Modeling-based Approach Towards Quality by Design for a Telescoped Process

A telescoped, two-step synthesis was investigated by applying Quality by Design principles. A kinetic model consisting of 12 individual reactions was successfully established to describe the synthesis and side reactions. The resulting model predicts the effects of changes in process parameters on total yield and quality. Contour plots were created by varying process parameters and displaying the model predicted process response. The areas in which the process response fulfils predetermined quality requirements are called design spaces. New ranges for process parameters were explored within these design spaces. New conditions were found that increased the robustness of the process and allowed for a considerable reduction of the used amounts of a reagent. Further optimizations, based on the newly generated knowledge, are expected. Improvements can either be direct process improvements or enhancements to control strategies. The developed strategies can also be applied to other processes, enhancing upcoming and preexisting research and development efforts

Additive Manufacturing of Structural Cores and Washout Tooling for Autoclave Curing of Hybrid Composite Structures

This paper presents a study combining additive manufactured (AM) elements with carbon fiber-reinforced polymers (CFRP) for the autoclave curing of complex-shaped, lightweight structures. Two approaches were developed: First, structural cores were produced with AM, over-laminated with CFRP, and co-cured in the autoclave. Second, a functional hull is produced with AM, filled with a temperature- and pressure-resistant material, and over-laminated with CFRP. After curing, the filler-material is removed to obtain a hollow lightweight structure. The approaches were applied to hat stiffeners, which were modeled, fabricated, and tested in three-point bending. Results show weight savings by up to 5% compared to a foam core reference. Moreover, the AM element contributes to the mechanical performance of the hat stiffener, which is highlighted by an increase in the specific bending stiffness and the first failure load by up to 18% and 310%. Results indicate that the approaches are appropriate for composite structures with complex geometries

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Time to ease sanctions on Russia

Sanctions have largely failed to thwart Russian aggression in Ukraine since 2014. In search of diplomatic solutions, it is high time to adapt the strategy and allow for a gradual easing of sanctions - if Russia takes de-escalatory steps.ISSN:2296-647

Online Condition Monitoring Tool for Automated Machinery

In order to increase machinery resource, energy and time efficiency, Condition Monitoring (CM) offers a wide set of beneficial tools. Those tools can basically be segmented in maintenance improvements or the optimization of process parameters. CM requires data input from a component, which is then analyzed using data based or physical models, which return an estimate of the component_s current condition. The use of high quality sensors in a stable laboratory environment generally leads to an overemphasizing of the results which CM systems achieve in an industrial environment. Additionally, the installation of sensors is not always economically feasible for low-cost machinery. To overcome this, the CM system which is presented in this paper uses data, which is usually present in the PLC, as a consequence thereof, the data quality is significantly lower compared to dedicated sensor equipment. A real production machinery is further used to demonstrate the capabilities of condition monitoring in an industrial environment. The data driven CM process, which is used in this application example is compared to a model driven approach, conducted on a test equipment machine.ISSN:2212-827

New Scale-Up Technologies for Hydrogenation Reactions in Multipurpose Pharmaceutical Production Plants

The classical scale-up approach for hydrogenation reaction processes usually includes numerous laboratory and pilot scale experiments. With a novel scale-up strategy a significant number of these experiments may be replaced by modern computational simulations in combination with scale-down experiments. With only a few laboratory scale experiments and information about the production scale reactor, a chemical process model is developed. This computational model can be used to simulate the production scale process with a range of different process parameters. Those simulations are then validated by only a few experiments in an advanced scale-down reactor. The scale-down reactor has to be geometrically identical to the corresponding production scale reactor and should show a similar mass transfer behaviour. Closest similarity in terms of heat transfer behaviour is ensured by a sophisticated 3D-printed heating / cooling finger, offering the same heat exchange area per volume as in production scale. The proposed scale-up strategy and the custom-designed scale-down reactor will be tested by proof of concept with model reactions and those results will be described in a future publication. This project is an excellent example of a collaboration between academia and industry, which was funded by the Aargau Research Fund. The interest of academia is to study and understand all physical and chemical processes involved, whereas industry is interested in generating a robust and simple to use tool to improve scale-up and make reliable predictions

Condition-based Maintenance: Model vs. Statistics A Performance Comparison

The current development in industrial applications shows a variety of approaches to perform maintenance: With reactive maintenance, only parts which fail will be replaced. This causes high costs and high unexpected failure rates. Preventive maintenance uses a predefined service plan and also a wear part exchange schedule. The plan or schedule is often based on real-time or an operation time. This often results in fixed maintenance cycles or an operation time-based maintenance. This can lead to a replacement or maintenance of a completely healthy component or to ignoring components that need to be replaced more frequently. Condition-based maintenance is an advanced approach which is based on measured component data to identify the current status of a component. This status is used to determine the date of maintenance or exchange as estimated end of life. Thus, only damaged components are maintained or exchanged. The scope of this paper is to implement a model-based maintenance algorithm in a real industrial application to determine the remaining lifetime of a component. A very important requirement is a good identification process for the model and the component. However, short commissioning times and a variety of different components pose an increased effort to identify the parameters. Thus, this paper presents an approach for a parameter identification which solely relies on data being present in the numerical control of the machine. The model-based approach is then compared to a simpler statistical approach using data from a running production machine.ISSN:2212-827