Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a ...commercial synthetic process has been established to make belzutifan, a further optimized process with fewer steps, improved cost-effectiveness, and a smaller environmental footprint is always in demand. In the new commercial synthetic route, a single-step biocatalytic hydroxylation reaction was used to replace the five chemical steps required in the previous route. In developing this new biocatalytic reaction, multiple process analytical technologies (PATs), such as Fourier transform infrared spectroscopy (FTIR), in situ imaging, dissolved oxygen monitoring, etc., were used to track important reaction parameters under complex reaction conditions (e.g., multiphases and dense slurry). With quantitative modeling, the product concentration and yield can be tracked in real time based on FTIR. This is particularly important for dense slurry reactions, for which offline sampling becomes challenging due to the sample inhomogeneity. In-depth mechanistic insights were also obtained using PATs revealing reaction kinetics controlled by different mass transfer limited processes, as well as the unique role of 1-octanol. These PAT-enabled capabilities for reaction tracking and understanding facilitated process development from the laboratory to the pilot scale and ensured a robust process for the hydroxylation reaction.
In this paper, we investigate a novel framework for achieving prescribed-time (PAT), fixed-time (FXT) and finite-time (FNT) stochastic synchronization control of semi-Markov switching ...quaternion-valued neural networks (SMS-QVNNs), where the setting time (ST) of PAT/FXT/FNT stochastic synchronization control is effectively preassigned beforehand and estimated. Different from the existing frameworks of PAT/FXT/FNT control and PAT/FXT control (where PAT control is deeply dependent on FXT control, meaning that if the FXT control task is removed, it is impossible to implement the PAT control task), and different from the existing frameworks of PAT control (where a time-varying control gain such as μ(t)=T/(T−t) with t∈0,T) was employed, leading to an unbounded control gain as t→T− from the initial time to prescribed time T), the investigated framework is only built on a control strategy, which can accomplish its three control tasks (PAT/FXT/FNT control), and the control gains are bounded even though time t tends to the prescribed time T. Four numerical examples and an application of image encryption/decryption are given to illustrate the feasibility of our proposed framework.
, as a main postharvest pathogen of fruits, can secrete patulin (PAT), causing fruit decay and health problems. In this study, the antifungal test, SEM (scanning electron microscope) observation, ...transcriptional profile, PAT biosynthesis, and physiological characters of
exposed to cinnamaldehyde and citral combination (Cin/Cit) were evaluated. Cin/Cit could inhibit the mycelial growth and spore germination of
in a dose-dependent manner. Besides, Cin/Cit caused spores and mycelia wrinkled and depressed by SEM observation. Gene expression profiles of
were conducted by RNA sequencing (RNA-seq) in the presence or absence of Cin/Cit treatment. A total of 1713 differentially expressed genes (DEGs) were obtained, including 793 down-regulated and 920 up-regulated genes. Most of the DEGs participated in the biosynthesis of secondary metabolites, amino acid metabolism, and oxidation-reduction process, etc. Cin/Cit induced the dysfunction of the mitochondrial membrane, causing the potential influence on energy metabolism and reactive oxidative species production. The changes of superoxide dismutase (SOD) and catalase (CAT) activities combing with the increase of hydrogen peroxide content indicated the oxidative stress on
induced by Cin/Cit, which corresponded well with the transcriptional results. Moreover, both the RNA-seq data and the qRT-PCR showed the remarkable down-regulation of genes included in the PAT biosynthetic pathway under the Cin/Cit treatment. These findings provided more useful information about the antifungal mechanism of Cin/Cit against
at molecular and gene levels and suggested that Cin/Cit is a potential candidate to control
.
Continuous manufacturing of pharmaceuticals offers several benefits, such as increased production efficiency, enhanced product quality control, and lower environmental footprint. To fully exploit ...these benefits, standard operation mode (production processes with no or minimal disturbance mitigation measures) should be supported by adopting novel quality-by-control (QbC) methodologies. The paper at hand is the first part of a study focused on developing QbC algorithms for optimizing twin-screw wet granulation in the industrial manufacturing line ConsiGmaTM-25, specifically addressing granule composition.
This work relies on previously established process-analytical-technology (PAT) equipment for real-time monitoring of the granule composition, i.e., the active pharmaceutical ingredient (API) and liquid content in wet granules. The developed control platform integrates model-based process control algorithms that aim to keep the API- and liquid content at target values through real-time adjustments of the process parameters. Furthermore, the platform integrates a digital operator assistant, which aims to detect and classify granulation disturbances and provides messages and instructions for the plant operator.
The present manuscript systematically outlines all design steps from the development phase in the simulation environment to the final real system application and validation. The control platform’s performance is demonstrated through selected test scenarios on the ConsiGmaTM-25 manufacturing line. The obtained results indicate improved disturbance robustness and an increase in intermediate/final product quality (compared to conventional operating modes): The process control algorithms successfully maintained the API- and liquid content at target values despite process disturbances. Furthermore, realistic disturbances (feeder, pump, and material) were accurately detected and classified by the digital assistant algorithm. The information was provided through a user interface, offering real-time support for plant personnel.
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Automation plays a vital role in reducing development time in the pharmaceutical industry, both for drug substance (DS) and drug product (DP). Many aspects of crystallization development (solubility, ...kinetics, solid form characterization, concentration) have been positively impacted by automation; both in hardware and data processing, in the last two decades. However, wet milling, a critical unit operation used to manipulate particle properties in a crystallization process, has been non-conducive for automation. This study discusses efforts towards automation of wet milling, coupled with off-the-shelf automation tools for faster execution of physical property design workflows. The hardware and software configuration used, along with challenges and prospects to achieve milling automation are discussed. Lovastatin was used as a model compound to demonstrate the capabilities of the automated platform to achieve morphology and size manipulation. Five different batches of lovastatin were produced using different combinations of milling and thermal cycling. Milling followed by thermal cycling led to formation of rougher, fused particles with a lower aspect ratio compared to those produced by thermal cycling followed by milling. In-situ particle video microscopy was used to decipher that the initial increase in particle size during thermal cycling was driven by a fusion of primary particles followed by growth. Key material property descriptors such as bulk/tap density, flow function coefficient, surface area, and particle size by laser diffraction were collected using traditional means while particle size, aspect ratio and smoothness were also measured using image analysis. Lastly, principal component analysis (dimensionality reduction) was performed to determine the key property relationships impacting flowability. It was found that fines as measured by d10 (10th percentile of the volumetric size distribution) and Hausner ratio had a high positive and negative correlation, respectively with flowability. The on demand milling platform combined with data rich trials using PAT is estimated to accelerate process development for particle engineering and reduce the drug substance delivery time to drug product team.
•Development of first in class on-demand milling platform.•Accelerated process development for particle engineering at DS/DP interface.•PATs leveraged to deduce crystallization mechanisms.•Successful manipulation of crystal morphology and size to improve physical properties.
N-acetyl-d-glucosamine (GlcNAc) is a microbial fermentation product, and NIR spectroscopy is an effective process analytical technology (PAT) tool in detecting the key quality attribute: the GlcNAc ...content. Meanwhile, the design of NIR spectrometers is under the trend of miniaturization, portability and low-cost nowadays. The aim of this study was to explore a portable micro NIR spectrometer with the fermentation process. First, FT-NIR spectrometer and Micro-NIR 1700 spectrometer were compared with simulated fermentation process solutions. The Rc2, Rp2, RMSECV and RMSEP of the optimal FT-NIR and Micro-NIR 1700 models were 0.999, 0.999, 3.226 g/L, 1.388 g/L and 0.999, 0.999, 1.821 g/L, 0.967 g/L. Passing-Bablok regression method and paired t-test results showed there were no significant differences between the two instruments. Then the Micro-NIR 1700 was selected for the practical fermentation process, 135 samples from 10 batches were collected. Spectral pretreatment methods and variables selection methods (BiPLS, FiPLS, MWPLS and CARS-PLS) for PLS modeling were discussed. The Rc2, Rp2, RMSECV and RMSEP of the optimal GlcNAc content PLS model of the practical fermentation process were 0.994, 0.995, 2.792 g/L and 1.946 g/L. The results have a positive reference for application of the Micro-NIR spectrometer. To some extent, it could provide theoretical supports in guiding the microbial fermentation or the further assessment of bioprocess.
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•A portable NIR spectrometer was proposed with comparison and accuracy in term of prediction ability of PLS model was discussed.•Passing-Bablok regression method was used in comparison of two instruments predicted values.•Four variable selection methods were discussed in PLS modeling.•NIRS as a PAT tool to monitor the practical microbial fermentation process.
Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, ...reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine‐chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self‐optimization tools.
Continuous manufacturing in the pharmaceutical and fine‐chemical industry requires a detailed understanding of ongoing reaction processes. Artificial intelligence and machine learning in conjunction with process analytical technology tools that help control and optimize the operation of continuous manufacturing reactors and the related chemical transformations enable chemists to optimize synthetic processes.
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