAcademy Prospeckt Revolutsii, 19349000-VoronezhRussia Tel: +7 732 55 42 67 Fax: +7 732 55 38 56 Email: [email protected] Web: www.vgta.vrn.ru/forum/inf-engl.htm

Other events



International Symposium on Biological andEnvironmental ReferenceMaterials (BERM 9)

June 15–19, 2003Berlin, Germany

This conference is a continuation of asuccessful series of symposia that have beenheld alternately in the EU and the USAsince 1983. The BERM series is an on-goingforum, addressing issues related to the roleof biological and environmental referencematerials in the assurance of quality inanalytical measurements. BERM 9’sscientific programme will focus on the roleof certified reference materials in themeasurement process in fields of globalhuman and political concern, such as foodsafety and labelling, including novel foodand feed, biotechnology, public health andenvironmental monitoring.

Further information:EUROLAB-Deutschland SecretariatVerein deutscher Prüflaboratoriene.V.Unter den Eichen 87, 12205 Berlin,GermanyContact: Gudrun Neumann Tel: +49 30 8104 3769Fax: +49 30 8104 3717Email: [email protected] Web: www.eurolab.org/berm9

15th InternationalBioanalytical Forum

July 1–4, 2003University of Surrey, Guildford

The main themes of this conference are druganalysis, biofluids, method development,HPLC-MS, validation and sample preparation.

Further information:Mrs G CaminowChromatographic SocietyClarendon Chambers32 Clarendon StreetNottingham, NG1 5JDTel: 0115 9500596 Fax: 0115 9500614 Email: [email protected]: www.chromsoc.com

16th International MassSpectrometry Conference

August 31 – September 5, 2003Edinburgh International ConferenceCentre, Edinburgh, Scotland

The organisers have rejuvenated theconference format with a boldly forward-looking scientific programme, which willfocus on key aspects of modern MassSpectrometry and relevant fundamentalstudies. Each day selected ‘hot topics’ will beaddressed, with oral presentations andposter contributions. Each themed segmentwill conclude with an interactive workshop.In order to complete the ‘state-of-the-art ofMS’ overview that the conference aims tooffer delegates, posters featuring outstandinglate breaking results will be accepted up tothe last minute. Preceding the conferencewill be a range of relevant short coursescovering: ‘Solving Real-World Problemswith LC/MS’; ‘Mass Spectrometry forProtein and Peptide Scientists’, ‘PracticalAspects of High Throughput Proteomics’;and ‘Interpretation of Mass Spectra andHigh Resolution MS using FTICR’.

Further information:Web: www.imsc-edinburgh2003.com

8th International Conferenceon Environmental Scienceand Technology

September 1–3, 2003Lemnos Island, Greece

The aim of the Conference is to presentresults of research and innovatedtechnologies related to environmentalproblems, which threaten the quality of lifein our planet. In view of the success of theprevious Conferences it is expected that themajor part of the Greek environmentalscientists and engineers as well as a largenumber of international participantsspecialising in environmental technology willtake part in this event.

Further information:Email: [email protected]: www.gnest.org/cest

11th International MetrologyCongress

October 20–23, 2003Toulon, France

Further information:Email: [email protected]

2nd International Conferenceon Metrology – Trends andApplications in Calibrationand Testing Laboratories

November 4–6, 2003Eilat, Israel

The meeting is organised by the NationalConference of Standard Laboratories -International (NCSL), Co-operation onInternational Traceability in AnalyticalChemistry (CITAC) and the IsraeliMetrological Society (IMS). Topics fordiscussion will centre around:

• metrology both as a science and as an integral part of business in industryand trade;

• requirements to calibration and testing(analytical) laboratories;

• new measurement methods andinstruments;

• regional metrological organisation;

• interlaboratory comparisons;

• proficiency testing;

• traceability;

• ethical problems in metrology andeducation in the third millennium.

Further information: Dr Henry Horowitz, Conference Secretariat ISAS-International Seminars PO Box 34001JERUSALEM 91340ISRAELTel +972 2 6520574 Fax +972 2 6520558 Email [email protected]


Further information on theVAM programme

The VAM HelpdeskLGC

National Measurement System DirectorateDepartment of Trade and Industry151 Buckingham Palace RoadLONDON SW1W 9SS

Tel: 020 7215 1358Email: [email protected]: www.dti.gov.uk

VAM Contractors

Aerosol Science CentreAEA Technology plcE6 Culham, ABINGDONOxfordshire OX14 3DBTel: 01235 463677Email: [email protected]: www.aeat.co.uk

Cambridge Consultants LtdScience ParkMilton RoadCAMBRIDGE CB4 0DWTel: 01223 420024Email: [email protected]: www.cambridge-consultants.com

LGCQueens Road, TEDDINGTONMiddlesex TW11 0LYTel: 020 8943 7000Email: [email protected]: www.lgc.co.uk

NPLQueens Road, TEDDINGTONMiddlesex, TW11 0LWTel: 020 8977 3222 (switchboard)Email: [email protected]: www.npl.co.uk

Sira LtdSouth Hill, CHISLEHURSTKent BR7 5EHTel: 020 8467 2636Email: [email protected]: www.sira.co.uk

For advice on:

• Analytical quality assurance;• Chemical nomenclature;• Proficiency testing;• Reference materials; • Statistics.

Contact:

The VAM HelpdeskLGCTel: 020 8943 7393Email: [email protected]: www.vam.org.uk

For information and advice on:

• Traceable gas standards;• Gas analysis and analyser performance testing;• Analysis of Gas Awareness Club;• Gas proficiency testing;• Trace water vapour and odour;• Industrial process monitoring;• Quality assurance of ambient air measurements;• Surface and nano-analysis;• European standards (norms) on gas analysis.

Contact:

Peter WoodsAnalytical Science GroupCentre for Optical and Analytical Measurement, NPLTel: 020 8943 7095 Email: [email protected]: www.npl.co.uk/npl/environment

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