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See detailA quality by design approach for liposomes production by innovative method using supercritical fluids: which parameters use to obtain good physicochemical characteristics?
Penoy, Noémie ULiege; Avohou, Tonakpon Hermane ULiege; Lebrun, Pierre ULiege et al

Scientific conference (2019, December 11)

Liposomes are nanoparticles made of phospholipids, able to encapsulate many active molecules, protecting and transporting them in a targeted way. Liposomes are thus widely studied as vectors of numerous ... [more ▼]

Liposomes are nanoparticles made of phospholipids, able to encapsulate many active molecules, protecting and transporting them in a targeted way. Liposomes are thus widely studied as vectors of numerous active molecules, improving their therapeutic window. However, the usual production methods at the laboratory scale have many disadvantages and are generally difficult to transfer to the industrial scale under GMP conditions [1], [2]. Supercritical fluids are increasingly used in the pharmaceutical industry. One of the pharmaceutical applications of supercritical fluids is the production of particles. For the liposomes production, the use of supercritical CO2 as a dispersing agent has been preferred because of the total absence of organic solvent. Since this process involves many parameters such as pressure, temperature, stirring speed, lipid concentration, volume and contact time, a quality by design approach was used in order to determine the influence of each parameters on the physicochemical properties of liposomes such as the size and the polydispersity. These experimental analyses helped us to find two production areas. These conditions were validated with five different liposome formulations regarding the size and polydispersity expectations. We will now focus on the impact of each parameter on the physicochemical properties of liposomes but also their impact on the integrity of the phospholipids used. [less ▲]

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See detailA quality by design approach for liposomes production by innovative method using supercritical fluids: which parameters use to obtain good physicochemical characteristics?
Penoy, Noémie ULiege; Avohou, Tonakpon Hermane ULiege; Lebrun, Pierre ULiege et al

Scientific conference (2019, December 11)

Liposomes are nanoparticles made of phospholipids, able to encapsulate many active molecules, protecting and transporting them in a targeted way. Liposomes are thus widely studied as vectors of numerous ... [more ▼]

Liposomes are nanoparticles made of phospholipids, able to encapsulate many active molecules, protecting and transporting them in a targeted way. Liposomes are thus widely studied as vectors of numerous active molecules, improving their therapeutic window. However, the usual production methods at the laboratory scale have many disadvantages and are generally difficult to transfer to the industrial scale under GMP conditions [1], [2]. Supercritical fluids are increasingly used in the pharmaceutical industry. One of the pharmaceutical applications of supercritical fluids is the production of particles. For the liposomes production, the use of supercritical CO2 as a dispersing agent has been preferred because of the total absence of organic solvent. Since this process involves many parameters such as pressure, temperature, stirring speed, lipid concentration, volume and contact time, a quality by design approach was used in order to determine the influence of each parameters on the physicochemical properties of liposomes such as the size and the polydispersity. These experimental analyses helped us to find two production areas. These conditions were validated with five different liposome formulations regarding the size and polydispersity expectations. We will now focus on the impact of each parameter on the physicochemical properties of liposomes but also their impact on the integrity of the phospholipids used. References [1] C. Tikshdeep, A. Sonia, P. Bharat, and C. Abhishek, “Liposome Drug Delivery,” Int. J. Pharm. Chem. Sci., vol. 1, no. 3, pp. 1103–1113, 2012. [2] L. A. Meure, N. R. Foster, and F. Dehghani, “Conventional and Dense Gas Techniques for the Production of Liposomes: A Review,” AAPS PharmSciTech, vol. 9, no. 3, pp. 798–809, 2008. [3] B. S. Sekhon, “Supercritical fluid technology: An overview of pharmaceutical applications,” Int. J. PharmTech Res., vol. 2, no. 1, pp. 810–826, 2010 [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 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 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 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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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)

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See detailImplementation of SFC for the quality control of pharmaceuticals
Dispas, Amandine ULiege; Andri, Bertyl ULiege; Lebrun, Pierre ULiege et al

Conference (2017, May 17)

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See detailCycle de vie des méthodes, vers une maîtrise intégrée des performances quantitatives
Hubert, Cédric ULiege; Lebrun, Pierre ULiege; Boulanger, Bruno ULiege et al

Scientific conference (2017, May 11)

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See detailLa chromatographie en phase supercritique : une alternative aux méthodes de référence de la Pharmacopée Européenne ?
Dispas, Amandine ULiege; Desfontaine, Vincent; Andri, Bertyl ULiege et al

Conference (2017, March 30)

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See detailQuantitative determination of salbutamol sulfate impurities using achiral supercritical fluid chromatography
Dispas, Amandine ULiege; Desfontaine, Vincent; Andri, Bertyl ULiege et al

in Journal of Pharmaceutical and Biomedical Analysis (2017), 134

In the last years, supercritical fluid chromatography has largely been acknowledged as a singular and performing technique in the field of separation sciences. Recent studies highlighted the interest of ... [more ▼]

In the last years, supercritical fluid chromatography has largely been acknowledged as a singular and performing technique in the field of separation sciences. Recent studies highlighted the interest of SFC for the quality control of pharmaceuticals, especially in the case of the determination of the active pharmaceutical ingredient (API).Nevertheless, quality control requires also the determination of impurities. The objectives of the present work were to i) demonstrate the interest of SFC as a reference technique for the determination of impurities in salbutamol sulfate API and ii) to propose an alternative to a reference HPLC method from the European Pharmacopeia (EP) involving ionpairing reagent. Firstly, a screening was carried out to select the most adequate and selective stationary phase. Secondly, in the context of robust optimization strategy, the method was developed using design space methodology. The separation of salbutamol sulfate and related impurities was achieved in 7 minutes, which is seven times faster than the LC-UV method proposed by European Pharmacopeia (total run time of 50 minutes). Finally, full validation using accuracy profile approach was successfully achieved for the determination of impurities B, D, F and G in salbutamol sulfate raw material. The validated dosing range covered 50 to 150 % of the targeted concentration (corresponding to 0.3 % concentration level), LODs close to 0.5 μg/mL were estimated. The SFC method proposed in this study could be presented as a suitable fast alternative to EP LC method for the quantitative determination of salbutamol impurities. [less ▲]

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See detailChapter 11 - Validation of Supercritical Fluid Chromatography Methods
Dispas, Amandine ULiege; Lebrun, Pierre ULiege; Hubert, Philippe ULiege

in Poole, Colin (Ed.) Supercritical Fluid Chromatography - Handbook in Separation Science (2017)

Method validation is the process of proving that an analytical method is acceptable for its intended purpose. The present chapter defines the validation criteria described in regulatory documents. Despite ... [more ▼]

Method validation is the process of proving that an analytical method is acceptable for its intended purpose. The present chapter defines the validation criteria described in regulatory documents. Despite the abundance of guidelines, the conclusion about method validity remains confused. In this context, the state-of-the-art validation methodology named total error approach is briefly explained as the methodology that should be followed for all method validations. Finally, a review of literature presents quantitative development and validation of supercritical fluid chromatography (SFC) methods considering a wide range of applications and analytical fields. [less ▲]

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See detailOptimization and validation of a fast Supercritical Fluid Chromatography method for the quantitative determination of vitamin D3 and its related impurities.
Andri, Bertyl ULiege; Lebrun, Pierre ULiege; Dispas, Amandine ULiege et al

in Journal of Chromatography. A (2017)

In the uprising context of green analytical chemistry, Supercritical Fluid Chromatography (SFC) is often suggested as an alternative to Normal Phase Liquid Chromatography. Indeed, SFC provides fast ... [more ▼]

In the uprising context of green analytical chemistry, Supercritical Fluid Chromatography (SFC) is often suggested as an alternative to Normal Phase Liquid Chromatography. Indeed, SFC provides fast, efficient and green separations. In this report, the quantitative performances of SFC were challenged on a real-life case study: the Quality Control (QC) of vitamin D3. A rapid and green SFC method was optimized thanks to the Design of Experiments–Design Space (DoE–DS) methodology. It provided robust and high quality separation of the compounds within a 2 min timeframe, using a gradient of ethanol as co-solvent of the carbon dioxide. The analytical method was fully validated according to the total error approach, demon- strating the compliance of the method to the specifications of U.S. Pharmacopeia (USP: 97.0–103.0%) and European Pharmacopeia (EP: 97.0–102.0%) for an interval of [50–150%] of the target concentration. In order to allow quantification of impurities using vitamin D3 as an external standard in SFC-UV, correction factors were determined and verified during method validation. Thus, accurate quantification of impu- rities was demonstrated at the specified levels (0.1 and 1.0% of the main compound) for a 70.0–130.0% dosing range. This work demonstrates the validity of an SFC method for the QC of vitamin D3 raw material and its application to real samples. Therefore, it supports the switch to a greener and faster separative technique as an alternative to NPLC in the pharmaceutical industry. [less ▲]

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