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Modèles statistiques Bayésiens et méthodologies pour calculer le Design Space (OPTIMAL-DS) Marini Djang'Eing'A, Roland ; Lebrun, Pierre ; Hubert, Philippe Report (2011) 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 ▲] Detailed reference viewed: 37 (1 ULg)New Methodology for the Development of Chromatographic Methods Rozet, Eric ; Debrus, Benjamin ; Lebrun, Pierre et al Conference (2011, September 08) As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process ... [more ▼] As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management”. A risk–based QbD–compliant approach is proposed for the robust development of analytical methods. This methodology based on Design of Experiments (DoE) to study the experimental domain models the retention times at the beginning, the apex and the end of each peak corresponding to the compounds of a mixture and uses the separation criterion (S) rather than the resolution (RS) as a Critical Quality Attribute. Stepwise multiple linear regressions are used to create the models. The estimated error is propagated from the modelled responses to the separation criterion (S) using Monte Carlo simulations in order to estimate the predictive distribution of the separation criterion (S) over the whole experimental domain. This allows finding ranges of operating conditions that will guarantee a satisfactory quality of the method in its future use. These ranges define the Design Space (DS) of the method. In chromatographic terms, the chromatograms processed at operating conditions within the DS will assuredly show high quality, with well separated peaks and short run time, for instance. This Design Space can thus be defined as the subspace, necessarily encompassed in the experimental domain (i.e. the knowledge space), within which the probability for the criterion to be higher than an advisedly selected threshold is higher than a minimum quality level. Precisely, the DS is defined as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” [1]. Therefore, this DS defines a region of operating conditions that provide prediction of assurance of quality rather than only quality as obtained with traditional mean response surface optimisation strategies. For instance, in the liquid chromatography there is a great difference in e.g. predicting a resolution (RS) higher than 1.5 vs. predicting that the probability for RS to be higher than 1.5 (i.e. P(RS> 1.5)) is high. The presentation of this global methodology will be illustrated for the robust optimisation and DS definition of several liquid chromatographic methods dedicated to the separation of different mixtures: pharmaceutical formulations, API and impurities/degradation products, plant extracts, separation of enantiomers, … References [1] International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q8(R2): Pharmaceutical development, Geneva, 2009. Acknowledgements A research grant from the Belgium National Fund for Scientific Research (F.R.S-FNRS) to E. Rozet is gratefully acknowledged. [less ▲] Detailed reference viewed: 76 (7 ULg)GENERIC MEKC METHOD FOR THE SEPARATION OF 15 ANTIMALARIAL DRUGS Lamalle, Caroline ; Marini Djang'Eing'A, Roland ; Debrus, Benjamin et al Poster (2011, September) Detailed reference viewed: 68 (22 ULg)IMPLEMENTATION OF GENERIC ANALYTICAL METHODS TO FIGHT AGAINST COUNTERFEIT MEDICINES Marini Djang'Eing'A, Roland ; Mbinze Kindenge, Jérémie ; Debrus, Benjamin et al Conference (2011, September) Detailed reference viewed: 66 (33 ULg)A BAYESIAN PREDICTIVE PROBABILITY CRITERION TO ASSESS ANALYTICAL METHODS VALIDITY Rozet, Eric ; Marini Djang'Eing'A, Roland ; Lebrun, Pierre et al Poster (2011, September) Detailed reference viewed: 74 (16 ULg)La spectroscopie vibrationnelle, outil indispensable pour l'industrie pharmaceutique ? Ziemons, Eric ; Mantanus, Jérôme ; Rozet, Eric et al Scientific conference (2011, June) Detailed reference viewed: 94 (13 ULg)Development of a Generic MEKC Method for the Separation of 15 Antimalarial Drugs by a Design Space Approach Lamalle, Caroline ; Marini Djang'Eing'A, Roland ; Debrus, Benjamin et al Poster (2011, June) Detailed reference viewed: 46 (14 ULg)Une solution analytique verte pour le PAT: la spectroscopie proche infrarouge. Mantanus, Jérôme ; Rozet, Eric ; Lebrun, Pierre et al Conference (2011, May 19) Detailed reference viewed: 67 (16 ULg)Validation and Routine of Ligand-Binding Assays, a Bayesian Perspective Lebrun, Pierre ; ; Hubert, Philippe Conference (2011, April 29) The way to apply Bayesian modeling is illustrated to validate a ligand-binding assay such as ELISA. Hierarchical non-linear model and the associated predictive distribution of back-calculated responses ... [more ▼] The way to apply Bayesian modeling is illustrated to validate a ligand-binding assay such as ELISA. Hierarchical non-linear model and the associated predictive distribution of back-calculated responses allow quantifying the total uncertainty of every future measurement with the assays, through the use of precision and risk profiles. It is also shown how the obtained posterior distribution of the parameters can be used as prior for new the calibration curves during routine. [less ▲] Detailed reference viewed: 30 (6 ULg)Modèles statistiques Bayésiens et méthodologies pour calculer le Design Space (OPTIMAL-DS) Marini Djang'Eing'A, Roland ; Lebrun, Pierre ; Hubert, Philippe Report (2011) 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 ▲] Detailed reference viewed: 10 (1 ULg)Design Space and desirability index. A Bayesian predictive risk-based approach to flexibly achieve multi-criteria decision methods. Lebrun, Pierre ; ; Hubert, Philippe et al Conference (2011, March 02) The Design Space (DS) is defined as the set of factors settings (input conditions) that will provide results at least better than pre-defined acceptance limits. The proposed methodology aims at ... [more ▼] The Design Space (DS) is defined as the set of factors settings (input conditions) that will provide results at least better than pre-defined acceptance limits. The proposed methodology aims at identifying a region in the space of factors that will likely provide satisfactory results during the future use of an analytical method or process in routine, through an optimization process. In a Bayesian framework, the responses are modelled using a multivariate multiple regression model allowing deriving their joint predictive posterior distribution. On the basis of this consequent distribution, a multi-criteria risk-based decision is taken with respect to the pre-defined acceptance limits. This aims to identify the DS. In this context, desirability methodologies are also applied to take the risk-based decision in a more flexible way. An example based on high-performance liquid chromatography illustrates the applicability of the methodology with highly correlated and constrained responses. [less ▲] Detailed reference viewed: 68 (18 ULg)Trial predictions vs. trial simulations in Model-based Drug Development: integrating uncertainties to evaluate the predictive probability of success. Lebrun, Pierre ; ; Conference (2011, March 02) In a Model-Based Drug Development strategy, the first objective is to design studies such that the most reliable model estimates are obtained, in order to optimize the design of future studies and to take ... [more ▼] In a Model-Based Drug Development strategy, the first objective is to design studies such that the most reliable model estimates are obtained, in order to optimize the design of future studies and to take decisions based on predictions. The objectives of the work is to present from a theoretical and practical point of view how to perform trial predictions, as opposed to trial simulations, by integrating the uncertainty of the parameters. The difference between prediction and simulation is important in early development when limited data or prior information are available. Indeed ignoring the uncertainty of parameter estimates can lead to wrong decisions. First, will be provided methodology, derived from Bayesian statistics, to perform trial predictions from the parameter estimates and their uncertainty, when obtained with conventional frequentist population methods. Second, a practical implementation in R will be shown. This generalized prediction shell can cope with any kind of structural population models: Ordinary Differential Equation, single & multiple doses, infusion, etc... The proposed shell is also flexible to allow the testing of various scenarios and study designs, and therefore evaluate the predictive probability of success of different protocols. When joint models for efficacy and safety are established, the Prediction-based Clinical Utility Index (p-CUI) and its distribution can directly be obtained for more riskless decision making. Examples will be shown to highlight in early phases the differences existing between trial prediction and trial simulation. This approach is required to permit Model-Based Drug Development strategy, and impact successfully decision in early clinical phases. [less ▲] Detailed reference viewed: 20 (1 ULg)Innovative methodology to transfer conventional GC-MS heroin profiling to UHPLC-MS/MS Debrus, Benjamin ; ; et al in Analytical and Bioanalytical Chemistry (2011), 399(8), 2719-2730 Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good ... [more ▼] Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good sensitivity and reproducibility, and allows the use of large databases. Despite those benefits, recently introduced analytical techniques, such as ultra-high-pressure liquid chromatography (UHPLC), could offer better chromatographic performance, which needs to be considered to increase the analysis throughput for heroin profiling. With the latter, chromatographic conditions were optimized through commercial modeling software and two atmospheric pressure ionization sources were evaluated. Data obtained from UHPLC–MS/MS were thus transferred, thanks to mathematical models to mimic GC-MS data. A calibration and a validation set of representative heroin samples were selected among the database to establish a transfer methodology and assess the models’ abilities to transfer using principal component analysis and hierarchical classification analysis. These abilities were evaluated by computing the frequency of successful classification of UHPLC–MS/MS data among GC-MS database. Seven mathematical models were tested to adjust UHPLC–MS/MS data to GC-MS data. A simplified mathematical model was finally selected and offered a frequency of successful transfer equal to 95%. [less ▲] Detailed reference viewed: 157 (31 ULg)Application of new methodologies based on design of experiments, independent component analysis and design space for robust optimization in liquid chromatography Debrus, Benjamin ; Lebrun, Pierre ; Ceccato, Attilio et al in Analytica Chimica Acta (2011), 691 HPLC separations of an unknown sample mixture and a pharmaceutical formulation have been optimized using a recently developed chemometric methodology proposed by W. Dewé et al. in 2004 and improved by P ... [more ▼] HPLC separations of an unknown sample mixture and a pharmaceutical formulation have been optimized using a recently developed chemometric methodology proposed by W. Dewé et al. in 2004 and improved by P. Lebrun et al. in 2008. This methodology is based on experimental designs which are used to model retention times of compounds of interest. Then, the prediction accuracy and the optimal separation robustness, including the uncertainty study, were evaluated. Finally, the design space (ICH Q8(R2) guideline) was computed as the probability for a criterion to lie in a selected range of acceptance. Furthermore, the chromatograms were automatically read. Peak detection and peak matching were carried out with a previously developed methodology using independent component analysis published by B. Debrus et al. in 2009. The present successful applications strengthen the high potential of these methodologies for the automated development of chromatographic methods. [less ▲] Detailed reference viewed: 158 (43 ULg)Implementation of a design space approach for enatiomeric separations in polar organic solvent chromatography Nistor, Iolanda ; Lebrun, Pierre ; Ceccato, Attilio et al Poster (2011) Detailed reference viewed: 49 (16 ULg)Application of a new optimization strategy for the separation of tertiary alkaloids extracted from Strychnos usambarensis leaves Nistor, Iolanda ; Cao, Martine ; Debrus, Benjamin et al in Journal of Pharmaceutical & Biomedical Analysis (2011), 56 The HPLC separation of six alkaloids extracted from Strychnos usambarensis leaves has been developed and optimized by means of a powerful methodology for modelling chromatographic responses, based on ... [more ▼] The HPLC separation of six alkaloids extracted from Strychnos usambarensis leaves has been developed and optimized by means of a powerful methodology for modelling chromatographic responses, based on three steps, i.e. design of experiments (DoE), independent component analysis (ICA) and design space (DS). This study was the first application of a new optimization strategy to a complex natural matrix. The compounds separated are the isomers isostrychnopentamine and strychnopentamine, 10-hydroxyusambarine and 11-hydroxyusambarine, also strychnophylline and strychnofoline. Three LC parameters have been optimized using a multifactorial design comprising 29 experiments that includes 2 center point replicates. The parameters were the percentage of organic modifiers used at the beginning of a gradient profile which consisted in different proportions of methanol (MeOH) and acetonitrile (MeCN), the gradient time to reach 70% of organic modifiers starting from the initial percentage and the percentage of MeCN found in the mobile phase. Subsequent to the experimental design application, predictive multilinear models were developed and used in order to provide optimal analytical conditions. The optimum assay conditions were: methanol/acetonitrile-sodium pentane sulfonate (pH 2.2; 7.5 mM) (33.4:66.6, v/v) at a mobile phase flow rate of 1mL/min during a 40.6 minutes gradient time. The initial organic phase contained 3.7% MeCN and 96.3% MeOH. The method showed good agreement between the experimental data and predictive value throughout the studied parameters space. Improvement of the analysis time and optimized separation for the compounds of interest was possible due to the original and powerful tools applied. Finally, this study permitted the acquisition of isomers profiles allowing the identification of the optimal collecting period of Strychnos usambarensis. [less ▲] Detailed reference viewed: 91 (50 ULg)Evaluating the reliability of analytical results using a probability criterion: a Bayesian perspective Rozet, Eric ; ; Lebrun, Pierre et al in Analytica Chimica Acta (2011), 705 Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the ... [more ▼] Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the individual results that will be generated during the routine application of the method. Regulatory guidelines provide a general framework to assess the validity of a method, but none address the issue of results reliability. In this study, a Bayesian approach is proposed to address this concern. Results reliability is defined here as “the probability of an analytical method to provide analytical results within predefined acceptance limits around their reference or conventional true concentration values over a defined concentration range and under given environmental and operating conditions.” By providing the minimum reliability probability needed for the subsequent routine application of the method, as well as specifications or acceptance limits , the proposed Bayesian approach provides the effective probability of obtaining reliable future analytical results over the whole concentration range investigated. This is summarized in a single graph: the reliability profile. This Bayesian reliability profile is also compared to two frequentist approaches, the first one derived from the work of Dewé et al. [Dewé W., Govaerts B., Boulanger B., Rozet E., Chiap P., Hubert Ph., Chemometr. Intell. Lab. Syst. 85 (2007) 262-268] and the second proposed by Govaerts et al. [B. Govaerts, W. Dewé, M. Maumy, B. Boulanger, Qual. Reliab. Engng. Int. 24 (2008) 667-680]. Furthermore, to illustrate the applicability of the Bayesian reliability profile, this approach is also applied here to a bioanalytical method dedicated to the determination of ketoglutaric acid (KG) and hydroxymethylfurfural (HMF) in human plasma by SPE-HPLC-UV. [less ▲] Detailed reference viewed: 83 (26 ULg)Innovative high-performance liquid chromatography method development for the screening of 19 antimalarial drugs based on a generic approach, using design of experiments, independent component analysis and design space Debrus, Benjamin ; Lebrun, Pierre ; et al in Journal of Chromatography. A (2011), 1218 An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 ... [more ▼] An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE–ICA–DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE–ICA–DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE–ICA–DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study. [less ▲] Detailed reference viewed: 131 (39 ULg)Determination of binary polymorphic mixtures of fluconazole using near infrared spectroscopy and X-ray powder diffraction: A comparative study based on the pre-validation stage results Ziemons, Eric ; ; Mantanus, Jérôme et al in Journal of Pharmaceutical & Biomedical Analysis (2011), 55 The aim of the present study was to develop near infrared (NIR) and X-ray powder diffraction methods (XRPD) able to determine pure crystalline form II of fluconazole in a binary polymorphic mixtures ... [more ▼] The aim of the present study was to develop near infrared (NIR) and X-ray powder diffraction methods (XRPD) able to determine pure crystalline form II of fluconazole in a binary polymorphic mixtures containing form II and III. In order to give a first performance estimation of both methods, these latters were pre-validated using accuracy profiles, a statistical approach based on β-expectation tolerance intervals. Both methods showed a good trueness, precision and accuracy and their β-expectation tolerance intervals were fully included within the acceptance limits. The comparative study was carried out using statistical analysis based on the work of Bland and Altman. A good agreement between the two methods was demonstrated indicating the interchangeability of NIR method with XRPD method. [less ▲] Detailed reference viewed: 79 (16 ULg)Optimisation and validation of a fast HPLC method for the quantification of sulindac and its related impurities Krier, Fabrice ; ; Debrus, Benjamin et al in Journal of Pharmaceutical & Biomedical Analysis (2011), 54 The European Pharmacopoeia describes a liquid chromatography (LC) method for the quantification of sulindac, using a quaternary mobile phase including chloroform and with a rather long run time. In the ... [more ▼] The European Pharmacopoeia describes a liquid chromatography (LC) method for the quantification of sulindac, using a quaternary mobile phase including chloroform and with a rather long run time. In the present study, a new method using a short sub-2μm column, which can be used on a classical HPLC system, was developed. The new LC conditions (without chloroform) were optimised by means of a new methodology based on design of experiments in order to obtain an optimal separation. Four factors were studied: the duration of the initial isocratic step, the percentage of organic modifier at the beginning of the gradient, the percentage of organic modifier at the end of the gradient and the gradient time. The optimal condition allows the separation of sulindac and of its 3 related impurities in six minutes instead of 18 min. Finally, the method was successfully validated using an accuracy profile approach in order to demonstrate its ability to accurately quantify these compounds. [less ▲] Detailed reference viewed: 169 (53 ULg) |
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