Comparing Low-Dose Carvedilol Continuous Manufacturing by Solid and Liquid Feeding in Self-Emulsifying Delivery Systems via Hot Melt EXtrusion (SEDEX).

This study compared two pilot scale continuous manufacturing methods of solid self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME). : A model poorly water-soluble drug carvedilol in low dose (0.5-1.

Real-time prediction of dissolution profiles of coated oral dosage forms.

Optical coherence tomography (OCT) has emerged as an in-line monitoring technique for pharmaceutical coating processes based on a representative number of samples. In this study, an approach was developed to correlate the coating thickness measured in-line via OCT with the resultant tablet dissolution profile. This strategy enables prediction of the dissolution profile of coated oral dosage forms for each individual state of the coating process in real-time.

In-line porosity and hardness monitoring of tablets by means of optical coherence tomography.

In-line monitoring of critical quality attributes (CQAs) during a tableting process is an essential step toward a real-time release strategy. Such CQAs can be the tablet mass, the API content, dissolution, hardness and tensile strength. Since dissolution testing is laborious and time-consuming and cannot be performed in-line, it is desirable to replace dissolution testing with predictive models based on other CQAs that affect the dissolution characteristics, such as the tablet porosity and hardness.

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 2. Validation of calibration workflow.

This paper is the second in a series of two that describes the application of discrete element method (DEM) and reduced order modeling to predict the effect of disturbances in the concentration of drug substance at the inlet of a continuous powder mixer on the concentration of the drug substance at the outlet of the mixer. In the companion publication, small-scale material characterization tests, a careful DEM parameter calibration and DEM simulations of the manufacturing process were used to develop a reliable RTD models. In the current work, the same calibration workflow was employed to evaluate the predictive ability of the resulting reduced-order model for an extended design space.

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 1. Calibration workflow.

In this work, a high-fidelity digital twin was developed to support the design and testing of control strategies for drug product manufacturing via direct compression. The high-fidelity digital twin platform was based on typical pharmaceutical equipment, materials, and direct compression continuous processes. The paper describes in detail the material characterization, the Discrete Element Method (DEM) model and the DEM model parameter calibration approach and provides a comparison of the system's response to the experimental results for stepwise changes in the API concentration at the mixer inlet.

Demonstrating scalability between two blender types using DEM.

Powder blending is a critical step in pharmaceutical manufacturing that can impact product quality such as tablet tensile strength. This study utilized the Discrete Element Method (DEM) to investigate blending in a 5-liter mini-batch and a 2-liter Turbula blender. DEM parameters were calibrated using small-scale powder characterization tests, so that the particle behavior in the DEM simulations matches the measured behavior.

Archaeosomes for Oral Drug Delivery: From Continuous Microfluidics Production to Powdered Formulations.

Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for oral drug delivery, with a focus on powdered formulations. The archaeosomes were negatively charged with a size of approximately 100 nm and a low polydispersity index. To assess their suitability for oral delivery, the archaeosomes were loaded with two model drugs: calcein, a fluorescent compound, and insulin, a peptide hormone.

In-situ monitoring of in vitro drug release processes in tablets using optical coherence tomography.

Film-coated modified-release tablets are an important dosage form amenable to targeted, controlled, or delayed drug release in the specific region of the gastrointestinal (GI) tract. Depending on the film composition and interaction with the GI fluid, such coated products can modulate the local bioavailability, systemic absorption, protection as an enteric barrier, etc. Although the interaction of a dosage form with the surrounding dissolution medium is vital for the resulting release behavior, the underlying physicochemical phenomena at the film and core levels occurring during the drug release process have not yet been well described.

Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations.

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of repose tester to the experimentally observed response. A simulation of the 25-minute bin blending process predicted inhomogeneous API distributions along the rotation axis of the blending container.

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGma-25: Part 1 Granule Composition.

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 ConsiGma-25, specifically addressing granule composition.

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGma-25: Part 2 Granule Size.

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of production processes can mitigate the effect of diverse process disturbances and enhance process efficiency, particularly in terms of production costs and environmental footprint. This paper explores the potential of QbC algorithms for optimizing twin-screw wet granulation in the ConsiGma-25 manufacturing line, specifically addressing granule size.

Extending the Use of Optical Coherence Tomography to Scattering Coatings Containing Pigments.

Coating thickness is a critical quality attribute of many coated tablets. Functional coatings ensure correct drug release kinetics or protection from light, while non-functional coatings are generally applied for cosmetic reasons. Traditionally, coating thickness is assessed indirectly via offline methods, such as weight gain or diameter growth.

Liquid API feeding in pharmaceutical HME: Novel options in solid dosage manufacturing.

Hot melt extrusion (HME) is a common unit operation. It is broadly applicable in the pharmaceutical industry and can be implemented in a continuous manufacturing line. However, the conventional way of active pharmaceutical ingredient (API) feeding with a pre-blend consisting of a powdered API and a polymer does not allow the flexibility and agility to adjust the process parameters, which is generally an essential part of continuous manufacturing.

Evidence of Reliable Gastro-Resistance of Novel Enteric Ready-to-Fill Capsules Simplifying Pharmaceutical Manufacturing.

Developing delayed-release formulations for acid-sensitive actives can be a costly and time-consuming process. However, ready-to-fill functional capsules, such as EUDRACAP can significantly mitigate these challenges. The in vitro performance of EUDRACAP enteric was evaluated in two typical delayed-release scenarios: for diclofenac (a drug that can cause irritation to gastric mucosa), and for omeprazole (a drug susceptible to degradation due to the acidity of gastric fluid).

Single-tablet-scale direct-compression: An on-demand manufacturing route for personalized tablets.

Today's pharmaceutical industry is facing various challenges. Two of them are issues with supply chain security and the increasing demand for personalized medicine. Both can be addressed by increasing flexibility and a more decentralized approach to pharmaceutical manufacturing.

Prediction of dissolution performance of uncoated solid oral dosage forms via optical coherence tomography.

Real-time prediction of the dissolution behavior of solid oral dosage forms is an important research topic. Although methods such as Terahertz and Raman can provide measurements that can be linked to the dissolution performance, they typically require a longer time off-line for analysis. In this paper, we present a novel strategy for analyzing uncoated compressed tablets by means of optical coherence tomography (OCT).

A multi-step machine learning approach for accelerating QbD-based process development of protein spray drying.

This study proposes a new material-efficient multi-step machine learning (ML) approach for the development of a design space (DS) for spray drying proteins. Typically, a DS is developed by performing a design of experiments (DoE) with the spray dryer and the protein of interest, followed by deriving the DoE models via multi-variate regression. This approach was followed as a benchmark to the ML approach.

On the influence of raw material attributes on process behaviour and product quality in a continuous WET granulation tableting line.

Continuous manufacturing of oral solids is a complex process in which critical material attributes (CMAs), formulation and critical process parameters (CPPs) play a fundamental role. However, assessing their effect on the intermediate and final product's critical quality attributes (CQAs) remains challenging. The aim of this study was to tackle this shortcoming by evaluating the influence of raw material properties and formulation composition on the processability and quality of granules and tablets on a continuous manufacturing line.

Control oriented modeling of twin-screw granulation in the ConsiGma-25 production plant.

ConsiGma-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw granulation affect the quality of intermediate and final products. This paper proposes methods for real-time monitoring of these quantities and control-oriented modeling of the granulator.

A DEM model to evaluate refill strategies of a twin-screw feeder.

Residence time distribution (RTD) modeling has proven to be a valuable tool for material tracking in continuous pharmaceutical processes. Refilling is thoroughly studied in the literature, but the main focus lies on the feed rate disturbances. The impact of the feeders themselves on intermixing of different material batches is often overlooked.

Steady-state modeling of a new continuous API dryer: Reduced-order model and investigation of dryer performance.

In the present study, a reduced-order model is proposed to analyze a novel continuous dryer with an application in the pharmaceutical industry. The model was validated using process data from ibuprofen drying test runs, and the results were in good agreement with the experimental data. The test substance was an ibuprofen paste with an initial LOD of up to 30 w%.

Pharmaceutical hot melt extrusion process development using QbD and digital twins.

Pharmaceutical product development guided by Quality by Design (QbD) is based on a complete understanding of the critical process parameters (CPPs) that are important for achieving the desired product critical quality attributes (CQAs). The effect of process settings, such as the screw speed, the throughput, the barrel temperature, and the screw configuration, is a well-known factor in the setup of pharmaceutical hot melt extrusion (HME) processes. A CPP that has not yet been extensively researched is the type of cross-section geometry of the screw elements.

Predicting powder feedability: A workflow for assessing the risk of flow stagnation and defining the operating space for different powder-feeder combinations.

Powder feeding is of critical importance for continuous manufacturing (CM) since next to in-process segregation it is the phenomenon primarily responsible for fluctuations in content uniformity and for content deviations in the final drug product. So far, feeding studies have focused on the characterization of specific feeders and the prediction of their performance for various materials. This work presents a more holistic approach, an early general assessment of the "feedability" of raw materials.

Continuous Processing of Micropellets via Hot-Melt Extrusion.

Microparticulate drug delivery systems, e.g., micropellets (MPs), are used in a variety of pharmaceutical formulations such as suspensions, injectable systems, and capsules.

Analyzing the effect of using axial impellers in large-scale bioreactors.

In high-performance industrial fermentation processes, stirring and aeration may account for significant production costs. Compared to the widely applied Rushton impellers, axial-pumping impellers are known to yield a lower power draw and at the same time improve mixing. However, their lower gas dispersion capability requires stronger agitation, compromising these benefits.