We make the case for why continuous pharmaceutical manufacturing is essential, what the barriers are, and how to overcome them. To overcome them, government action is needed in terms of tax incentives or regulatory incentives that affect time. 相似文献
Control and prevention of rapid influenza spread among humans depend on the availability of efficient and safe seasonal and pandemic vaccines, made primarily from inactivated influenza virus particles. Current influenza virus production processes rely heavily on embryonated chicken eggs or on cell culture as substrate for virus propagation. Today’s efforts towards process intensification in animal cell culture could innovate viral vaccine manufacturing using high-yield suspension cells in high cell density perfusion processes. In this work, we present a MDCK cell line adapted to grow as single cell suspension with a doubling time of less than 20 h, achieving cell concentrations over 1 × 107 cells/mL in batch mode. Influenza A virus titer obtained in batch infections were 3.6 log10(HAU/100 µL) for total- and 109 virions/mL for infectious virus particles (TCID50), respectively. In semi-perfusion mode concentrations up to 6 × 107 cells/mL, accumulated virus titer of 4.5 log10(HAU/100 µL) and infectious titer of almost 1010 virions/mL (TCID50) were possible. This exceeds results reported previously for cell culture-based influenza virus propagation by far and suggests perfusion cultures as the preferred method in viral vaccine manufacturing. 相似文献
Variable selection is a crucial issue in model building and it has received considerable attention in the literature of survival analysis. However, available approaches in this direction have mainly focused on time-to-event data with right censoring. Moreover, a majority of existing variable selection procedures for survival models are developed in a frequentist framework. In this article, we consider additive hazards model in the presence of current status data. We propose a Bayesian adaptive least absolute shrinkage and selection operator procedure to conduct a simultaneous variable selection and parameter estimation. Efficient Markov chain Monte Carlo methods are developed to implement posterior sampling and inference. The empirical performance of the proposed method is demonstrated by simulation studies. An application to a study on the risk factors of heart failure disease for type 2 diabetes patients is presented. 相似文献
The purpose of the present review was to survey the available literature on computer-aided design/computer-aided manufacturing (CAD/CAM)-produced resin composite materials to provide clinicians with a current overview of the key components necessary for daily clinical use. An electronic search was conducted in the PubMed database. Peer-reviewed articles in English language on the use of resin composites in CAD/CAM dental crowns were included. A total of 122 full-text articles were identified, 15 of which were selected during the initial review. Two additional articles were also discovered through a manual search, to obtain a final total of 17 articles included in the present review. Of these, 16 were to in vitro studies, and one was an in vivo study. Findings from the in vitro studies indicate that resin composite block materials for CAD/CAM applications demonstrate excellent physical properties and are appropriate for the clinical restoration of premolars and molars. However, the in vivo study reported a low 3-year success rate, but high survival rate for resin composite CAD/CAM crowns placed in the premolar region. The key to ensuring the successful prognosis of a resin composite CAD/CAM crown is to ensure that all steps—such as proper case selection, abutment tooth preparation, occlusal adjustment, and bonding—are accurately performed. 相似文献
PurposeThe purpose of this study was to evaluate internal porosities, retentive force values and survival of cobalt–chromium (Co–Cr) alloy clasps fabricated by direct metal laser-sintering (DMLS) and compare them to conventionally cast clasps.MethodsEmbrasure clasps were digitally designed fitting teeth 35 and 36 on identical metal models (N = 32). Sixteen clasps were fabricated using DMLS (group DMLS) and another sixteen clasps were additively manufactured from wax and then cast from a Co–Cr alloy (group CAST). Internal porosities were examined using micro-focus X-ray (micro-CT) and analyzed applying Kolmogorov–Smirnov test, Mann–Whitney test, and T test (significance level: p < 0.050). A universal testing machine was used to determine the retentive force values at baseline and after 1095, 5475, 10,950 and 65,000 cycles of simulated aging. Data were analyzed employing Kolmogorov–Smirnov test, one-way ANOVA, and Scheffé’s post-hoc test (significance level: p < 0.050). Survival was estimated for 65,000 cycles of artificial aging using Kaplan–Meier analysis.ResultsMicro-CT analysis revealed a higher prevalence (p < 0.001), but a more homogeneous size and a significantly smaller mean (p = 0.009) and total volume (p < 0.001) of internal porosities for group DMLS. The groups showed mean initial retentive force values of 13.57 N (CAST) and 15.74 N (DMLS), which significantly declined over aging for group CAST (p = 0.003), but not for group DMLS (p = 0.107). Survival was considerably higher for group DMLS (93.8%) than for group CAST (43.8%) after 65,000 cycles of aging.ConclusionsClasps made by laser-sintering could be an alternative to conventional cast clasps for the fabrication of removable partial denture frameworks. 相似文献
AbstractNon-invasive ventilation (NIV) is assisted mechanical ventilation delivered via a facemask for people with chronic conditions that affect breathing. NIV is most commonly delivered via an interface (mask) covering the nose (nasal mask) or the nose and mouth (oronasal mask). The number of children in the UK requiring NIV is currently estimated to be around 5000. Mass-produced masks are available for both the adult and paediatric markets but masks that fit well are difficult to find for children who are small or have asymmetrical facial features. A good conforming fit between the mask and the patient’s face to minimise unintentional air leakage is essential to deliver the treatment effectively; most ventilators will trigger an alarm requiring action if such leakage is detected. We present an innovative use of 3D scanning and manufacturing technologies to deliver novel mask-face interfaces to optimise mask fit to the needs of individual patients. Ahead of planned user trials with paediatric patients, the project team trialled the feasibility of the process of creating and printing bespoke masks from 3D scan data and carried out testing of the masks in adult volunteers to select the strongest design concept for the paediatric trial. The evaluation of the process of designing a bespoke mask from scan data, arranging for its manufacture and carrying out user testing has been invaluable in gaining knowledge and discovering the pitfalls and timing bottlenecks in the processes. This allowed the team to iteratively refine the techniques and methods involved, informing user trials later on in the project. It has also provided indicative cost estimates for 3D printed mask prototype components which are useful in project decision making and trial planning. The value of the process extends to considerations for future implementation of the process within a clinical pathway. 相似文献
In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration.To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains. 相似文献
Introduction: Currently, hot melt extrusion (HME) is a promising technology in the pharmaceutical industry, as evidenced by its application to manufacture various FDA-approved commercial products in the market. HME is extensively researched for enhancing the solubility and bioavailability of poor water-soluble drugs, taste masking, and modifying release in drug delivery systems. Additionally, its other novel opportunities or pharmaceutical applications, and capability for continuous manufacturing are being investigated. This efficient, industrially scalable, solvent-free, continuous process can be easily automated and coupled with other novel platforms for continuous manufacturing of pharmaceutical products.
Areas covered: This review focuses on updates on solubility enhancement of poorly water-soluble drugs and process analytical tools such as UV/visible spectrophotometry; near-infrared spectroscopy; Raman spectroscopy; and rheometry for continuous manufacturing, with a special emphasis on fused deposition modeling 3D printing.
Expert opinion: The strengths, weakness, opportunities, threats (SWOT) and availability of commercial products confirmed wide HME applicability in pharmaceutical research. Increased interest in continuous manufacturing processes makes HME a promising strategy for this application. However, there is a need for extensive research using process analytical tools to establish HME as a dependable continuous manufacturing process. 相似文献