Abstract Background [68Ga]Ga-PentixaFor is a promising radiotracer for positron emission tomography imaging of several human tumors overexpressing the chemokine receptor-4 (CXCR4). CXCR4 overexpression has been demonstrated in patients with hematologic malignancies, solid cancers, as well as cardiovascular pathologies of inflammatory origins. However, its radio synthesis is not yet fully developed in France, and existing methods do not use our type of synthesis module. Therefore, we aimed at developing a [68Ga]Ga-PentixaFor synthesis with Gaia/Luna Elysia-Raytest module to use it in clinical purpose. Results 12 syntheses were carried out by varying the temperature conditions and radiolabeling times, and led to choose specific labelling conditions with the Gaia/Luna Elysia-Raytest module: 97 °C, 4 min. The mean synthesis time of the 3 validation runs under good manufacturing practice (GMP) was 24 min 27 s (± 8 s), and the mean radiochemical yield was 87.0% [standard deviation (SD) 6.67%]. Different quality control parameters were also evaluated in accordance with European Pharmacopeia: radiochemical and radionuclidic purity, pH, sterility, stability and endotoxins levels. The average radiochemical purity was 99.1% (SD 0.25%) assessed by instant thin layer chromatography and 99.8% (SD 0.092%) assessed by high pressure liquid chromatography. average [68Ge] breakthrough was 1.48 × 10–5%, under the recommended level of 0.001%. We assessed the stability of the radiotracer up to 4 h at room temperature (no augmentation of the [68Ga] chloride in the final product, i.e. radiochemical purity (RCP) > 98.5%). The endotoxins levels were < 5 EU/mL, and the pH was 6.5 (same for the three syntheses). Conclusion The [68Ga]Ga-PentixaFor synthesis process developed on the Gaia/Luna Elysia-Raytest module has fulfilled all acceptance criteria for injectable radiopharmaceutical products regarding the European Pharmacopeia. The radiochemical purity, stability, efficacy, as well as the microbiological quality of the three GMP batches were found to be good. The robustness of the synthesis process may be suitable for multi-dose application in clinical settings.

BACKGROUND:Access to accurate information in health care is a key point for caregivers to avoid medication errors, especially with the reorganization of staff and drug circuits during health crises such as the COVID‑19 pandemic. It is, therefore, the role of the hospital pharmacy to answer caregivers' questions. Some may require the expertise of a pharmacist, some should be answered by pharmacy technicians, but others are simple and redundant, and automated responses may be provided.OBJECTIVE:We aimed at developing and implementing a chatbot to answer questions from hospital caregivers about drugs and pharmacy organization 24 hours a day and to evaluate this tool.METHODS:The ADDIE (Analysis, Design, Development, Implementation, and Evaluation) model was used by a multiprofessional team composed of 3 hospital pharmacists, 2 members of the Innovation and Transformation Department, and the IT service provider. Based on an analysis of the caregivers' needs about drugs and pharmacy organization, we designed and developed a chatbot. The tool was then evaluated before its implementation into the hospital intranet. Its relevance and conversations with testers were monitored via the IT provider's back office.RESULTS:Needs analysis with 5 hospital pharmacists and 33 caregivers from 5 health services allowed us to identify 7 themes about drugs and pharmacy organization (such as opening hours and specific prescriptions). After a year of chatbot design and development, the test version obtained good evaluation scores: its speed was rated 8.2 out of 10, usability 8.1 out of 10, and appearance 7.5 out of 10. Testers were generally satisfied (70%) and were hoping for the content to be enhanced.CONCLUSIONS:The chatbot seems to be a relevant tool for hospital caregivers, helping them obtain reliable and verified information they need on drugs and pharmacy organization. In the context of significant mobility of nursing staff during the health crisis due to the COVID-19 pandemic, the chatbot could be a suitable tool for transmitting relevant information related to drug circuits or specific procedures. To our knowledge, this is the first time that such a tool has been designed for caregivers. Its development further continued by means of tests conducted with other users such as pharmacy technicians and via the integration of additional data before the implementation on the 2 hospital sites.

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.

Compounded therapeutic mAbs used in a hospital require quality control (QC). In our hospital, analytical QC process intended to mAbs identification and quantification is based on flow injection analysis associated with second-derivative UV spectroscopy and matching method algorithm. We studied the influence of degraded mAbs after compounding on this validated QC. Three forced stress conditions including mechanical, thermal, and freeze-thawing stresses were studied to yield degraded mAbs from 2 model compounds, that is, bevacizumab (IgG1) and nivolumab (IgG4). Different degraded mAbs were generated and were analyzed in terms of turbidity, the percentage of aggregation, size distribution, and changes in tertiary structure. Stresses showed to be mAb-dependent in terms of aggregation. Tertiary structural changes were observed in most of the stressed samples by principal component analysis of the UV second-derivative data. The structural and physicochemical modifications conducted to mismatch depending on the nature of the stress. The mismatch ranged from 17% to 72% for the mAbs, except for freeze-thawed bevacizumab for which a perfect match (100%) was reached. The quantification with an unfulfilled relative error of the concentration (i.e., > ±15%) was detected only for mechanically stressed mAbs. In conclusion, the study revealed that the influence of the mAbs and the type of stress impact on the QC of compounded mAbs.

We have investigated the formation of 2-adamantanethiolate self-assembled monolayers on Au{III} and their displacement by n-dodecanethiol, using scanning tunneling microscopy, X-ray photoelectron spectroscopy, and infrared reflection absorption spectroscopy. Well-ordered 2-adamantanethiolate monolayers undergo rapid and significant molecular exchange upon exposure to n-dodecanethiol solutions, but their structures and intermolecular interactions template the growth of n-dodecanethiolate domains. Annealing 2-adamantanethiolate monolayers at 78 degrees C decreases the density of vacancy islands, while increasing the overall order and the average domain sizes in the films. This results in slower displacement by n-dodecanethiol molecules, as compared to unannealed monolayers. The secondary sulfur position on the adamantyl cage influences the lattice structure and exchange of 2-adamantanethiolate monolayers by alkanethiols.