Residence Time Distribution-Based Smith Predictor: an Advanced Feedback Control for Dead Time–Dominated Continuous Powder Blending Process (original) (raw)
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Process Design of Continuous Powder Blending Using Residence Time Distribution and Feeding Models
Pharmaceutics
The present paper reports a thorough continuous powder blending process design of acetylsalicylic acid (ASA) and microcrystalline cellulose (MCC) based on the Process Analytical Technology (PAT) guideline. A NIR-based method was applied using multivariate data analysis to achieve in-line process monitoring. The process dynamics were described with residence time distribution (RTD) models to achieve deep process understanding. The RTD was determined using the active pharmaceutical ingredient (API) as a tracer with multiple designs of experiment (DoE) studies to determine the effect of critical process parameters (CPPs) on the process dynamics. To achieve quality control through material diversion from feeding data, soft sensor-based process control tools were designed using the RTD model. The operation block model of the system was designed to select feasible experimental setups using the RTD model, and feeder characterizations as digital twins, therefore visualizing the output of th...
Journal of Pharmaceutical Sciences, 2006
The successful implementation of near-infrared spectroscopy (NIRS) in process control of powder blending requires constructing an inclusive spectral database that reflects the anticipated voluntary or involuntary changes in processing conditions, thereby minimizing bias in prediction of blending behavior. In this study, experimental design was utilized as an efficient way of generating blend experiments conducted under varying processing conditions such as humidity, blender speed and component concentration. NIR spectral data, collected from different blending experiments, was used to build qualitative models for prediction of blend homogeneity. Two pattern recognition algorithms: Soft Independent Modeling of Class Analogies (SIMCA) and Principal Component Modified Bootstrap Error-adjusted Single-sample Technique (PC-MBEST) were evaluated for qualitative analysis of NIR blending data. Optimization of NIR models, for the two algorithms, was achieved by proper selection of spectral processing, and training set samples. The models developed were successful in predicting blend homogeneity of independent blend samples under different processing conditions.
International journal of pharmaceutics, 2017
In-line monitoring of continuous powder flow is an integral part of the continuous manufacturing process of solid oral dosage forms in the pharmaceutical industry. Specifically, monitoring downstream from loss-in-weight (LIW) feeders and/or continuous mixers provides important data about the state of the process. Such measurements support control of the process and thereby enhance product quality. Near Infrared Spectroscopy (NIRS) is a potential PAT tool to monitor the homogeneity of a continuous powder flow stream in pharmaceutical manufacturing. However, the association of analytical results from NIR sampling of the powder stream and the homogeneity (content uniformity) of the resulting tablets provides several challenges; appropriate sampling strategies, adequately robust modeling techniques and poor sensitivities (for low dose APIs) are amongst them. Information from reflectance-based NIRS sampling is limited. The region of the powder bed that is interrogated is confined to the ...
Continuous quantitative monitoring of powder mixing dynamics by near-infrared spectroscopy
Powder Technology, 2011
FT-NIR spectroscopy with a fiber optical reflection probe was applied as a process analytical technology tool for the continuous quantitative in-line monitoring of pharmaceutical powder mixing processes in a bladed mixer. Two powders, acetyl salicylic acid as an active pharmaceutical ingredient (API) and α-lactose monohydrate as an excipient were characterized in advance in terms of shear cell tests, flowability tests and particle-size determination to deduce flow properties of the powders. For the quantitative monitoring of the API content, two predictive models were developed with partial-least-squares calibration based on off-line calibration. On the basis of these predictive models, powder agitation and mixing times until blend uniformity were quantitatively monitored. Mixing experiments with systematically varied filling levels and filling protocols showed a strong variation in mixing, but eventually yielded uniform powder blend. Simulation results from the literature were linked to our experimental findings in order to identify and elucidate the effects of convective and diffusive mixing. In accordance to the international conference on harmonization acceptance level of 5% for the nominal API content, UV/Vis reference measurements were performed to verify the blend uniformity as predicted by the NIR measurements.
European Journal of Pharmaceutics and Biopharmaceutics, 2013
The aim of this study was to develop a quantitative Near-Infrared (NIR) method which monitors the homogeneity of a pharmaceutical formulation coming out of a continuous blender. For this purpose, a NIR diode array spectrometer with fast data acquisition was selected. Additionally, the dynamic aspects of a continuous blending process were studied; the results showed a well-defined cluster for the steady state, and the paths for the start-up and emptying stages were clearly identified. The end point of the start-up phase was detected by moving block of standard deviation, relative standard deviation, and principal component analysis.
Journal of Pharmaceutical Innovation, 2012
Introduction A process analytical technology (PAT) method using a near infrared (NIR) spectrometer attached to a drum blender was developed for real-time end-point detection for an extragranular blend. Methods and theory The method and corresponding documentation are part of the control strategy for a recently filed and approved pharmaceutical product, and the method is currently in place and in use for manufacturing of this pharmaceutical product at GlaxoSmithKline. Results and discussion The immediate benefits are a dramatic reduction in blend time as well as real-time verification of blend homogeneity for every batch. The development of the blending end-point method is presented and a set of fundamental requirements for developing any PAT method is proposed. Conclusion It is discussed how the reported PAT end-point method fits with the proposed PAT framework, and the validation aspects required to achieve a compliant method for use in drug product manufacturing are presented.
Journal of Pharmaceutical Innovation, 2017
The paradigm shift in the pharmaceutical industry to continuous manufacturing, which has recently progressed from conceptual demonstration to pilot production, has stimulated the development and application of process systems engineering (PSE) tools for implementing efficient and robust control strategies. In this study, a systematic framework for process control design and risk analysis for continuous pharmaceutical solid-dosage manufacturing is proposed, consisting of system identification with state-space models; control design and analysis metrics; hierarchical three-layer control structures; risk mapping, assessment and planning (Risk MAP) strategies; and control performance indicators. The framework is applied to a feeding-blending system, wherein the major source of variance in the product quality arises. It can be demonstrated that the variance in the feeding-blending system can be mitigated and managed through the proposed systematic framework for control design and risk analysis. The process analytical technology (PAT) tool for mass fraction measurement of active pharmaceutical ingredient (API) and its relative standard deviation (RSD) were indispensable to achieve an efficient control design at the advanced layers. Specifically, the improvements in control performance by implementing advanced model-based control strategy are found to be limited by model-plant mismatch and the sampling time of the PAT tools.
A review on the continuous blending of powders
Chemical Engineering Science, 2006
This review traces the underlying theory and practice of continuous powder blending to provide a foundation for its development. Apart from reviewing the experimental studies reported in literature, some of the monitoring techniques used in blending research with applications in continuous blending also are considered. This review attempts to identify the synergy that can be realized by studying powder behavior in batch blenders and applying similar techniques to continuous blenders. Predictive modeling in the design of continuous blenders is identified as a long-term objective in this growing body of knowledge.