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Simulation of intraluminal performance of lipophilic weak bases in fasted healthy adults using the DDDPlusTM Artificial Stomach Duodenum model
No full textThe majority of newly developed drug molecules exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studied in vivo and extensively in vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the less favorable small-intestinal environment. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenum in silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior.
The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. The simulated amounts per volume were compared to intraluminal data collected fasted healthy adults. Four different in silico transfer models running on a continuous or a stepwise mode were utilized for the simulations.
Each transfer model exhibited different capabilities to simulate observed intraluminal drug presence. Three in silico models overestimated the total drug amount measured in vivo (dissolved and solid), while two models matched the intraluminal drug concentrations. The stepwise model enabled adequate simulations of both drug concentration and total drug. The present investigation highlighted the importance of simulating drug transfer (total drug amount) appropriately within the applied methodology prior to estimating precipitation kinetics. As a future step, optimization of ASD-D+ model would be required to enable continuous simulations of solid/semi-solid dosage forms and enable further evaluation. Lastly, prediction of drug precipitation kinetics following simulation of gastrointestinal transfer may provide mechanistic understanding of drug absorption and appropriate justification of drug formulated parameters within physiologically-based pharmacokinetic models
Influence of ligand density variations on the two peak elution behavior of a monoclonal antibody in cation exchange chromatography
No full textCation exchange chromatography, as part of the monoclonal antibody purification train, is known as a mild polishing technique. However, in the last couple of years, more and more publications have shown unusual elution behavior, resulting from e.g. on-column (reversible) unfolding and aggregation of the predominantly mAb molecules. The stability of the investigated protein seems to play a significant role in this phenomenon. We have used a glycosylated IgG1 antibody as a model protein and investigated several influencing factors, including pH value and ligand density variations of three prototype Fractogel® cation exchange resins. Ligand density, pH and salt concentration are the main contributing factors in the Donnan effect, i.e. distribution of ions, between resin pore volume and bulk volume. This leads to a significantly lower pH value the protein is subjected to during the on-column hold time and therefore influences the conformational stability of our protein. Nano-DSF and kinetic SEC measurements show that the protein is destabilized at low pH values, but also, that the binding to the CEX resin and the elution with increasing salt concentration is responsible for the resulting two-peak elution behavior and partially reversible unfolding and aggregation
Design, Development, and Testing of a Device for Gene Electrotransfer to Skin Cells In Vivo
No full textGene electrotransfer (GET) is considered one of the most efficient, safe, reproducible, and cost-effective methods of gene therapy, in which a gene is delivered to the cells in the form of a plasmid DNA vector by a method known as electroporation. To achieve successful electroporation, cells must be exposed to sufficiently high electric fields generated by short-duration, high-voltage electrical pulses that result in a temporary increase in plasma membrane permeability. The electrical pulses are generated by pulse generators (electroporators) and delivered to the cells via electrodes (applicators). However, there is a lack of standardized pulse delivery protocols as well as certified clinical pulse generators and applicators for gene delivery. In this paper, the development of a new pulse generator, applicator, and pulse delivery protocol for GET to skin cells is presented. A numerical model of electroporated skin developed and tested for two electrode configurations and two different pulse delivery protocols is also presented. An alternative pulse delivery protocol was proposed. The developed pulse generator, applicator, and the proposed pulse delivery protocol were then used in vivo for GET to skin cells in mice. The results showed high efficiency of the proposed pulse delivery protocol for the purpose of GET in mouse skin cells. Specifically, electroporation with the developed pulse generator, applicator, and proposed pulse delivery protocol resulted in higher gene expression in skin cells compared to the currently used pulse generator, applicator, and pulse delivery protocol
Computational fluid dynamic simulations of temperature, cryoconcentration, and stress time during large-scale freezing and thawing of monoclonal antibody solutions.
No full textLarge-scale freezing and thawing experiments of monoclonal antibody (mAb) solutions are time and material consuming. Computational Fluid Dynamic (CFD) modeling of temperature, solute composition as well as the stress time, defined as the time between start of freezing and reaching Tg' at any point in the container, could be a promising approach to ease and speed up process development.Temperature profiles at six positions were recorded during freezing and thawing of a 2L rectangular bottle and compared to CFD simulations via OpenFOAM. Furthermore, cryoconcentration upon freezing and concentration gradients upon thawing of a mAb solution were predicted and the stress time calculated.Temperature profiles during freezing were accurately matched by the CFD simulation. Thawing time was only 45 min to 60 min longer in the model. The macroscopic cryoconcentration of the mAb was also matched by the simulation; only a highly concentrated region in the top and a diluted core in the geometrical centre of the 2 L bottle were not well reflected in the simulation. The concentration gradient after thawing obtained by simulation as well agreed with the experimental result. In addition, CFD simulations allowed to extract the global temperature distribution, the formation of ice, and thus the distribution of stress in the freezing liquid.CFD simulations via OpenFOAM are a promising tool to describe large-scale freezing and thawing of mAb solutions and can help to generate a deeper understanding and to improve testing of the robustness of the processes
Scientific and Regulatory Policy Committee (SRPC): 2019 Survey on Use of Digital Histopathology Systems in Nonclinical Toxicology Studies
No full textHistopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relatively new medium for assessing nonclinical toxicology studies in Good Laboratory Practice (GLP) environments. To better understand the present and future use of digital pathology in nonclinical toxicology studies, the Society of Toxicologic Pathology (STP) formed a working group to survey STP members with the goal of creating recommendations for implementation. The survey was administered in December 2019, immediately before the COVID-19 pandemic, and the results suggested that the use of digital histopathology for routine GLP histopathology assessment was not widespread. Subsequently, in follow-up correspondence during the pandemic, many responding institutions either began investigating or adopting digital WSI systems to reduce employee exposure to COVID-19. Therefore, the working group presents the survey results as a pre-pandemic baseline data set. Recommendations for use of WSI systems in GLP environments will be the subject of a separate publication
The Facets of Diversity: The EFMC Perspective.
No full textDiversity in science refers to cultivating talent, while promoting full inclusion across the community. In medicinal chemistry and chemical biology, it enhances creativity and encourages contributions from multiple perspectives, leading to better decision making and broader scientific impact. The European Federation for Medicinal chemistry and Chemical biology (EFMC) embraces and promotes diversity, to ensure representation of all talents, and enable equality of opportunity through fairness and transparency. EFMC has historically paid continuous attention to diversity in terms of culture, geography and equilibrium between academia and industry, with over the last few years a focus on increasing gender balance, aiming at a fair representation of the scientific community and equal opportunities independently of gender. EFMC promotes cultural diversity as it reinforces openness and mutual respect. All scientific organizations of a scope compatible with its remit are welcome within EFMC, where their members benefit from a welcoming, psychologically safe, and stimulating environment. Herein, we describe the state of diversity within the EFMC, how the situation has evolved over the years and where diversity should be further encouraged
Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction.
No full textNo abstract part in this lette
Dissolution Method Troubleshooting: An Industry Perspective
No full textQuality control dissolution testing represents a key product performance test for solid oral dosage forms and is the most likely QC test to result in laboratory investigations because of the relatively complex relationship between the dissolution performance, the drug product properties, and the systems necessary to measure the quality attribute. The Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has pooled our collective knowledge to outline some common ways that dissolution methods can fail. Examples and case studies have been highlighted focusing on errors of equipment, method, materials, measurement, people, and the environment, while providing best practices for building method understanding and avoiding the exemplified issues. The case studies have highlighted the importance of buffer preparation, potential impact of contamination of the dissolution medium, additive-induced degradation, risks in the use of automation, differences between dissolution systems, and the effect of filter selection. By applying the learnings in this article and investing in analyst training programs, understanding the capabilities of your equipment portfolio, and well-designed robustness and ruggedness studies will reduce dissolution method investigations and improve compliance and productivity during the method lifecycle
People of TM: Video of Axel Vicart
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content