National Measurement System Programme for

Chemical & Biological Metrology

Programme Strategy June 2013

National Measurement System

Chemical & Biological Metrology Programme

Programme Strategy

June 2013

© Crown copyright 2013 Reproduced with the permission of the Controller of HMSO

And Queen’s Printer for Scotland © LGC Limited 2013

This document has been produced with the financial support of the UK Department for Business, Innovation and Skills (BIS) National Measurement System. It is not for general distribution and should not be cited as a reference other than in accordance

with the aforementioned contracts. Prepared by:

Julian Braybrook Helen Compton

LGC Limited NPL

Authorised by:

Julian Braybrook Helen Compton

LGC Limited NPL

LGC Report Number: NPL Report Number:

Contents Executive Summary 1

Introduction 3

Objectives 4

Strategic Priority Themes 6

Documentary Standards, Regulations and Directives 21 International Dimension 22

Support for SI 28

Resources and Competences 28

Impact 28

Alignment with Other NMS Programmes and Wider Government Priorities

29

Formulation

30

Conclusions

30

Annex 1: Top Level Programme Roadmap Overview

32

Annex 2: Programme Balance

33

Annex 3: Programme Roadmaps

33

1. Executive Summary This Executive Summary highlights some of the major influences to the ChemBio Programme over the last year:

• Changes to the ChemBio Programme – review of strategy and roadmaps NPL and LGC reviewed the main text as part of the 2012 revision to the strategy document. The ongoing focus over the last 12 months has been on the complete revision of the roadmaps and their production in the new roadmapping format. Currently not all of the roadmaps are available but they have all been revised in light of the publication of the NMS Strategy in 2011 and will be published on the new NMS roadmap webpage under their programme “banner” when available. The address for the webpage is http://interactive.npl.co.uk/roadmaps/ (this currently only opens with full functionality in internet explorer). The webpage is password protected as the roadmaps are still undergoing development and the username and password are: Username: nms Password: ro@dmap5 Annex 3 has been updated as appropriate to include the new roadmaps.

• Wider NMI roadmap review conducted in 2012 Additionally, 2012 saw the publication of new draft EURAMET roadmaps. The UK is an active and leading participant in many EURAMET committees and scientists from both NPL and LGC contributed to the revision of these EURAMET roadmaps. The result is that there is good alignment to the NMS roadmaps where national interests overlap with those of Europe. The suite of roadmaps can be found at: http://www.euramet.org/fileadmin/docs/Publications/roadmaps/EURAMET_Science_and_Technology_Roadmaps_for_Metrology.pdf

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2. Introduction The Chemical and Biological Metrology Programme is an NMS Knowledge Base Programme, which underpins some of the most challenging chemical, physical and biological, and internationally-recognised, measurement capability important to UK regulation, industrial competitiveness and trade, and quality of life. Current priority issues in the UK include healthcare, food safety, environmental sustainability, advanced manufacturing, energy generation and supply, and personal and national security. The Programme is concerned with the realisation and maintenance of measurements and standards for the determination of the quantity of matter, for which the mole is the SI unit. In addition, the Programme maintains and develops the UK’s primary measurement capability for pH. The Programme therefore delivers valid and traceable analytical measurements for the UK and establishes equivalence of these analytical measurements with our trading partners. The Programme started on 1 April 2007 as a result of the merger of much of the work carried out under the former Valid Analytical Measurement Chemical and Physical (VAM-C and VAM-P) Programmes and the Measurements for Biotechnology (MFB) Programme, and covers both ‘chemical and physical metrology’ projects that started in October 2006 and ‘biometrology’ projects that started in April 2007. The programme is delivered by two main contractors, LGC and NPL, and comprises ~16% of the total NMS budget. It is split into five main strategic priority Themes that are aligned to global strategy and activity as directed by national governments and the Bureau International des Poids et Mesures (BIPM):

• Bioanalysis (Genes, Proteins, and Cells and Tissues) • Gas analysis • Chemical Measurement and Calibration (Organic, and Inorganic and Speciation) • Particles and Trace analysis • Surface analysis.

Management and Knowledge Transfer is an inherent activity within the priority Themes. This Programme has established expertise and facilities at NPL and LGC that are recognised as centres of excellence for measurements of environmental and gas analysis, surface analysis, micro and nanoparticle measurement, mass spectrometry, molecular and cell biology, and purity analysis, both within the UK and internationally. This expertise includes:

• Provision of standards and measurement of gaseous and particulate matter in both ambient conditions and from vehicles, combustion sources and other industrial emissions;

• Provision of underpinning metrology capability for new imaging technologies at nanometre length scales;

• Provision of measurement capability for determining chemical composition and the properties of surfaces and interfaces using innovative depth profiling techniques;

• Standardisation of the use of cell-based measurements and quality metrics for micro-array technology application;

• Characterisation capability for quality control and regulatory compliance of biopharmaceutical products;

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• Accurate quantitation of DNA, genes and protein identity, structure and correlation with biological function;

• High accuracy trace analysis of organometallic and non-metal species, and robust low level detection down to single molecules in liquids and on surfaces;

• Provision of reference materials and measurement calibration services. The establishment of related facilities such as the UK Chemical Calibration Facility allows internationally recognised analytical scientists with a unique combination of state-of the-art purity, chromatography and mass spectrometry methods to be able to offer security of supply for a range of highly specialist calibration and measurement services, advice and solutions including certified chemical calibrants, and matrix reference materials for the traceable quantitative measurement of food, clinical and environmental-related species to:

− Calibration service providers − Proficiency testing scheme organisers − Reference material producers − Standards and regulatory bodies − Quality assurance and testing laboratories.

This document sets out strategic priorities for the Programme, and the requirements for the future development of the NMS to address them, to ensure that the UK NMS remains world leading in appropriate technical areas to support a competitive UK economy and to meet UK social challenges. 3. Objectives The objectives of the Programme are to:

• Provide the technical and administrative infrastructure required to ensure cost- effective, valid and traceable chemical, physical and biological measurements important to the UK’s industrial competitiveness and quality of life and that support existing or forthcoming legislation/ regulation and ensure user confidence;

• Establish the global equivalence of these measurements with our trading partners; • Provide leadership amongst the relevant UK and international communities in the

application of leading-edge science and technological innovation; • Transfer the outputs of the Programme in terms of knowledge and technology to

improve awareness and support uptake and implementation by UK users, particularly at the interfaces key to exploitation, between:

- Discoverer and developer - Small company and large company - Company and contract research organisation - Industry (and its trade bodies) and regulator/user.

4. Strategic Priority Themes The Programme will deliver the mission and aims by addressing 9 challenge-driven strategic priorities set out in the Overview Roadmap included at Annex 1. These were selected after wide-consultations with stakeholders, and with advice of the Programme Working Group. The relative importance of investment in these priorities is difficult to evaluate since they are at different stages of maturity and of very different sizes.

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They differ, too, in their relative contributions to wealth creation and quality of life. Nevertheless, it is possible to make some crude assessments of relative impact at the level of generic measurement themes, based on the most important criteria for the health and wealth of the nation and for the delivery of the NMS strategy. These are:

• UK Economic impact – judged by current and expected contribution to the UK economy of that sector, and the importance of measurement within that sector;

• UK Quality of Life – judged by benefits such as improved health, environmental impact, and safety and security of UK citizens;

• UK Science and Innovation – judged by the importance of leading-edge scientific innovation to the success and sustainability of that sector;

• Standards and Regulation – judged by the importance of maintaining a regulatory framework underpinned by standards and measurement science;

• International Leadership – judged by the extent to which investment will maintain or develop a leading world-wide position for the UK;

• Metrology and SI (NMS) – judged by the level of support coming from the current SI system and the importance of developing the SI system to support emerging measurement needs;

• Cross Sector Impact – judged by the extent to which measurement needs addressed will have an impact elsewhere in industry.

Overview of Themes Details of how these priority themes map onto the Chemical and Biological Metrology Programme are given below. All the themes in the programme address economic or quality of life priority areas for the UK where the measurement needs are challenging and growing. The apportionment of the available Programme budget across these strategic priory themes can be found in Annex 2 in the form of a pie chart. Although the relative importance of specific application areas may change, expenditure on all the strategic themes needs to increase over the next few years in order to respond to:

• The ageing population and increasing healthcare costs making preventative medicine and early diagnosis attractive, where fast-moving genomics technologies are offering new approaches, and metallomics and elemental imaging are the future hot application areas of atomic spectrometry;

• Environmental protection where gaseous and particulate pollution and emission monitoring underpin regulation and carbon trading, and soil, water, wastewater and oceanic monitoring ensure environmental certification and address the increasing issues related to maintenance of biodiversity;

• Safety issues associated with the introduction of new technologies where characterisation and toxicity monitoring of nanoparticles in products and environmental matrices are challenging existing understanding and capabilities;

• Support for innovation, industrial competitiveness and trade in high added value industries such as plastic electronics, regenerative medicine, consumer products and industrial biotechnology where the UK has a strong international presence;

• Security and forensics where accurate measurements of trace chemicals in complex matrices and on surfaces underpin the ability to reliably identify threats and provide evidence.

• Sustainability and the low carbon economy through the use of industrial biotechnology, alternative energy sources (such as hydrogen and biofuels), resource efficiency and for the development of emissions trading schemes;

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• The establishment of measurement traceability – ideally to the SI – especially for the life sciences where most key biological characteristics have no traceable units.

Strategic Priority Theme 1: Bioanalysis (Genes, Proteins, Cells and Tissues) The Bioanalysis theme aims to provide a sound international basis for accurate and reliable measurements, which underpin the development and exploitation of biotechnology, principally by the healthcare industry in the UK, but also contribute to the emerging issues associated with sustainability (e.g. biodiversity and the low carbon economy). The theme has six areas of priority focus: 1.1 Biopharmaceutical Manufacture Biopharmaceutical products are biological entities that are produced using biological production processes. Examples of products include therapeutic antibodies, blood-derived products, vaccines and gene therapy products. Biopharmaceutical manufacture includes:

• Processing – understanding, optimising and controlling the production process • Product assurance – ensuring the quality, safety and efficacy of the final product • Product formulation – ensuring effective delivery of biologically active material to the

patient. The UK biopharmaceutical manufacturing community consists of a small number of vertically integrated major manufacturers, dedicated contract manufacturing companies, and small organisations providing Good Manufacturing Practice (GMP) material for initial clinical work (e.g. the High Value Manufacturing Catapult and specialist GMP production centres). Smaller companies often have limited analytical capability and regulatory expertise. Contract analytical labs range from multinationals to university spinouts. The Programme has close contact with the industrial community (multinationals, contract manufacturers, analytical service providers - through the BIA, the relevant bioprocess Sector Industry Groups (SIGs) of the Healthcare Knowledge Transfer Network (KTN) and regulatory agencies (EMEA, FDA). The projects in this priority theme support the industrial community by improving measurements and thus regulatory confidence in the safety and quality of biopharmaceutical products. Key areas of focus include:

• Quantitation and characterisation for compliance and regulation • Robust methods to correlate key process parameters for routine quality control of

product quality • Formulation effects on product activity, immunogenicity, bioavailability and stability.

1.2. Drug Discovery In recent years there has been a paradigm shift in the strategies used for drug discovery screening. With technological developments, large numbers of candidate small drug molecules can be generated, and screened rapidly in highly parallel biological assays to identify pharmacological activity. Successful small molecule lead compounds are optimised to identify more suitable drug substances, which are tested in cell- or animal-based assays to understand the toxicity and pharmacokinetics of the drug substance. The situation with respect to biopharmaceutical discovery and optimisation is somewhat different. In most cases, although monoclonal antibodies are an exception, the product will be derived from human sequence, and optimisation depends on ensuring the development

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of effective expression systems. High throughput methods for optimising monoclonal antibody variable domains exist and more complex products that combine different biological activities are under development. This is matched by a major therapeutic need to identify disease targets currently inaccessible by conventional antibodies and unsusceptible to small molecule drugs, and to assess their dynamic biomolecular structural changes in cellular environments, over different time and length scales. The key elements are:

• Lead development – high throughput and high content screening for lead identification and optimisation

• Safety evaluation – immunogenicity, bioavailability, toxicity and safety testing of lead compounds (with reduced use of animal models), and

• Biomolecular structure determination in native environments that enable correlation of structure-activity relationships with the origin of diseases.

The UK pharmaceutical industry traditionally consists of a small number of vertically integrated multinational companies. The sector has one of the highest R&D intensities of any in the UK, but its product pipeline is decreasing and under threat from ‘biosimilar’ manufacturing. To reduce human and economic burden, there is a refocusing of effort towards seeking improved stability from identified synthetic compounds. There are also other niche discovery and service companies often using proprietary approaches. Some of these have diversified to address issues relating to lifestyle management, contributing to individual health and personalised medicine. Biopharmaceutical discovery is dominated by a large number of small university spinouts and venture capital funded companies, who tend to develop products through early stage discovery, with commercial development achieved in partnership with large multinationals. These small companies tend to have limited access to analytical capabilities and regulatory expertise. Many operate on limited funds and short timescales. Key players and regulators (ECVAM, the EU Innovative Medicines Initiative (IMI) and FDA reports) have confirmed that the reliability of the screening platforms and approaches is a universal weakness and that improvements are required in the prediction and evaluation of drug efficacy and safety, making better use of biomarkers. Key areas of focus include:

• High throughput/content screening • Improved functional bioassays for (bio)pharmaceutical products • Chemical characterisation across the length scale to understand ‘molecular

individualism’ and the behaviour of complex molecules in bulk • Spatial and temporal screening of ligand-induced structural changes at cell interfaces • Underpinning standards support for validation of biomarkers for safety and efficacy • Animal replacement models for improved safety, immunogenicity, bioavailability and

efficacy testing • Robustness determination of emerging direct-analysis technologies • Characterisation of improved stability novel synthetic products.

1.3 Diagnostics The diagnostics market faces a period of significant change and new challenges. NHS policy is aligned with an increased prominence of point-of-care testing and early diagnosis. Technical developments promise much benefit from faster and more reliable biomarker, genetic and proteomic testing. Rapid, on-site detection of pathogens and infectious diseases from human and non-human origin assumes greater importance not only in healthcare but

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also for food safety and counter-terrorism. The target for diagnostics is very diverse - covering identification, quantitation and population analysis of genes, proteins, metabolites, and simple chemical ions as dynamic biomarkers. Therefore, methods allowing rapid and accurate detection and measurement of such biomarkers to secure robust and detailed diagnosis, ideally at point of care, together with novel affinity reagents that may overcome any limitations of antibody-based systems are of increasing demand. The key elements considered within this priority are therefore:

• Clinical diagnostics – controlled laboratory testing for disease state diagnosis and prognosis

• Point of test diagnostics – rapid and accurate diagnostic testing at point of care • Medical imaging – from single molecules to cells to whole tissue or body imaging

used in combination with other tests to diagnose and treat disease • Stratified medicine – testing for susceptibility of groups of individuals to manifest

disease symptoms and respond to treatment. The UK diagnostics manufacturing community consists of a small number of major and medium-sized international manufacturers, and a large number of small research spinout organisations developing novel platforms and biomarkers. Laboratory-based tests comprise the majority of the global in-vitro diagnostics (IVD) market but patient self-testing ‘over the counter’ (OTC) and ‘point of care’ (POC) products are growing most strongly. Smaller companies often have limited analytical capability and regulatory expertise. Barriers to entry to laboratory diagnostics are high whereas those for emerging segments are relatively low. Diagnostics trade representatives and individual companies (Diagnox, OGT, BlueGnome, DxS, Stratophase), the Technology Strategy Board Infectious Diseases Innovation Platform, the NHS National Genetic Reference Laboratories (NGRLs), the International Federation of Clinical Chemistry (IFCC) and the Joint Committee on Traceability in Clinical Measurements (JCTLM) represent interested parties. Key areas of focus include:

• Reference standards and control materials for molecular and protein diagnostics • Reliable methods for sample handling and low-level detection in complex matrices • Confidence in, and traceability between, clinical laboratory and point-of-care

measurements • Development of quantitative reference methods and standards traceable to higher

order required by the EU IVD Directive • Standardisation framework support, including synthetic standard mimics, for novel

gene regulation and sequencing technologies • Underpinning standards and performance metrics for biomarker validation.

1.4 Regenerative Medicine Healthcare technologies are combined systems that target prevention, diagnosis, treatment and rehabilitation. Biotechnology has opened the way to developing replacement biological functions, organs and tissues, through regenerative medicine (cell-based therapeutics and tissue engineered medical products), gene therapy and smart medical devices for monitoring and treating disease. The centre of gravity of the technology is moving to translational research, with the UK’s balanced regulatory regime bringing competitive advantage. This prompts the need to measure the performance of responsive and ‘intelligent’ medical implants (sub-cellular to tissue scales) and provide early measurement support for emergent disruptive cell-based therapies (tissue engineered scaffolds, cell therapies, gene therapy vectors).

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The key elements considered within this priority are: • Cell-based therapeutics – methods to induce the body to regenerate healthy

functional tissue (for instance using stem cells or instructive matrices and scaffolds) • Tissue Engineered Medical Products – artificial tissues based on cells integrated into

three-dimensional extracellular structures and microenvironments. • Gene therapy vectors – materials to support systemic use and clinical trials of gene

transfer medicines. • Medical Implants – surgically implanted tissues or devices.

The Health Technologies sector consists of several international and medium-sized companies making ‘traditional’ medical devices and with a greater or lesser interest in tissue engineering. The majority of UK companies are small enterprises. Traditional implants represent a mature market with developments being mainly incremental (drug-device combinations) such that UK-based activities of high value mainly lie in emerging sectors such as tissue engineering. A number of small spinout companies, based on the world-renowned and burgeoning science base in the UK, are exploiting novel biological technologies such as stem cells and instructive implants for diagnostic or therapeutic applications. These smaller companies generally have very limited analytical capability and lack guidance, methodologies and regulatory support. They are susceptible to market conditions and some large pharmaceutical and custom manufacturing companies have entered the marketplace. Existing barriers to commercialisation include high costs associated with processing and managing personalised medicine treatments (grafts, transplants) prompting a need to assess the performance of responsive and “intelligent” implants (scaffolds, cells) to support gene and cell-based regenerative therapies for wide scale use. Consultation has secured advice from the Association of British Healthcare Industries (ABHI), established and emergent companies (GSK, MedImmune, Procter & Gamble, Smith & Nephew, Pfizer/Neusensis, Reneuron) and leading academics (Cambridge, KCL, UCL, Durham/Newcastle). There is close monitoring of the development of the Cell Therapy Catapult at KCL/Guy’s. Several reports have identified consistent trends that supported the advice. Key areas of focus include:

• Physicochemical nature of extracellular guidance on cell development • Screening methods to predict tissue engineered product safety • Robust methods for controlling, monitoring and validating cell growth, differentiation

and stability during development and manipulation/scaling of cell-based systems and products, and during product shipment

• Process optimisation • Quantitative and traceable measurements of intracellular delivery to relate delivery

vectors with gene transfer efficiencies • Generic standards for reagents and biochemical markers of cell identity/authenticity

and functionality • Traceable methods for assessment of active component function within cell-based

products • Validation and standardisation of 3D cell systems as models • Cell imaging and tracking • Horizontal technical and regulatory advisory support.

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1.5 Bioscience Industrial biotechnology, the use of biological substances, systems and processes to transform raw materials into useful chemical and energy/fuel commodities, will play an essential part in the creation of a low carbon knowledge-based economy across the highly diverse chemistry-using industries. The key areas for focus here are:

• Bioprocessing – the development, utilisation and monitoring of biological processes used for manufacturing products

• Biocatalysis and fermentation – the exploitation of biological molecules (i.e. enzymes) for manufacturing products (usually chemicals)

• Bioenergy – provision of suitable metrological analytical methods and standards for the analysis of biofuels, and the use of biological processes to generate renewable energy sources from biomass.

The UK marketplace is currently dominated by a small number of large multinational and smaller companies in a loosely regulated environment (due to the nature of the products). Investment has traditionally been driven by cost-reduction, rather than adding value. However, the drive towards sustainability has led to a revival of interest in the use of biological systems in industrial production as an alternative to fossil resources as raw material and new initiatives such as the Biorenewables Development Centre at the University of York aim to bridge the current gap between laboratory exploration and commercial production by the chemicals industry. Advice has been secured from the Biosciences KTN, the Centre for Excellence in Biocatalysis, Biotransformation and Biocatalytic Manufacture (CoEBio3), EuropaBio and the EU Biodiversity Action Plan, focusing upon metrology for manufacturing and process control, and to support derivation and inter-operability of ecosystem data. Climate change affects biodiversity directly and tools are emerging for monitoring biodiversity through oceanic monitoring and study of ecosystems as subtle climate change indicators. Environmental biotechnology exploits biological processes and organisms to monitor, protect and restore the environment. There is a growing interest in functional foods and potential new technologies for product monitoring. The key elements considered within this heading are:

• Bioremediation – using micro-organisms or plants to degrade or accumulate pollutants and consequently decontaminate land and water

• Environmental monitoring – using diagnostic technologies for the detection of microbial contamination within the environment, or using micro-organisms or plants as indicators of the state of the environment

• Bioprospecting – isolating and identifying novel biological functions or useful molecules from nature (e.g. the isolation of novel catalysts from extremophiles or fluorescent proteins from coral)

• Functional foods and nutraceuticals – the modification of crop materials to produce enhanced nutritional values or even pharmaceutical effects.

In terms of the food safety and environmental monitoring areas, there is a strong cross-over of requirements for improved monitoring methods with those identified for the diagnostics sector, with a strong emphasis on solving problems of complex matrices. However, key areas for focus are:

• Rapid on-site monitoring of environmental matrices, traceable to laboratory data

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• Validation of technologies for functional food and nutraceutical assessment • Provision of a standards infrastructure enabling inter-operability of key national

biodiversity data, including robust, accurate and traceable determination and quantification of functional effects/markers of climate change.

1.6 Long-Term Biometrology Establishing traceability of measurements – ideally to the SI - is a key goal of the NMS. For the life sciences this is ambitious. The present physical model (SI traceability to the mole) fails to connect with biological identity and activity. Most key biological characteristics have no traceable units. However, the infrastructure has been established in the CCQM Bioanalysis Working Group (BAWG) through mutually accepted roadmaps that find expression in:

• Primary reference methods and measurands • Higher order reference standards/calibrants • Measurement uncertainty (ISO 17025).

The projects in this sub-theme support a proactive UK lead in the development of international biometrology. Strategic Priority Theme 2: Gas Analysis and Environmental Technologies Gas metrology underpins the requirements of UK industry and regulators for traceable measurements of ambient, emission level, forensic, occupational health and indoor air gases. These measurements are required by a wide range of industrial sectors including energy, chemical/petrochemical, oil and other fuels, transport, electronics, water, waste, public health, analytical instrumentation (including sensors), metal and non-metal processing, and pharmaceuticals.

Facilities developed at NPL to fulfil the requirements for valid and traceable gas measurements in the UK include: • Primary gas concentration standards prepared by absolute gravimetric techniques,

validated comprehensively and with demonstrated international comparability, covering industrial emissions, natural gas, flammability, occupational exposure, forensic applications, and ambient air quality

• Absolute gas calibration facilities, which employ dynamic methods where gas standards cannot be prepared gravimetrically with known concentrations

• National calibration and test facilities to evaluate the performance or type-test analysers for certain industrial emission, process control and ambient air quality applications.

Standards are replaced and facilities maintained where the requirements are strongest. Key international comparisons have been carried out that enable the UK to demonstrate acceptable international comparability. Key drivers for the work can be grouped into three areas: 2.1 Industrial competitiveness and trade There are continuing requirements to increase the enterprise, innovation, and competitiveness of the UK’s manufacturing industries. Gas measurement contributes to this strongly through the optimisation of industrial process efficiency, and by providing cost-effective environmental monitoring technologies. These can both be achieved by the utilisation of advanced on-line instrumentation, calibrated with valid standards. In addition,

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there is a move towards ‘self-calibrating’, ‘remotely calibrated’ and ‘remote sensing’ instrumentation, which need to be implemented accurately to be of benefit to industry. The field of analytical instrumentation is highly competitive, and includes many SMEs. National and international trade are also facilitated by accurate gas measurements, for example, by enabling valid natural gas (and other energy gases) trade between different organisations and countries (towards a single European natural gas market), and for aspects of emissions trading that require measurement. 2.2 Supporting regulation The field of gas measurements is the subject of a large and increasing range of regulations. These include both national regulations, and increasingly, new EC Directives (requiring Member states to enact them into national law). Examples include:

• EC Directives that limit the emissions of industrial sources to the environment (e.g. the recent Industrial Emissions Directive, which recast the Integrated Pollution Prevention and Control, Waste Incineration and Large Combustion Plants directives, together with the solvent directives, as a combined directive, which came into force in January 2011—);

• EC Directives that seek to control the quality of ambient air in both urban and rural locations, and related Clean Air for Europe (CAFE) Programme requirements, which set out objectives and measures for European air quality policy to 2020;

• National regulations for the routine measurement of gases covered by international legal metrology regulations (e.g. breath alcohol and vehicle MOT tests);

• EU requirements (Euro IV and V) and future ones covering emissions from cleaner vehicles using new technologies;

• EC proposals for a single European market for natural gas; • International protocols (e.g. Kyoto climate change, UN/ECE trans-boundary pollution,

OECD toxicity, Stockholm Convention on Persistent Organic Pollutants) to which the UK is a signatory leading to controls on greenhouse gas emissions and pollutant emissions trading, including possible expansion of the EU emissions trading scheme to include aviation, agriculture, maritime, petrochemicals, ammonia and aluminium sectors as well as new gases.

In addition, new mandatory CEN standards are being drafted to underpin EC Directives and to provide prescriptive measurement methods that require traceability to National standards. Furthermore, the accreditation standard ISO EN 17025 has now been implemented across Europe – this emphasises the requirement for national traceability. The Gas Analysis Theme enables industry to demonstrate compliance with regulations and statutes in a fair and cost-effective manner. It ensures the acceptability of results by regulators accreditation bodies and the public, and provides support to regulators to enable them to enforce legislation in a technically sound and impartial way. 2.3 Environmental monitoring and sustainable environmental technologies The environment has increased steadily in political importance as a result of increased public awareness and concern such that topics like climate change and environmental pollution are readily debated in mainstream media channels. Government initiatives to measure, understand and mitigate the effects of climate change are evident through the setting of technology strategy priorities, such as the low carbon and hydrogen economy, to respond to the emerging requirements. Remote sensing technologies for emissions control (including the detection of release of potentially hazardous materials) and validation of the carbon-trading system are also seen as vital underpinning technologies.

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Strategic areas for future focus include: • Provision of the underpinning metrology for technologies required to adapt to and

mitigate the effects of climate change (including carbon trading, carbon capture and storage and geoengineering solutions).

• Support for an innovative and competitive hydrogen economy through the development of reliable measurements of purity and storage capacity.

• Evaluation and extension of current environmental monitoring technologies for remote sensing.

• Provision of highly stable standards for use in global monitoring of background pollutant species e.g. reactive and short-lived species.

• Standards for measurements at ultra-trace concentration levels of water vapour and other species in pure gases required for advanced manufacture.

Strategic Priority Theme 3: Chemical Measurement and Calibration (Organic, Inorganic and Speciation) Organic Analysis is focussed mainly on mass spectrometry, the dominant technique for high accuracy determination of trace organics. It aims to provide a sound international basis for the uptake, or direct use, of accurate and reliable measurements, many from novel technologies, for application in the key areas of healthcare, food and environmental sustainability and security in the UK. It aims to achieve this through underpinning metrology capability for new ‘information-rich’ technologies that offer significant potential for improved methods of screening/monitoring and biomedical research and materials science, and through certified reference materials (CRMs) that reduce barriers to innovation by way of providing a means for validation. Inorganic and Speciation Analysis, focussed mainly on inductively coupled plasma (ICP) and mass spectrometry, aims to provide a sound international basis for the use of accurate and reliable organometallic and non-metal speciation (where the precise chemical binding of elements of interest can very significantly affect toxicity or bioavailability), and trace element and isotope ratio measurements to underpin the key application areas of food and beverage, clinical, consumer product and environmental analysis in the UK. The theme has five areas of priority focus: 3.1 Food & Feed Manufacture There is strong commercial interest in tackling current metal species’ deficiencies in, and allergenic potential associated with, the UK diet. Understanding the mechanisms by which enriched foods & feeds (e.g. wheat flour, mushrooms, Brassica and Allium plants) and food supplements (e.g. selenised yeast) benefit animal and human health are crucial to their regulatory approval. Industry self-assessment or the monitoring of set threshold levels, for known allergen materials is essential to maintain human health. The capability for achieving improved product quantitation and characterisation also allows for commercial improvements in the product processes. The UK food & feed manufacturing community consists of a number of vertically integrated major manufacturers, dedicated contract manufacturing companies and small organisations providing material for the food chain/healthcare market. These are supported by the research associations, government agency and sections of academia. The smaller companies often have limited analytical capability and regulatory expertise. The Programme has close contact with national measurement institutes, the small industrial community, research associations and related agency bodies (e.g. FSA).

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Projects in this priority support the industrial and regulatory community by improving measurements and thus regulatory confidence in the safety and quality of enriched food & feeds and food supplement products. Key areas of focus include:

• High accuracy determination and identification, particularly for naturally occurring and bioavailable species, for compliance

• Matrix reference materials for product quality control • Isotopically-labelled tracers • Competitive metal/non-metal species identification.

3.2 Drug Development, Diagnostics/Therapeutics The In Vitro Diagnostic Devices (IVDD) Directive has produced a demand for metrologically sound clinical reference materials, which can be used as calibrants. Furthermore, significant technological advances are being made in new imaging techniques for mass spectrometry. These have the ability to spatially analyse/map detailed chemical composition of a sample, such as biological tissue, solid surface or drug suspension, and are of interest to the healthcare industry in particular. There is significant interest in the potential use of metal species in disease therapy/protection and emerging interest in trace metal mapping for disease diagnosis, but the role of non-metals, such as phosphorus and sulphur, is broadening this scope further to the interaction of metals and non-metals with molecules of biological interest, such as DNA, oligonucleotides and peptides. Furthermore, advances in mass spectrometry have made possible the detection of counterfeit goods and the tracing of a sample to its origin using trace element analysis and/or subtle differences in both stable (e.g. δ34S, δ13C) and radiogenic (e.g. 207Pb/206Pb, 87Sr/86Sr) isotope composition. The UK community consists of a small number of vertically integrated multinational companies, niche discovery and service companies, contract research organisations, charities, a number of specialist clinical research centres, small university spin-outs, the research community and venture-capital funded companies. The Programme has close contact with the industrial community (multinationals, e.g. GSK, AZ, Abbott), specialist clinical research centres (e.g. Guys and St Thomas), instrument manufacturers, national measurement institutes, the research community and regulatory agencies (MHRA). Projects in this priority support the (bio)pharmaceutical, industrial and regulatory community by improving measurements and thus regulatory confidence in the authenticity of drug products, disease diagnosis and the safety and efficacy of potential novel products, assessing the likelihood of uptake/success of novel technologies and improving confidence in their application and data interpretation and comparability. Key areas of focus include:

• Quantitation and characterisation of drug metabolism pathways and clinical efficacy for compliance and regulation

• Reliability and full characterisation assessment of post-translational modification (PTM)/structure, novel (accelerated) analytical technologies/platforms, separation and desorption methods, calibration strategies and (matrix) reference materials providing confidence for evidential acceptability in court, diagnosis (increasingly at point of care) and supporting key clinical trials

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• Competitive metal/non-metal and biological molecule identification • Quantitation and identification of metabolic intermediates of disease treatment for

optimization of drug efficacy • Novel calibration strategies for elemental and isotope ratio imaging.

3.3 Sustainability The high level of concern that environmental toxins, such as steroid oestrogens in wastewater, can exhibit significant endocrine disruptive effects at extremely low levels (sub-ng/L) on wildlife and human health means that legislation (such as the Water Framework Directive) to control these substances will stretch current analytical capability. Action needs to be taken now to develop the measurement infrastructure, in the form reference methods suitable for assigning reference values to key samples and certified reference materials, which will enable enforcement. Projects in this priority support robust analytical techniques for the environmental community by providing guidance to field laboratories to enable appropriate method selection, underpinning current field studies on the removal of endocrine disrupters from wastewaters and metal speciation analysis in plants, and improving confidence in their application and legislative framework. The shift from total metals to reliable information on both the amount and composition of metal-containing species in accumulating plants is of importance for their successful use in removing environmental pollutants from soils and waters (phytoremediation) for land reclamation and effluent treatment and for regulatory purposes. Sustainable energy sources continue to attract debate. The potential for provision of biofuels is highlighting the requirement for characterisation methods supported by CRMs capable of determining origin, purity etc. The UK environmental sector consists of the large water companies, environmental consultancies, research associations, research and testing organisations, the research community and regulatory agencies. The Programme has close contact with research associations (e.g. Forest Research), national measurement institutes, the research community and regulatory agencies (DEFRA, EA). Key areas of focus include:

• High accuracy, traceable reference methodology for reference value assignment • Improved technologies for quantitation and characterisation • Novel technologies for sample fractionation • Interaction of multi-element species • Mass balance (distribution) of metal species • Matrix reference materials for compliance.

3.4 Consumer Products Accurate measurement of restricted substances in consumer products and wider industrial (e.g. construction) products supports sustainable development by enabling effective waste management and recycling strategies and underpins assurances about human health. The Restriction of Hazardous Substances (ROHS) Directive targets the use of certain organic compounds and metal and non-metal substances, such as polybrominated substances, in electronic and electrical equipment and volatile organic compounds (VOCs)

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emitted from building products to ensure human exposure to harmful substances does not exceed regulatory limits. Manufacturers test products to supplement material declarations and to verify supply chain declarations of component composition. Enforcement authorities perform testing to verify individual supplier compliance and as part of broader surveillance programmes. Accurate measurement of restricted substances in consumer products and wider industrial (e.g. construction) products (such as vinyl flooring, paints and coatings) supports sustainable development by enabling material improvement strategies, effective waste management and recycling strategies and underpinning assurances about human health. Concern about accuracy and reproducibility of screening procedures close to regulatory limits has led UK stakeholders (e.g. NMO and ERA Technology) to highlight the need for reference materials more representative of the type of products tested in the UK to ensure the validity and fitness for purpose of these tests. The increasing use of nanoparticles/nanomaterials in a wide range of consumer products raises issues relating to potential changes in material toxicity. The potential application areas for such innovative technologies are challenging for currently accepted separation, characterisation and toxicity models/tests. Projects in this priority support the industrial and regulatory community by improving measurements and regulatory confidence in the safety and quality of consumer and wider industrial products. Key areas of focus include:

• High accuracy methods for the determination and identification of organic compounds and/or metals at or below regulatory limits

• The global equivalence of these measurements with trading partners • Future requirements for matrix reference materials supporting legislation.

3.5 National Security/Forensics There is strong interest in reducing the threat from, and improving the response to, large-scale chemical- and bio-agent emergencies and for enhanced counter-terrorist screening and application in the forensic field of novel ‘information-rich’, non-invasive real-time measurement technologies and confirmatory measurement technologies for trace detection. Information on geographic origin & movement is invaluable for suspect identification in acts of terrorism & provides forensic intelligence for establishing victim identity in murder enquiries & natural disasters. Stable isotope ratio mass spectrometry (IRMS) data with trace element analysis &/or DNA fingerprinting could provide evaluation of a novel human provenance tool. Multivariate data analysis techniques will analyse data obtained. The UK security and forensic communities consists of a very small number of vertically integrated major manufacturers or service suppliers and smaller niche service suppliers, the security services, independent consultants, the research community (particularly consortia such as the Forensic Isotope Ratio Mass Spectrometry (FIRMS) group and the UK National Initiative on Ion Mobility Spectrometry (NIIMS)) and instrument manufacturers. Issues lay with the transfer of military use applications to the urban environment and an increased number of interferences and false positive reporting. The Programme has close contact with NIIMS, FIRMS, the Forensic Regulator, instrument manufacturers, security forces and the industrial community.

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Projects in this priority support the security and forensic communities by improving the measurements from novel technologies and therefore confidence in their application in the field. Key areas of focus include:

• Sampling strategies for the urban environment • Accuracy of portable (miniaturised) detection technologies for complex measurands

in challenging matrices • Accuracy of compound identification and high precision measurements in the field • Quantitative specificity standards for use in the field.

Strategic Priority Theme 4: Particles and Trace Analysis The Particles and Trace Analysis Theme aims to develop validated analytical methods with robust uncertainty statements, provide and disseminate underpinning traceability, and promulgate best practice for the measurement of physical and chemical parameters associated with nano- , micro- and macro-sized particles in ambient air and in emissions from stationary and vehicular sources. The outputs of the theme will enhance quality of life in the UK by protecting the health of the population and the environment, and will improve the competitiveness and efficiency of UK industry. The challenges and issues in this area surround the requirement to provide measurement science solutions to protect health, support legislation and develop new and innovative measurement methods with an emphasis on decreasing cost, increasing throughput, and reducing uncertainties. The benefits of this work are to reduce the burden of compliance with legislation for UK industry whilst also protecting the health of UK citizens and the natural environment. The traceability provided by the theme ensures measurements are comparable across Europe and stable over time so trends may be accurately assessed and the UK can defensibly prove compliance with legislative requirements. The ultimate aim of the theme is to deliver real-time, in-situ measurements of the complete compositions of particulates, preferably using miniaturised solutions to deliver these aims with multiple devices, in the field and on very small sample sizes – signalling a step-change in the way air quality measurements are delivered. These aims have clear synergy with the vision in NPL’s Metrology 2020 document to provide embedded, ubiquitous and ‘always-on’ sensors systems, using intelligent calibration strategies to provide a smart and interconnected web of air quality measurements. The theme also has significant synergy with the centre for carbon measurement in providing accurate measurements of species associated with radiative forcing, such as black carbon, and of emissions of a variety of species from stationary sources and vehicular sources. The diverse physico-chemical characteristics of particles lead to many measurement issues. The components and properties most relevant to health have not been determined. Current legislation refers only to total mass concentration of particles below 10 µm in size (PM10), or below 2.5 µm (PM2.5). Work is therefore being aimed directly at measuring and characterising airborne particles as a necessary part of understanding their health and climate effects. Airborne particles are extremely diverse, varying in size, composition and origin. Sooty particles from diesel engines are just a few nanometres in size, while windblown dust particles, typically rich in silicon, can be tens of micrometres. Some particles originate from natural processes, such as sea salt particle formation, while others arise from human

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activities. Many particles are formed by the reaction of gases in the air, for example ammonia (from agricultural sources) reacts with nitrogen dioxide (from vehicle exhausts) to form particles of ammonium nitrate. Particles in ambient and work place air are widely implicated in many pulmonary and cardio related illnesses and deaths. Consequently, anthropogenic particles from combustion, vehicles and other processes are closely monitored and regulated within Europe. Recently, there has been mounting concern about fine and ultrafine particles and new technologies based around engineered nanoparticles, which offer great promise for novel processes and products. The toxicology and eco-toxicology impacts of these nanoparticles are largely unknown and there are substantial, world-wide efforts to understand the properties of these particles in order to avoid potential major health related problems as occurred for asbestos. The trace analysis area applies measurement science to the identification and quantification of trace (and even ultra-trace) components. The focus is on undertaking measurement science and research underpinning present and future requirements for trace chemical analysis in pH measurement, ambient particulate composition analysis, mercury vapour, biofuels and the use of novel electroanalytical techniques. For example, the most common technique for analysing ionic components of airborne particles is ion chromatography. Underpinning work in pH and related ion analysis topics builds on existing strengths in these areas. Key areas of focus include:

• Underpinning traceability for airborne particle size, number density measurements and new method development for measurement of particle characteristics (e.g. surface area) not readily determined with existing technology;

• The provision of metrological support for measurements of organic and elemental carbon, and for relevant properties such as reflectivity and non-volatile mass;

• The development of novel analytical methods to accurately measure mercury vapour and chemical composition of airborne particles, including persistent organic pollutants;

• Providing experimental and scientific input to the revision of reference methods for PM10 and PM2.5 whose major flaws have been exposed in the years since its publication;

• Establishment of the UK’s link to primary standards of pH and solution conductivity; and

• The development of practical, sensor-based, pH and ion measurements in on-line, in-situ environments, particularly fuel cells.

Strategic Priority Theme 5: Surface and Nanoanalysis Nano- and micro-technologies have massive potential to increase economic wealth through improved and innovative products. For such emerging technologies there is an urgent requirement for more detailed understanding and characterisation of surfaces, interfaces and nanostructures than is currently possible. For example: organic electronics are complex nanostructured devices where it is critical to measure the 3D chemical composition to improve device performance and lifetime; personal care products have complex formulations and the interaction with skin and hair needs to be measured, medical devices have advanced surface treatments and controlled drug release layers to give antibacterial properties and reduce inflammatory responses. The characterisation of nanoparticles is of major importance for both regulatory requirements for health and product innovation. There is a growing need to provide chemical and nanomechanical analysis on surfaces that are not vacuum compatible such as creams for topological application, skin and tissues as well

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as analyses suitable for on-line measurement. In addition, future requirements will require analysis in liquids and in vivo especially in the biomolecular and medical sectors. Key areas of focus include: • To provide word-class metrology and advancing measurement capability for the

chemistry at surfaces and interfaces maximum impact to UK industry for competitiveness and UK quality of life;

• Provide international leadership in the development of standards and reference methods and data;

• To underpin the development of high-quality instrumentation in this area hence supporting a dynamic UK industry, and the emerging markets for this instrumentation;

• To ensure that UK measurements are fit-for-purpose, provide international comparability of measurements and ensure that the measurement infrastructure is in place to underpin systems for accreditation and quality control; and

• To provide leadership in frontier issues in surface and nano-analysis measurement in the UK and internationally.

The stakeholder group for this theme is large and diverse. The main drivers are for industries competing in the knowledge-based economy through high added-value products and where the understanding and manipulation of surface chemistry is important. Examples of technologies where drivers are strongest include healthcare (medical devices, tissue engineering, wound healing and diagnostics), personal care (fibres, biofilms and cosmetics), pharmaceuticals (drug delivery, patent protection, quality control), organic electronics (OLEDS, displays and photovoltaics), "ink-jet" printing (control of surface chemistry and wettability) and security (molecule identification, anti-counterfeit). For example, the relationships between the surface concentration, orientation, structure and activity of immobilised biomolecules on engineered surfaces play a crucial role in determining the performance of biomedical devices and assays. Therefore, there is an ongoing requirement to develop methods to detect, quantify and characterise biomolecules at surfaces. Previously, the opportunities and areas for action in nanotechnology have been identified in the Royal Society and Royal Academy of Engineering report "Nanoscience and nanotechnologies: opportunities and uncertainties". A key conclusion that was highlighted is the importance of metrology to underpin nanoscience and nanotechnology. This report specifically recommended the standardisation of measurement at the nanoscale through the National Measurement System portfolio of programmes. The 2010 BIS UK Nanotechnologies Strategy report highlights the Nanotechnology Research Strategy Group’s Research Priorities, including nanotechnology metrology and characterization, standardization and reference materials and the environment, health and safety aspects of nanotechnology, which are of rapidly growing importance, especially for nanoparticles. It is widely recognised by experts within the field that the toxicity of nanoparticles is influenced by a range of factors such as chemical composition, surface chemistry, shape, surface charge, aggregation and solubility. This makes generalisation about potential human health risks almost impossible and requires each material to be assessed individually, which can incur great expense (costs can be as high as £2M per material). Therefore, there is a major need to develop the metrology to characterise nanoparticle properties and support the development of robust, standardised in vitro screening tools to ensure that faster, cheaper and more reliable toxicology tests can be performed. The surface and nanoanalysis theme has a track record in responsiveness to change, for example playing a key role in supporting the standardisation in nanotechnologies. Strategic forward looks have identified key measurement gaps (see Fig. 2) that have allowed the NMS to take an international lead in important new metrology areas. An analysis of industry requirements shows clearly that there is an increasing need for chemical analysis in ambient

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conditions and the use of label-free, non-contact 3D techniques such as stimulated Raman spectroscopy. For example, new ambient mass spectrometries for surfaces have been developed (e.g. DESI) and are growing very rapidly. NPL and LGC have successfully collaborated to rapidly introduce metrology to support this growth.

Figure 1 A map of surface analytical techniques showing the chemical information provided and the spatial resolution.

Strategic Priority Interfacial Theme 6: Nanobiotechnology Nanobiotechnology encompasses the integration of biological molecules and systems with synthetic materials to create highly advanced and efficient functional devices. It includes many aspects of nanomedicine - the application of nanotechnology in healthcare - and is of major importance for new therapies and diagnostics for a healthy society. It has been identified as a major route to innovation and the achievement of step-changes in healthcare provision. Also included in this area are measurements to support safety assessment of nanotechnology products in general. The underlying measurement problem for nanobiotechnology is to understand the interaction between the biological and synthetic phases and to engineer this interaction to enhance or regulate the activity and specificity of the devices. Addressing the problem requires a multidisciplinary approach and therefore this is a crosscutting theme that relies upon the fundamental expertise developed within Theme 1 and Theme 5. For example, the surface and nanoanalysis theme has responded quickly to the challenging requirements in nanobiotechnology by providing strong unpinning support, especially for quantification, distribution, orientation and structure of biomolecules on surfaces.

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The key areas for focus here relate to the measurement of nanostructured materials to support their applications in nanomedicine, including their use as drug delivery vectors, contrast agents and in diagnostic devices. The measurement of biomolecule attachment, structure and activity at interfaces is also a primary aim. A further important, focus is to support toxicological studies of nanoparticles. Work will therefore develop key underpinning metrology to support: • The development of reliable leading-edge nanoparticle measurements, particularly

those identified by the cross-departmental Nanotechnology Strategy Forum (formerly the Research Strategy Group (NRSG))

• Accurate and reliable measurements of nanoparticle toxicity in biologically relevant in vitro and ex vivo systems

• The quantification, identification, structure and activity of biomolecules at planar and nanoparticle surfaces and live cell interfaces, from monolayers to single molecule measurements

• Measurements to underpin the designed self-assembly of functional nano-to-microscopic structures and devices

• Combining spectroscopy and imaging methods to measure and characterise nanostructures in dynamic cellular environments

• International leadership in the standardisation of nanobiotechnology measurements • Well characterised reference materials.

The Royal Society and Royal Academy of Engineering’s report ‘Nanoscience and Nanotechnologies: Opportunities and Uncertainties’ has been instrumental in informing government strategy and a specific section is devoted to bio-nanotechnology. The report pointed out that applications in the medical field will not emerge within the next ten years due to stringent regulatory requirements. The enormous potential of targeted drug and gene delivery were highlighted, along with the possibility of novel ‘nanoelectronic’ medical implants. The use of biomolecules as ‘bottom-up’ templates for the construction of devices was also highlighted. In recent years, the UK government has responded to the report through an ongoing funding of nanotechnology research via the research councils (~£50 million per annum) and the TSB. At this stage, there is no established ‘nanobiotechnology’ industry, but the potential benefits of major developments in this area cannot be ignored. The likelihood and rate of such developments will be enhanced by the development and validation of the necessary analytical tools. The characterisation of nanoparticle size, shape and chemistry for toxicological studies will be developed in conjunction with the Surface and Nanoanalysis strategic priority theme. Techniques to establish the concentration, identity, distribution, structure and activity of biomolecules on surfaces and nanoparticles will be developed and validated. These will include single molecule detection methods. It is expected that this work will lead to new insights into the methods that are currently used to attach biomolecules to surfaces. By understanding biomolecular interactions at a fundamental level, we will provide guidance on the design of nanobiotechnological systems. Within five years, we will be able to provide authoritative guidance on the attachment and measurement of composite systems utilised in nanobiotechnology.

5. Documentary Standards, Regulations and Directives The Programme will identify documentary standards, regulations and Directives, which depend upon measurements underpinned by the Programme. The Programme will provide

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advice on best measurement practice to those implementing these standards and regulations, and to those developing or creating new standards and regulations. The Programme will also ensure that the UK NMS meets the requirements of standards and regulations. 6. International Dimension Internationally priority is currently being given to similar strategic priority themes as presented above, largely because they are of global significance and increasingly require multi-disciplinary and collaborative approaches to gain significant step changes in scientific knowledge. As a result there is increasing coordination of research between the national measurement systems of different countries, particularly in Europe; with the aim to reduce duplication and increase cooperative measurement research. In Europe the main funding mechanism is that of the European Metrology Research Programme (EMRP) and the ongoing projects that relate to this Programme are: • Characterisation of energy gases; • Metrology for biofuels; • Metrology for ocean salinity and acidity; • Traceable quantitative surface chemical analysis for industrial applications; • Traceable measurements for monitoring critical pollutants under the “European Water

Framework Directive; • Chemical and optical characterisation of nanomaterials in biological systems; • Primary standards for challenging elements; • Novel mathematical and statistical approaches to uncertainty evaluation; • Metrology for the characterisation of biomolecular interfaces for diagnostic devices; • Metrology for Raman spectroscopy; • Traceable characterisation of nanostructured devices (TReND); • Metrology for chemical pollutants in air; and • Emerging requirements for measuring pollutants from automotive exhaust emissions.

Already completed projects relevant to this Programme have been: • Traceability of complex biomolecules and biomarkers in diagnostics effecting

measurement comparability in clinical medicine; • Metrology on a cellular scale for regenerative medicine; • Traceable measurements for biospecies and ion activity in clinical chemistry • Traceability of complex biomolecules and biomarkers in diagnostics;

Additionally the outputs of this Programme, particularly national measurement standards, are coordinated and recognised internationally and they are funded through the NMS programmes themselves. This involves participation the network of the following committees:

Committees supported by the ChemBio Programme Committee Working Groups Remit

AQUILA European committee of air quality experts - provides advice to the EC

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Committees supported by the ChemBio Programme Committee Working Groups Remit

ASTM ASTM E42, 01/03/04/06&07 AES/XPS/SPM/depth profiling documentary standards

ASTM ASTM D03-14 Gaseous fuels – hydrogen and fuel cells

ASTM F04 Surgical materials Tissue engineering

AVS AVS Board of Directors Overall responsibility for the society

AVS AVS BI Programme Committee Develops Biological Interfaces Science programme for AVS conference.

BIOPROCESS UK Biopharmaceutical Working Party

Validation of biopharmaceutical analytical methods

BIA Biotechnology Industries Association – Manufacturing advisory committee

Member

BMSS Main Committee & Education Committee

Promotes and supports the education and use of mass spectrometry

BSI CH/212 UK mirror group for CEN and ISO IVD work BSI EH2 - Air Quality - Main UK mirror for CEN Air quality work BSI EH/2/3 'Ambient Air UK mirror group for all European and

International ambient air standards BSI EH/2/4 UK mirror for European and international

emissions monitoring methods BSI LBI/016 Glass electrodes and the pH scale BSI PTI/015 UK mirror to CEN on gas analysis methods BSI CII 60 UK mirror group to ISO surface chemical

analysis BSI NT1 UK mirror group for ISO TC229 BSI PAS 84 & 86 Steering

Committees Advisory input to Publicly Available Specifications relating to cell-based therapeutics and glossary of terms

BSI RGM/1 (chair) Regenerative medicine committee

BSI RMI/1 Reference materials committee

BSI SS/6 Precision of test methods – proficiency testing

BSI SS/6/-/1 Precision of test methods revision of ISO 5725

BSI SS/6/-/3 Precision of test methods and measurement uncertainty

BSI MI/2 Bio-based products

BTC ETG Vehicle testing covering both particles and gases

BVC (British Vacuum Council)

British member society of IUVSTA

CAFÉ Steering group Air quality CCQM Main Committee Main metrology committee

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Committees supported by the ChemBio Programme Committee Working Groups Remit

CCQM Bioanalysis WG (chair) Bioanalysis metrology CCQM Gases WG (chair) Gas analysis metrology CCQM Inorganic Analysis WG (chair) Inorganic analysis metrology CCQM Organic Analysis WG Organic analysis metrology CCQM Surface Analysis WG Surface analysis metrology CCQM Key Comparison WG Oversees claims for comparability between

NMIs CCQM Microbial identity WG To establish metrological principles in

assigning microbial identity CCQM Microbial identity WG To establish metrological principles in

assigning microbial quantification CCQM Electrochemical Analysis WG Electrochemistry metrology CCQM/GAW VOC WG Joint CCQM GAW committee with focus on

measurement of VOCs in the atmosphere. CCQM Re-definition of the Mole WG

(Chair) Developing new definition for the mole

CCQM Strategic planning WG

CEN TC 264 Main Committee Air quality/emissions CEN TC 264 WG 9 Quality assurance of automated

measurement systems for stack emissions CEN TC 264 WG 11 & WG 5. Covers diffusive sampling

CEN TC 264 WG 15 (PM10 and PM2.5) Reference gravimetric measurement method for the determination of the PM2.5 mass fraction of suspended matter in ambient air.

CEN TC264 WG18 Emissions and ambient air monitoring using open path measurement techniques, including FTIR and other optical techniques

CEN TC264 WG20 Standard method for metals deposition

CEN TC264 WG21 Standard methods for B[a]P measurement and PAH deposition.

CEN TC264 WG22 – Type testing Type testing schemes for instrumentation CEN TC264 WG23 – Flow measurements Documentary standards CEN TC264 WG25 – Mercury Standard method for mercury measurement

in ambient air CEN TC 264 WG26 – Indoor air Measurement of emissions into indoor air CEN TC 264 WG34 – Anions and cations in

particulate matter Standard method for the measurement of anions and cations in particulate matter

CEN TC 264 WG35 OC/EC Standard method for the measurement of elemental carbon and organic carbon in particulate matter

CITAC Plenary European metrology committee CLSI (Clinical Laboratory Standards Institute)

Molecular Methods Area Committee

Identify the need for, prioritise, and manage the development of standards and guidelines that address molecular methods used in the clinical laboratory for screening for and diagnosis of infectious, malignant and inherited diseases.

CODEX CCMAS CODEX committee on methods of analysis and sampling

Inter-governmental committee on methods of analysis and sampling for food analysis

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Committees supported by the ChemBio Programme Committee Working Groups Remit

Defra NO2 measurement harmonisation EA Laboratory committee Laboratory accreditation issues

EA/Eurolab/ Eurachem

Proficiency testing WG PT in accreditation

ECASIA Steering committee International science committee for conference

EEEE/CEOC Chairs meeting (as Eurachem vice chair)

Accreditation policy

Eurachem Executive (vice-chair) European metrology committee

Eurachem Plenary WG chairs committee

Eurachem General Assembly European metrology committee

Eurachem Education and training WG Development of guidance

Eurachem Measurement uncertainty and traceability WG (Secretariat and drafting support)

Development of guidance

Eurachem Proficiency testing WG Development of guidance

Eurachem Qualitative analysis WG (chair)

EURAMET Plenary Main coordinating group for metrology in Europe

EURAMET Gases WG Covers gas analysis EURAMET Organic Analysis (chair) Covers organic analysis EURAMET Electrochemical Analysis Covers electrochemical analysis FIRMS Main Committee Promotes the use of standards and

measurement comparability in isotope ratio mass spectrometry

GAW Global Atmosphere Watch Joint WG on Gas Analysis ILAC Laboratory committee Stakeholder group ILAC Proficiency testing consultative

group PT in accreditation

IOM3 BMAD Special Interest Group representing materials engineers and related technical disciplines with interests across biomedical materials applications

ISO TC 69 SC4, 6 & 7 Precision of test methods and Standardisation of ISO 21748 using repeatability and reproducibility information for measurement uncertainty estimation

ISO TC 158 TC (plenary) Committee concerned with gas analysis ISO TC 158 WG3 Quality assurance for gas analysis ISO TC 158 WG4 Gravimetry for gas standards preparation/

analysis ISO TC 158 WG1 Vocabulary ISO TC 158 WG2 Quality and traceability ISO TC 158 WG5 Strategy ISO TC 193 TC (plenary) Natural gas

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Committees supported by the ChemBio Programme Committee Working Groups Remit

ISO TC 193 WG 14

Analytical requirements for hydrocarbon content/dewpoint calculation

ISO TC 193 WG 15 Uncertainty calculation ISO TC 193 New WG Analysis of natural gas by micro-GC (and

similar multi-channel instruments) ISO TC 193 WGs 17 & 18 Other natural gas methods ISO TC 197 WG12 Hydrogen fuel specification for PEM fuel cell

applications for road vehicles ISO TC 197 WG14 Hydrogen fuel specification for other PEM)fuel

cell applications ISO TC 201 Plenary Main TC for surface chemical analysis ISO TC 201 SC1 Oversight committee for all SC1 WGs ISO TC 201 SC1 WG2 (chair) Terminology ISO TC 201 SC 2 WGs 1, 2 & 3 Specimen handling ISO TC 201 SC3 WGs 1(chair), 2 & 4 Data management and treatment ISO TC 201 SC4 WGs 1 & 2 Depth profiling ISO TC 201 SC5 WGs 1, 2 & 3 Auger electron spectroscopy ISO TC 201 SC6 WGs 1, 2, 3 & 4

(Convener) Standards for static SIMS

ISO TC 201 SC7 WGs 1, 2(chair) & 3 Standards for XPS ISO TC 201 SC9 WGs 1,2,3,4, 5 (convenor),

6 Scanning probe microscopy

ISO TC 229 WG2 Measurement standards for nanotechnology ISO REMCO WG (chair) IUPAC pH sub committee International definition of pH and standard

methods IUPAC/CODEX/ EURACHEM

Interagency meeting Harmonisation of measurement practices in food analysis

JCTLM Main WG I & II Committees – Reference materials and reference methods

Expert international committee (IFCC, ILAC, BIPM) formed to facilitate the implementation by industry and clinicians of traceability to higher order RMs and measurements as driven by the EU in vitro diagnostics directive

JCTLM WGI Nucleic Acids Review Team (chair)

Provide expert opinion on quality criteria for nucleic acid RMs and methods. Review nominations of nucleic acid RMs for JCTLM database

LBMSDG Regional discussion group Biological mass spectrometry methodology and approaches

OECD Working Party Guidance on Sample Preparation and Dosimetry for the Testing of Nanomaterials

Development of analytical methods and testing guidelines for nanomaterials

OECD Technical committee for alternative testing of engineered nanoparticles

Alternative testing for engineered nanoparticle toxicity testing

NRSF Nanotechnology Research Strategy Group - directing UK nanotechnology research

PASG Pharmaceutical Analytical Science Group - Biopharmaceutical Working Party

Validation of biopharmaceutical analytical methods

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Committees supported by the ChemBio Programme Committee Working Groups Remit

RSC AAMG A mechanism for arranging or providing input to meetings and conferences, such as Particles in Europe and the Annual meetings in London.

RSC Analytical Methods Committee – Main, and 4 SCs (3 as chair)

The highest profile UK analytical chemistry committee; sampling, mass spectrometry, validation, and pesticides

RSC Atomic spectroscopy group Support and networking for scientists and researchers in the field

RSC Biomaterials chemistry group Special Interest Group to enhance the understanding of chemistries underlying biomaterials applications

RSC Electrochemical analysis and sensing systems group

Special interest RSC group to promote the study and application of Electroanalytical Chemistry

RSS Royal Statistical Society Business and Industry Section committee

Statistics for business and industrial applications

STA Quality and Technical Task Group

Emissions monitoring

STA Laboratory analysis group Covers laboratory based analytical measurements required for stationary source testing

SEMI Gas purity WG Gas purity for the semiconductor industry Society of Chemistry and Industry (SCI)

Electrochemical Group Electrochemistry

UK PT WG Proficiency testing forum UK RMWG Reference Materials WG UKSAF UK surface analysis group VAMAS TWA 2 Surface chemical analysis

7. Support for SI This Programme is concerned with the realisation and maintenance of measurements and standards for the determination of the quantity of matter, for which the mole is the SI unit. In addition, the programme maintains and develops the UK’s primary measurement capability for pH. The Programme will provide the UK with traceability to these units through calibration and measurement services. Where appropriate these services will be offered for international review under the requirements of the CIPM Mutual Recognition Agreement, the Calibration and Measurement Capability (CMC) recorded in the BIPM MRA Database, and the higher-order reference materials, measurement methods/procedures and services recorded in the JCTLM database. Establishment of traceability of measurements is a key goal of the NMS and for the long-term sustainability of the measurement system, traceability to the SI is desirable – although this is not always easy to achieve. High-level traceability is central to the NMS strategy and should continue to be supported, since it represents a foundation stone of international (bio)metrology.

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8. Resources and Competences The theme roadmaps indicate the likely shift in focus over time for all theme areas and are currently under review. The Knowledge Base Programmes will become proportionally smaller to accommodate the formation of the Strategic Capability Programme and this will necessarily stimulate a review of the current resources in order to ensure alignment for maximum impact delivery. A watching brief on potentially competitive technologies will also be maintained. 9. Impact The outputs of the Programme are of six main types. These are listed in the table below, with a description of the main exploitation routes. Output type Exploitation Route Take-up target per annum Measurement standards Measurement service Revenue Measurement best practice, skills

Best practice guides; books; training tools Documentary standards Training courses Studentships Consultancies and secondments) Helpdesk enquiries

Downloads; Number distributed Number Number trainees Number Financial value; Number Nature; Number

Intellectual Property Patenting and licensing Number New science Publication Number New UK capability R&D and consultancy

contracts from third parties Revenue

Network developed Clubs; dissemination & formulation events

Number attendees

The NMS have introduced a Value Scorecard – an approach to demonstrate progress toward achieving impact – across the NMS Programme portfolio. It combines the strategic perspectives used in a traditional balanced scorecard approach with key stakeholder perspectives of value. Using a core set of measures to provide consistent reporting combined with tailored narrative and case studies to address more immediate drivers, the Value Scorecard provides a way of actively monitoring impact. Targets are now to be set for the achievement of impact by individual Programmes. In addition, case studies will be prepared to provide examples of how the take-up of outputs from the Programme is delivering impact.

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10. Alignment with Other NMS Programmes and Wider Government Priorities 10.1 Knowledge Base Programmes

There are five Knowledge Base Programmes in the NMS and they are designed to be the NMS Programmes closest to uptake by a wide range of stakeholders in the UK and to provide the shortest time to economic impact. They develop and maintain the UK’s measurement infrastructure, providing traceability to SI and organised science disciplines. Knowledge Base Programmes influence sectors such that more than one Programme can impact a given sector. For instance, several Knowledge Base Programmes within the NMS portfolio have found applications within the life sciences community:

• Acoustics and Ionising Radiation Programme and the TQEM (Time, quantum and electromagnetics) Programme – work relating to the safety of medical imaging and therapy, i.e. underpinning dosimetry for ultrasound, ionising radiation and ultra-violet radiation;

• Engineering and flow Programme – work relating to biophotonics that includes work on terahertz (THz) and optical coherence tomography (OCT) imaging techniques; and

• Materials and Modelling Programme – work supporting the area of plastic electronics and characterisation of surfaces.

Additionally Knowledge Base Programmes may also work together to achieve sector impact, for instance the ChemBio Programme directly supports the energy sector by working with:

• Engineering and Flow Programme to provide gas purity measurements for critical applications such as the Boltzmann constant, and works with the;

• Materials and Modelling Programme to provide gas purity measurements for fuel cell research; and more widely

• Acoustics and Ionising Radiation Programme by providing chemical amount content measurements when radiochemical measurements are too insensitive.

10.2 Interaction of Knowledge Base Programmes with Programmes of mid-long term view

The Knowledge Base Programmes will also take forward the measurement expertise and capability developed in the longer term Innovation R&D Programme where appropriate to ensure uptake by stakeholders. Currently, the expertise held within the ChemBio Programme is supporting research across all the Innovation R&D Themes (health and biotechnology, security, ICT and transport, energy and the environment) and will logically be expected to integrate the Innovation R&D outputs into the ChemBio Programme where relevant. Current projects expected to integrate into the ChemBio Programme are around support for emissions trading, chemical pollutants in air, thin-film manufacturing, bioprocess engineering for advanced therapy products, microarray technology for point of care diagnostics, surface analysis for plastic electronics and gas purity for fuel cell applications. The Programme will also work with the new Strategic Capability Programme to bring new capability, technology and expertise developed by this Programme into the ChemBio Programme as they are required to meet new user needs. 10.3 Role of Knowledge base Programmes with wider Government priorities

The technical aspects of government strategies, particularly the Technology Strategy Board’s key technology areas, will be regularly reviewed to identify where there is the requirement for the development of, or access to, the NMS Knowledge Base provided by

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this Programme. Currently the following technology priorities have been identified for the Programme:

Table 1 Current mapping of programme themes on to Technology Strategy Board Key Technology Areas 11. Formulation The requirements for the future development of the Programme will be captured continuously as those delivering the Programme meet with stakeholders. In addition, focused studies will be carried out to research technological, market or policy developments that are expected to impact on the priorities of the Programme in the future. The Programme Advisory Working Group will provide advice and help in prioritising the requirements identified by the continuous consultation and review progress of the Programme, and updating the Programme strategy and roadmap(s) as necessary. Annually, new areas of work will be prepared for the Programme as uncommitted budget becomes available. The work will be prioritised against the main strategic priority themes. 12. Conclusions The Chemical and Biological Metrology Programme is a programme that delivers high impact in both:

• Innovation in key, high added value manufacturing sectors such as biotechnology, pharmaceuticals, medical devices, plastic electronics and alternative fuels where the UK has a significant share of the global marketplace;

• Quality of life issues such as human health, food safety, climate change and its mitigation, protection of the environment, detection and prevention of security threats and nanoparticle safety.

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The major objective of the programme is to ensure valid and traceable analytical measurements in the UK and to establish the equivalence of analytical measurements with our trading partners. The programme also represents UK interests in a vast array of different national and international committees ensuring that the UK’s competitive position is enhanced by the development of appropriate standards and regulations.

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Annex 1: Top-Level Programme Roadmap Overview

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Annex 2: Programme Balance

Annex 3 Programme Roadmaps The technical capability required for delivery of the aims of the Programme, and the requirements for its future development, are set out in the following roadmaps. These need to be seen as indicative because of the nature of scientific research progress and the ‘nonlinear’ development of associated knowledge. As a result the roadmaps are only a reliable predictor of the best route to a set target if they are regularly reviewed. Following the development of new programme roadmaps, a web page for the new NMS roadmaps has been established that allows the interactivity of the new format to be explored. The address is http://interactive.npl.co.uk/roadmaps/ (this currently only opens with full functionality in internet explorer). The webpage is password protected as the roadmaps are still undergoing development but the username and password are: Username: nms Password: ro@dmap5 PDF files of the new format are enclosed here along with those in the old style format that were not ready for inclusion at this time.

Figure 3 The pie chart shows the relative proportions of effort between the strategic measurement themes of the Chemical and Biological Metrology Programme as at June 2013.

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INSERT roadmap PDFs in A3 for: • biotechnology • surface analysis • speciation • Gas analysis, • particles and trace, • environmental technologies

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2010 2013 2016

Deliverables

Enabling Science

ChemBio Programme: Theme Roadmap – Organic

Technologies

Targets

Drivers or Challenges

Food SafetyDiagnosticsForensics

Drug Discovery Sustainability

Biopharmaceuticals Environment

single cell characterisation

early diagnosis

reference value assignments

synthetic & non-synthetic labels

pure standards

accurate characterisation/i.d.

stable isotope tracing

single cell mass spectrometry

labelling strategies

metabolomics

separation strategies

purity determination

advanced mass spectrometry platforms

multivariate isotope ratio analysis

matrix certified RMs

isotope dilution MS (IDMS)

supporting UK policing & security agenda

meeting UK policy to build a strong bioscience sector

improved healthcare

improved environmental (WFD) & food safety

bio-agent strategies

BioterrorismConsumer Safety

improved consumer protection (ROSH, WEEE)

measurement uncertainty

MS imaging

enhanced MS i.d.

biomarker i.d.

screening

process control

biofuels

2010 2013 2016

Deliverables

Enabling Science

ChemBio Programme: Theme Roadmap – Inorganic

Technologies

Targets

Drivers or Challenges

Food SafetyDiagnosticsForensics

Drug DiscoverySustainabilityEnvironment

reference value assignments

synthetic & non-synthetic labels

pure standards

accurate characterisation/i.d. stable isotope tracing

labelling strategies separation strategies

purity determination

advanced mass spectrometry platforms

multivariate isotope ratio analysis

matrix certified RMs

isotope dilution MS (IDMS)

supporting UK policing & security agenda

meeting UK policy to build a strong bioscience sector

improved healthcare

improved environmental (WFD) & food safety

bio-agent strategies

BioterrorismConsumer Safety

improved consumer protection (ROSH, WEEE)

measurement uncertainty

enhanced MS i.d.

screening

counterfeit detection

IRMS human provenance

nanoparticle risk profilingbiofuels metal mapping

elemental fingerprinting

spatial mapping

laser ablation

early diagnosis

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The National Measurement System is the UK’s national infrastructure of measurement Laboratories, which deliver world-class measurement science and technology through four National Measurement Institutes (NMIs): LGC, NPL the National Physical Laboratory, TUV NEL The former National Engineering Laboratory, and the National Measurement Office (NMO).

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