Stochastic analysis and modeling of pharmaceutical screw feeder mass flow rates.

Screw feeders, as the initial operation in continuous manufacturing of drug product processes, greatly influence the mass flow rate of pharmaceutical powders downstream. Existing flowsheet models can quickly simulate the average powder mass flow rate while custom Discrete Element Method models require prohibitively long times to simulate a minute of realistic, high-variance particle flow. We propose a hybrid deterministic-stochastic feeder flowsheet model that leverages time series analysis and an Autoregressive Moving Average (ARMA) model to quantify and simulate the observed non-random variation in feeder powder flow. To allow for improved process and controller design, our approach is quick-to-solve, high-variance, and has a low experimental overhead. By examining the deterministic model errors of three different volumetrically fed excipients, we demonstrate that the errors are leptokurtic, heavy-tailed, and display a linear dependence on their prior two seconds of state. These errors are all reasonably modeled by an ARMA(2,1) model and are parametrically distinct from each other. Furthermore, we show that refilling the feeder online significantly alters the error distribution, autocorrelation structure, and ARMA parameters. These findings lay the groundwork necessary to model and predict the realistic feeder dynamics of a much broader range of powders and operating conditions.

Characteristics of multi-component formulation granules formed using distributive mixing elements in twin screw granulation.

This work examines the influence of pharmaceutical powder formulation characteristics on granule properties formed using distributive mixing elements (DMEs) in twin screw granulation. High and low drug dose formulations with three different active pharmaceutical ingredients (APIs) were considered. The type and concentration of the API in the formulation significantly affected the dry blend particle size distribution and the wet blend dynamic yield strength. However, despite the differences in blend properties, the granule size distributions were not significantly affected by the type of API used. The granule size distributions were solely the functions of the liquid-to-solid ratio and screw element geometry. However, the granule porosities were observed to be dependent on both the liquid-to-solid ratio and the dynamic yield strength of the blends. This work is the first to study the influence of drug loading and API type on the granule attributes produced using distributive mixing elements.

Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: Effect of process parameters on critical granule attributes and granulation mechanisms.

This study is concerned with identifying the design space of two different continuous granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes.

Multi-scale flowsheet simulation of an integrated continuous purification-downstream pharmaceutical manufacturing process.

Properties of active pharmaceutical ingredients influence the critical quality attributes (CQAs) of final solid dosage forms (e.g. tablets). In the last decade, continuous manufacturing has been shown to be a promising alternative to batch processing in the pharmaceutical industry. Therefore, a quantitative model-based analysis of the influence of upstream API properties on downstream processing quality metrics will lead to enhanced QbD in pharmaceutical drug product manufacturing (Benyahia et al., 2012). In this study, a dynamic flowsheet simulation of an integrated API purification step (crystallization), followed by filtration and drying, with a downstream process (powder mixing) is presented. Results show that the temperature profile of a cooling crystallization process influences the crystal size distribution which in turn impacts the RSD and API concentration of the powder mixing process, which in turn has a direct effect on tablet properties (Boukouvala et al., 2012). A hybrid PBM-DEM model is also presented to demonstrate the coupling of particle-scale information with process-scale information leading to enhanced elucidation of the dynamics of the overall flowsheet simulation.