This diplomathesis work is dealing with a concept of volumetric calibration of vessels using the volumetric method. The analysis considers current regulations together with influence of uncertainties in measurements. The principal part of the thesis is analysis of metrological uncertainties resulting from application of various volumetric methods during the calibration process. A practical outcome from this research is development of metrological process for calibration of vessels that could be used by the accredited laboratories.

Doctor of Philosophy / Department of Physics / Kristan L. Corwin / Optical frequency references have been widely used in applications such as navigation, remote sensing, and telecommunication industry. For stable frequency references in the near-infrared (NIR), lasers can be locked to narrow absorption features in gases such as acetylene. Currently, most Near NIR references are realized in free space setups. In this thesis, a low-loss hollow-core optical fiber with a diameter of sub millimeters is integrated into the reference setup to provide long interaction lengths between the filling gas and the laser field, also facilitate the optical interaction with low power levels. To make portable NIR reference, gas can be sealed inside the hollow-core fiber, by creating a photonic microcell. This work has demonstrated all-fiber optical frequency references in the Near IR by fabricating and integrating gas sealed photonic microcells in the reference setup. Also, a thoughtful study regarding the lineshape of the fiber-based reference has been accomplished. According the proper modeling of a shift due to lineshape, a correction was applied to our previous absolute frequency measurement of an NIR optical frequency reference. Furthermore, effects of the hollow-core fibers, including mode-dependence frequency shift related to surface modes are explored. In addition, angle splicing techniques, which will improve the performance of the fiber-based frequency reference have been created. Low transmission and return loss angle splices of photonic bandgap fiber, single mode PCF, and large core kagome to SMF-28 are developed and those fibers are demonstrated to be promising for photonic microcell based optical frequency references. Finally, a potentially portable optical metrology system is demonstrated by stabilizing a fiber-laser based frequency comb to an acetylene-filled optical fiber frequency reference. Further work is necessary to fabricate an all-fiber portable optical metrology system with high optical transmission and low molecular contamination.

Os Programas Interlaboratoriais (PIs) de proficiência são parte integrante do processo de obtenção de confiabilidade metrológica para medições e resultados analíticos gerados em laboratórios, ambientes de prática da atividade metrológica. Entre as diretrizes estratégicas do Comitê Brasileiro de Metrologia (CBM) estão incentivar a implantação de PIs que permitam aos laboratórios verificar e demonstrar a confiabilidade de seus resultados e acreditar provedores de PIs. O Instituto de Pesquisas Tecnológicas do Estado de São Paulo IPT, órgão subordinado à Secretaria de Desenvolvimento do Estado de São Paulo, apesar de ter sido um dos pioneiros na oferta de PIs, não é atualmente um grande provedor. O objetivo desta pesquisa é propor um modelo de estrutura organizacional de provedor de Programas Interlaboratoriais (PIs), aplicado ao Instituto de Pesquisas Tecnológicas do Estado de São Paulo IPT. O desenvolvimento deste modelo se apoia em revisão teórica, em estratégias advindas da análise SWOT do estudo de dez programas interlaboratoriais oferecidos pelo IPT no período de 2000 a 2009, em fatores condicionantes do IPT, em políticas governamentais atuais, em modelos de estrutura existentes no mercado e em componentes principais de uma estrutura organizacional. O modelo proposto, constituído de dois núcleos principais, o de Coordenação dos Provedores de PIs (COPPI) e o de Gerentes de PIs (GEPI), apresenta os elementos necessários para elevar o IPT à condição de provedor de PIs que atenda, de modo sustentável, às demandas governamentais e de setores produtivos. / The Proficiency Interlaboratory Programs (IPs) are part of the process to obtain metrological reliability for measurements and analytical results generated in laboratories, practice settings of metrological activity. Among the strategical directives of the Brazilian Metrology Committee (BMC) are the accreditation of brazilian IPs providers and the encouragement to establish IPs that allow the laboratories to assess and demonstrate the reliability of the datas they are producing. The Institute for Technological Research of the State of São Paulo IPT, body reporting to the Development Secretary of the State of São Paulo, in spite of being one of the pioneers in offering IPs, is not currently a major provider. The objective of this research was to propose, to the Institute for Technological Research of São Paulo State- IPT, a model of organizational structure for Interlaboratory Programs (IPs). The development of this model was based on the theoretical platform constructed, on strategies resulted from the SWOT analysis of ten Interlaboratory Programs offered by IPT in the period 2000 to 2009, on the IPT conditioning factors, on existing government policies, on models presented on the market and on major components of organizational structure. The proposed model, with two main cores, the IPs Providers Coordination (COPPI) and the IPs Mangers (GEPI), has the necessary elements to raise IPT to the status of a great provider, that fulfills, in sustainable way the demands from governments and productive sectors.

Os Programas Interlaboratoriais (PIs) de proficiência são parte integrante do processo de obtenção de confiabilidade metrológica para medições e resultados analíticos gerados em laboratórios, ambientes de prática da atividade metrológica. Entre as diretrizes estratégicas do Comitê Brasileiro de Metrologia (CBM) estão incentivar a implantação de PIs que permitam aos laboratórios verificar e demonstrar a confiabilidade de seus resultados e acreditar provedores de PIs. O Instituto de Pesquisas Tecnológicas do Estado de São Paulo IPT, órgão subordinado à Secretaria de Desenvolvimento do Estado de São Paulo, apesar de ter sido um dos pioneiros na oferta de PIs, não é atualmente um grande provedor. O objetivo desta pesquisa é propor um modelo de estrutura organizacional de provedor de Programas Interlaboratoriais (PIs), aplicado ao Instituto de Pesquisas Tecnológicas do Estado de São Paulo IPT. O desenvolvimento deste modelo se apoia em revisão teórica, em estratégias advindas da análise SWOT do estudo de dez programas interlaboratoriais oferecidos pelo IPT no período de 2000 a 2009, em fatores condicionantes do IPT, em políticas governamentais atuais, em modelos de estrutura existentes no mercado e em componentes principais de uma estrutura organizacional. O modelo proposto, constituído de dois núcleos principais, o de Coordenação dos Provedores de PIs (COPPI) e o de Gerentes de PIs (GEPI), apresenta os elementos necessários para elevar o IPT à condição de provedor de PIs que atenda, de modo sustentável, às demandas governamentais e de setores produtivos. / The Proficiency Interlaboratory Programs (IPs) are part of the process to obtain metrological reliability for measurements and analytical results generated in laboratories, practice settings of metrological activity. Among the strategical directives of the Brazilian Metrology Committee (BMC) are the accreditation of brazilian IPs providers and the encouragement to establish IPs that allow the laboratories to assess and demonstrate the reliability of the datas they are producing. The Institute for Technological Research of the State of São Paulo IPT, body reporting to the Development Secretary of the State of São Paulo, in spite of being one of the pioneers in offering IPs, is not currently a major provider. The objective of this research was to propose, to the Institute for Technological Research of São Paulo State- IPT, a model of organizational structure for Interlaboratory Programs (IPs). The development of this model was based on the theoretical platform constructed, on strategies resulted from the SWOT analysis of ten Interlaboratory Programs offered by IPT in the period 2000 to 2009, on the IPT conditioning factors, on existing government policies, on models presented on the market and on major components of organizational structure. The proposed model, with two main cores, the IPs Providers Coordination (COPPI) and the IPs Mangers (GEPI), has the necessary elements to raise IPT to the status of a great provider, that fulfills, in sustainable way the demands from governments and productive sectors.

[pt] A confiabilidade dos resultados das medições é garantida por meio da rastreabilidade às unidades do Sistema Internacional de Unidades (SI). A cadeia de rastreabilidade dos padrões metrológicos dos diversos laboratórios de cada país é implantada, mantida e referenciada aos padrões internacionais pelos Institutos Nacionais de Metrologia (INM). No Brasil, apesar de uma demanda crescente originária de diversos setores (regulatório, industrial, serviços, etc.), a rastreabilidade de grandezas magnéticas não foi implantada. No presente trabalho é realizado levantamento da demanda nacional por rastreabilidade metrológica de grandezas magnéticas e caracterizadas as competências, iniciativas e infraestrutura nacionais já disponíveis. As iniciativas para realização das unidades SI de grandezas magnéticas já em implantação no INM apresentam a abrangência necessária ao atendimento das demandas regulatórias recentemente estabelecidas no país, mas não são suficientes para atender às faixas de intensidade e de frequência de densidade de fluxo magnético correspondentes às demandas identificadas nos setores da indústria e de pesquisa e desenvolvimento. / [en] The traceability to the International System of Units (SI) guarantees the reliability of measurement results. For each country, the metrological traceability chain to an international measurement standard is supported by the National Metrological Institute (NMI). Despite a growing demand from various sectors (regulatory, industrial, services, etc.), the traceability of magnetic quantities has not been implemented in Brazil. In the present work, the national demand for metrological traceability of magnetic measurement results is investigated; and the potential infrastructure and competencies already available are characterized. The measurement infrastructure presently being built for realization of the SI unit of magnetic flux density enables compliance to the regulatory requirements recently established, but it is not sufficient for the range of magnitudes and frequencies of this quantity that have been identified in other sectors, like Industry and Research e Development .

Este trabalho tem como objetivo fazer uma análise do desempenho dos Laboratórios de Massa da Força Aérea Brasileira (FAB), no processo de calibração de massa absoluta, para atender aos princípios da ABNT NBR ISO/IEC 17025:2005 Requisitos Gerais para a Competência de Laboratórios de Ensaio e Calibração, documento elaborado especificamente para laboratórios de ensaio e de calibração que necessitem comprovar sua competência a organismos acreditadores. Laboratórios pertencentes à FAB, ao INMETRO e a empresas prestadoras de serviços de calibração, foram responsáveis pelo fornecimento de informações a respeito das calibrações, nas quais foram utilizadas massas de 500 mg, 100 g e 1 kg. Para avaliar os desempenhos dos laboratórios foi utilizado o critério de Erro Normalizado. Nos laboratórios da FAB foram utilizados ainda os testes de Cochran e Grubbs, os quais são utilizados tradicionalmente em ensaios químicos. Sua utilização para avaliação de laboratórios de calibração, como verificado neste trabalho, mostra que informações relevantes são obtidas neste caso em que os laboratórios possuem o mesmo nível hierárquico metrológico. Mediante a análise dos dados obtidos, foi possível identificar os laboratórios de calibração que, devido a algumas não-conformidades no processo metrológico, apresentaram desempenho considerado insatisfatório sob uma análise conjunta das ferramentas supracitadas. A esses participantes foram propostas algumas ações de melhoria, a qual, espera-se, que contribuam para o aprimoramento de suas competências metrológicas. / This study aims to analyze the performance of Brazilian Air Force (FAB) mass laboratories, in the process of calibration of absolute mass, according to the principles of NBR ISO / IEC 17025:2005 General Requirements for the Competence of Testing and Calibration Laboratories, a document prepared specifically for testing and calibration laboratories, who need to prove their competence to accredited bodies. Laboratories belonging to the FAB, INMETRO and companies that provide calibration services were responsible for providing information about the calibration of masses of 500 mg, 100 g and 1 kg. To evaluate the performance of the laboratories the criterion of Normalized Error was used. In the laboratories of FAB, were still used Cochrans tests and Grubbs, which are used traditionally in chemical tests. Their use for evaluation of calibration laboratories, as verified in this study, shows that relevant information are obtained in this case where laboratories possess the same metrological hierarchical level. By the analysis of the obtained data, it was possible to identify the calibration laboratories that, due to some no-conformities in the metrological process, presented unsatisfactory performance under a joint analysis of the mentioned tools. Some improvement actions were proposed to these participants. It is expected that these actions contribute for the improvement of their metrological competences.

Les microscopes en champ proche sont très largement utilisés pour caractériser des propriétés physiques à l’échelle du nanomètre. Afin d’assurer la cohérence et l’exactitude des mesures dimensionnelles qu’ils retournent, ces microscopes ont besoin d’être étalonnés périodiquement. Le raccordement à la définition du mètre SI est assuré par le biais d’étalons de transfert dont les caractéristiques dimensionnelles sont étalonnées à l’aide d’un Microscope à Force Atomique métrologique (mAFM).Les travaux de thèse portent sur la contribution à la mise en place du Microscope à Force Atomique métrologique du LNE dans le but de caractériser et réduire l’incertitude de mesure. Une tête AFM passive thermiquement et spécifiquement conçue pour des applications de nanométrologie dimensionnelle a été développée et intégrée au mAFM. Elle comporte un système original pour mesurer les déflexions du levier nécessaire à la détection des forces s’exerçant à l’extrémité de la pointe. Il utilise une évolution de la méthode du levier optique qui permet de déporter les sources de chaleurs à l’extérieur de l’instrument. Pour cela, un nouveau capteur a été développé. Il est basé sur l’utilisation d’un bundle composé de 40 000 microfibres optiques structurées en quatre quadrants. Il remplace avantageusement une photodiode quatre quadrants et permet de transporter le signal lumineux jusqu’à des photodiodes placées à l’extérieur de l’instrument. Ce système a été modélisé, caractérisé et validé expérimentalement. La tête AFM ainsi développée est passive thermiquement. Sa conception repose sur la dissociation complète de la chaine métrologique, constituée en Zerodur, afin de lui conférer une excellente stabilité thermique et mécanique. Pour les mêmes raisons, le châssis de la tête qui supporte l’ensemble des composants et notamment le système de mesure des déflexions du levier est entièrement conçu en Invar. Cette tête repose sur une structure motorisée constituée de trois moteurs à reptation permettant l’approche de pointe mais également le réglage des interféromètres. Après intégration de la tête dans le mAFM, l’ensemble de l’instrument a été caractérisé afin d’établir son bilan d’incertitude. Plusieurs composantes ont ainsi été évaluées expérimentalement comme la non-linéarité et la stabilité de la mesure de position par interférométrie, les rotations parasites du scanner, les erreurs d’Abbe, les défauts de rugosité et de planéité des miroirs ainsi que les erreurs de bras mort. L’impact de chaque composante a été quantifié et listé dans le bilan d’incertitude. Ces travaux ont permis d’avoir une première estimation de l’incertitude de mesure du mAFM. / Scanning probe microscopes are very well used for characterization at the manometer scale. To ensure the measurement coherency and the accuracy of the results, those microscopes need to be periodically calibrated. It’s done thanks to reference standards whose dimensional characteristics are measured by a metrological atomic force microscope (mAFM) for example.The aim of this thesis work is the improvement of the metrological AFM of the LNE in order to reduce the measurement uncertainty. To reach this goal, a thermally passive AFM head has been developed and integrated on the instrument. It contains an original system to measure the cantilever deflexion and thus detect the force acting between the sample and the tip. This system is based on the optical beam deflection method but allow deporting the heat sources outside the instrument. To reach this goal, a new specific sensor has been developed. It is based on a four quadrant optic fibre bundle that contains 40 000 micro-fibre and which is ideal to replace the existing four quadrant photodiode and its conditioning electronic circuit with the bundle and its conditioning electronic circuit placed outside the instrument. This sensor has been modelled, and experimentally validated.The Developed AFM head which integrates the deflection measurement system is then thermally passive. Its design is based on the complete dissociation of the metrological loop and the structural loop. The metrological loop is made of Zerodur® in other to acquire an excellent mechanical and thermal stability and thus reduce the thermal dilatation. For the same reason, the AFM head support frame is fully made of Invar. The AFM head is placed on a motorized frame based on three piezo-leg motors (tripod) to make the tip/sample approach but also to set the interferometer signal quality. The interferometer signal is improved by combining the linear displacements of the three motors to generate small rotations. This allows setting the parallelism of the mirrors linked to the head with those linked to the translation stage.Once the AFM head integrated on the instrument, the assembly is characterized in order to establish the uncertainty budget. Different uncertainty components have been experimentally evaluated as for example: the interferometer non linearity, the drift of the XYZ position, the parasitic rotations of the translation stage, the Abbe error, the roughness and the flatness of the mirrors and the dead path errors. The impact of the each component has been quantified and listed in the uncertainty budget. This allowed getting a first estimation of the combined uncertainty of the instrument.

[pt] Líquidos criogênicos são amplamente empregados em diversos segmentos da atuação humana, destacando-se a Medicina, Engenharia Genética, setor industrial e no desenvolvimento cientifico. Sendo assim, efetuar o controle metrológico sobre os dispositivos e sistemas utilizados na comercialização de tais materiais é fundamental. Nesta dissertação propomos a implementação do controle metrológico neste segmento como forma de estabelecer confiabilidade e garantir trocas cada vez mais justas, sem prejuízos as partes envolvidas. Para tal, a estrutura legal é amparada pela regulamentação vigente no âmbito brasileiro, a qual é abordada e confrontada com as diretrizes internacionais. Os diferentes sistemas de medição atualmente adotados são abordados, com o intuito de julgar a adequação dos mesmos e estabelecer requisitos mínimos. Diante da inexistência de uma regulamentação ampla, capaz de agregar aspectos não só inerentes às boas práticas, mas que contemplem a realidade do mercado nacional, são estabelecidas proposições e diretrizes a serem seguidas na implementação e efetivação do controle metrológico. / [en] Cryogenic liquids are widely employed in several fields of human activity,such as in Medicine, Genetics Engineering, the industrial sector and for the scientific development. This way, applying the metrological controls in devices and systems used for the commercialization of cryogenic liquids is essential. In this dissertation we proposed the implementation of the metrological controls in this area, objectifying to establish the reliability and the guarantee of fair trade,without damages for the involved parts. Thus, the legal structure is supported by the valid regulamentation in the Brazilian case, that is mentioned and faced against international policies. The different measurement systems adopted nowadays are approached, for judging their adequacy and establishing minimum requests. Considering that there is not a broad regulamentaion, capable of aggregate aspects of the good practice and to heed the national reality, proposals and guidelines are presented for reaching the implementation of effective metrological controls.

En raison du vieillissement de la population, la maladie d’Alzheimer (MA) est devenue un problème majeur en santé public. Le dosage des biomarqueurs présents dans le liquide céphalorachidien (Ab 1-42, tau et hepcidine) étant de bons indicateurs précoces de l’apparition et de l’évolution de la MA, il paraît essentiel de disposer de mesures fiables. Etablir la traçabilité métrologique des résultats aux unités du système international par le biais de méthodes de référence primaires ou de matériaux de référence certifiés d’ordre supérieur est un moyen privilégié pour évaluer et améliorer la fiabilité et la comparabilité des résultats dans le temps et entre les laboratoires. Des méthodes de dosages par LC-MS/MS pour ces trois biomarqueurs ont été développées et validées. Pour le dosage de l’hepcidine, la pureté de l’étalon peptidique a fait l’objet d’une caractérisation approfondie par spectrométrie de masse haute résolution qui permettra de standardiser les dosages de routine à l’échelle internationale.Mots clés : Peptides b amyloïdes, Protéine tau, Hepcidine, Biomarqueurs, Protéomique Clinique, Traçabilité métrologique, Spectrométrie de masse / Due to the aging of population, Alzheimer’s disease (AD), is becoming a major public health concern. Measurement of biomarkers (Amyloid Beta, tau and hepcidin) in cerebrospinal fluid being early diagnostic indicators of AD, reliable measurements are needed to detect and quantify them accurately. Establishing metrological traceability of results to the International System of Units through primary reference methods or higher-order certified reference materials is a privileged mean to assess and improve results accuracy and comparability across laboratories. Assays for these three biomarkers were set up and validated by LC-MS/MS. The hepcidin standard was further characterized by high resolution mass spectrometry, paving the road toward standardization at the international scale of results.Key words : b amyloids peptides, Tau protein, Hepcidin, Biomarkers, Clinical proteomic, Metrological traceability, Mass spectrometry

[pt] Contribuindo para o desenvolvimento da confiabilidade metrológica, a presente dissertação de mestrado propõe um modelo integrado de gestão dos padrões metrológicos de referência utilizados na fabricação de medicamentos. Em sintonia às práticas laboratoriais e normas internacionais, o modelo proposto também incorpora o monitoramento de desempenho desses padrões e de instrumentos de processo utilizado entre calibrações sucessivas. O trabalho respalda-se em pesquisa relacionada às práticas correntes de gestão laboratorial conduzida junto a tradicionais laboratórios de calibração de instrumentos de processo da indústria farmacêutica. No contexto de distintas vertentes de análise, o modelo proposto incorpora os seguintes atributos considerados essenciais (i) gestão de padrões metrológicos; (ii) avaliação da relevância da instrumentação de processo para a qualidade; (iii) gestão para tratamento de não- conformidades; (iv) gestão da freqüência de calibração dos instrumentos de processo; (v) gestão da calibração na fabricação e (vi) gestão da calibração na validação de processos críticos de fabricação de medicamentos. A referida pesquisa realizada junto a esse setor de fabricação de medicamentos envolveu 36 laboratórios selecionados dentre aqueles com comprovada experiência e tradição no setor, localizados nos Estados do Rio de Janeiro e de São Paulo, pólo industrial onde se concentram expressiva produção nacional de medicamentos (cerca de 70%). Cada uma das linhas de análise relacionadas aos seis atributos de gestão laboratorial acima mencionados fundamenta-se nos critérios de avaliação: qualidade, produtividade e confiabilidade metrológica. / [en] The development of metrological reliability has received in recent years increasingly attention from metrologists. Confidence in measurements is a prerequisite in the manufacturing of pharmaceutical products The present Master`s Dissertation formulates an integrated managerial model for dealing with metrological reference measuring standards (étalons) used in the pharmaceutical sector. In full compliance with international standards and best laboratory practices, the proposed model incorporates the monitoring of performance of standards and instruments used during two successive calibrations. The work is based on a search related to the best current laboratorial practices developed in connection with laboratorial management in their relation with traditional calibration labs of process instruments operating in the pharmaceutical industry. In this context, the proposed model incorporates the following lines of analysis considered as essential ingredients in the proposed metrological reliability approach: (i) management of metrological standards; (ii) evaluation of the relevance of the process instrumentation for quality control; (iii) management for non-conformity treatment; (iv) management of the frequency of calibration of the process instruments; (v) management of the calibration in the manufacturing process and (vi) management of the calibration in the validation of the critical processes of the pharmaceutical industry. 36 among the most traditional pharmaceutical labs located in the states of Rio de Janeiro and São Paulo - responsible for nearly 70% of all pharmaceutical products in the country - were selected for the survey. For the sake of metrological analyses, each one of the 6 requisites listed above, was based on assessment criteria which included quality, productivity and metrological reliability.