Search

Continuous blenders are a key unit operation in Continuous Direct Compaction, a route to solid oral dosage forms that is receiving significant interest. Mass holdup in these blenders is a crucial variable; understanding how it is influenced by material properties, equipment configuration and process settings is key. The present work evaluated a Gericke GCM-450 blender for range of outlet weir aperture geometries (angled or horizontal), material properties (pure components and blends) and process settings (throughput and impeller speed). Results show opposing mass holdup behaviour depending on weir choice, material density and flowability, likely linked to the propensity of the material to form an inclined powder surface that matches – or does not – the chosen weir geometry. The present work underscores the need for fundamental process phenomena understanding, especially when insight is sought for how blender performance varies across multiple dimensions (throughput, impeller speed, material properties) and discrete equipment choices (weir geometry). [Display omitted] • Interaction between equipment geometry and material properties highlighted. • Opposing behaviour of high-density free-flowing material and low-density cohesive material. • Impact on mass hold up behaviour of process settings and material properties (equipment configuration dependant). • Impact on continuous direct compression operation. [ABSTRACT FROM AUTHOR]

Process integration efforts in the pharmaceutical industry have led to an increased interest in Direct Compression, including Continuous Direct Compression. Accurate scale-up of powder blending and prediction of blend Critical Quality Attributes (CQAs) is key. The present work takes a modified approach for blend CQA characterisation in a high-shear semi-continuous blender (originally developed for low-shear batch blenders), and combines it with a blend content uniformity model (developed for high-shear continuous blenders) to characterise content uniformity responses of a high-shear semi-continuous blender (Gericke GBM-10-P Mini Blender). Blend content uniformity assessed across process conditions and formulations shows that for a given formulation one set of model parameters can be regressed for all datapoints, allowing insight to be transferred between blender scales and types. This infers that lab-scale low-shear batch blenders can be used to predict the content uniformity response of the high-shear semi-continuous blender, minimising materials consumption and experimental burden. [Display omitted] • Equation for transferrable process conditions of a semi-batch Gericke Mini Blender. • Demonstrated application to a low-dose formulation. • Process intensification compared to traditional tumble blending. • Rapid axial dispersion of components throughout the bulk of the powder. • Limiting content uniformity based on particle size of active ingredient. [ABSTRACT FROM AUTHOR]

The aim of this study is to show the robustness of a commercial direct compression system running continuously under relevant process conditions for over 120 h. The study will apply a representative commercial control strategy including real time monitoring of process parameters, rejection of OOS material, use of in-line NIR prediction for blend potency monitoring, application of mathematical RTD modelling for real-time prediction of product potency, and tablet concentration prediction by tablet NIR. The study showed that the process can produce in specification product robustly over significant operating times. Across 122 h of actual run time (including pauses) the process manufactured over 15 million tablets to give a product yield of 99.2%. Whilst the purpose of this study was to evaluate the process for over 120 h, this process is not limited to running longer periods of time given the performance of the equipment and the control strategy. Unlabelled Image • Continuous direct compression manufacturing demonstrated over 120 h. • Application of commercial control strategy including PAT. • Real time control of product quality. • Demonstration of high process capability throughout the entire run. • Yield of 99.2%, producing 15 million tablets. [ABSTRACT FROM AUTHOR]

This work aims to expand the typical raw material attributes that can successfully be processed on a continuous direct compression line with a particular focus on the continuous dry powder blender. Three grades of Acetaminophen were investigated as model active pharmaceutical ingredients and chosen to span a broad range of material attributes wider than what would normally be considered for a direct compression process. An experimental design was set-up for each grade of Acetaminophen to investigate the effect of throughput, impeller speed and impeller configuration on the critical process responses and attributes. The strain experienced by the in-process material was found critical to improve content uniformity. The impeller speed and design can be optimised at a given throughput to obtain a strain which would deliver the required content homogeneity. The content uniformity of the final tablets can be modelled as a function of the strain using an exponential decay model. Unlabelled Image • Wide range of parameters deliver acceptable tablet content uniformity. • Blender throughput, speed and configuration significantly affect residence mass. • Final tablet uniformity is a function of the mean residence time and impeller speed. • Prediction of final tablet content uniformity from process imparted strain. [ABSTRACT FROM AUTHOR]

A flowsheet model for a continuous direct compression tableting process is developed and applied to process data generated at production scale. The model contains powder feeding, blending and tablet compaction unit operations. The dataset was provided by Merck & Co., Inc., Kenilworth, NJ USA using a GEA ConsiGma™ continuous direct compression process designed for approximately 50 kg/h throughput using a six ingredient, potentially commercial, formulation. A tanks-in-series methodology is used to model the transport of powders through the blending units and a number of tablet compaction equations are selectable which can illustrate how upstream changes in composition are propagated to tablet properties. The flowsheet model performed well based on the available dataset with accurate predictions of API concentration and tablet hardness. Monte Carlo simulations were used along with the flowsheet model to investigate the contribution of feeder flowrate variability to measurement noise and the sensitivity of tablet hardness to process parameters and material properties. Unlabelled Image • Tanks in series approach provides simple and accurate residence time model results. • Model performed well over a wide range of operating conditions. • Flowsheet model could simulate realistic failure modes for risk assessment purposes. • Impact of process parameters and material properties were investigated. • Process parameters more significant than material properties for tablet compaction. [ABSTRACT FROM AUTHOR]

The production of pharmaceutical tablets is shifting towards continuous manufacturing. Therefore, individual unit operations such as powder blending need to be re-designed. Continuous powder blending has been implemented successfully, but for low-dose formulations this is challenging due to difficulties with continuously dosing small amounts of powder. To overcome such challenges, a semi-continuous mini-blending operation combined with batch-wise dosing can be introduced in a continuous process. The objective of this study is to investigate key factors that affect blending performance of a novel, semi-continuous mini-blending process. A design of experiments is performed, varying both process settings and blend formulations. This reveals that blending performance of the mini-blending process is largely controlled by process settings. These results show that the mini-blender design, with high mixing intensity and short mixing times, supports process intensification of powder blending. The results obtained can be used for Quality by Design-based formulation development for continuous direct compression. [Display omitted] • Demonstration of a semi-continuous powder mini-blender for process intensification. • Mini-blender design supports continuous direct compression of low drug loads. • Extend of process intensification is impacted by blending regime. • Powder flow and tablet properties are affected by blending process and excipients. • Mixing process intensification allows product optimization to focus on other CQA's. [ABSTRACT FROM AUTHOR]