References of "Lebrun, Pierre"
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See detailEvaluation of the quantitative performances of Supercritical Fluid Chromatography : from method development to validation
Dispas, Amandine ULg; Lebrun, Pierre ULg; Ziemons, Eric ULg et al

in Journal of Chromatography. A (2014), 1353(Method Validation), 78-88

Recently, the number of papers about SFC increased drastically but scientists did not truly focus their work on quantitative performances of this technique. In order to prove the potential of UHPSFC, the ... [more ▼]

Recently, the number of papers about SFC increased drastically but scientists did not truly focus their work on quantitative performances of this technique. In order to prove the potential of UHPSFC, the present work discussed about the different steps of the analytical life cycle of a method: from development to validation and application. Moreover, the UHPSFC quantitative performances were evaluated in comparison with UHPLC, which is the main technique used for quality control in the pharmaceutical industry and then could be considered as a reference. The methods were developed using Design Space strategy, leading to the optimization of robust method. In this context, when the Design Space optimization shows guarantee of quality, no more robustness study is required prior to the validation. Then, the methods were geometrically transferred in order to reduce the analysis time. The UHPSFC and UHPLC methods were validated based on the total error approach using accuracy profile. Even if UHPLC showed better precision and sensitivity, UHPSFC method is able to give accurate results in a dosing range larger than the 80–120% range required by the European Medicines Agency. Consequently, UHPSFC results are valid and could be used for the control of active substance in a finished pharmaceutical product. Finally, UHPSFC validated method was used to analyse real samples and gave similar results than the reference method (UHPLC). [less ▲]

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See detailMéthodes chromatographiques génériques de criblage pour lutter contre les médicaments de qualité inférieure
Habyalimana, Védaste; Kalenda Tshilombo, Nicodème; Dispas, Amandine ULg et al

in Spectra Analyse (2014), 43

Poor quality medicines are a danger and a threat to public health. In this context, several generic analytical methods have been developed to screen molecules of interest grouped by pharmacological class ... [more ▼]

Poor quality medicines are a danger and a threat to public health. In this context, several generic analytical methods have been developed to screen molecules of interest grouped by pharmacological class using an innovative strategy based on design of experiments followed in some cases by independent component analysis and calculation of design space. Once validated via the classical total error measurement approach, these methods were applied to quantify antimalarial, non-steroidal anti-inflammatory and antibiotic medicines. Alarming results regarding the dosage of these drugs widely used by people confirm the need to fight against this scourge. [less ▲]

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See detailImprovement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: A case of a learning process
Hubert, Cédric ULg; Lebrun, Pierre ULg; Houari, Sabah ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 88

The understanding of the method is a major concern when developing a stability-indicating method and even more so when dealing with impurity assays from complex matrices. In the presented case study, a ... [more ▼]

The understanding of the method is a major concern when developing a stability-indicating method and even more so when dealing with impurity assays from complex matrices. In the presented case study, a Quality-by-Design approach was applied in order to optimize a routinely used method. An analytical issue occurring at the last stage of a long-term stability study involving unexpected impurities perturbing the monitoring of characterized impurities needed to be resolved. A compliant Quality-by-Design (QbD) methodology based on a Design of Experiments (DoE) approach was evaluated within the framework of a Liquid Chromatography (LC) method. This approach allows the investigation of Critical Process Parameters (CPPs), which have an impact on Critical Quality Attributes (CQAs) and, consequently, on LC selectivity. Using polynomial regression response modeling as well as Monte Carlo simulations for error propagation, Design Space (DS) was computed in order to determine robust working conditions for the developed stability-indicating method. This QbD compliant development was conducted in two phases allowing the use of the Design Space knowledge acquired during the first phase to define the experimental domain of the second phase, which constitutes a learning process. The selected working condition was then fully validated using accuracy profiles based on statistical tolerance intervals in order to evaluate the reliability of the results generated by this LC/ESI-MS stability-indicating method. A comparison was made between the traditional Quality-by-Testing (QbT) approach and the QbD strategy, highlighting the benefit of this QbD strategy in the case of an unexpected impurities issue. On this basis, the advantages of a systematic use of the QbD methodology were discussed. [less ▲]

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See detailQuantitative approaches based on Surface-Enhanced Raman Scattering (SERS) and Surface-Enhanced Raman Chemical Imaging (SER-CI)
De Bleye, Charlotte ULg; Sacre, Pierre-Yves ULg; Dumont, Elodie ULg et al

Conference (2014, January 20)

Surface-enhanced Raman scattering (SERS), discovered in 1978, is a recent technique enabling to circumvent the main limitations of classical Raman spectroscopy by dramatically exalting the Raman ... [more ▼]

Surface-enhanced Raman scattering (SERS), discovered in 1978, is a recent technique enabling to circumvent the main limitations of classical Raman spectroscopy by dramatically exalting the Raman scattering of the target molecules which are adsorbed or very closed to metallic surfaces while reducing the fluorescence impact on spectra [1]. This technique combines the sensitivity of the fluorescence keeping the structural information of molecules obtained from the SERS spectrum [2]. This last point allows to implement multiplex analyses. Moreover, it is possible to perform Surface-enhanced Raman chemical imaging (SER-CI) analyses which enable to acquire a visual representation of samples combining spectral and spatial measurements. Therefore SERS could become an attractive technique in numerous fields such as pharmaceutical and biomedical research. In this context, the feasibility of developing quantitative approaches using SERS and SER-CI on a pharmaceutical model was studied. The aim was to develop methods allowing the quantification of 4-aminophenol (4-AP) in a pharmaceutical formulation based on paracetamol. 4-AP is the main impurity of paracetamol and is actively research because of its toxicity. This pharmaceutical model was first investigated using SERS and a quantitative method enabling to quantify 4-AP from 3 to15 µg/mL was developed and validated using the standard addition method as a calibration method [3]. From these results, the possibility of developing a quantitative approach using SER-CI was investigated. Tablets based on paracetamol comprising different concentrations of 4-AP were prepared. Different ways to cover the sample surface by the SERS substrate were tested and a homogeneity study was performed to improve the repeatability of SER-CI analyses. Different spectral intensity normalizations were also tested in order to optimize the SER-CI method. Finally, a quantitative approach using SER-CI was developed allowing the quantification of 4-AP from 0.025% to 0.2% (w/w) in paracetamol tablets [4]. This first quantitative approach could pave the way to quantitative analysis of small molecules using SER-CI in complex matrices. References [1] P.L. Stiles, J.A. Dieringer, N.C. Shah, R.P. Van Duyne, Annu. Rev. Anal. Chem. 1 (2008) 601-626. [2] R.F. Aroca, R.A. Alvarez-Puebla, N. Pieczonka, S. Sanchez-Cortez, J.V. Garcia-Ramos, Adv. Colloid Interface Sci. 116 (2005) 45-61. [3] C. De Bleye, E. Dumont, E. Rozet, P.-Y. Sacré, P.-F. Chavez, L. Netchacovitch, G. Piel, Ph. Hubert, E. Ziemons, Talanta 116 (2013) 899-905. [4] C. De Bleye, P.-Y. Sacré, E. Dumont, L. Netchacovitch, P.-F. Chavez, G. Piel, P. Lebrun, Ph. Hubert, E. Ziemons, J. Pharm. Biomed. Anal. (in Press) [less ▲]

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See detailRobust method optimization strategy – a useful tool for method transfer: the case of SFC
Dispas, Amandine ULg; Lebrun, Pierre ULg; Andri, Bertyl ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2014), 88

The concept of Quality by Design (QbD) is now well established in pharmaceutical industry and should be applied to the development of any analytical methods. In this context, the key concept of Design ... [more ▼]

The concept of Quality by Design (QbD) is now well established in pharmaceutical industry and should be applied to the development of any analytical methods. In this context, the key concept of Design Space (DS) was introduced in the field of analytical method optimization. In chromatographic words, the DS is the space of chromatographic conditions that will ensure the quality of peaks separation, thus DS is a zone of robustness. In the present study, the interest of robust method optimization strategy was investigated in the context of direct method transfer from sending to receiving laboratory. The benefit of this approach is to speed up the method life cycle by performing only one quantitative validation step in the final environment of method use. A Supercritical Fluid Chromatography (SFC) method previously developed was used as a case study in this work. Moreover, the interest of geometric transfer was investigated simultaneously in order to stress a little bit more the transfer exercise and, by the way, emphasize the additional benefit of DS strategy in this particular context. Three successful transfers were performed on two column geometries. In order to compare original and transferred methods, the observed relative retention times (RT) were modelled as a function of the predicted relative RT and of the method type (original or transferred). The observed relative RT of the original and transferred methods are not statistically different and thus the method transfer is successfully achieved thanks to the robust optimization strategy. Furthermore, the analytical method was improved considering analysis time (reduced five times) and peak capacity (increased three times). To conclude, the advantage of using a DS strategy implemented for the optimization and transfer of SFC method was successfully demonstrated in this work. [less ▲]

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See detailA new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms
Sacre, Pierre-Yves ULg; Lebrun, Pierre ULg; Chavez, Pierre-François ULg et al

in Analytica Chimica Acta (2014), 818

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of ... [more ▼]

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution. Actually, most authors assess homogeneity using parameters of the histogram of intensities (e.g. mean, skewness and kurtosis). However, this approach does not take into account spatial information and loses the main advantage of imaging. To overcome this limitation, we propose a new criterion: Distributional Homogeneity Index (DHI). DHI has been tested on simulated maps and formulation development samples. The distribution maps of the samples were obtained without validated calibration model since different formulations were under investigation. The results obtained showed a linear relationship between content uniformity values and DHI values of distribution maps. Therefore, DHI methodology appears to be a suitable tool for the analysis of homogeneity of distribution maps even without calibration during formulation development. [less ▲]

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See detailApplication of an innovative design space optimization strategy to thedevelopment of LC methods for the simultaneous screening of antibiotics to combat poor quality medicines
Mbinze Kindenge, Jérémie ULg; Dispas, Amandine ULg; Lebrun, Pierre ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 85

The poor quality of medicines is a crucial problem of public health. Therefore, it is important to haveanalytical tools to attend decisions of the legal authorities while combating this offense. In this ... [more ▼]

The poor quality of medicines is a crucial problem of public health. Therefore, it is important to haveanalytical tools to attend decisions of the legal authorities while combating this offense. In this context,the main objective of this study was to develop generic methods able to trace, screen and determineseveral antibiotics and common associated molecules by mean of liquid chromatographic techniques.For that purpose, an innovative Design Space optimization strategy was applied, targeting 16 antibioticsand 3 beta-lactamase inhibitors. The robustness of the developed method allowed using its use in anenvironment where operational factors such as temperature are not easy to control and eased its trans-fer to Ultra High Performance Liquid Chromatography. To demonstrate its ability to quantify the targetedmolecules, the developed and transferred method was fully validated for two active ingredients com-monly used in association, sulbactam and ceftriaxone, using the accuracy profile as decision tool. Basedon this successful step, the method was then used for the quantitative determination of these two activeingredients in three pharmaceutical brands marketed in the Democratic Republic of Congo. Two out ofthe three pharmaceutical products did not comply with the specifications [less ▲]

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See detailNiveaux du plomb sanguin, du plomb urinaire, de l’acide δ-aminolévulinique et des porphyrines urinaires chez les personnes vivant à Kinshasa, R.D. Congo : une étude pilote de biosurveillance
Mputu Malolo, Corneille-Liévin; Ndelo di Phanzu, Josaphat; Marini Djang'Eing'A, Roland ULg et al

Conference (2013, October 18)

Objectives: Existing naturally in the earth’s crust, Lead is a widely used heavy metal. It is an environment toxicant that may deleteriously affect nervous, hematopoietic, skeletal, renal, endocrine and ... [more ▼]

Objectives: Existing naturally in the earth’s crust, Lead is a widely used heavy metal. It is an environment toxicant that may deleteriously affect nervous, hematopoietic, skeletal, renal, endocrine and reproductive systems. Lead is classified in its inorganic form as possible human carcinogen (group 2A) by IARC. Exposure to lead in the environment continues to be a serious public health problem for all ages. Children are particularly susceptible to lead poisoning. They absorb more lead from their environment and their developing central nervous systems are vulnerable to the toxicant. During the last twenty years, important measures of public health were undertaken in several countries to decrease lead exposure. In the best of our knowledge, this is not the case in D.R. Congo. A study indicated a relatively important lead impregnation of the Kinshasa population (mean 120 μg/L). However, there have been no reported studies in the evaluation of the relationship between urinary lead, urinary δ-aminolevulinic acid (δ-AlaU) and urinary porphyrins and lead blood level in Congolese people. This is the aim of this study targeting at first people living in Kinshasa. Methods: Blood lead and urinary lead levels were measured using inductively coupled plasma mass spectrometry. The Bio-Rad ALA/PBG by Column Test and spectrophotometer method were used to quantify the concentration of δ-Ala in urine. The separation of porphyrins was carried out by HPLC coupled with fluorescence detector. Results: 37% of studied population presented blood lead levels above the 100 μg/L threshold (geometric mean: 133.29 μg/L) with a higher concentration in women than in men (140.30 μg/L vs 130.78 μg/L). 50% of children (0-17 years) presented blood lead levels above the 100 μg/L threshold and 43% of the same population presented blood lead levels above 50 μg/L as accepted nowadays in US. In the adult population, some targeted occupations were found to be associated with high blood lead. A small correlation was observed between urinary lead and blood lead, but no correlation was noticed between δ-AlaU and Porphyrins with lead blood levels. Conclusion: This study confirmed a relatively important Pb impregnation of the Kinshasa population and the existence of a major public health issue requiring corrective actions and the implementation of an appropriate regulation. Also, urinary lead, urinary δ-Ala and urinary porphyrins seems to not to be sensitive markers for monitoring exposure to lead. [less ▲]

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See detailRobust SFC method optimization using design space strategy
Dispas, Amandine ULg; Lebrun, Pierre ULg; Hubert, Philippe ULg

Conference (2013, October)

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See detailVibrational spectroscopy as PAT compliant tools
Ziemons, Eric ULg; De Bleye, Charlotte ULg; Chavez, Pierre-François ULg et al

Scientific conference (2013, September 10)

In the last decades, intensive research and development dealing with NIR and Raman spectroscopy have taken place in industrial field, espacially in pharmaceutical industry. This enthusiasm can be ... [more ▼]

In the last decades, intensive research and development dealing with NIR and Raman spectroscopy have taken place in industrial field, espacially in pharmaceutical industry. This enthusiasm can be explained by the fact that this technique are regarded as promising and attractive tools in PAT, R&D and Green Chemistry frameworks. Their advantages such as non-invasive, non-destructive, fast data acquisition, minization of sample preparation step and the use of probes in on-line, in-line and at-line are expected to reach the aims of PAT, R&D and Green Chemistry. [less ▲]

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See detailA new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms
Sacre, Pierre-Yves ULg; Lebrun, Pierre ULg; Chavez, Pierre-François ULg et al

Conference (2013, September)

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Several techniques exist to assess this ... [more ▼]

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Several techniques exist to assess this homogeneity, the most used and recognized being HPLC. However, these techniques are destructive, time consuming and uses a lot of organic solvents. Vibrational spectroscopies are promising green chemistry techniques that may replace HPLC for several analysis tasks thanks of their rapid, non-destructive and non-pollutant characteristics. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution. When dealing with hyperspectral imaging, multivariate data analysis is necessary to extract the concentration map of the compound of interest that will be used to assess sample homogeneity. Actually, most authors assess homogeneity using parameters of the histogram of intensities (e.g. mean, skewness and kurtosis). However, this approach does not take into account spatial information and loses the main advantage of imaging. Recently, Rosas et al. proposed a homogeneity index based on the Poole index. However, it necessitates cutting the maps in non-overlapping macropixels and is therefore quickly limited with small maps. To overcome this limitation, we propose a new criterion that combines Continuous Level Moving Blocks and homogeneity curves with a randomization step to assess the distributional homogeneity. This distributional homogeneity index (DHI) enables analysis of hyperspectral maps without apriori knowledge. It has been applied on five pharmaceutical formulations with different blending conditions. The uniformity content values of the API (present at a concentration of 7% w/w) measured by HPLC ranged from RSD: 0.46% to 11.04%. Ten tablets per formulation have been mapped over a region of interest of 4 mm². After extracting pure spectra by MCR-ALS, the concentration maps of the API were computed using classical least squares analysis. DHI have been computed with a hundred simulations for the randomization step for each concentration map. Afterwards, a mean DHI and standard deviation values were computed per formulation. A linear relationship has been observed between the RSD values and the mean DHI. These results enabled us to select the formulation with the best homogeneity. Further experiments are in progress to check whether hyperspectral imaging combined with DHI could be used in routine to assess blending homogeneity of well-known formulations. [less ▲]

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See detailInnovative Methodology for the Definition of Design Spaces of Chromatographic Methods
Rozet, Eric ULg; Debrus, B; Lebrun, Pierre ULg et al

Conference (2013, June 06)

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, … [less ▲]

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