References of "Boulanger, Bruno"
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See detailA New Method for Quality by Design Robust Optimization in Liquid Chromatography
Debrus, Benjamin ULg; Lebrun, Pierre ULg; Rozet, Eric ULg et al

in LC-GC Europe (2013), -(-), -

A new method to optimize liquid chromatography (LC) methods using a Quality by Design (QbD) approach is presented. This method is based on the use of design of experiments (DOE) and independent component ... [more ▼]

A new method to optimize liquid chromatography (LC) methods using a Quality by Design (QbD) approach is presented. This method is based on the use of design of experiments (DOE) and independent component analysis (ICA) to accurately estimate the modelled responses (that is, the retention times at the beginning, the apex, and the end) of each peak, even for coeluted peaks. The modelling of these responses usesmultiple linear regressions, while the propagation of the error affecting the responses and coming from the models is carried out by Monte Carlo simulation. The design space is determined as the region of assay factors where the probability to reach baseline-resolved peaks is higher than the desired level of quality. This method was applied to the optimization of the separation of nine compounds in a mixture, yielding the design space and the demonstration of robustness of the method. Finally, the method was validated. [less ▲]

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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 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 detailFlexibility and Applicability of β-expectation tolerance interval approach to assess the fitness of purpose of pharmaceutical analytical methods
Bouabidi, Abderrahim; Talbi, M.; Bourichi, H. et al

in Drug Testing and Analysis (2012), 4(12), 1014-1027

An innovative versatile strategy using Total Error has been proposed to decide about the method’s validity that controls the risk of accepting an unsuitable assay together with the ability to predict the ... [more ▼]

An innovative versatile strategy using Total Error has been proposed to decide about the method’s validity that controls the risk of accepting an unsuitable assay together with the ability to predict the reliability of future results. This strategy is based on the simultaneous combination of systematic (bias) and random (imprecision) error of analytical methods. Using validation standards both types of error are combined through the use of a prediction interval or β-expectation tolerance interval. Finally, an accuracy profile is built by connecting, on one hand all the upper tolerance limits, and on the other hand all the lower tolerance limits. This profile combined with pre-specified acceptance limits allows to evaluate the validity of any quantitative analytical method and thus their fitness for their intended purpose. In this work, the approach of accuracy profile was evaluated on several types of analytical methods encountered in pharmaceutical industrial field and also covering different pharmaceutical matrices. The four studied examples depicted the flexibility and applicability of this approach for different matrices ranging from tablets to syrups, different techniques such as liquid chromatography, or UV spectrophotometry and for different categories of assays commonly encountered in the pharmaceutical industry that are content assays, dissolution assays and quantitative impurity assays. The accuracy profile approach assesses the fitness of purpose of these methods for their future routine application,. It also allows to select the most suitable calibration curve, to evaluate adequately a potential matrix effect and propose efficient solution and to define correctly the limits of quantification of the studied analytical procedures. [less ▲]

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See detailDesign space approach in the optimization of the spray-drying process
Lebrun, Pierre ULg; Krier, Fabrice ULg; Mantanus, Jérôme ULg et al

in European Journal of Pharmaceutics & Biopharmaceutics (2012), 80(1), 226-234

From a quality by design perspective, the aim of the present study was to demonstrate the applicability of a Bayesian statistical methodology to identify the design space (DS) of a spray-drying process ... [more ▼]

From a quality by design perspective, the aim of the present study was to demonstrate the applicability of a Bayesian statistical methodology to identify the design space (DS) of a spray-drying process. Following the ICH Q8 guideline, the DS is defined as the “multidimensional combination and interaction of input variables (e.g., materials attributes) and process parameters that have been demonstrated to provide assurance of quality”. Thus, a predictive risk-based approach was set up in order to account for the uncertainties and correlations found in the process and in the derived critical quality attributes such as the yield, the moisture content, the inhalable fraction of powder, the compressibility index and the Hausner ratio. This allowed quantifying the guarantees and the risks to observe whether the process shall run according to specifications. These specifications describe satisfactory quality outputs and were defined a priori given safety, efficiency and economical reasons. Within the identified DS, validation of the optimal condition was effectuated. The optimized process was shown to perform as expected, providing a product for which the quality is built in by the design and controlled set-up of the equipment, regarding identified critical process parameters: the inlet temperature, the feed rate and the spray flow rate. [less ▲]

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See detailModels to estimate overall analytical measurements uncertainty: assumptions, comparisons and applications
Rozet, Eric ULg; Rudaz, S.; Marini Djang'Eing'A, Roland ULg et al

in Analytica Chimica Acta (2011), 702

Evaluation of analytical results reliability is of core importance as crucial decisions are taken with them. From the various methodologies to evaluate the fitness of purpose of analytical methods ... [more ▼]

Evaluation of analytical results reliability is of core importance as crucial decisions are taken with them. From the various methodologies to evaluate the fitness of purpose of analytical methods, overall measurement uncertainty estimation is more and more applied. Overall measurement uncertainty allows to combine simultaneously the remaining systematic influences to the random sources of uncertainty and allows assessing the reliability of results generated by analytical methods. However there are various interpretations on how to estimate overall measurement uncertainty, and thus various models for estimating it. Each model together with its assumptions has great impacts on the risks to abusively declare that analytical methods are suitable for their intended purpose. This review paper aims at i) summarizing the various models used to estimate overall measurement uncertainty, ii) provide their pros and cons, iii) review the main areas of application and iv) as a conclusion provide some recommendations when evaluating overall measurement uncertainty. [less ▲]

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See detailInnovative 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 ULg; Lebrun, Pierre ULg; Mbinze Kindenge, Jérémie 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 ▲]

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See detailApplication of new methodologies based on design of experiments, independent component analysis and design space for robust optimization in liquid chromatography
Debrus, Benjamin ULg; Lebrun, Pierre ULg; Ceccato, Attilio ULg 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 ▲]

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See detailEvaluating analytical results reliability using a Bayesian probability criterion
Rozet, Eric ULg; Lebrun, Pierre ULg; Boulanger, Bruno ULg et al

Poster (2010, December 02)

In pharmaceutical industries, quantitative analytical methods such as HPLC play a key role. Indeed, the analytical results obtained from them are used to make crucial decisions such as the release of ... [more ▼]

In pharmaceutical industries, quantitative analytical methods such as HPLC play a key role. Indeed, the analytical results obtained from them are used to make crucial decisions such as the release of batches of drugs, the evaluation of safety and efficacy of new drug candidates or the monitoring of patients health. Prior to their routine use, analytical methods are submitted to a stringent validation study where they have to demonstrate that they are fit for their final purpose, i.e. providing accurate result . Typically this demonstration is made by either providing point estimates of systematic error (bias) and random error (variance) or sometimes by providing interval estimates of these statistical parameters at several well defined concentration levels of the target analyte. They are then compared to maximum acceptable levels. More recently, tolerance intervals approaches have been proposed that are evaluated in a similar way at these key concentration levels. However none of these decision approaches allow knowing the probability to obtain accurate results over the whole concentration range of interest. Frequentist approximations have been proposed to estimate this probability but only at the concentration levels experimentally tested and not for the whole range of interest. In this work, a linear hierarchical Bayesian approach is proposed. It takes into account the potential random characteristic of the slope and intercept observed from one analytical run to the other, and also integrates the possible covariance between the parameters. Additionally, heteroscedasticity of the residual variance over the concentration range investigated is taken into account. A situation regularly observed in practice. Finally a reliability profile for the whole concentration range studied is obtained using MCMC sampling. This profile provides the probability (Prel) to obtain accurate results over the full concentration range investigated. This profile is then compared to a minimum reliability probability (Pmin) that will define the valid concentration range of the analytical method. The usefulness of this approach is illustrated through the validation of a bioanalytical method and also compared with a one concentration level at a time frequentist approach derived from tolerance intervals. [less ▲]

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See detailHow can QbD be used and implemented to optimize method development and validation?
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Hubert, Philippe ULg

Conference (2010, November 04)

Through an example, the way to apply Design of Experiments and the Bayesian modeling to develop robust optimal ligand-binding assays (LBA) will be presented. The objectives of a LBA will be re-examined ... [more ▼]

Through an example, the way to apply Design of Experiments and the Bayesian modeling to develop robust optimal ligand-binding assays (LBA) will be presented. The objectives of a LBA will be re-examined and response of interest derived (precision profile). The concept of Design Space specific for LBA will be introduced in relation with validation, routine and transfer [less ▲]

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See detailPlans expérimentaux
Boulanger, Bruno ULg; Govaerts, B.; Le Boulengé, E. et al

Learning material (2010)

Vidéos du cours intitulé "Plans expérimentaux"

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See detailRISK MANAGMENT IN THE VALIDATION OF ANALYTICAL METHODS
Hubert, Philippe ULg; Ziemons, Eric ULg; Mantanus, Jérôme ULg et al

Conference (2010, October)

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See detailOptimization of ligand-binding assay in a QbD environment. Use of Bayesian non-linear regression to set up probability profile as quality response
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Hubert, Philippe ULg

Conference (2010, September 28)

For ligan-binding assay, different parameters are controlled in routine. In a development phase, we will show how design of experiment can be used to select these parameters to obtain reliable results in ... [more ▼]

For ligan-binding assay, different parameters are controlled in routine. In a development phase, we will show how design of experiment can be used to select these parameters to obtain reliable results in the future use of the ELISA test. Uncertainties of measurements and models should be taken into account in a predictive manner. Bayesian modelling and MCMC simulations are well suited for this purpose and are flexible enough to include random effects on the parameters on non-linear model. We will focus on 4PL regression as it is encountered in most applications. We will also show that deriving a quality response such as a precision profile is clear and direct in the Bayesian setting. The approach is fully compliant with QbD guidelines and Design Space definition. [less ▲]

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See detailTotal error as natural decision criteria for analytical methods validation and transfer
Rozet, Eric ULg; Boulanger, Bruno ULg; Dewe et al

Conference (2010, September)

Detailed reference viewed: 191 (43 ULg)