Introduction Dans le cadre de la sécurisation du circuit du médicament, les conditions de conservation des préparations injectables à 2–8°C constituent un élément majeur conditionnant leur stabilité. De la production à l’administration du produit, le respect de la chaîne du froid est essentiel et est soumis à différents facteurs, environnementaux ou spécifiques à chaque préparation. Les étapes critiques de mise en température des poches sont (1) le stockage post-production, (2) le transport vers les services et (3) l’administration. Toutefois, les délais permettant d’atteindre les températures cibles de ces différentes étapes sont peu décrits. L’objectif de ce projet a été d’évaluer le délai de refroidissement après fabrication (temps nécessaire pour atteindre une température T<8°C après introduction dans l’enceinte réfrigérée), le délai d’excursion (temps nécessaire pour atteindre T>8°C en sortie de réfrigérateur) et le délai avant administration (temps nécessaire pour atteindre une T>15°C en sortie de réfrigérateur). Matériels & méthode Les essais ont été réalisés sans agitation sur des poches de chlorure de sodium 0,9% de 50, 100 ou 250mL, pour deux températures ambiantes fixées à 25 et 35°C (Tamb). Pour chaque type de poche, des expériences de descente en température (de Tamb à 5°C) et de montée en température (de 5°C à Tamb) ont été simulées à l’aide d’enceintes thermiques calibrées. Six poches ont été étudiées simultanément avec un relevé continu de leur température (1 mesure/min) à l’aide de sondes étalonnées placées à l’intérieur. Afin d’évaluer la précision de la méthode, l’essai pour les poches de 100mL à une Tamb de 25°C a été répété pendant 3jours consécutifs. Résultats & discussion Les résultats obtenus confirment l’influence du volume des poches et de la température ambiante sur les délais de mise en température des préparations, avec une bonne reproductibilité des mesures (CV%<10%). Les essais ont permis de déterminer : (1) un délai de refroidissement moyen de 114min (délai minimal de 84min obtenu pour les poches de 50mL à Tamb 25°C ; délai maximal de 158min pour les poches de 250mL à 35°C), (2) un délai d’excursion moyen de 10,8min (minimum 7,3min pour 50mL à 25°C ; maximum 18,5min pour 250mL à 25°C) et (3) un délai avant administration de 47min (minimum 32min pour 50mL à 35°C ; maximum 84min pour 250mL à 25°C). Conclusion Cette étude met en évidence l’importance des différentes étapes de mise en température pour le bon respect de la chaîne du froid et des conditions d’utilisation des médicaments. Ces délais sont souvent sous-estimés en pratique courante. La pertinence de l’étape de descente en température peut être questionnée pour les poches produites pour une administration extemporanée. Il serait intéressant d’étendre cette expérience à d’autres matériaux, solvants et conditionnements. Par ailleurs, un audit des pratiques en conditions réelles permettrait de replacer ce travail dans une vision plus globale du bon usage des produits de santé.

Residual contamination by intravenous antineoplastic drugs on hospital surfaces remains a critical concern, as highlighted by numerous studies. This study presents a novel, rapid and highly sensitive analytical method for quantifying a wide range of antineoplastic drugs and detecting other potentially harmful molecules on wiped surfaces. Utilizing hydrophilic interaction liquid chromatography (HILIC) coupled with high-resolution spectrometry, the method combines the quantification of eight commonly used antineoplastic drugs: 5-fluorouracil, ifosfamide, cyclophosphamide, gemcitabine, doxorubicin, methotrexate, epirubicin and irinotecan, with the identification of unknown compounds offering a comprehensive solution for monitoring hospital surface contamination. While HILIC-MS/MS has been extensively applied in various matrices, its use for surface contamination monitoring in healthcare settings has been relatively underexplored. Chromatographic separation was achieved using gradient elution on an HILIC ZORBAX 120 column (150 mm × 2.1 mm, 4 µm), enabling rapid analysis within 8 min. The method demonstrated exceptional sensitivity, achieving limits of quantification below 0.04 ng/cm2 for all targeted molecules. Applied to 28 surfaces in the day hospital of a medical oncology unit at a French hospital, the method revealed contamination on 22 surfaces with at least one antineoplastic drug. Additionally, unknown molecules, including a compound associated with cleaning detergents, were detected, highlighting the complexity of hospital surface contamination underscoring the ongoing risks faced by healthcare workers and patients. This innovative approach represents a significant advancement in analytical chemistry and hospital hygiene monitoring, providing a faster, more efficient and versatile alternative to traditional techniques, as it allows 5-FU quantification within the same run time with other molecules. By addressing critical gaps in current methodologies, this study offers valuable insights into occupational safety and supports efforts to reduce exposure risks for healthcare workers and patients. Further research is needed to identify the unknown molecules detected and fully assess their potential risks.

Vinca alkaloids represent a major class of antineoplastic agents used against cancer. They are prepared in centralized production units by pharmacy technicians. Control of the preparation is indispensable to secure their preparation and avoid any errors, which can have serious consequences for the patient because antineoplastic agents are very toxic. Analytical quality control was proven to be the most efficient control to ensure the right drug at the right dose to the patient. The study focused on vinca alkaloids: vinblastine, vincristine, vindesine, vinflunine, and vinorelbine, in the form of commercially diluted solutions in 0.9% NaCl at therapeutic concentrations. The aim of this study was to develop an analytical methodology for quality control capable of discriminating and quantifying these molecules. The primary objective was to assess the capability of Flow Injection Analysis with UV detection (FIA-UV), combined with chemometrics, for rapid classification and quantification of these alkaloids. A rapid High-Performance Liquid Chromatography with UV-visible detection (HPLC-UV) method was also developed and established as a reference standard. HPLC-UV discrimination was based on retention time, whereas FIA-UV relied on spectral analysis. Therefore, to improve discrimination in FIA-UV, Partial Least Squares Discriminant Analysis (PLS-DA) was incorporated. FIA-UV achieved 100% sensitivity and specificity in discriminating the five alkaloids, demonstrating non-inferiority to HPLC-UV. This method offers a streamlined workflow, reduces iatrogenic risk, and is well suited for antineoplastic agent preparation environments.

In this work, an investigation on plasmonic hotspots of Au tilted nanocolumns and their application to the uracil detection by surface-enhanced Raman scattering (SERS) is addressed. These Au tilted nanocolumns are fabricated by employing a low-cost and easy-to-implement fabrication technique, which is the glancing angle deposition with magnetron sputtering. Moreover, these Au nanocolumns can generate a great density of highly confined electric field zones, called hotspots, located in the nanogaps between the nearest nanocolumns. The photoemission electron microscopy is employed to obtain the statistics on the distribution of these plasmonic hotspots with a high accuracy (spatial resolution of 10-20 nm) in the spectral range from 680 nm to 1080 nm. Thus, the SERS intensity can be correlated with the density and the intensity distribution of these plasmonic hotspots. Finally, the plasmonic hotspots of the Au nanocolumns are used to assess the limit of detection (LOD) of the uracil molecule by SERS. This LOD is determined at 6 nM demonstrating the good sensitivity of our Au nanocolumns compared to the existing literature.

The demand for monoclonal antibodies (mAbs) in hospitals is continually rising due to the advancement of targeted therapy or immunotherapy. Typically, mAbs are produced in centralized chemotherapy production units and require rigorous control to ensure the right drug at the right dose before administration to patients.This study aimed to develop a robust discriminant analysis method using a large dataset comprising 22 mAbs used in cancer therapy. The discriminant analysis was based on UV spectroscopy coupled with chemometrics. A dataset consisting of 404 samples was prepared and analyzed using various preprocessing methods, wavelength selection and discriminant analysis algorithms to maximize overall accuracy. Validation of the newly developed discriminant analysis was conducted using samples collected from real manufactured preparations for patient (over 1,380 samples). The study achieved an overall accuracy of 99.6% and 99.8% on the 22 mAbs using partial least squares-discriminant analysis (PLS-DA) and k-nearest neighbors (kNN), respectively. The utilization of chemometrics for discriminating mAbs based on their UV spectra, following total area normalization, has been successfully demonstrated. This method has undergone validation, affirming its capability to swiftly and dependably distinguish different mAbs. Moreover, it effortlessly integrates within the workflow involved in the preparation of mAbs drugs within a cancer hospital setting. This advancement holds promise for streamlining processes and enhancing efficiency in the production and use of mAbs, thereby potentially benefiting patient care and treatment outcomes.

ABSTRACT The quality and the security of preparations in hospital centres are essential to guarantee the patient's safety. The development of fast and efficient analytical methods is required to control the finished product before use. In this context, the study aimed to compare the performance and interchangeability of two spectral analytical methods: the flow injection analysis (FIA) with UV detection and the Raman spectroscopy for the quality control of preparation before use to quantify the remdesivir as a SARS‐CoV‐2 drug. A quantitative study of remdesivir was performed using clinically relevant concentration solutions ranging from 0.25 to 1.625 mg.mL −1 in 0.9% NaCl. Samples were analysed by FIA‐UV at 245 nm and by a handheld Raman spectroscopy at 785 nm. Quantitative models were developed using a calibration set ( n = 45 samples) and optimized using a validation set ( n = 27). An external validation test set ( n = 58) was used to compare the two methods by a Bland–Altman plot. Partial least square regression was used to analyse Raman spectra, while univariate analysis was performed at 245 nm for FIA‐UV. The regression coefficient was higher than 0.990 for both methods, and the root mean square error of prediction was 0.031 mg.mL −1 for Raman spectroscopy. The Bland–Altman plot confirmed the interchangeability of the two methods and the potential of Raman spectroscopy to control remdesivir during clinical preparation in the hospital.

A transmission detection mode was investigated with SERS analyses (SETRS). A comparison between backscattering and transmission detection modes was conducted to demonstrate the feasibility of performing SETRS analyses. The impact of various parameters on the SERS signal intensity such as sample volume, lens collection optic, laser beam size and laser power were then examined. The analytical performances of SETRS were further evaluated through the quantification of an impurity (4-aminophenol) ranging from 3 to 20 µg/mL in a commercial pharmaceutical product using a total error risk-based approach. To account for expected variability of routine analysis, 9 batches of silver nanoparticles suspensions were used and experiments were performed over 5 different days and by 2 operators. Univariate spectral analysis based on a quadratic regression was compared to a multivariate approach using a partial least square regression. The presented results demonstrated that SETRS can be used to determine an impurity in a complex matrix opening new perspectives for quantitative applications.

Surface enhanced Raman scattering (SERS) has become widely used for identification, quantification and providing structural information about molecular structure in low concentrations as it allows signal Raman enhancement using metallic nanoparticles (NPs). Controlling interaction between analyte and NPs is a major point for the optimization of signal exaltation in SERS analysis. The objective of this study is the improvement and the control of SERS analysis by aggregation/self-assembly optimization of AuNPs using quaternized chitosan. The interest of this approach is to allow stable and reliable measurements with a simple and low cost approach compatible with a massive use in the field. In this work, we used design of experiments by Box-Behnken design to fix optimized conditions to increase signal sensibility of epinephrine water solutions. We also tested SERS signal stability in isotonic sodium chloride 0.9% and glucose 5% matrices. Our results demonstrate that globally neutral AuNPs aggregates were stabilized at a nanometric size by the subsequent addition of polyelectrolyte chains and allows for significant Raman signal enhancement of epinephrine. We succeed to prepare the SERS active material and measure a stable signal of epinephrine at a concentration as down as 0.1 mu g mL(-1) in less than 5 min. The signal remained stable and exploitable for at least 2 h. Our results reveal a strong correlation between intensity and logarithm of the concentration (concentration before dilution from 0.1 to 10 mu g mL(-1)) suggesting a possible quantification. Furthermore, the signal of epinephrine at 10 mu g mL(-1) were also exploitable and stable in complex media as isotonic sodium chloride 0.9% and glucose 5%. This represents a particularly interesting application that would allow direct analysis of drugs complex media and open the way to analysis in biological samples.

Surface Enhanced Raman Scattering (SERS) spectroscopy is a rapid and innovative analysis technique involving metallic nanoparticles (NPs ). The interaction between NPs and norepinephrine gives an exaltation of the Raman signal under certain experimental conditions. The control of the signal exaltation, crucial for sensitive analyses, remains one of the main limitations of this technique. The aim of this work is to optimize the exaltation conditions for an optimal SERS signal at two concentrations of norepinephrine (NOR) and spherical gold NPs in suspension. This first work will fix the optimal experimental conditions essential for the development of robust discriminant and quantitative analysis of catecholamine. Two complete 3-factors 3-levels experiment designs were performed at 20 mu g.mL(-1) and 100 mu g.mL(-1) norepinephrine concentrations, each experiment being repeated 3 times. The optimization factors were the process of synthesis (variation of the quantity of gold and citrate used for the three synthesis SA, SB and SC) and HCl (0.3 M, 0.5 M, 0.7 M) as well as the volume ratio of NPs and norepinephrine (0.5, 2, 3.5) for SERS acquisition. Spectral acquisitions were performed with a handheld Raman spectrometer with an excitation source at 785 nm. For each sample, 31 acquisitions were realized during 3 s every 8 s. The optimization parameter was the intensity of the characteristic band of norepinephrine at 1280 cm(-)(1). A total of 5,042 spectra were acquired and the pre-treatment selected for all spectra was asymmetric least square combined to a smoothing of Savistsky Golay (ALS - SG). The optimal contact time between norepinephrine and NPs depends on the experimental conditions and was determined for each experiment according to the mean intensity between the three replicates. After interpretation of the experimental designs, the optimal conditions retained were the quantity of gold corresponding to SA and the HCl-concentration 0.7 M for the two concentrations of norepinephrine. Indeed, the optimal volume ratio depend on the NOR concentration. (C) 2021 Elsevier B.V. All rights reserved.

Single daily dose (SDD) is a good way to improve adherence by simplifying treatment. Efficacy data concerning patients with Wilson disease (WD) taking an SDD are lacking.To report the effectiveness of the use of SDD for the treatment of WD.This retrospective study included WD patients followed in the French National Network who received an SDD in maintenance phase. The treatment failure was defined as a composite criterion with the occurrence of at least one of the following criterion: death, transplantation, increase of transaminases >2xULN, hepatic decompensation, neurological aggravation, severe side effects related to treatment, and/or discontinuation of treatment.A total of 26 patients received an SDD (D-penicillamine=13, trientine=8, zinc=5) after a median interval of 152 months after diagnosis. After one year, two patients had treatment failure: transaminitis in one, continuation of neurological deterioration in the other related to a poor compliance. After a median duration of 41 months on SDD, 3 other patients had treatment failure (transaminitis=2, treatment discontinuation=1). There was no death, no liver transplantation, no hepatic decompensation, and no severe side effects related to treatment during the follow-up. Moreover, transaminases and serum exchangeable copper were not significantly different 1 year post-switch and at last follow-up compared to baseline.Maintenance therapy simplification through the use of an SDD could be considered in some WD patients. In this pilot study, SDD was effective in 21/26 patients (81%) without any concern regarding safety.

Background. - One diagnosis of cystic fibrosis involves measuring the nasal transepithelial potential difference (NPD) as a complementary technique in the forms of the disease, where the sweat test is non-discriminating. The NPD is measured using solutions with and without chlorides, containing a variety of substances whose activities on nasal mucus membranes are studied or assessed. Among the solutions described in the literature and used in specialized centers, none seems to be best adapted for industrial production for reasons of stability (formulas of the international consensus of Rowe et al. and formulas of Knowles et al.) and/or potential toxicity (formulas of Middleton et al.). Objective(s). - Defining new formulas, according to those of the international consensus, with greater physicochemical and microbiological stability. Methods. - The reformulation tests were conducted on the formulas of Rowe et al., using CHESS (R) (CHemical Equilibrium of Species and Surfaces) software for modeling aqueous systems that substantially reduced the number of experiments. CHESS (R) software was first validated using models of ideal and non-ideal solutions. Thereafter, experimentation was carried out for the sake of comparison with theoretical data. Results. - CHESS (R) software using models of ideal and non-ideal solutions were validated. The experimentation confirmed the theoretical data, and new formulas were assessed based on their physicochemical (pH, content, Osmotality) and microbiological stability. Conclusion. - The new formulas defined here guarantee excellent physicochemical and microbiological stability of diagnostic solutions, indispensable criteria for harmonizing and comparing results from different specialized centers using NPD measurements. These new formulas apply to the harmonization approach of techniques for measuring the nasal transepithelial potential difference. (C) 2021 Academie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

This study aimed to explore the suitability of flow injection spectrophotometry (FIS) to analyze three degraded therapeutic monoclonal antibodies (bevacizumab, nivolumab, and rituximab). For this purpose, aggregates were generated with stirring, freeze-thaw, and heat stresses. The intact and stressed mab samples were filtered with 0.22 mm hydrophilic filters and analyzed by size exclusion chromatography (SEC), cation-exchange chromatography (CEX), and FIS. In terms of quantitative and qualitative analysis, protein loss and structural changes were assessed. Various aggregates profiles were obtained according to the mabs and the stresses. FIS allowed performing very satisfactory quantifications for each mab with intermediate precision RSD 3.0 % and recovery between 97.9 and 102.0 %. From the protein loss measurements, it appears that SEC underestimates the mab aggregate proportions up to two times less as compared with FIS since the latter avoids any non-specific interactions (electrostatic or hydrophobic interactions). Using second derivative spectroscopy and m ultivariate data analysis, we noticed apparent structural differences, located in the regions 245-265 nm for rituximab and nivolumab and 280-300 nm for bevacizumab, depending on the stress. The FIS complementarity with the other techniques used in this study allowed us to demonstrate that the three mabs behave differently for a given stress condition. While extreme mechanical stress formed large aggregates irrespective of the mabs, rituximab showed to be less stable and more sensitive than the two other mabs under freeze-thaw and heat stresses, generating large aggregates ( 200 nm) and partial unfolding. Nivolumab tends to form small aggregates less than 50 nm when heated and freeze-thawed. Moreover, freeze-thaw seems to generate native IgG-1 aggregates with rituximab. Similarly, bevacizumab showed to form these IgG-1 aggregates and was resistant to freeze-thaw, likely thanks to trehalose cryoprotectant from its formulation. Finally, FIS associated with multivariate analysis can provide rich information in one single run and appears to be a fast, simple, and reliable method to set complementary and orthogonal approaches for protein aggregates monitoring. (c) 2021 Elsevier B.V. All rights reserved.

Background In 2020, the first mRNA COVID vaccine was approved by the with six doses from single vial. In the context of material shortages, the aim of the study was to compare different protocols to extract doses using uncrimped materials with good trueness and reproducibility. Methods To optimize the extraction of the sixth dose from a single vial with uncrimped materials, alternative protocols of preparation were tested, derived from the drug information. Results The repeatability of injected volume was acceptable for all protocols (CV<5.3%). To prepare six 0.3mL doses using uncrimped materials, protocols with an air bubble were evaluated to offset the high dead volume inherent to uncrimped materials. Regarding the limited doses observed using long intramuscular needle (92.8% of the reference dose), the air bubble protocol with a liquid volume adjustment at 0.27mL was finally validated to respect the administration of full doses. Conclusion Results highlighted the necessity to adapt the drug information protocol for the preparation and administration of Cominarty®, due to the use of high dead volume materials. Despite the good reproducibility and accuracy of the air bubble protocols, some precautions have therefore to be taken to maintain the integrity of the vaccine suspension for efficient administration.

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient’s respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

OBJECTIVE:The development of oral chemotherapy (OC) has led to the recent establishment of multidisciplinary programmes involving pharmacists. We evaluated the utility of our local programme for detecting potential interactions with OCs, particularly drug-drug interactions (DDIs) and herbal-drug interactions (HDIs).METHODS:We performed a single-centre retrospective descriptive study of patients on OC attending a pharmaceutical consultation (PC) during a seven-month period. These consultations included the use of various complementary tools/databases to search for interactions.RESULTS:We analysed 308 treatments taken by 42 consecutive patients. Fifty-four potential interactions with OCs were detected in 26% (n = 79) of the treatments taken by patients: 46 DDIs (32 minor, 12 major, 2 contraindicated) and eight HDIs. Five interventions associated with interactions were suggested by pharmacists during the consultations (4 were taken into account by oncologists). The total mean time spent on each PC for an individual patient was 80 minutes (36 minutes of preparation, 44 minutes with the patient).CONCLUSION:This pilot study highlights the importance of studying interactions in such patients, and of the expertise of pharmacists for detecting interactions, which were found in more than one in four treatment lines. The further development of such activities, which already take up considerable amounts of time, is therefore warranted.

This case report relates to the first-in-man use of a vessel occluder gel medical device as a fistula occluder in a repurposing strategy. A patient with chronic colocutaneous fistula received an off-label treatment with a thermoresponsive Poloxamer 407 gel (20%) via percutaneous administration and injected under endoscopic control. Treatment consisted in the association of esophageal stent placement and gel injection. The product was administered just after the stent placement at<20°C in its liquid form, gelling at body temperature to form a fistula plug. However, the stent was removed at day 26 because of major pain and the fistula was still present. Treatment was continued a total of 14 administrations of thermoresponsive Poloxamer 407 gel during 7 weeks via the external fistula orifice. The treatment reduced fistula orifice diameter from 4.0±0.5 to 1mm and fistula daily output decreased from 425±65 to 23±4mL, when comparing the months before and after treatment. Gel administration was not associated with any toxic effects. The therapeutic outcome remained stable 1 year after treatment. The external fistula diameter and the fistula output were similar to what was observed after the last Poloxamer 407 gel administration.

Antineoplastic agents are, for most of them, highly toxic drugs prepared at hospital following individualized prescription. To protect patients and healthcare workers, it is important to develop analytical tools able to identify and quantify such drugs on a wide concentration range. In this context, surface enhanced Raman spectroscopy (SERS) has been tested as a specific and sensitive technique. Despite the standardization of the nanoparticle synthesis, a polydispersity of nanoparticles in the suspension and a lack of reproducibility persist. This study focuses on the development of a new mathematical approach to deal with this nanoparticle polydispersity and its consequences on SERS signal variability through the feasibility of 5-fluorouracil (5FU) quantification using silver nanoparticles (AgNPs) and a handled Raman spectrophotometer. Variability has been maximized by synthetizing six different batches of AgNPs for an average size of 24.9 nm determined by transmission electron microscopy, with residual standard deviation of 17.0%. Regarding low performances of the standard multivariate data processing, an alternative approach based on the nearest neighbors were developed to quantify 5FU. By this approach, the predictive performance of the 5FU concentration was significantly improved. The mean absolute relative error (MARE) decreased from 16.8% with the traditional approach based on PLS regression to 6.30% with the nearest neighbors approach (p-value < 0.001). This study highlights the importance of developing mathematics adapted to SERS analysis which could be a step to overcome the spectral variability in SERS and thus participate in the development of this technique as an analytical tool in quality control to quantify molecules with good performances, particularly in the pharmaceutical field.

Nasopharyngeal swab is the reference sampling method to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as recommended by the World Health Organization (WHO) (1). However, nasal specimens may have a slightly lower sensitivity than nasopharyngeal specimens (2, 3). We herein validated an alternative procedure to collect nasal secretions with a swab routinely used in medical bacteriology for which there is no risk of supply disruption in order to perform the molecular diagnosis of SARS-CoV-2 infection.

In 2018, the World Health Organization （WHO） reported 9.6 million cancer deaths worldwide, in accordance with the data collected by the International Agency for Research on Cancer （IARC）.The fight against cancer and other noncommunicable diseases is now a global priority, with cancer being a primary priority.