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See detailPrinciples of Analytical Quality by Design for the development of quality control methods in a pharmaceutical context
Deidda, Riccardo ULiege; Avohou, Tonakpon Hermane ULiege; Jambo, Hugues ULiege et al

Conference (2019, May 20)

Pharmaceutical regulatory agencies increasingly require the implementation of systematic approaches covering the entire life-cycle of pharmaceutical products, from manufacturing processes to quality ... [more ▼]

Pharmaceutical regulatory agencies increasingly require the implementation of systematic approaches covering the entire life-cycle of pharmaceutical products, from manufacturing processes to quality control tests. In 2009, the International Council for Harmonisation (ICH) of technical requirements for pharmaceuticals for human use proposed a systematic approach named “Quality by Design” (QbD) to be implemented in the pharmaceutical field [1]. In this context, the QbD strategy have been progressively applied also to other aspects of the pharmaceutical chain, such as the analytical method development in quality control laboratories. The QbD applied to analytical chemistry is commonly named “Analytical Quality by Design” (AQbD) and in the last decade it has been widely applied in academia for the development of separation methods, involving different techniques such as LC, CE as well as SFC. However, its implementation in quality control laboratories still remains limited and then its advantages not completely exploited. Indeed, this approach presents a lot of conveniences, such as the deep knowledge acquired during the method development/optimisation by studying how critical method parameters (CMPs) affect critical method attributes (CMAs). Moreover, this strategy allows the possibility to define a method operable design region (MODR) consisting of a multitude of possible working points and for each of them a specific probability of success (π) is given. Indeed, the concept of risk plays a central role in this strategy as the MODR is considered of a zone of theoretical robustness limited by the so-called edges of failure, outside which the method performances are not accepted [2]. This presentation focuses first on the theoretical aspects regarding each step of this strategy. The analytical target profile definition, the selection of CMPs and CMAs, as well as screening and optimisation of CMPs and MODR definition are accurately described and illustrated. Some considerations about the choice of the working point, its validation and the planning of an efficient control strategy are also given. In the second part of this presentation all these concepts are once again showcased but from a practical point of view, by giving two concrete case-studies following the AQbD approach. The first one concerns the development of a liquid chromatography coupled to UV (LC-UV) method aimed at quantifying the cannabinoids content in cannabis extracts used for medicinal purposes [3]. The second one shows the approach applied to the development of a stability indicating method by using another analytical technique, the supercritical-fluid-chromatography coupled to mass spectrometry (SFC-MS). This latter is intended to be used for the quantification of hydro-soluble vitamins and amino acids in a complex medium. References [1] ICH Harmonised Tripartite guideline. Pharmaceutical Development Q8(R2) (2009) International Council for harmonisation of technical Requirements for Pharmaceutical for Human Use. [2] R. Deidda, S. Orlandini, Ph. Hubert, C. Hubert, Risk-based approach for method development in pharmaceutical quality control context: A critical review, J. Pharm. Biomed. Anal. 161 (2018) 110-121. [3] R. Deidda, H.T. Avohou, R. Baronti, P.L. Davolio, B. Pasquini, M. Del Bubba, C. Hubert, Ph. Hubert, S. Orlandini, S. Furlanetto, Analytical quality by design: Development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts, J. Pharm. Biomed. Anal. 166 (2019) 326-335. [less ▲]

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See detailDéveloppement d’une méthode SFC-MS pour le dosage de vitamines en matrice complexe : Application de la stratégie « Analytical Quality by Design »
Deidda, Riccardo ULiege; Mignolet, Marie ULiege; Jambo, Hugues ULiege et al

Conference (2019, March 26)

Les agences réglementaires pharmaceutiques exigent de plus en plus fréquemment la mise en œuvre des approches systématiques couvrant l'ensemble du cycle de vie des produits pharmaceutiques, des processus ... [more ▼]

Les agences réglementaires pharmaceutiques exigent de plus en plus fréquemment la mise en œuvre des approches systématiques couvrant l'ensemble du cycle de vie des produits pharmaceutiques, des processus de fabrication jusqu’aux tests de contrôle qualité. En 2009, the International Council for Harmonisation of Technical Requirements for Pharmaceutical for Human Use (ICH) a proposé une approche systématique appelée « quality by design » appliqué à la production pharmaceutique. Ce concept étendu aux méthodes analytiques, « analytical quality by design (AQbD) », fait l’objet de recherches approfondies dans les milieux universitaires. Cette stratégie est appliquée aux méthodes séparatives telles que la LC, la CE et la SFC, mais reste actuellement relativement peu étendu au niveau des laboratoires de contrôle de qualité des industries pharmaceutiques. Pourtant, la stratégie AQbD présente un avantage considérable. En effet, elle permet d’obtenir une connaissance approfondie de la méthode et ce, tout au long du développement et de l’optimisation de celle-ci. L’évaluation des paramètres critiques de la méthode (CMPs) sur base de ses attributs critiques (CMAs) rend possible la définition d’une région opérationnelle probable (MODR). Cette région consiste en une multitude de conditions de travail possibles, où pour chacune d’elles, une probabilité de succès spécifique (π) est attribuée. En effet, la notion de risque joue un rôle primordial permettant ainsi d’assurer la robustesse de la méthode tout au long de son cycle de vie. Ce projet s'est concentré sur les aspects pratiques de cette stratégie en donnant un exemple concret de développement d'une méthode SFC-MS (entièrement conforme à la stratégie AQbD) pour une étude de stabilité d’une matrice complexe dans un contexte de contrôle de la qualité. Le développement de la méthode AQbD commence par la définition des requis analytiques (ATP), qui représentent l'objectif de la méthode dans le cadre de son utilisation spécifique. Dans ce cas-ci, l'échantillon étudié est constitué d'un milieu de culture cellulaire complexe constitué de plus de 40 composés et pour lequel les données relatives à la composition qualitative et quantitative ne sont pas complètement disponibles. Ensuite, plusieurs vitamines hydrophiles doivent être quantifiées afin de contrôler la stabilité de ce milieu. Dans la mesure où un effet matrice conséquent avait été mis en évidence dans une étude antérieure (UHPLC-MS), la chromatographie en phase supercritique couplée à la spectrométrie de masse a été choisie comme technique analytique alternative. En effet, dans certaines conditions, la SFC-MS peut être moins affectée par les effets de matrice que la LC-MS [3]. Afin de mettre en place correctement la stratégie AQbD, des expériences préliminaires ont été menées de manière rationnelle dans le but de sélectionner les meilleures conditions de départ. Dans cette phase, appelée « scouting », plusieurs phases stationnaires ont été testées et les colonnes les plus prometteuses ont été sélectionnées afin de mener des essais complémentaires. Différents gradients et modificateurs ont également été préalablement testés afin de sélectionner les conditions permettant l’élution des analytes d’intérêt. En effet, les vitamines ciblées présentent un comportement chromatographique varié entrainant des rétentions très différentes. Les critères de séparation et l'effet de matrice ont été étudiés et optimisés, en prenant en compte non seulement les aspects chromatographiques mais également ceux liés à la détection par MS. Dans ce contexte, une phase « screening » a été menée pour identifier les CMPs ayant une incidence importante sur les CMAs. Ensuite, les CMPs ont fait l’objet d’une étude approfondie au cours de la phase d’optimisation afin de mieux comprendre leur influence sur les performances de séparation et détection de la méthode. Cette dernière partie permettra d’introduire le concept de risque en appliquant des simulations de Monte-Carlo et une approche bayésienne capable d’évaluer l’incertitude du model proposé [4]. Par conséquent, une MODR liée à une probabilité de réussite définie, en termes de respect des spécifications données aux CMAs, sera obtenue. La MODR représente une zone de robustesse théorique dont chacun des points peut être sélectionné comme une condition opératoire en vue d’être validée. Cela démontre l'utilité de cette approche pour la mise au point d'une méthode analytique appliquée aux études de stabilité et ce, dans un contexte de contrôle de la qualité [2]. References [1] ICH Harmonised Tripartite guideline. Pharmaceutical Development Q8(R2) (2009) International Council for harmonisation of technical Requirements for Pharmaceutical for Human Use. [2] R. Deidda, S. Orlandini, Ph. Hubert, C. Hubert, Risk-based approach for method development in pharmaceutical quality control context: A critical review, J. Pharm. Biomed. Anal. 161 (2018) 110-121. [3] V. Desfontaine, F. Capetti, R. Nicoli, T. Kuuranne, J.-L. Veuthey, D. Guillarme, Systematic evaluation of matrix effects in supercritical fluid chromatography versus liquid chromatography coupled to mass spectrometry for biological samples, J. Chromatogr. B 1079 (2018) 51-61. [4] E. Rozet, P. Lebrun, Ph. Hubert, B. Debrus, B. Boulanger, Design Spaces for analytical methods, Trends Anal. Chem. 42 (2013) 157-167. [less ▲]

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See detailProcess Analysis - Overview
Ziemons, Eric ULiege; Hubert, Cédric ULiege; Hubert, Philippe ULiege

in Miro, Manuel; Worsfold, Paul; Townshend, Alan (Eds.) et al Encyclopedia of Analytical Science (2019)

Process analysis is the application of analytical science to the monitoring and control of industrial processes. The data obtained from process analysis allow the optimization, dynamic changes, monitoring ... [more ▼]

Process analysis is the application of analytical science to the monitoring and control of industrial processes. The data obtained from process analysis allow the optimization, dynamic changes, monitoring or quality control of industrial processes by providing information from which the chemical and/or physical composition of the process stream can be inferred. [less ▲]

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See detailProcess Analysis: Maintenance, Reliability, and Training
Hubert, Cédric ULiege; Widart, Joëlle ULiege; Ziemons, Eric ULiege et al

in Encyclopedia of Analytical Science 3rd Edition (2019)

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See detailOptimisation of a surface enhanced Raman scattering method using design of experiments and Bayesian design space modelling
Deidda, Riccardo ULiege; Avohou, Tonakpon Hermane ULiege; Kasemiire, Alice ULiege et al

Poster (2019, January 30)

Surface enhanced Raman scattering (SERS) is an alternative technique based on Raman spectroscopy, which has been increasingly applied to pharmaceutical analytical chemistry in the last decade. It consists ... [more ▼]

Surface enhanced Raman scattering (SERS) is an alternative technique based on Raman spectroscopy, which has been increasingly applied to pharmaceutical analytical chemistry in the last decade. It consists in enhancing the Raman effect by performing analyses using metallic surfaces, such as silver and gold colloids, on which the target molecules are adsorbed to be detected. It has been observed that in this way, an enhancement factor of 103-106 times can be obtained and the lack of sensibility related to conventional Raman scattering overcome [1]. Nowadays, design of experiment (DoE) is widely employed for modelling phenomena in analytical method development and optimisation, especially in the context of separation techniques. It is a structured approach that allows correlating key responses to controllable variables. Ideally, a certain number of factors may affect the critical method attributes (CMAs) of an analytical process in a negative or positive way. These factors are named critical method parameters (CMPs). DoE is employed, as a chemometric tool, to individuate CMPs and then, deeply study how they affect the process under study. To do so, CMAs are linked to CMPs by a regression model built by means of multivariate linear or partial least squares regression. Generally, the designs can be classified in two categories: screening and optimization designs. The formers are generally implemented when a high number of parameters are supposed to influence the analytical process and no much prior information is available. They result in useful tools to study the effects of both continuous and discontinuous factors. Instead, the optimisation designs are principally used to study wisely selected continuous factors [2]. The design space (DS) is defined as a multidimensional area in which the specifications given to the CMAs are met with a defined level of probability. Obviously, the larger the DS is, the more robust the method is. Its computation is achieved by several approaches, such as Monte-Carlo simulations, Bayesian methods as well as bootstrapping techniques [3]. The aim of this project was to combine and apply two potent chemometric tools such as DoE and Bayesian DS to SERS method development and optimisation. [1] Cailletaud, J., De Bleye, C., Dumont, E., Sacré, P.-Y., Netchacovitch, L., Gut, Y., Boiret, M., Ginot, Y.-M., Hubert, P., Ziemons, E., Critical review of surface-enhanced Raman spectroscopy applications in the pharmaceutical field. J. Pharm. Biomed. Anal. 147, 458-472, 2018. [2] Sahu, P.K., Ramisetti, N.R., Cecchi, T., Swain, S., Patro, C.S., Panda, J., An overview of experimental design in HPLC method development and validation, J. Pharm. Biomed. Anal. 147, 590-611, 2018. [3] Deidda, R., Orlandini, S., Hubert, P., Hubert, C., Risk-based approach for method development in pharmaceutical quality control context: A critical review. J. Pharm. Biomed. Anal. 161, 110-121, 2018. [less ▲]

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See detailAnalytical quality by design: development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts
Deidda, Riccardo ULiege; Avohou, Tonakpon Hermane ULiege; Baronti, Roberto et al

in Journal of Pharmaceutical and Biomedical Analysis (2019)

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are considered as the most interesting cannabinoids in Cannabis sativa L. for the clinical practice. Since 2013, the Italian law allows pharmacists ... [more ▼]

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are considered as the most interesting cannabinoids in Cannabis sativa L. for the clinical practice. Since 2013, the Italian law allows pharmacists to prepare and dispense cannabis extracts to patients under medical prescription, and requires the evaluation of CBD and Δ9-THC content in cannabis extracts before sale. Cannabis olive oil extracts are prepared from dried female cannabis inflorescences, but a standard protocol is still missing. In this study, a fast RP-HPLC/UV method has been developed to quantify CBD and Δ9-THC in cannabis olive oil extracts. The analytical quality by design strategy has been applied to the method development, setting critical resolution and total analysis time as critical method attributes (CMAs), and selecting column temperature, buffer pH and flow rate as critical method parameters. Information from Doehlert Design in response surface methodology combined to Monte-Carlo simulations led to draw the risk of failure maps and to identify the method operable design region. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and then implemented in routine analysis. A control strategy based on system control charts was planned to monitor the developed method performances. Evaluation data were recorded over a period of one year of routine use, and both the CMAs showed values within the specifications in every analysis performed. Hence, a new risk evaluation for the future performances of the method was achieved by using a Bayesian approach based on the routine use data, computing the future distribution of the two CMAs. Finally, a study focusing on the monitoring of CBD and Δ9-THC concentrations in cannabis olive oil extracts was carried out. The developed method was applied to 459 extracts. The statistical analysis of the obtained results highlighted a wide variability in terms of concentrations among different samples from the same starting typology of cannabis, underlining the compelling need of a standardised procedure to harmonise the preparation of the extracts. [less ▲]

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See detailControl strategy applied to a LC-DAD quality control method as part of the analytical quality by design approach: one year of routine use
Deidda, Riccardo ULiege; Avohou, Tonakpon Hermane ULiege; Orlandini, Serena et al

Scientific conference (2018, December 19)

The analytical quality by design approach has been previously applied to the method development. The analytical target profile (ATP) was defined as the baseline separation of the two analytes of interest ... [more ▼]

The analytical quality by design approach has been previously applied to the method development. The analytical target profile (ATP) was defined as the baseline separation of the two analytes of interest, cannabidiol and Δ9-tetrahydrocannabinol. The critical method attributes (CMAs) were set as the critical resolution between a peak pair (Rs) and the analysis time (t). Critical method parameters were studied, and the response surface methodology was used to optimise the method. The method operable design region (MODR) was obtained by Monte-Carlo simulations and risk of failure maps setting the probability of meeting the specifications (Rs ≥ 0.85 and t ≤ 6 min) at 95%. A working point within the MODR was chosen, validated, and implemented in routine analyses. The information collected during the optimisation studies was conveyed to the planning of the control strategy consisting in system suitability test and control charts. The CMAs used for method optimisation were chosen as system suitability criteria to monitor the behaviour of the method performance. The evaluation was conducted over a period of one year of routine use. Both the CMAs showed values within the specifications in each analysis performed. On the basis of these results, a new and more complete risk evaluation was achieved. [less ▲]

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See detailSFC-MS for the quality control of cannabis: addressing the potential adulteration with synthetic cannabinoids
Jambo, Hugues ULiege; Dispas, Amandine ULiege; Avohou, Tonakpon Hermane ULiege et al

Scientific conference (2018, December 19)

Recent years have been the stage to a shift in cannabis policies and trends that have impacted cannabis usage and public perception. On the other hand, there has also been a rise in the development and ... [more ▼]

Recent years have been the stage to a shift in cannabis policies and trends that have impacted cannabis usage and public perception. On the other hand, there has also been a rise in the development and distribution of synthetic cannabinoids which are synthetic compounds that also act on the endocannabinoid receptors. They are mostly used as recreational drugs and because their potency and toxicity are not always known, they can lead to severe adverse effects after consumption. The detection of cannabis counterfeiting with synthetic cannabinoids is essential to produce safe cannabis-based medicines and we aimed to develop a generic supercritical fluid chromatography hyphenated to mass spectrometry (SFC-MS) method that could help in detecting such adulterations using representative synthetic cannabinoids from multiple classes. Method development started with a screening of stationary phases using seven different SFC-dedicated columns. Then, an optimization following analytical quality-by-design principles was performed followed by an assessment of the quantitative performances with a validation according to the total-error strategy. This innovative tool should prove useful in the context of counterfeit drugs tracking in the challenges to come. [less ▲]

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See detailSFC-MS as a preventive tool for the quality control of potentially adulterated cannabis with synthetic cannabinoids
Jambo, Hugues ULiege; Dispas, Amandine ULiege; Avohou, Tonakpon Hermane ULiege et al

Conference (2018, October 19)

Recent years have been the stage to a shift in cannabis policies and trends that have impacted cannabis usage and public perception. It has also caught the attention of the pharmaceutical industry and ... [more ▼]

Recent years have been the stage to a shift in cannabis policies and trends that have impacted cannabis usage and public perception. It has also caught the attention of the pharmaceutical industry and cannabis is increasingly evaluated as a medicine in the treatment of various conditions. On the other hand, there has also been a rise in the development and distribution of synthetic cannabinoids which are synthetic compounds that have the same pharmacological action as the natural cannabinoids found in the plant. They are mostly used as recreational drugs and because their potency and toxicity are not always known, they can lead to severe adverse effects after consumption. The detection of counterfeiting cannabis with synthetic cannabinoids is essential to produce safe cannabis-based medicines. Our aim was to develop a generic supercritical fluid chromatography hyphenated to mass spectrometry (SFC-MS) method that could help in detecting such adulterations using representative synthetic cannabinoids from multiple classes. Method development started with a screening of stationary phases using seven different SFC-dedicated columns. The Torus 1-AA (amino-anthracene) provided the best retention and resolution for the analytes and was selected for the study. Likewise, the mobile phase modifier composition (methanol/water 98:2 v/v) was set after these preliminary tests. The next step performed was the optimization of the method using a design of experiments (DoE) and Bayesian design space (DS) methodology. The temperature, pressure, isocratic and gradient time were selected as parameters for the DoE (central composite design). The separation criterion (S) was set to -0.5 to maximize the separation capacity of the generic method. This Quality by Design (QbD) approach is advantageous as it permits the testing of various conditions within the design space (DS) to achieve a desirable separation since unassessed compounds will probably be encountered during routine analysis. Finally, the quantitative performances were demonstrated by means method validation based on total error approach for the quantification of a selected synthetic cannabinoid in fiber type cannabis plant matrix. Sample preparation was performed with solid-liquid extraction (SLE) followed by filtration and dilution. The acceptance limits were set at ±15% and the β-expectation tolerance limits at 90 % probability level. The results show that the method is valid over the whole dosing range assessed of 2.5 - 7.5% (w/w) with the LOD equal to 14.40 ng/mL. The implementation of this method should be straightforward considering the ease of sample preparation, the use of a fast and green SFC separation and the high specificity and sensitivity achieved with mass spectrometry. Ensuring medicinal cannabis quality is challenging and this work adds an innovative tool that should prove useful in the context of counterfeit drugs tracking. [less ▲]

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See detailAnalytical Quality by Design: development and control strategy for a RP-HPLC method implemented in routine to evaluate the cannabinoids content in cannabis olive oil extracts
Deidda, Riccardo ULiege; Avohou, Tonakpon Hermane ULiege; Orlandini, Serena et al

Poster (2018, September)

Cannabis sativa L. is characterized by having a remarkable number of chemical compounds: cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ-9-THC) are the cannabinoids considered as the most interesting ... [more ▼]

Cannabis sativa L. is characterized by having a remarkable number of chemical compounds: cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ-9-THC) are the cannabinoids considered as the most interesting for the clinical practice. Since 2015, the Italian law allows pharmacists to prepare and dispense cannabis extracts to patients under medical prescription. Cannabis olive oil extracts are prepared as magistral preparation from dried cannabis inflorescences, but a standard protocol is still missing. In fact, each pharmacist is allowed to prepare magistral preparations according to his/her own technical experience, leading to products with a wide variability in cannabinoids concentrations. The evaluation of Δ-9-THC and CBD content in cannabis extracts before sale is a regulatory requirement in Italy. Consequently, a quick and simple RP-HPLC/UV method has been developed to quantify them in the cannabis olive oil extracts. The analytical quality by design principles (AQbD) have been applied to the method development [1]. The analytical target profile (ATP) was defined by the baseline separation of CBD and Δ-9THC. The critical method attributes (CMAs) were set as the critical resolution between a peak pair (Rs) and the analysis time (t). Column temperature, pH of buffer part of the mobile phase and flow rate were selected as critical method parameters (CMPs); the other parameters were fixed according to the laboratory expertise and preliminary experiments. A response surface methodology (RSM) was used to optimize the method: a Doehlert design and a polynomial quadratic model were employed to approximate the relationship between the CMPs and the CMAs. Then, the method operable design region (MODR) was obtained by Monte-Carlo simulations and risk of failure maps. The probability of meeting the specifications (Rs ≥ 0.85 and t ≤ 6 min) was set at 95%. The method was validated according to the ICH Q2 guidelines and then implemented in routine analysis. A control strategy, based on system suitability tests (SST) and control charts, was planned. The evaluation was conducted over a period of six months of routine use. Both the CMAs, Rs and t showed values within the specifications in every analysis performed with this method. On the basis of such results, a new and more complete risk evaluation was achieved. It confirmed that the method performances have been maintaining the quality required by analysts during the method design. In the last part of this work, a study focusing on the concentrations monitoring of CBD and Δ-9THC in the olive oil extracts was carried out. The analysis was conducted on 228 extracts: 39.91 % from Bedrocan®, 35.09 % from FM2®, 14.91 % from Bediol® and 10.09 % from Bedrolite®. The statistical analysis highlighted and confirmed a wide variability in the concentrations among different samples from the same starting typology of cannabis. This study underlines the compelling need of a standardized procedure to harmonize the preparation of the extracts. [less ▲]

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See detailRisk-based approach for method development in pharmaceutical quality control context: A critical review
Deidda, Riccardo ULiege; Orlandini, Serena; Hubert, Philippe ULiege et al

in Journal of Pharmaceutical and Biomedical Analysis (2018), 161

Pharmaceutical regulatory bodies increasingly require the implementation of systematic approaches in pharmaceutical product development. Quality control methods play a key role in the control strategy of ... [more ▼]

Pharmaceutical regulatory bodies increasingly require the implementation of systematic approaches in pharmaceutical product development. Quality control methods play a key role in the control strategy of drugs manufacturing to assure their quality. A risk-based approach in the analytical method development is strongly recommended to ensure that the method performances fit the purpose of the method during its entire life-cycle. In the last decade, analytical quality by design (AQbD), as risk management oriented methodology, has been progressively integrated with method development for fulfilling this objective. This approach has successfully allowed the quality to be designed into the analytical processes by obtaining a deep understanding of the procedures. In this paper the AQbD workflow and its application in the development of methods to be used for pharmaceutical quality control have been treated and discussed. Recent publications regarding how AQbD has been applied in separation techniques were reviewed. The different development strategies have been also showcased, highlighting their advantages and disadvantages, in order to give a useful overview. [less ▲]

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See detailComment garantir la fiabilité de vos futurs résultats ?
Jambo, Hugues ULiege; Hubert, Cédric ULiege; Hubert, Philippe ULiege

Scientific conference (2018, June 21)

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See detail‘Quality by Design’ approach for the analysis of impurities in pharmaceutical drug products and drug substances
Dispas, Amandine ULiege; Avohou, Tonakpon Hermane ULiege; Lebrun, Pierre ULiege et al

in TrAC: Trends in Analytical Chemistry (2018), 101

The pharmaceutical industry is highly regulated by quality policies. The concept of risk management is strongly integrated into the quality assurance system to ensure pharmaceuticals’ quality and ... [more ▼]

The pharmaceutical industry is highly regulated by quality policies. The concept of risk management is strongly integrated into the quality assurance system to ensure pharmaceuticals’ quality and patients’ safety. In the context of quality control, the detection of impurities in raw materials and finished products is a major concern. It can be challenging for analytical scientists to meet specificity/selectivity and sensitivity requirements. Obviously, separation techniques are widely used for the detection of impurities but the method development required to achieve Analytical Target Profile (ATP) concerns is often challenging. Therefore, to ensure pragmatic and systematic methods development and simultaneously manage the risk associated with analytical methods, the principles of Quality by Design (QbD) should be applied. This paper provides an overview of QbD principles and statistical strategies (mainly DoE-DS approach) which can be applied to impurity detection methods, as well as a review of the literature where QbD has been applied to these types of analytical methods. [less ▲]

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See detailStatistical methods in Quality by Design approach to Liquid Chromatography method development
Avohou, Tonakpon Hermane ULiege; Hubert, Cédric ULiege; Debrus, Benjamin ULiege et al

in Fekete, Szabolcs; Molnar, Imre (Eds.) Software-Assisted Method Development for Modeling High Performance Liquid Chromatography (2018)

Analytical quality by design (AQbD) approach is more and more advocated for the development of analytical methods. In brief, AQbD is a systematic and risk-based approach to method development and ... [more ▼]

Analytical quality by design (AQbD) approach is more and more advocated for the development of analytical methods. In brief, AQbD is a systematic and risk-based approach to method development and optimization that begins with predefined objectives, seeks method understanding and defines a method control strategy based on scientific knowledge and quality risk management tools. Contrary to the classical quality-by-testing (QbT) approach, which is rather unstructured and proceeds mostly by trial-and-error, AQbD approach is a structured and science-based. It enables an efficient search for optimal conditions and a deeper understanding of the underlying separation processes. As results, effective optimization of the method, robustness building and quality risks management as required by regulations may be more easily achieved. A key output of the AQbD strategy is the design space, which defines an envelope of operable region of method parameters that guarantees with a high probability acceptable method performances in routine. <br />Statistical methods play a prominent role in the learning process and computation of the design space in the QbD process. Therefore, any statistical method that is meant to support a liquid chromatography (LC) method development by QbD should not only be statistically correct but also QbD-compliant. To be concrete, this means the statistical method should: (1) enable a deep understanding of the LC method, that is how important method parameters and uncertainty factors combine to affect the method performances; (2) help to build robustness and provide assurance that the method is fit for use in routine. <br />Several statistical methods are currently used in the development method by a QbD approach, each claiming to be innovative, accurate and QbD-compliant. Unfortunately, very few of these methods are both statistically correct and QbD-compliant. A major part of them is misleading and often falls into pitfalls of poorly statistically defined robustness. These statistical methods do not truly reflect the goals of AQbD strategy and the related concepts of quality assurance, design space and robustness. <br />In this chapter, we present a critical review of current and emerging statistical methods supporting the development of LC methods by a QbD approach. We discuss the concept and components of a QbD approach to method development, with an emphasis on the meaning of the key concepts of robustness and analytical design space. Then, we present the current and most common statistical methods supporting QbD methods development. We distinguish between two categories of statistical methods. First, the design of experiments (DoE) and semi-empirical retention models-based methods are discussed. These methods combine in a fully automated approach, the DoE and retention models such as linear solvent strength (LSS) or the quantitative structure retention relationships (QSRR) models derived from the solvophobic theory. Second, the DoE and fully empirical (i.e. data-driven) models-based methods which are based on empirical models such as the multivariate multiple linear regression and similar techniques are presented. We argue that the empirical models-based methods are totally risk-oriented and interestingly more flexible and open to innovations. Two case studies illustrating the DoE and Bayesian method for design space — what the authors believe is the most appropriate risk-oriented empirical method — in LC methods development are presented. [less ▲]

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See detailQuality control of medicinal cannabis: implementation of a generic sfc-ms method to address counterfeiting with synthetic cannabinoids
Jambo, Hugues ULiege; Dispas, Amandine ULiege; Avohou, Tonakpon Hermane ULiege et al

Poster (2018)

There is a growing interest in using cannabis for medicinal purposes as research shows evidence of its therapeutic properties. However, to be successfully ported in the pharmaceutical field, several ... [more ▼]

There is a growing interest in using cannabis for medicinal purposes as research shows evidence of its therapeutic properties. However, to be successfully ported in the pharmaceutical field, several aspects such as its quality must be evaluated and ensured. In this context, we address the possibility of counterfeiting of cannabis with synthetic cannabinoids and report the development of a robust method based on supercritical fluid chromatography coupled with mass spectrometry (SFC-MS) that could help in detecting such adulterations. Considering the high number of already available synthetic cannabinoids and the high rate of development of novel structures, we aimed to develop a generic method suitable for the analysis of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as model compounds. Firstly, a suitable column was chosen after a screening phase. The mobile phase (modifier composition) was also set after these preliminary tests. Secondly, a method optimization was carried out using a design of experiments (DoE) and Bayesian design space (DS) methodology that follows ICH Q8 R2 guideline recommendations. This approach is increasingly recommended for the robust optimization of analytical methods. The DoE selected was a four-factor central composite design. Then, according to the goal of adequately analyzing future unknown compounds, the criterion separation S was set to -0.5 to obtain a method with the highest separation capacity. This quality by design (QbD) approach shows flexibility as it permits the testing of various conditions within the DS to tune the separation taking into account that some adaptations might be needed during routine analysis, since it is impossible to predict which compound will be found. Finally, the quantitative performances of the method were demonstrated by means of a validation step based on total error approach for the quantification of a selected synthetic cannabinoid in fiber type cannabis plant matrix. Sample preparation was performed with solid-liquid extraction (SLE) followed by filtration and dilution. The acceptance limits were set at ±15% and the β- expectation tolerance limits at 90 % probability level. The results show that the method is valid over the whole dosing range assessed of 2.5 - 7.5% (w/w) and the LOD equal to 14.40 ng/mL. The implementation of this method should be straightforward considering the ease of sample preparation, the use of a simple modifier composition and the high specificity and sensitivity achieved with mass spectrometry. This work adds an innovative tool to address the challenges of ensuring medicinal cannabis quality and will prove useful in the context of counterfeit drugs tracking. [less ▲]

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Peer Reviewed
See detailImplementation of a generic SFC-MS method for the quality control of potentially counterfeited medicinal cannabis with synthetic cannabinoids
Jambo, Hugues ULiege; Dispas, Amandine ULiege; Avohou, Tonakpon Hermane ULiege et al

in Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences (2018), 1092

In this study, we describe the development of a SFC-MS method for the quality control of cannabis plants that could be potentially adulterated with synthetic cannabinoids. Considering the high number of ... [more ▼]

In this study, we describe the development of a SFC-MS method for the quality control of cannabis plants that could be potentially adulterated with synthetic cannabinoids. Considering the high number of already available synthetic cannabinoids and the high rate of development of novel structures, we aimed to develop a generic method suitable for the analysis of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as model compounds. Firstly, a suitable column was chosen after a screening phase. Secondly, optimal operating conditions were obtained following a robust optimization strategy based on a design of ex- periments and design space methodology (DoE-DS). Finally, the quantitative performances of the method were assessed with a validation according to the total error approach. The developed method has a run time of 9.4 min. It uses a simple modifier composition of methanol with 2% H2O and requires minimal sample pre- paration. It can chromatographically separate natural cannabinoids (except THC-A and CBD-A) from the syn- thetics assessed. Also, the use of mass spectrometry provides sensitivity and specificity. Moreover, this quality by design (QbD) approach permits the tuning of the method (within the DS) during routine analysis to achieve a desirable separation since the future compounds that should be analyzed could be unknown. The method was validated for the quantitation of a selected synthetic cannabinoid in fiber-type cannabis matrix over the range of 2.5% – 7.5% (w/w) with LOD value as low as 14.4 ng/mL. This generic method should be easy to implement in customs or QC laboratories in the context of counterfeit drugs tracking. [less ▲]

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See detailIntégration de la validation dans le concept AQbD
Hubert, Cédric ULiege; Lebrun, Pierre ULiege; Boulanger, Bruno ULiege et al

Scientific conference (2017, November 23)

Detailed reference viewed: 20 (4 ULiège)