Abstract
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 theoretical setups. The concept significantly reduces the material and instrumental costs of process design and implementation.
Highlights
The pharmaceutical industry is traditionally batch-dominated, in recent years, a shift could be observed towards continuous technologies owing to their benefits such as more efficient quality control, better uniformity, and higher performance [1,2,3]
The introduction of continuous technologies was accelerated by the Process Analytical Technology (PAT, list of abbreviations is given at the end of the paper) framework proposed by the Food and Drug Administration (FDA), published in 2004 [5]
These works mainly focus on in-line process analyzers, and multivariate tools needed for the analysis of the spectra, and they demonstrate only a few applications in control strategies [6,7]
Summary
The pharmaceutical industry is traditionally batch-dominated, in recent years, a shift could be observed towards continuous technologies owing to their benefits such as more efficient quality control, better uniformity, and higher performance [1,2,3]. The FDA and International Conference on Harmonization (ICH) are working on guidelines for continuous manufacturing (CM) based on the approval of these products to encourage further development [8,9] These recommend proper process monitoring with PAT tools, understanding the process dynamics, and developing advanced control strategies [8]. Gain-in-weight (GIW) measurements using a catch scale under the feeder were used to characterize feeding errors during operation and refill [34,35] This method is applicable to build digital twins, because the mass flow fluctuations of the feeders are measured and can be used as a high-resolution input for simulations as it has the characteristics of the investigated feeder. RTD was determined with impulse disturbances according to design of experiment (DoE) studies around two different mass flow scales to investigate the effect of the critical process parameters (CPPs) on the CU. This study intends to provide a thorough concept for process design applicable to many CM process in the pharmaceutical technology
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