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See detailComparing the qualitative performances of handheld NIR and Raman spectrophotometers for the detection of falsified pharmaceutical products
Ciza Hamuli, Patient ULiege; Sacre, Pierre-Yves ULiege; Waffo Tchounga, Christelle ULiege et al

in Talanta (2019), 202

Over the last decade, the growth of the global pharmaceutical market has led to an overall increase of substandard and falsified drugs especially on the African market (or emerging countries). Recently ... [more ▼]

Over the last decade, the growth of the global pharmaceutical market has led to an overall increase of substandard and falsified drugs especially on the African market (or emerging countries). Recently, several methods using handheld/portable vibrational spectroscopy have been developed for rapid and on-field drug analysis. The objective of this work was evaluate the performances of various NIR and Raman handheld spectrophotometers in specific brand identification of medicines through their primary packaging. Three groups of drug samples (artemether-lumefantrine, paracetamol, and ibuprofen) were used in tablet or capsule forms. In order to perform a critical comparison, the analytical performances of the two analytical systems was compared statistically using three methods: hierarchical clustering algorithm (HCA), data-driven soft independent modeling of class analogy (DD-SIMCA) and hit quality index (HQI). The overall results show good detection abilities for NIR systems compared to Raman systems based on Matthews’s correlation coefficients, generally close to one. Raman systems are less sensitive to the physical state of the samples than the NIR systems, it also suffers of the auto-fluorescence phenomenon and the signal of highly dosed active pharmaceutical ingredient (e.g. paracetamol or lumefantrine) may mask the signal of low-dosed and weaker Raman active compounds (e.g. artemether). Hence, Raman systems are less effective for specific product identification purposes but are interesting in the context of falsification because they allow a visual interpretation of the spectral signature (presence or absence of API). [less ▲]

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See detailIntegrated microfluidic device for in-line monitoring of glyphosate assisted by Surface Enhanced Raman Spectroscopy
Emonds-Alt, Gauthier ULiege; Avohou, Tonakpon Hermane ULiege; Kasemiire, Alice ULiege et al

Conference (2019, June 17)

Glyphosate is one of the most widely used pesticides as it is a non-selective systemic herbicide that is quickly degrade in soil. Glyphosate disrupts the biochemical shikimate pathway, which produces ... [more ▼]

Glyphosate is one of the most widely used pesticides as it is a non-selective systemic herbicide that is quickly degrade in soil. Glyphosate disrupts the biochemical shikimate pathway, which produces aromatic amino acids that are essential for plant growth and development. It acts as a competitive inhibitor of the 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, an enzyme absent from mammals. Therefore, glyphosate has been presented as (a) non-toxic for humans and (b) non-persistent. However, these premises have been recently questioned since traces of glyphosate and its main metabolite (aminomethylphosphonic acid, AMPA) have been detected in surface water, groundwater, soil as well as in cotton products. Quantifying and monitoring trace amounts of glyphosate and pesticide residues in the environment typically relies on analytical methods such as Gas Chromatography (GC) or Liquid Chromatography (LC) coupled with mass spectrometry (MS). However, these types of methods are expensive and often not suitable for in situ field analysis. Surface Enhanced Raman Spectroscopy (SERS) coupled with microfluidic could be an alternative method, which allows a fast and direct quantification on the field with miniaturised instrumentation. Indeed, SERS combines the advantage of Raman spectroscopy and is able to detect traces due to the signal enhancement resulting from the adsorption of the analyte on the rough nanoparticle surface. Here we focus on the development of an inline analytical method for water monitoring assisted by SERS. The inline detection of glyphosate is performed in a microfluidic setup, constructed with high-purity PFA coils (1/16" o.d., 0.01" i.d.), divided in three compartments (Figure 1) : (a) in situ synthesis of silver nanoparticles (Ag NPs), (b) mixing of the analyte with the Ag NPs and (c) the detection zone. Experimental parameters such as the type of micromixers for the synthesis of Ag NPs and the mixing between glyphosate and Ag NPs, the concentration of reagents for the synthesis of Ag NPs, the residence time or the flow applied in the setup were investigated and optimized through D-optimal (26 runs) and I-optimal design of experiments. In particular, we will discuss how the experimental parameters influence the quantitative detection of SERS intensity. [less ▲]

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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 detailVibrational spectroscopy in analysis of pharmaceuticals: Critical review of innovative portable and handheld NIR and Raman spectrophotometers
Deidda, Riccardo ULiege; Sacre, Pierre-Yves ULiege; Clavaud, Matthieu et al

in TrAC: Trends in Analytical Chemistry (2019), 114

The fast pace of changes occurring in the pharmaceutical world emphasizes the need for powerful technologies that allow checking the quality of pharmaceutical products. Infrared and Raman spectroscopies ... [more ▼]

The fast pace of changes occurring in the pharmaceutical world emphasizes the need for powerful technologies that allow checking the quality of pharmaceutical products. Infrared and Raman spectroscopies have shown great potentialities for drug analysis in the last decades and consequently caught the attention of the scientific world as well as of industrial developers, leading to major technological advancements. These fast, eco-friendly, and non-destructive techniques help gather essential information about the samples under examination with consistent advantages. This review focuses on the application of portable/handheld NIR and Raman spectrophotometers in the analysis of pharmaceutical products for both in-process and quality control tests. Moreover, several analytical methods developed by several authors are described in order to illustrate the applications explored until now. [less ▲]

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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 detailAuthentication of falsified medicine tablets by handheld Raman spectroscopy class modeling
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege et al

Conference (2019, January 01)

Since last decades, the world has known significant changes in the pharmaceutical products sale. The emergence of the internet trade is an important issue because it is easy to sell medicines without ... [more ▼]

Since last decades, the world has known significant changes in the pharmaceutical products sale. The emergence of the internet trade is an important issue because it is easy to sell medicines without passing any control. Moreover, in low- and middle-income countries (LMIC), the number of local pharmacies has grown, increasing the risk to have substandard or falsified medicines. Indeed, according to the World Health Organization (WHO) it is difficult to ensure quality medicines due to areas conflict, corrupted governments and poor health system [1]. For that reason, several analytical techniques have been developed since last decade. One of the most interesting tool is the Minilab, developed by the Global Pharma Health Fund (GPHF), which is a mobile mini-laboratory for fast drug quality control. Moreover, Raman spectroscopy has gained a great interest because it can be used at any step of analytical chain or on the fieldwork with handheld devices. However, spectroscopic data implies development of chemometrics models to gather relevant information. Several unsupervised techniques have already been used to authenticate drug products [2-3]. Due to the intrinsic properties of classification methods, class modeling is more appropriated to this kind of analysis. Indeed, falsified medicines can be quite different from the calibration set, so that, it does not have sense to attribute a class meanwhile it is dissimilar to the calibration set. In this study, the performances of two class-modeling techniques will be evaluated on handheld Raman spectra, to separate falsified medicines from authentic drugs. Three different generics of paracetamol, ibuprofen and artemether-lumefantrine with different dosage, dosage form and formulations were analyzed. Most of them were gathered in local Belgium pharmacies and other were gathered in Africa (artemether-lumefantrine formulations). Samples were analyzed with a handheld Raman spectrophotometer Pharma 21CFR part 11 qualified (Truscan RM, Thermo Scientific, USA) directly through the blister. In order to have a good representativeness of intra-batch variability, 10 tablets were analyzed per sample. The acquisition parameters were set to default. Two models were tested: one-class PLS (OC-PLS) [4] and the data driven-soft independent modeling class analogy (DD-SIMCA) [5]. All the computations were done in Matlab® (R2017b). The calibration and validation set was the same for each model and composed of 60 spectra for each, with different batch number. Because of the nature of each algorithm, there is a significant difference in terms of separation. Looking at Figure 1, the separation of dosage form for ibuprofen is much different between the two models. For the DD-SIMCA, it is more difficult to separate the long acting release from the soft capsule/coated tablet compared to the OC-PLS model. For the other API, similar results are obtained for the dosage and for the brand. It seems that the OC-PLS is more sensitive to the small spectral variabilities. In the case of artemether-lumefantrine formulations, the separation between samples is much more difficult. Indeed, the lumefantrine is a high Raman scatterer. This can explain that the signal of artemether and excipients is difficult to access. Elsewhere, in terms of development, the DD-SIMCA is much harder to optimize because there are more tunable parameters than for OC-PLS. Furthermore, both models are really influenced by spectral pretreatment. An optimization has to be done for each. The authentication of pharmaceutical products by handheld Raman spectroscopy has been possible thanks to class modeling. Both tested algorithms shown interesting results regarding the separation of samples depending on their characteristics. The optimization of data processing and pre-processing is the key-step to improve as sensitivity as specificity of both class modeling methods. [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 detailSolving composition of falsified artemether/lumefantrine formulation by hyperspectral imaging
Coic, Laureen ULiege; Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege et al

Poster (2018, September)

The emerging internet trade and its potential significant profitability cause falsified drugs to be one of the major public health issues of the 21st century. Although some preventing measures - such as ... [more ▼]

The emerging internet trade and its potential significant profitability cause falsified drugs to be one of the major public health issues of the 21st century. Although some preventing measures - such as the new European Parliament Directive 2011/62/UE - have been taken during the last decade, drugs are subject to more frequent monitoring from the authorities. New techniques thus have to be developed in order to help them investigate the relationships between falsified drugs and industries. Some preliminary tests such as visual inspection or colorimetric testing can be performed in order to check drug authenticity. When these tests are inconclusive, spectroscopy and hyperspectral imaging can be used to provide more information, especially to characterize the composition of presumed falsified samples. The efficiency of this technique has no longer to be proven. Vibrational hyperspectral imaging has many advantages such as the non-destruction of the sample and the possibility to combine spectral and spatial information. Once obtained, the hyperspectral data may be decomposed in its various spectral (qualitative) and spatial (quantitative) components using resolution algorithms such as MCR-ALS. The resolution of the spectral component allows the elucidation of the complete formulation composition without a priori knowledge, including mineral and organic compounds. This composition may be used as a production fingerprint for further forensic investigations. In this study, six artemether/lumefantrine formulations (two batches of Combiart 20/120 and four batches of Coartem 20/120) have been analyzed for falsification suspicion. First, a handheld Raman spectroscopic analysis has been performed confirming the falsification. The analysis confirmed the supposed absence of active compounds. In order to complete the knowledge of the formulations, one tablet per sample has been further analyzed by hyperspectral imaging. The MCR-ALS decomposition of the hyperspectral data cube shows that five out of the six samples (2 Combiart and 3 Coartem) have the same composition. Those samples are composed by two active compounds: sildenafil and ciprofloxacine chlorhydrate monohydrate at traces level by same excipients (organic and inorganic). This finding seems to indicate that despite different brand names, packaging and tablet shapes, these samples come from the same production. [less ▲]

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See detailForensic formulation fingerprinting of falsified medicine by Raman hyperspectral imaging
Sacre, Pierre-Yves ULiege; Coic, Laureen ULiege; Avohou, Tonakpon Hermane ULiege et al

Conference (2018, September)

With the Medicrime convention (in 2010) and the European Parliament directive 2011/62/UE (in 2011), the notion of pharmaceutical crime appeared allowing effective, proportionate, and deterring sanctions ... [more ▼]

With the Medicrime convention (in 2010) and the European Parliament directive 2011/62/UE (in 2011), the notion of pharmaceutical crime appeared allowing effective, proportionate, and deterring sanctions against the falsifiers. However, to be able to apply these sanctions, the authorities must collect information allowing them to go up to the manufacturing sites. This is however extremely complex at a global scale. The opportunity to link several falsification cases is one more brick laid in building the investigation. Hyperspectral imaging is not a new analytical tool and has been used in many research papers some of them about falsified medicines. However, the time has come to re-evaluate its place in the suspect formulation workflow. From our point of view, after a formulation is confirmed falsified (or substandard) by a first line investigation (e.g. visual inspection, handheld Raman or colorimetric testing), hyperspectral imaging should always be performed when possible (solid pharmaceutical forms). Indeed, in a single imaging analysis, one may access qualitative, semi-quantitative and distributional homogeneity of organic and inorganic constituents of the formulation. These inform on the risk of taking the medicine but most of all it provides a unique fingerprint of the production allowing the linking of falsification cases. To illustrate this, six artémether/luméfantrine formulations (two batches of Combiart 20/120 and four batches of Coartem 20/120) have been analyzed for falsification suspicion. Handheld Raman spectroscopic analysis rapidly confirmed the falsification and possibly the absence of active compound. Once confirmed falsified, one tablet of each formulation underwent Raman hyperspectral imaging on the whole sample surface. A chemometric analysis of the spectral data revealed the presence of traces of two active compounds (sildenafil and ciprofloxacine chlorhydrate monohydrate) and the same excipients (organic and inorganic) in five formulations (2 Combiart and 3 Coartem) allowing us to link these cases. [less ▲]

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See detailBayesian securing of the pharmaceutical supply chain
Sacre, Pierre-Yves ULiege; Avohou, Tonakpon Hermane ULiege; Lebrun, Pierre ULiege et al

Conference (2018, September)

Introduced in 2011, the European Union Falsified Medicines Directive asks for an enhanced security of the pharmaceutical supply chain. In this frame, manufacturers must apply safety measures to enable the ... [more ▼]

Introduced in 2011, the European Union Falsified Medicines Directive asks for an enhanced security of the pharmaceutical supply chain. In this frame, manufacturers must apply safety measures to enable the verification of authenticity and identification of individual packs. This is the so-called serialization of the pharmaceutical supply chain. However, these measures are only dedicated to the analysis of the secondary packaging and do not enable the analysis of the product’s quality. Therefore, we propose an end-to-end strategy based on spectroscopic fingerprints and risk-oriented statistical models for the verification of the quality of medicines along the supply chain. They can provide a precise description of the chemical composition of samples, and hence can be used to fingerprint a pharmaceutical product. A representative set of these spectra is sampled from each batch at release using appropriate devices. This sample is used to build a statistical tolerance band, that is assumed to contain a high proportion, say at least 90% of the future spectra of the product. The construction of such a band relies on the newly emerging chemometrics techniques such as functional data analysis (e.g. Bayesian wavelet or splines regressions). The upper and lower limits of the tolerance band are used as threshold or reference spectra for the conformity of a new spectrum. This allows us to declare the conformity of a product with a certain probability confidence. Compared to classical measures (p-values, Hit Quality Indexes), this functional data analysis and risk-oriented approach enables to detect very small perturbations of the spectrum caused, for example by degradation, batch inversion, etc. The computed tolerance band may be stored in a cloud server and accessed throughout the supply chain to check the conformity of the product itself. The spectral serialization of pharmaceutical batches is another brick in the wall of pharmaceutical supply chain securing. [less ▲]

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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 detailNOTA‐PRGD2 and NODAGA‐PRGD2: Bioconjugation, characterization, radiolabelling, and design space
Salvé, Mallory ULiege; Avohou, Tonakpon Hermane ULiege; Monbaliu, Jean-Christophe ULiege et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was ... [more ▼]

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was fully optimized using Design of Experiments and Design Space approaches, hence targeting robust labelling yields in routine. Optimal labelling conditions were defined insodium acetate buffer as 168 μg/mL peptide concentration, 4.9 pH, 47.5°C temperature, and 12.5‐minute reaction time. Upon optimization, the Gallium‐68 radiolabelling was fully automated. All the work was designed to be compliant to the GMP environment and to support the pharmaceuticalscale‐up. [less ▲]

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See detailDe l'intérêt de la spectroscopie Raman pour l'analyse pharmaceutique
Avohou, Tonakpon Hermane ULiege; Cailletaud, Johan ULiege; Clavaud, Matthieu et al

Scientific conference (2018, January 15)

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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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