References of "Hubert, Philippe"
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See detailA Bayesian Design Space for analytical methods based on multivariate models and predictions
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Debrus, Benjamin ULg et al

in Journal of Biopharmaceutical Statistics (2013), 23

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of ... [more ▼]

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of factor settings providing satisfactory results. However, ICH Q8 does not propose any practical methodology to define, derive and compute Design Space. In parallel, in the last decades, it has been observed that the diversity and the quality of analytical methods have evolved exponentially allowing substantial gains in selectivity and sensitivity. However, there is still a lack for a rationale towards the development of robust separation methods in a systematic way. Applying ICH Q8 to analytical methods provides a methodology for predicting a region of the space of factors in which results will be reliable. Combining design of experiments and Bayesian standard multivariate regression, an identified form of the predictive distribution of a new response vector has been identified and used, under non-informative as well as informative prior distributions of the parameters. From the responses and their predictive distribution, various critical quality attributes can be easily derived. This Bayesian framework was then extended to the multi-criteria setting to estimate the predictive probability that several critical quality attributes will be jointly achieved in the future use of an analytical method. An example based on a high-performance liquid chromatography (HPLC) method is given. For this example, a constrained sampling scheme was applied to ensure the modeled responses have desirable properties. [less ▲]

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See detailDesign Spaces for Analytical Methods
Rozet, Eric ULg; Lebrun, Pierre ULg; Debrus, Benjamin ULg et al

in Trends in Analytical Chemistry [=TRAC] (2013), 42

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a Quality by Design (QbD) approach, there have been many discussions on the opportunity for ... [more ▼]

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a Quality by Design (QbD) approach, there have been many discussions on the opportunity for analytical method developments to follow a similar approach. A key component of the QbD paradigm is the definition of the Design Space of analytical methods where assurance of quality is provided. Several Design Spaces for analytical methods have been published, stressing the importance of this concept. This paper aims at explaining what is an analytical method Design Space, why it is useful for the robust development and optimization of analytical methods and how to build such a Design Space. A strong emphasis is made by distinguishing the usual mean response surface approach, overlapping mean response surfaces and the desirability function one to other probabilistic approaches as only these last ones correctly define a Design Space. In addition, recent publications assessing the Design Space of analytical methods are reviewed and discussed. [less ▲]

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See detailATR-IR and Raman spectroscopic study of interaction between major calixarene derivatives and oral anticoagulants
Tiuca, Ioana; Saponar, Alina; Bodoki, Andreea et al

in Farmacia (2013), 61(5), 874-882

In this study we analyzed by ATR-IR and Raman spectroscopy the interaction between six major calixarene derivatives and two anticoagulants: warfarin and acenocoumarol. The six calixarene derivatives were ... [more ▼]

In this study we analyzed by ATR-IR and Raman spectroscopy the interaction between six major calixarene derivatives and two anticoagulants: warfarin and acenocoumarol. The six calixarene derivatives were: p-tert-butyl-calix[4]arene (C4), p-tert- butyl-calix[6]arene (C6) and p-tert-butyl-calix[8]arene (C8) and their ethyl-ester- derivatives: tetraester-p-tert-butyl-calix[4]arene (C4Es4), hexaester-p-tert-butyl- calix[6]arene (C6Es6), octaester-p-tert-butyl-calix[8]arene (C8Es8). The results showed the most intense interaction in terms of complex formation for the C6-acenocoumarol couple and for the C6-warfarin couple, respectively. [less ▲]

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See detailPAT tools for the control of co-extrusion implants manufacturing process
Krier, Fabrice ULg; Mantanus, Jérome; Sacre, Pierre-Yves ULg et al

in International Journal of Pharmaceutics (2013), 458

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt ... [more ▼]

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively. These two different spectroscopic techniques provided comparable results. In fact, the RMSEC and RMSECV were very close in each PAT technique but NIR spectroscopy was easier to use and less sensitive to external changes. For the control of the homogeneity of API distribution and the thickness of the membrane, we used successfully Raman spectroscopy imaging. These PAT tools help reducing analysis time. [less ▲]

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See detailUsefulness of Information Criteria for the Selection of Calibration Curves
Rozet, Eric ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytical Chemistry (2013), 85

The reliability of analytical results obtained with quantitative analytical methods is highly dependant upon the selection of the adequate model used as calibration curve. To select the adequate response ... [more ▼]

The reliability of analytical results obtained with quantitative analytical methods is highly dependant upon the selection of the adequate model used as calibration curve. To select the adequate response function or model the most used and known parameter is the determination coefficient R². However it is well known that it suffers many inconvenient, such as leading to overfitting the data. A solution proposed is to use the adjusted determination coefficient R²adj that aims at reducing this problem. However there is another family of criteria that exists to allow the selection of an adequate model: the information criteria AIC, AICc and BIC. These criteria have rarely been used in analytical chemistry to select the adequate calibration curve. This works aims at assessing the performance of the statistical information criteria as well as R² and R²adj for the selection of an adequate calibration curve. They are applied to several analytical methods covering liquid chromatographic methods as well as electrophoretic ones involved in the analysis of active substances in biological fluids or aimed at quantifying impurities in drug substances. In addition, Monte-Carlo simulations are performed to assess the efficacy of these statistical criteria to select the adequate calibration curve. [less ▲]

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See detailMethodology for the Validation of Analytical Methods involved in Uniformity of Dosage Units tests
Rozet, Eric ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytica Chimica Acta (2013), 760

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving ... [more ▼]

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving the quality of the end products starting from its early design stage. However, no regulatory guideline or none of the published methodologies to assess method validation propose decision methodologies that effectively take into account the final purpose of developed analytical methods. In this work a solution is proposed for the specific case of validating analytical methods involved in the assessment of the Content Uniformity or Uniformity of Dosage Units of a batch of pharmaceutical drug products as proposed in the European or US pharmacopoeias. This methodology uses statistical tolerance intervals as decision tools. Moreover it adequately defines the Analytical Target Profile of analytical methods in order to obtain analytical methods that allow to make correct decisions about Content Uniformity or Uniformity of Dosage Units with high probability. The applicability of the proposed methodology is further illustrated using an HPLC-UV assay as well as a Near Infra-Red Spectrophotometric method. [less ▲]

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See detailImplementation of a Design Space Approach for Enantiomeric Separations in Polar Organic Solvent Chromatography
Nistor, Iolanda; Lebrun, Pierre ULg; Ceccato, Attilio ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 74

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 ... [more ▼]

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures. Good correlations were found between the observed data obtained after using a central composite design and the expected chromatographic behaviours predicted by applying the design of experiments-design space (DoE-DS) methodology. The critical quality attribute represented here by the separation criterion (Scrit) allowed assessing the quality of the enantioseparation. Baseline separation for the compounds of interest in an analysis time of less than 20 minutes was possible due to the original and powerful tools applied which facilitated an enhanced method comprehension. Finally, the advantage of the DoE-DS approach resides in granting the possibility to concurrently assess robustness and identify the optimal conditions which are compound dependent. [less ▲]

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See detailIntérêt de la microscopie vibrationnelle dans la recherche de nouvelles formulations pharma-ceutiques à haute valeur ajoutée.
Sacre, Pierre-Yves ULg; Marini Djang'Eing'A, Roland ULg; Ziemons, Eric ULg et al

Report (2012)

La grande majorité des nouvelles molécules actives présente une faible biodisponibilité dans des formulations pharmaceutiques simples contenant principalement un ou plusieurs constituants et l’actif ... [more ▼]

La grande majorité des nouvelles molécules actives présente une faible biodisponibilité dans des formulations pharmaceutiques simples contenant principalement un ou plusieurs constituants et l’actif faiblement soluble dans l’eau. Dès lors, il est primordial d’investir dans la recherche de nouvelles formulations « plus sophistiquées » (formulations de demain) favorisant la solubilité de l’actif. Cependant cette recherche est limitée par celle de nouveaux outils analytiques pointus permettant de les caractériser, d’étudier les interactions au sein des formulations pharmaceutiques, de comprendre les mécanismes liès à leur formation et in fine de contrôler et garantir leur conformité. Par ailleurs, la Technologie Analytique des Procédés (PAT) est un concept développé par l’Administration Américaine des Aliments et des Médicaments (FDA) et soutenu par l’Agence Européenne des Médicaments (EMA). Ce concept qui devient de plus en plus incontournable (au niveau des dossiers d’Autorisation de Mise sur le Marché). La rapidité de mesure et le caractère non destructif de la spectroscopie vibrationnelle dont fait partie la microscopie Raman la rendent particulièrement compatibles avec ce concept. De plus, les techniques vibrationnelles de part l’absence de préparation de l’échantillon et de l’utilisation de solvant organique rencontrent également le concept de Chimie Verte et donc s’incrivent parfaitement dans un contexte de développement durable et respectueux de l’environnement. L’objectif du présent projet est d’explorer les potentialités de la microscopie Raman dans l’étude pointue des matrices complexes afin d’en améliorer les connaissances tant au niveau de leur charactérisation, des intéractions analyte-matrice que des mécanismes liés à leur formation. L’obtention de ces informations nécéssiteront la recherche de nouvelles méthodologies, outils et règles de décision dédicacés aux aspects qualitatifs et plus encore aux aspects quantiftatifs où l’accès à de telles données est très marginal. L’ensemble de cette recherche sera réalisée sur un modèle complexe, une formulation à haute valeur ajoutée issue de l’industrie pharmaceutique. [less ▲]

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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 (2012)

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 detailAPPLICATION OF AN INNOVATIVE DESIGN SPACE OPTIMIZATION STRATEGY TO THE DEVELOPMENT OF LC METHODS TO COMBAT POTENTIALLY COUNTERFEIT NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Mbinze Kindenge, Jérémie ULg; Lebrun, Pierre ULg; Debrus, Benjamin ULg et al

in Journal of Chromatography. A (2012), 1263

In the context of the battle against counterfeit medicines, an innovative methodology has been used to develop rapid and specific high performance liquid chromatographic methods to detect and determine 18 ... [more ▼]

In the context of the battle against counterfeit medicines, an innovative methodology has been used to develop rapid and specific high performance liquid chromatographic methods to detect and determine 18 non-steroidal anti-inflammatory drugs, 5 pharmaceutical conservatives, paracetamol, chlorzoxazone, caffeine and salicylic acid. These molecules are commonly encountered alone or in combination on the market. Regrettably, a significant proportion of these consumed medicines are counterfeit or substandard, with a strong negative impact in countries of Central Africa. In this context, an innovative design space optimization strategy was successfully applied to the development of LC screening methods allowing the detection of substandard or counterfeit medicines. Using the results of a unique experimental design, the design spaces of 5 potentially relevant HPLC methods have been developed, and transferred to an ultra high performance liquid chromatographic system to evaluate the robustness of the predicted DS while providing rapid methods of analysis. Moreover, one of the methods has been fully validated using the accuracy profile as decision tool, and was then used for the quantitative determination of three active ingredients and one impurity in a common and widely used pharmaceutical formulation. The method was applied to 5 pharmaceuticals sold in the Democratic Republic of Congo. None of these pharmaceuticals was found compliant to the European Medicines Agency specifications [less ▲]

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See detailInnovative green supercritical fluid chromatography development for the determination of polar compounds
Dispas, Amandine ULg; Lebrun, Pierre ULg; Sassiat, Patrick et al

in Journal of Chromatography. A (2012), 1256

In the context of green analytical chemistry, a supercritical fluid chromatography method was developed. In order to prove the potential of this technology, a worst case was selected, i.e. the separation ... [more ▼]

In the context of green analytical chemistry, a supercritical fluid chromatography method was developed. In order to prove the potential of this technology, a worst case was selected, i.e. the separation of very polar compounds. For that purpose, an innovative methodology based on design of experiments (DoE) and design space (DS) was previously developed and successfully tested on liquid chromatography. For the first time, this methodology was applied to a supercritical fluid chromatography (SFC) separation. First, a screening design was used to select the stationary phase and the nature of the mobile phase based on a maximization of the number of peaks eluted and a minimization of the number of co-eluted peaks. Then, a central composite design with orthogonal blocks defined a set of experiments used to model the retention times of each peak at the beginning, the apex, and the end. The gradient slope, the isocratic plateau before the gradient, the temperature, and the concentration of trifluoroacetic acid (TFA) in the mobile phase were the potentially influential factors. The critical quality attributes (CQAs), i.e. the separation (S) between peaks of the most critical pair, and the analysis time were the responses considered to assess the quality of the separation. The DS was computed as the multidimensional subspace where the probability for the separation and analysis time criteria to be within acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modeled responses to the quality criterion using Monte Carlo simulations. The optimal condition was predicted at a gradient slope of 3.8% min−1 to linearly modify the modifier proportion between 5 and 40%, an isocratic time of 3 minutes, a concentration of TFA of 25 mM, and a temperature of 60.5 °C. This optimal condition was experimentally tested to confirm the prediction. Furthermore, chromatographic conditions included in the DS and on the limits of the DS were experimentally tested to assess the robustness of the developed SFC method. [less ▲]

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See detailDevelopment of a generic micellar electrokinetic chromatography method for the separation of 15 antimalarial drugs as a tool to detect medicine counterfeiting
Lamalle, Caroline ULg; Marini Djang'Eing'A, Roland ULg; Debrus, Benjamin ULg et al

in Electrophoresis (2012), 33

Since antimalarial drugs counterfeiting is dramatically present on the African market, the development of simple analytical methods for their quality control is of great importance. This work consists in ... [more ▼]

Since antimalarial drugs counterfeiting is dramatically present on the African market, the development of simple analytical methods for their quality control is of great importance. This work consists in the CE analysis of 15 antimalarials (artesunate, artemether, amodiaquine, chloroquine, piperaquine, primaquine, quinine, cinchonine, mefloquine, halofantrine, sulfadoxine, sulfalen, atovaquone, proguanil, and pyrimethamine). Since all these molecules cannot be ionized at the same pH, MEKC was preferred because it also allows separation of neutral compounds. Preliminary experiments were first carried out to select the most crucial factors affecting the antimalarials separation. Several conditions were tested and four parameters as well as their investigation domain were chosen: pH (5–10), SDS concentration (20–90 mM), ACN proportion (10–40%), and temperature (20–35°C). Then, the experimental design methodology was used and a central composite design was selected. Mathematical modeling of the migration times allowed the prediction of optimal conditions (29°C, pH 6.6, 29 mM SDS, 36% ACN) regarding analyte separation. The prediction at this optimum was verified experimentally and led to the separation of 13 compounds within 8 min. Finally, the method was successfully applied to the quality control of African antimalarial medicines for their qualitative and quantitative content. [less ▲]

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See detailQUALITY ASSESSMENT OF MEDICINES MARKETED IN RWANDA, July-Oct. 2011
Habyalimana, Védaste; Mbinze Kindenge, Jérémie; Kadima Ntokamunda, Justin Léonard et al

Scientific conference (2012, July)

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