Particulate contamination in single-use systems: real versus perceived risk

Certainly final drug products must be “essentially free” of visible particulate contamination and visual inspection systems must meet USP 790 criteria. In addition, final drug products must meet USP 788 limits for sub-visible particles. It is however important to distinguish final drug product standards from requirements for single-use process containers and equipment, even though it is common to claim single-use systems (SUS) “meet USP 788 requirements”. USP 788 does not describe a method for determination of particulate counts in SUS process containers and equipment (1). Visible particles are “visible” and thus a visual indicator of SUS quality, and consequently sometimes lead to visceral reactions and the perception of major or even critical risk to product safety. However, guidance from PDA TR66 (2), ASME BPE-2016 (3) and the BPSA (4) published in the last few years provide valuable information on assessment of particulate risk in SUS processes. In most situations where SUS are currently applied, filtration and purification steps occur downstream, which essentially reduces the risk to zero for transfer of particulate contamination from SUS to the final drug product. However, any applications of SUS after final filtration (such as in ascetic processes or final filling operations) present significant risk to drug substance or drug product. So is risk to final drug product from SUS an essentially a binary situation: Prior to final filtration low risk, and after final filtration high risk? While assembly of SUS is a “clean build” process usually done in ISO 7 classified cleanrooms, incoming components and cleanroom processes such as cutting, welding and human assembly are unfortunately not particulate-free with current SUS manufacturing technologies. In addition, visual inspection of SUS components and assemblies is nowhere near 100% effective at detecting visible particles, especially for large complex assemblies or stirred tank reactor systems. Sartorius is currently implementing a “Visible Particle Test” (VPT: liquid extraction and microscopy) for process monitoring and continuous improvement efforts. Thus while most SUS manufactures strive to minimize particulate contamination, absence of particulates remains a goal but is not a currently feasible SUS specification. Particle contaminants may lie within the interior surfaces of SUS (in the fluid contact path), may be embedded within bag films or plastic components, or lie on the exterior surfaces of SUS. Particulates fall into two general categories: intrinsic (particles from SUS manufacturing process and component materials) and extrinsic (particles from human operators or the environment). Extrinsic particles potentially contain microbiological or viral contamination. These classifications of location and particle type lead to different assessments of risk. One concern are potential “secondary effects” of particulate contamination. Particle contamination could potentially nucleate protein aggregation. Particles embedded in SUS films or plastic components, or on the interior surfaces of the SUS assemblies could potentially leach out chemicals or release microbiological or viral contamination into the bioprocess fluids. In this presentation, the topic of particulate contamination risk is approached holistically and scientifically using literature data along with calculations. The goal of the presentation is to gain feedback from end users, and to facilitate the discussion between suppliers and end users based upon real rather than perceived risks. (1) Particulate Contamination in Single-Use Systems, J. D. Vogel and K. Wormuth, Bioprocess International, 15(9) 2017 (2) Application of Single-Use Systems in Pharmaceutical Manufacturing, PDA Technical Report No. 66, 2014 (3) Bioprocessing Equipment, ASME BPE-2016, American Society of Mechanical Engineers, 2016 Recommendations for Testing, Evaluation and Control of Particulates from Single-Use Process Equipment, Bio Process Systems Alliance, 201

Exploring the electrochemical behavior of InSb as negative electrode for Mg-ion batteries

International audienceMagnesium metal has a tendency to react with conventional electrolytes to form a barrier on its surface[1], rendering cations exchange impossible, and thus dramatically limiting reversible stripping/deposition of Mg. Unlike Mg metal, alloys based on p-block elements (Sn, Sb, In, Pb, Bi) do not appear to suffer from the formation of a blocking passivation layer in conventional electrolytes. These substitute electrodes appear therefore as a promising solution to overcome the problem of compatibility with electrolytes, even if the reaction mechanisms behind their operation in conventional electrolytes are still unsolved. In order to improve the performance of these electrodes, we evaluated a possible synergy effect between p-block elements, as already shown for SnSb[2] and BiSb[3]. We chose to work on InSb that may combine the high theoretical capacity of Sb and the lowest working potential reported for In. InSb, synthetized by ball-milling, shows an electrochemical behavior (Figure 1) drastically different from those of the lone elements. We will demonstrate that the combination of In and Sb is beneficial as it promotes the reactivity of Sb, similarly to BiSb alloy[3]. Structural and morphological ex situ characterization will also be described in details and correlated with the peculiar electrochemical behavior of InSb. Figure 1: Voltage profile of an InSb-based electrode cycled at a rate of C/100 in an electrolyte based of EtMgCl and Et2AlCl in THF

Spectral-phase interferometry for direct electric-field reconstruction applied to seeded extreme-ultraviolet free-electron lasers

We present a setup for complete characterization of femtosecond pulses generated by seeded free-electron lasers (FEL's) in the extreme-ultraviolet spectral region. Two delayed and spectrally shifted replicas are produced and used for spectral phase interferometry for direct electric field reconstruction (SPIDER). We show that it can be achieved by a simple arrangement of the seed laser. Temporal shape and phase obtained in FEL simulations are well retrieved by the SPIDER reconstruction, allowing to foresee the implementation of this diagnostic on existing and future sources. This will be a significant step towards an experimental investigation and control of FEL spectral phase

New insights into the electrode/electrolyte interface on positive electrodes in Li-Ion batteries

International audienceUnderstanding and controlling the reactivity at the electrode/electrolyte interface (EEI) is one of the key issues for the development of high capacity and efficient lithium-ion batteries. The heterogeneous and partially catalytic reaction of the electrode with the electrolyte triggers the formation of surface films on the electrode surface which can cause degradation of the cell performance. Whereas the EEI layer properties are quite well known for negative electrodes such as lithium metal and graphite [1,2], the EEI layer on positive electrode materials is still puzzling. Especially the interface layers on high voltage and high capacity positive electrodes, whose potentials approach the limit of electrolyte stability against oxidation [3], is quite unexplored. One of the challenges in understanding the reactions at the surface of the electrode is the complicated composition of the positive electrodes, containing not only the active material but also conductive agents and polymeric binders, that can modify the EEI layers on the electrode. To bypass these ambiguities, there is a need for study model electrodes such as thin films or pure active material electrodes, which allow for investigating solely the reactivity of the electrolyte at the active material surface. Here, combining X-ray Photoelectron Spectroscopy (XPS and X-ray Absorption and Emission Spectroscopy (XAS/XES), of model electrodes, we will show how the species formed at the electrode/electrolyte interface are affected by change in charging potential and the structure and nature of the transition metal in the material. XES and XAS will be used to shed light on the change of electronic structure upon delithiation

Cost-Effectiveness Of Treatments For Mild-To-Moderate Obstructive Sleep Apnea In France

International audienceObjectives: Untreated obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with excessive daytime sleepiness, increased risk of cardiovascular (CV) disease, and road traffic accidents (RTAs), which impact survival and health-related quality of life. This study, funded by the French National Authority for Health (HAS), aimed to assess the cost-effectiveness of different treatments (i.e., continuous positive airway pressure [CPAP], dental devices, lifestyle advice, and no treatment) in patients with mild-to-moderate OSAHS in France.Methods: A Markov model was developed to simulate the progression of two cohorts, stratified by CV risk, over a lifetime horizon. Daytime sleepiness and RTAs were taken into account for all patients while CV events were only considered for patients with high CV risk.Results: For patients with low CV risk, incremental cost-effectiveness ratio (ICER) of dental devices versus no treatment varied between 32,976 EUR (moderate OSAHS) and 45,579 EUR (mild OSAHS) per quality-adjusted life-year (QALY), and CPAP versus dental devices, above 256,000 EUR/QALY. For patients with high CV risk, CPAP was associated with a gain of 0.62 QALY compared with no treatment, resulting in an ICER of 10,128 EUR/QALY.Conclusion: The analysis suggests that it is efficient to treat all OSAHS patients with high CV risk with CPAP and that dental devices are more efficient than CPAP for mild-to-moderate OSAHS with low CV risk. However, out-of-pocket costs are currently much higher for dental devices than for CPAP (i.e., 3,326 EUR versus 2,430 EUR) as orthodontic treatment is mainly non-refundable in France

Role of AMP-activated protein kinase in regulating hypoxic survival and proliferation of mesenchymal stem cells

Aims Mesenchymal stem cells (MSCs) are widely used for cell therapy, particularly for the treatment of ischaemic heart disease. Mechanisms underlying control of their metabolism and proliferation capacity, critical elements for their survival and differentiation, have not been fully characterized. AMP-activated protein kinase (AMPK) is a key regulator known to metabolically protect cardiomyocytes against ischaemic injuries and, more generally, to inhibit cell proliferation. We hypothesized that AMPK plays a role in control of MSC metabolism and proliferation. Methods and results MSCs isolated from murine bone marrow exclusively expressed the AMPKα1 catalytic subunit. In contrast to cardiomyocytes, a chronic exposure of MSCs to hypoxia failed to induce cell death despite the absence of AMPK activation. This hypoxic tolerance was the consequence of a preference of MSC towards glycolytic metabolism independently of oxygen availability and AMPK signalling. On the other hand, A-769662, a well-characterized AMPK activator, was able to induce a robust and sustained AMPK activation. We showed that A-769662-induced AMPK activation inhibited MSC proliferation. Proliferation was not arrested in MSCs derived from AMPKα1-knockout mice, providing genetic evidence that AMPK is essential for this process. Among AMPK downstream targets proposed to regulate cell proliferation, we showed that neither the p70 ribosomal S6 protein kinase/eukaryotic elongation factor 2-dependent protein synthesis pathway nor p21 was involved, whereas p27 expression was increased by A-769662. Silencing p27 expression partially prevented the A-769662-dependent inhibition of MSC proliferation. Conclusion MSCs resist hypoxia independently of AMPK whereas chronic AMPK activation inhibits MSC proliferation, p27 being involved in this regulatio

Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification

Background HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases.Results We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers.Conclusions Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations

Euro Surveill

In September 2023, a severe outbreak of type B botulism with fifteen cases was linked to consumption of canned sardines at a restaurant in Bordeaux, France, during the Rugby World Cup. The cases were from seven countries. One death was recorded. Outbreak investigation using credit card data, rapid communication between health authorities of the affected countries and broad media communication allowed identification of cases and exposed persons and prevented further severe outcomes

Contributions and perspectives of Indigenous Peoples to the study of mercury in the Arctic

Arctic Indigenous Peoples are among the most exposed humans when it comes to foodborne mercury (Hg). In response, Hg monitoring and research have been on-going in the circumpolar Arctic since about 1991; this work has been mainly possible through the involvement of Arctic Indigenous Peoples. The present overview was initially conducted in the context of a broader assessment of Hg research organized by the Arctic Monitoring and Assessment Programme. This article provides examples of Indigenous Peoples' contributions to Hg monitoring and research in the Arctic, and discusses approaches that could be used, and improved upon, when carrying out future activities. Over 40 mercury projects conducted with/by Indigenous Peoples are identified for different circumpolar regions including the U.S., Canada, Greenland, Sweden, Finland, and Russia as well as instances where Indigenous Knowledge contributed to the understanding of Hg contamination in the Arctic. Perspectives and visions of future Hg research as well as recommendations are presented. The establishment of collaborative processes and partnership/co-production approaches with scientists and Indigenous Peoples, using good communication practices and transparency in research activities, are key to the success of research and monitoring activities in the Arctic. Sustainable funding for community-driven monitoring and research programs in Arctic countries would be beneficial and assist in developing more research/ monitoring capacity and would promote a more holistic approach to understanding Hg in the Arctic. These activities should be well connected to circumpolar/international initiatives to ensure broader availability of the information and uptake in policy development

Produire des contenus documentaires en ligne

Les bibliothèques sont confrontées à des nécessités d’exploitation de leurs collections qui ne passent plus seulement par la gestion du stock mais par l’appropriation et la restitution de contenus documentaires. Le plan de l’ouvrage s’articule autour de quatre parties : exploiter les collections ; la curation et la production de contenus ; produire en réseau, et enfin, connaître le contexte juridique et écrire pour le web. Ainsi, le professionnel est devenu médiateur, producteur et éditeur de matières documentaires élaborées. Chaque partie traite aussi des nouvelles compétences relationnelles et techniques à acquérir pour ce faire. Une quinzaine de professionnels abordent ces différents aspects, en s’appuyant sur des réalisations concrètes menées dans les bibliothèques, de lecture publique comme des universités