Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture.

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

Offline 20 Hz transcranial alternating current stimulation over the right inferior frontal gyrus increases theta activity during a motor response inhibition task.

OBJECTIVES: Previous studies have shown that the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (preSMA) play an important role in motor inhibitory control. The aim of the study was to use theta frequency transcranial alternating current stimulation (tACS) to modulate brain activity in the rIFG and preSMA and to test the effects of stimulation using a motor response inhibition task. METHODS: In four sessions, 20 healthy participants received tACS at 6 Hz over preSMA or rIFG, or 20 Hz over rIFG (to test frequency specificity), or sham stimulation before task processing. After each type of stimulation, the participants performed the Go/NoGo task with simultaneous electroencephalogram (EEG) recording. RESULTS: By stimulating rIFG and preSMA with 6 Hz tACS, we were not able to modulate either behavioral performance nor the EEG correlate. Interestingly, 20 Hz tACS over the rIFG significantly increased theta activity, however without behavioral effects. This increased theta activity did not coincide with the stimulation area and was localized in the fronto-central and centro-parietal areas. CONCLUSIONS: The inclusion of a control frequency is crucial to test for frequency specificity. Our findings are in accordance with previous studies showing that after effects of tACS are not restricted to the stimulation frequency but can also occur in other frequency bands.

Acute Effects of Air Pollution and Noise from Road Traffic in a Panel of Young Healthy Adults.

Panel studies are an efficient means to assess short-term effects of air pollution and other time-varying environmental exposures. Repeated examinations of volunteers allow for an in-depth analysis of physiological responses supporting the biological interpretation of environmental impacts. Twenty-four healthy students walked for 1 h at a minimum of four separate occasions under each of the following four settings: along a busy road, along a busy road wearing ear plugs, in a park, and in a park but exposed to traffic noise (65 dB) through headphones. Particle mass (PM2.5, PM1), particle number, and noise levels were measured throughout each walk. Lung function and exhaled nitrogen oxide (NO) were measured before, immediately after, 1 h after, and approximately 24 h after each walk. Blood pressure and heart rate variability were measured every 15 min during each walk. Recorded air pollution levels were found to correlate with reduced lung function. The effects were clearly significant for end-expiratory flows and remained visible up to 24 h after exposure. While immediate increases in airway resistance could be interpreted as protective (muscular) responses to particulate air pollution, the persisting effects indicate an induced inflammatory reaction. Noise levels reduced systolic blood pressure and heart rate variability. Maybe due to the small sample size, no effects were visible per specific setting (road vs. park).

Quantitative X-Ray Microcomputed Tomography Assessment of Internal Tablet Defects.

Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XµCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence-based image processing quantified the internal tablet fracture severity. XµCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XµCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XµCT with an artificial intelligence-based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.

Impulsive-like behavior in differential-reinforcement-of-low-rate 36 s responding in mice depends on training history.

Prior behavioral history in operant conditioning paradigms may induce impulsive-like responding as shown in rats. Little is known to what extent behavioral history influences subsequent behavior in mice, therefore the present study investigated the effects of lever-pressing under a fixed-ratio 5 schedule of reinforcement on subsequent differential-reinforcement-of-low-rate (DRL) 36 s performance in wild type mice compared to the behavior of 5-HT1B receptor knockout mice. Acquisition of both autoshaping and fixed-ratio 5 training was faster in 5-HT1B receptor knockout compared to wild type mice. Nevertheless, in the DRL 36 s procedure no differences were observed between genotypes. Both wild type and 5-HT1B receptor knockout mice displayed premature or impulsive-like responding in the DRL 36 s procedure, for example a peak location of responses around 20 s and high rates of responding. Taken together, the present data suggest that impulsive-like responding in the DRL 36 s procedure in mice depends on prior behavioral history.

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.

Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.