References of "Lebrun, Pierre"
     in
Bookmark and Share    
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 45 (26 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 77 (28 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 59 (9 ULg)
Full Text
Peer Reviewed
See detailRobust SFC method optimization using design space strategy
Dispas, Amandine ULg; Lebrun, Pierre ULg; Hubert, Philippe ULg

Conference (2013, October)

Detailed reference viewed: 30 (4 ULg)
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 ▲]

Detailed reference viewed: 47 (20 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 64 (23 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 51 (6 ULg)
Full Text
Peer Reviewed
See detailA BAYESIAN PROBABILITY CRITERION TO ASSESS ANALYTICAL RESULTS RELIABILITY
Rozet, Eric ULg; Lebrun, Pierre ULg; Boulanger, B et al

Conference (2013, May 21)

In pharmaceutical and biomedical 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 ... [more ▼]

In pharmaceutical and biomedical 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 [1] where they have to demonstrate that they are fit for their final purpose, i.e. providing accurate results: where is the analytical result, is the theoretical unknown true concentration of analyte in the sample analyzed and a regulatory acceptance limit. 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 [2]. 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 [3]. However none of these decision approaches allow knowing the probability to obtain accurate results over the whole concentration range of interest: is a vector of parameters and Pmin is a minimum reliability probability. Frequentist approximations have been proposed to estimate this probability but only at the concentration levels experimentally tested [4,5]. 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, but it 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 one concentration level at a time frequentist approaches [4,5]. [1] International Conference on Harmonization (ICH) of Technical Requirements for registration of Pharmaceuticals for Human Use Topic Q2 (R1): Validation of Analytical Procedures: Text and Methodology, Geneva, 2005. [2] A. Bouabidi and al., J. Chromatogr. A, 1217 (2010) 3180. [3] Ph. Hubert and al., J. Pharm. Biomed. Anal., 36 (2004) 579. [4] W. Dewé and al., Chemometr. Intell. Lab. Syst. 85 (2007) 262. [5] B. Govaerts and al., Qual. Reliab. Engng. Int. 24 (2008) 667. [less ▲]

Detailed reference viewed: 42 (4 ULg)
Full Text
Peer Reviewed
See detailDesign Spaces for Analytical Methods
Rozet, Eric ULg; Lebrun, Pierre ULg; Debrus, Benjamin ULg et al

in Trends in Analytical Chemistry (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 ▲]

Detailed reference viewed: 452 (31 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 221 (62 ULg)
Full Text
See detailBlood lead, urinary lead, urinary δ-aminolevulinic acid and urinary porphyrins levels among people living in kinshasa, D.R. Congo : a pilot biomonitoring study
Mputu Malolo, Corneille-Liévin; Ndelo di Phanzu, Josaphat; Marini Djang'Eing'A, Roland ULg et al

in Acta Clinica Belgica (2013), 68(6), 475

Detailed reference viewed: 29 (2 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 89 (24 ULg)
Full Text
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 ▲]

Detailed reference viewed: 35 (2 ULg)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 170 (28 ULg)