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.

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.

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.

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.

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.

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.

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.

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.

Ascertain a minimum coating thickness for acid protection of enteric coatings by means of optical coherence tomography.

Enteric coatings are designed to protect active pharmaceutical ingredients (APIs) against untimely release in the stomach. Acid protection of such coatings depends on the coating layer thickness and integrity, which must be determined in an accurate and reliable way to ensure the final product's desired performance. Our work addresses the use of optical coherence tomography (OCT) for characterizing the coating thickness and variability of an enteric-coated drug product and linking them to resistance against gastric fluid.

PAT implementation for advanced process control in solid dosage manufacturing - A practical guide.

The implementation of continuous pharmaceutical manufacturing requires advanced control strategies rather than traditional end product testing or an operation within a small range of controlled parameters. A high level of automation based on process models and hierarchical control concepts is desired. The relevant tools that have been developed and successfully tested in academic and industrial environments in recent years are now ready for utilization on the commercial scale.

Carrier particle emission and dispersion in transient CFD-DEM simulations of a capsule-based DPI.

The dispersion of carrier-based formulations in capsule-based dry powder inhalers depends on several factors, including the patient's inhalation profile and the motion of capsule within the device. In the present study, coupled computational fluid dynamics and discrete element method simulations of a polydisperse cohesive lactose carrier in an Aerolizer® inhaler were conducted at a constant flow rate of 100 L/min and considering an inhalation profile of asthmatic children between 5 and 17 years approximated from literature data. In relevant high-speed photography experiments, it was observed that the powder was distributed to both capsule ends before being ejected from the capsule.

X-ray imaging: A potential enabler of automated particulate detection and cake-structure analysis in lyophilized products?

The presence of particulate matter in parenteral products is a major concern since it affects the patients' safety and is one of the main reasons for product recalls. Conventional quality control is based on a visual inspection, which is a labour-intensive task. Limited to clear solutions and the surface of lyophilised products, it cannot be applied to opaque containers.

Development of a Controlled Continuous Low-Dose Feeding Process.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g.

Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations.

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition.

Feasibility of In-line monitoring of critical coating quality attributes via OCT: Thickness, variability, film homogeneity and roughness.

The feasibility of Optical Coherence Tomography (OCT) for in-line monitoring of pharmaceutical film coating processes has recently been demonstrated. OCT enables real-time acquisition of high-resolution cross-sectional images of coating layers and computation of coating thickness. In addition, coating quality attributes can be computed based on in-line data.

Deep convolutional neural networks: Outperforming established algorithms in the evaluation of industrial optical coherence tomography (OCT) images of pharmaceutical coatings.

This paper presents a novel evaluation approach for optical coherence tomography (OCT) image analysis of pharmaceutical solid dosage forms based on deep convolutional neural networks (CNNs). As a proof of concept, CNNs were applied to image data from both, in- and at-line OCT implementations, monitoring film-coated tablets as well as single- and multi-layered pellets. CNN results were compared against results from established algorithms based on ellipse-fitting, as well as to human-annotated ground truth data.

Validating a Numerical Simulation of the ConsiGma(R) Coater.

Continuous manufacturing is increasingly used in the pharmaceutical industry, as it promises to deliver better product quality while simultaneously increasing production flexibility. GEA developed a semi-continuous tablet coater which can be integrated into a continuous tableting line, accelerating the switch from traditional batch production to the continuous mode of operation. The latter offers certain advantages over batch production, e.

Performance Evaluation of a High-Precision Low-Dose Powder Feeder.

Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system.

A solution for low-dose feeding in continuous pharmaceutical processes.

Continuous feeding of small quantities of powder is increasingly applied in pharmaceutical manufacturing. With that regard, what is crucial is not only the feasibility, but also the accuracy and stability. To enable stable processing, low amounts of various agents, e.

Estimating inter-patient variability of dispersion in dry powder inhalers using CFD-DEM simulations.

Drug delivery from a capsule-based dry powder inhaler depends on the inhaler's design, the drug's formulation, and the inhalation maneuver. The latter affects both the air flow and the capsule motion in the inhaler. It is well known that patient-to-patient variability is a major challenge in the design of new inhaler types.

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch.

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation.

Filling of lactose-based formulations in a tamping-pin capsule filler.

We studied three lactose-based formulations in terms of bulk powder properties and capsule-filling behavior in a tamping-pin capsule filling system, to which several mechanical adaptions were made for process optimization in light of future continuous production. The model formulations were thoroughly characterized and filled into size 1 capsules according a well-defined design of experiments (DoE). Overall, the three entirely different formulations were successfully filled within the selected design space.

Particle-level residence time data in a twin-screw feeder.

A full discharge process of a twin-screw feeder has been simulated with DEM (discrete element method). The result files are available at the Mendeley Data repository (https://doi.org/10.