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See detailModèles statistiques Bayésiens et méthodologies pour calculer le Design Space (OPTIMAL-DS)
Marini Djang'Eing'A, Roland ULg; Lebrun, Pierre ULg; Hubert, Philippe ULg

Report (2009)

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de ... [more ▼]

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de conduites initiées par la FDA ou d'autres organismes de contrôles. Notamment, le document ICH Q8 introduit les notions de "Process Analytical Technology", de "Quality by Design" et de "Design Space", ayant attraits à la qualité des procédés industriels, des procédés d'analyse ainsi qu'à la qualité des produits finis. Cependant, si les lignes de conduites pour ces exigences sont expliquées, aucune méthodologie pour les atteindre n'est donnée. Or, un nombre considérable de nouvelles entités chimiques sont synthétisées par les laboratoires pharmaceutiques, biotechnologiques ou agroalimentaires. Les producteurs de matières premières et/ou d’excipients (secteur chimique) ont également besoin de disposer rapidement de méthodes analytiques de contrôle qui leur permettront de s’assurer de la qualité de leurs produits. On comprend aisément la nécessité pour ces secteurs de disposer rapidement de résultats fiables puisque les activités de recherches mais aussi des investissements, souvent importants, sont orientés ou stoppés sur base de données chiffrées, produits par les méthodes analytiques. La production de résultats fiables et la démonstration de cette fiabilité sont donc économiquement fondamentales. Ce projet vise la mise au point de stratégies et de modèles génériques de développement automatisé de nouvelles méthodes analytiques séparatives, en se basant sur la modélisation des temps de rétention, la planification expérimentale, et le concept de Design Space. L’objectif connexe est d’appliquer cette méthodologie à l’optimisation de n’importe quel procédé. Le fait de pouvoir disposer d’une méthodologie de mise au point automatique de méthodes analytiques ou de tous procédés analytiques aura un impact significatif. Cette nouvelle technologie permettra de réduire de façon drastique le temps d’optimisation des méthodes et procédés, permettant une production plus efficiente de produits (pharmaceutique, cosmétique, agro-alimentaire ou biotechnologique) répondant aux spécifications du client. [less ▲]

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See detailInnovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoïds in cannabis plant material
De Backer, Benjamin ULg; Debrus, Benjamin ULg; Lebrun, Pierre ULg et al

Poster (2009, August)

GC is commonly used for the analysis of cannabis samples, e.g. in forensic chemistry. However, as this method is based on heating of the sample, acidic forms of cannabinoids are decarboxylated into their ... [more ▼]

GC is commonly used for the analysis of cannabis samples, e.g. in forensic chemistry. However, as this method is based on heating of the sample, acidic forms of cannabinoids are decarboxylated into their neutral counterparts. Converely, HPLC permits the determination of the original composition of plant cannabinoids by direct analysis. Several HPLC methods have been described in the literature, but most of them failed to separate efficiently all the cannabinoids or were not validated according to general guidelines. By use of an innovative methodology for modelling chromatographic responses, a simple and accurate HPLC/DAD method was develop [less ▲]

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See detailA new statistical method for the automated detection of peaks in UV-DAD chromatograms of a sample mixture
Debrus, Benjamin ULg; Lebrun, Pierre ULg; Ceccato, Attilio ULg et al

in Talanta (2009), 79

One of the major issues within the context of the fully automated development of chromatographic methods consists of the automated detection and identification of peaks coming from complex samples such as ... [more ▼]

One of the major issues within the context of the fully automated development of chromatographic methods consists of the automated detection and identification of peaks coming from complex samples such as multi-component pharmaceutical formulations or stability studies of these formulations. The same problem can also occur with plant materials or biological matrices. This step is thus critical and time-consuming, especially when a Design of Experiments (DOE) approach is used to generate chromatograms. The use of DOE will often maximize the changes of the analytical conditions in order to explore an experimental domain. Unfortunately, this generally provides very different and “unpredictable” chromatograms which can be difficult to interpret, thus complicating peak detection and peak tracking (i.e. matching peaks among all the chromatograms). In this context, Independent Components Analysis (ICA), a new statistically based signal processing methods was investigated to solve this problem. The ICA principle assumes that the observed signal is the resultant of several phenomena (known as sources) and that all these sources are statistically independent. Under those assumptions, ICA is able to recover the sources which will have a high probability of representing the constitutive components of a chromatogram. In the present study, ICA was successfully applied for the first time to HPLC–UVDAD chromatograms and it was shown that ICA allows differentiation of noise and artifact components from those of interest by applying clustering methods based on high-order statistics computed on these components. Furthermore, on the basis of the described numerical strategy, itwas also possible to reconstruct a cleaned chromatogram with minimum influence of noise and baseline artifacts. This can present a significant advance towards the objective of providing helpful tools for the automated development of liquid chromatography (LC) methods. It seems that analytical investigations could be shortened when using this type of methodologies. [less ▲]

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See detailMoisture content determination of pharmaceutical pellets by near infrared spectroscopy: method development and validation.
Mantanus, Jérôme ULg; Ziemons, Eric ULg; Lebrun, Pierre ULg et al

in Analytica Chimica Acta (2009), 642(1-2), 186-92

The aim of the present study was to develop and validate a near infrared method able to accurately determine a moisture content of pharmaceutical pellets ranging from 1% to 8% in order to check their ... [more ▼]

The aim of the present study was to develop and validate a near infrared method able to accurately determine a moisture content of pharmaceutical pellets ranging from 1% to 8% in order to check their moisture content conformity. A calibration and validation set were designed for the conception and evaluation of the method adequacy. An experimental protocol was then followed, involving two operators, independent production campaign batches and different temperatures for data acquisition. On the basis of this protocol, prediction models based on partial least squares (PLS) regression were then carried out. Conventional criteria such as the R(2), the root mean square errors of calibration and prediction (RMSEC and RMSEP) as well as the number of PLS factors enabled the selection of three preliminary models. However, such criteria did not clearly demonstrate the model's ability to give accurate predictions over the whole analyzed water content range. Consequently, a novel approach based on accuracy profiles which allow the selection of the most fitted model for purpose was used. According to this novel approach, the model using multiplicative scatter correction (MSC) pre-treatment was obviously the most suitable. Indeed, the resulting accuracy profile clearly showed that this model was able to determine moisture content over the range of 1-8% with a very acceptable accuracy. The present study confirmed that NIR spectroscopy could be used in the PAT concept as a non-invasive, non-destructive and fast technique for moisture content determination in pharmaceutical pellets. In addition, facing the limit of the classical and commonly used criteria, the use of accuracy profiles proved to be useful as a powerful decision tool to demonstrate the suitability of the proposed analytical method. [less ▲]

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See detailNouvelle méthodologie pour le développement automatisé de méthodes analytiques en chromatographie liquide pour l’analyse de mélanges de composés inconnus
Debrus, Benjamin ULg; Lebrun, Pierre ULg; Rozet, Eric ULg et al

in Spectra Analyse (2009), 268

Nowadays, many strategies to optimize chromatographic methods are available. However, the development of chromatographic methods remains the most limiting step in the process of synthesis or ... [more ▼]

Nowadays, many strategies to optimize chromatographic methods are available. However, the development of chromatographic methods remains the most limiting step in the process of synthesis or identification of new molecules that could lead to therapeutic agents or new biomarkers despite the availability of new technologies both in chemistry (chemical combinatorial, high throughput screening...) and in analytical biochemistr y (proteomics, metabolomics, herbal ... fingerprinting). Therefore, the aim of this study is to test a new methodology for developing automated chromatographic methods combining experimental planning, independent component analysis, analysis of predictive error propagation and multiple linear regression modeling. Finally, this automated methodology has enabled us to successfully separate the components of an unknown mixture. [less ▲]

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See detailDesign Space for analytical methods. A Bayesian perspective based on multivariate models and prediction
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Jullion, Astrid et al

Conference (2008, September)

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See detailThe Expected Design Space for analytical methods: a new perspective based on modeling and prediction
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Debrus, Benjamin ULg et al

Conference (2008, June)

The Design Space (DS) of an analytical method is defined as the set of factor settings that provides satisfactory results, with respect to pre-defined constraints. The proposed methodology aims at ... [more ▼]

The Design Space (DS) of an analytical method is defined as the set of factor settings that provides satisfactory results, with respect to pre-defined constraints. The proposed methodology aims at identifying a region in the space of factors that will likely provide satisfactory results during the future use of the analytical method in routine, through an optimization process of this method. First, the DS is statistically defined as derived from the β-Expectation prediction interval. Second, multi-criteria perspective is added in this definition as it is often required for optimizing analytical method. Finally, a Monte-Carlo simulation is envisaged to numerically predict and identify the DS under uncertainty. Examples based on high-performance liquid chromatography (HPLC) methods will be given, illustrating the applicability of the methodology. [less ▲]

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See detailUse of Independent Component Analysis and clustering methods to find and identify relevant components in a matrix of UV-spectral data
Lebrun, Pierre ULg; Debrus, Benjamin ULg; Boulanger, Bruno ULg et al

Scientific conference (2008, May)

In the framework of the elaboration of new pharmaceutical formulations, statistical methodologies can accelerate and automate the development and optimization of quantitative methods. To fulfil this ... [more ▼]

In the framework of the elaboration of new pharmaceutical formulations, statistical methodologies can accelerate and automate the development and optimization of quantitative methods. To fulfil this objective, design of experiment (DOE) are widely used. In this context, the same mixture of analytes is injected while LC operating conditions are assessed. This gives plenty of very different chromatograms that can be tedious and time-consuming to interpret. Recently, the independent component analysis (ICA) has shown its usefulness to interpret chromatogram, i.e. to separate numerical signals from a matrix containing data provided by liquid chromatography system equipped with ultra violet diode array detector (LC-UV DAD). A matrix containing peaks corresponding to different analytes is then obtained. A brief summary of the ICA algorithm, applied to this problem, will be first given. The aim of the current work is to show that an automated methodology can be used to match together ICA-identified peaks that correspond to the same analytes in different chromatograms. In this way, this task, attributed to analytical experts, can be quickened and easier. This methodology uses classical hierarchical agglomerative clustering with special dissimilarity measures between spectra. [less ▲]

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See detailDevelopment of a new predictive modelling technique to find with confidence equivalence zone and design space of chromatographic analytical methods
Lebrun, Pierre ULg; Govaerts, Bernadette; Debrus, Benjamin ULg et al

in Chemometrics and Intelligent Laboratory Systems (2008), 91

A new method for modelling chromatographic responses is presented as a critical piece for the achievement of automated development of analytical methods. This methodology is based on four parts. First, we ... [more ▼]

A new method for modelling chromatographic responses is presented as a critical piece for the achievement of automated development of analytical methods. This methodology is based on four parts. First, we propose to use a very little set of statistical equations to create predictive models for retention time based responses as the apex, the width and the asymmetry of peaks. Second, an experimental design is set up to realize experiments. Third, using grid search over the domain, multi criteria decision is taken with respect to different local or global optimization criteria, used as desirability functions. This allows finding an optimal chromatogram. Fourth, we advice to investigate how the predictive error of the models propagates around optimal solution. This allows to give confidence in the optimal solution, in finding a set of zones that presumably will give an acceptable solution. Design spaces can be derived with a similar technique. The approach is exemplified with a real case and predictions of models at optimal analytical conditions are validated through new experiments. Flexibility is left over all the presented methodology. [less ▲]

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See detailReflexions, La Chimie Analytique Verte
Ziemons, Eric ULg; Mantanus, Jérôme ULg; Lebrun, Pierre ULg et al

Learning material (2008)

Au début des années 1990, est apparu le concept de “chimie verte” mieux connue sous le vocable anglais “Green Chemistry”. L’objectif principal de la chimie verte est de définir un cadre à la prévention de ... [more ▼]

Au début des années 1990, est apparu le concept de “chimie verte” mieux connue sous le vocable anglais “Green Chemistry”. L’objectif principal de la chimie verte est de définir un cadre à la prévention de la pollution résultante des activités chimiques prises au sens le plus large. Dans ce contexte, une partie des travaux de recherche du Service de Chimie Analytique du Département de Pharmacie porte sur le développement de nouveaux outils pour la préparation et l’analyse d’échantillons. [less ▲]

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