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- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 2. |
- Bacchus, Philip, et al.
(författare)
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Civil-military collaboration to facilitate rapid deployment of a mobile laboratory in early response to covid-19 : A high-readiness exercise
- 2021
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Ingår i: HEALTH SECURITY. - : Mary Ann Liebert. - 2326-5094 .- 2326-5108. ; 19:5, s. 488-497
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Tidskriftsartikel (refereegranskat)abstract
- Rapid and adaptable diagnostic capabilities are of great importance in the face of emerging infectious diseases. In an outbreak, timely establishment of diagnostic routines is crucial to identifying cases and preventing the spread of the disease, especially when faced with high-consequence pathogens. In this article, we describe a multiagency exercise including the rapid deployment and diagnostic adaptation of the Swedish Armed Forces mobile laboratory (biological field analysis laboratory) in the context of COVID-19. This deployment was initiated as a high-readiness exercise at the end of January 2020, when the global development of the outbreak was still uncertain. Through collaboration with the Public Health Agency of Sweden and a civilian hospital, a real-time reverse transcriptase polymerase chain reaction method specific to SARS-CoV-2 was made available and adapted to the mobile laboratory, and the team established and evaluated a functional and efficient diagnostic asset along with a logistical support chain. We also organized and evaluated mobile testing teams, and the method was later used in large-scale, national, cross-sectional COVID-19 surveys in several regions of Sweden. In this article, we focus on the challenges of overbridging the civil-military interface in this context and identifying lessons learned and added values to the response during the early pandemic. We propose that the experiences from this exercise and governmental agency collaboration are valuable in preparation for future outbreaks.
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| 4. |
- Sandberg, Christer, 1962-
(författare)
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Process intensification in mechanical pulping : Reduced process complexity and improved energy efficiency
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This work shows that, for newsprint quality grades, the production processes for mechanical pulp can be simplified, and the specific electrical energy demand can be reduced with around 600 kWh/ton (30%). The purpose of the work is to demonstrate how the production cost for mechanical pulps can be decreased through increased energy efficiency and reduced number of unit operations. The idea was to improve the main line refining conditions so that no additional fibre development or shive reduction is needed and thereby, the normal screening and rejects treatment system could be omitted.Mechanical pulp is used to produce a variety of products, where the two largest categories are printing papers and paperboard for packaging. The pulp is mainly produced by the breakdown of wood chips between rotating metal discs in machines called refiners with the product and process generally referred to as thermomechanical pulp(ing) (TMP). The refiner process requires high specific electrical energy to separate and develop the fibres to a pulp intended for the production of printing papers. Today, many processes need over 2000 kWh/ton of refining energy plus 200-300 kWh/ton of auxiliary energy (to drive pumps, agitators, screw conveyors, screens, presses, etc.).During the last two decades of the 20th century, the chemical processing industry underwent a transformation. The process development changed from being unit operation focused to function focused. The result is more compact processes with less equipment, higher yield and lower energy demand. When the development is made in an innovative way with such large effects on process performance, it is referred to as process intensification. My work is inspired by the concepts of process intensification, especially the striving for more compact processes with higher efficiency. This work is focused on mechanical pulp, intended for the manufacture of printing paper, produced in refiners with Norway spruce (Picea abies) as raw material. However, this approach could also be applied to mechanical pulp production in integrated paperboard mills and also using other raw materials e.g., pines or hardwoods. The investigated pulps and processes in this work are mainly intended for uncoated paper grades (newsprint, improved newsprint and book paper) printed by the offset printing process. In all studies, the pulps have been produced with full scale mill equipment and evaluated using laboratory measurements. However, in two studies, the produced pulps were evaluated on paper machines and at printing houses.A large number of process concepts have been evaluated in which different approaches have been used to reduce the specific energy and, in some cases, improve pulp quality. The approaches include:1. Impressafiner chip pretreatment 2. Primary high consistency (HC) refiner type (DD, RTS, CD, SD)3. Addition of low doses of sodium sulphite 4. Increased refining temperature (housing pressure)5. Refiner segments and centre plate design6. Increased production rate7. Low consistency (LC) refining in different process positions and in combination with different HC refiner typesThe separate effects of all these techniques have not been evaluated systematically neither have potential synergistic effects of all possible combinations been investigated. Even though a large number of combinations of unit operations have been studied, the emphasis has been on trying to do as much fibre development as possible in a single HC refining stage.The mill trials with spruce as raw material have shown that a low shive content and appropriate fibre development can be attained in a process without separate treatment of long fibres. High intensity primary stage refining (RTS and DD) was necessary to reach a low shive content at a low specific refining energy (SRE), with DD refiners appearing to be the most suitable for simplified processes. DD and RTS refining produced pulps with fibres exhibiting a higher degree of external fibrillation and share of split fibres than SD refining. DD refining produced fibres with lower cell wall thickness and higher light scattering at given fibre length than RTS refining. The lowest specific refining energy was attained for one of the trials using the process, denoted as S:HT:DD-LC-LC, consisting of DD refining at increased production rate, 18 adt/h, increased housing pressure, 6.6 bar(g), and with 5 kg/adt sodium sulphite added to the chips immediately before the refiner. After DD refining the pulp was refined in two LC refining stages. This process required only 1280 kWh/adt SRE to reach a tensile index of 52 Nm/g (Rapid-Köthen). This is 900 kWh/adt lower than the final pulp for newsprint based on SD HC refining, and over 500 kWh/adt lower than Scandinavian BAT processes (2014). Additionally, the auxiliary energy was around 150 kWh/adt lower for the processes without a conventional rejects treatment system. At 52 Nm/g tensile index, the light scattering coefficient was 2-3 m2/kg higher, and the length-weighted average fibre length was around 0.1 mm lower for this process than for SD TMP final pulp. The fibre bonding, indicated by density, tensile index and Z-strength of fibre fraction handsheets, was similar or higher for the S:HT:DD-LC-LC process than the reference SD TMP process with a rejects treatment system. Other interesting process configurations, with somewhat lower efficiencies, included:1. Impressafiner pretreatment of the chips with sodium sulphite before DD refining, with or without subsequent LC refining. Chip pretreatment with the Impressafiner enabled operating the DD refiner at higher intensity (feeding segments and increased production rate) without significant loss of quality and LC refining enabled increased production rate which increased the overall efficiency.2. RTS-SD refining with sodium sulphite added before the second stage SD refiner referred to as RTS-S:SD. The pulp from the RTS-S:SD process had similar fibre length as the S:HT:DD-LC-LC process but lower light scattering coefficient.3. A single-stage DD refiner operating at 15.5 adt/h and 4 bar(g) housing pressure (no sodium sulphite addition), which produced pulp with lower fibre length but higher light scattering coefficient than the S:HT:DD-LC-LC process. Two simplified processes were evaluated on paper machines and in printing houses. The first, denoted DD-LC-F, involved a combination of DD primary refining followed by LC refining and fractionation (screening). The screen rejects were mixed with the main line DD pulp before the LC refiner. The second process was the CPT:S-DD-LC process (№1 above). Good runnability was attained both on the paper machines and in the offset printing presses and the paper quality was similar to the reference paper.For printing paper applications, the proportion of fibre development in LC refining should preferably be relatively low, since it was shown that LC refiners have limited capacity to reduce fibre wall thickness and thereby develop light scattering and fibre fraction Z-strength.Explicit effects on the number of unit operations and production cost have not been evaluated in this work, but clearly both investment and variable costs as well as fixed costs can be reduced with a simplified process.
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