Mathematical modeling and digital design of an intensified filtration-washing-drying unit for pharmaceutical continuous manufacturing

Destro, Francesco; Hur, Inyoung; Wang, Vivian; Abdi, Mesfin; Feng, Xinliang; Coleman, Simon; Firth, Paul; Barton, Alastair; Barolo, Massimiliano; Nagy, Zoltán K.

doi:10.1016/j.ces.2021.116803

Cited by 22 publications

(18 citation statements)

References 31 publications

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“…The continuous carousel filter (CCF) consists of rotating hollow cylinders, which enable the different processes of filtration, washing, and drying. In the first publications, Acevedo et al and Ottoboni et al gained fundamental knowledge about the operating behavior of the CCF. , Recent studies show promising results for systematic isolation procedures, , integration with continuous crystallizers, ,, and modeling to gain process understanding. , The apparatus concept has several advantages, such as the material traceability required by the U.S. Food and Drug Administration (FDA), easy adaptation to typical batch experiments, and a deliquoring to final residual moistures below 10%. , However, the corresponding cycle times are coupled, and increased agglomeration was observed in several studies about the CCF. ,, …”

Section: Introductionmentioning

confidence: 99%

“…5,12 Recent studies show promising results for systematic isolation procedures, 13,14 integration with continuous crystallizers, 9,15,16 and modeling to gain process understanding. 9,17 The apparatus concept has several advantages, such as the material traceability required by the U.S. Food and Drug Administration (FDA), 18 easy adaptation to typical batch experiments, 13 and a deliquoring to final residual moistures below 10%. 15,16 However, the corresponding cycle times are coupled, and increased agglomeration was observed in several studies about the CCF.…”

Section: Introductionmentioning

confidence: 99%

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Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter

Steenweg

Seifert

Böttger

et al. 2021

Org. Process Res. Dev.

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A novel apparatus concept for integrated, small-scale continuous filtration, washing, and drying is presented. The continuous vacuum screw filter (CVSF) allows obtaining dried and free-flowing product particles from the continuously fed suspension. While the first study presented the CVSF concept in detail and focused on the characterization with respect to the product quality control and solid-phase residence time distribution (RTD S ) during sole filtration, the modular extension with washing modules and a vacuum-induced (pre-) drying setup is now presented here. For this purpose, a wash module was designed and implemented. The influence of single-stage and two-stage washing on the particle size distribution (PSD) and RTD S was investigated for the L-alanine/water model system. Single-stage washing increased the particle size of d 90,3 by 120 μm (+19%) due to a higher agglomeration degree, while using two-stage washing could completely preserve the particulate properties of the inlet suspension. To identify favorable operating conditions for efficient (pre-) drying, the effect of varying throughputs and mean residence times on the residual moisture of the product particles was quantified. High filling degrees (>30%) and increased mean residence times (>11 min), in combination with two-stage washing and efficient vacuum-induced airflow, ensured completely isolated, free-flowing, and almost dry particles with residual moistures of 1% and an entire maintenance of the PSD. Measurements of the RTD S showed a slight broadening due to the wash liquid used, still ensuring a narrow RTD S and thus almost plug-flow-like behavior. In summary, the CVSF offers unique features, such as its modularity and rapid start-up behavior, providing a promising concept for integrated continuous particle isolation from suspensions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter

Steenweg

Seifert

Böttger

et al. 2021

Org. Process Res. Dev.

View full text Add to dashboard Cite

show abstract

“…Alconbury Weston Ltd. launched the continuous filter carousel (CFC) to the market. A multitude of current publications shows the potential of automated, cyclic batch filtration in the CFC [9,[15][16][17][18][19][20][21][22]. A second concept, the continuous rotary plate filter (CRPF) was invented as part of an integrated continuous manufacturing pilot plant of Continuus Pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

2022

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The continuous vacuum screw filter (CVSF) for small-scale continuous product isolation of suspensions was operated for the first time with cuboid-shaped and needle-shaped particles. These high aspect ratio particles are very common in pharmaceutical manufacturing processes and provide challenges in filtration, washing, and drying processes. Moreover, the flowability decreases and undesired secondary processes of attrition, breakage, and agglomeration may occur intensively. Nevertheless, in this study, it is shown that even cuboid and needle-shaped particles (l-alanine) can be processed within the CVSF preserving the product quality in terms of particle size distribution (PSD) and preventing breakage or attrition effects. A dynamic image analysis-based approach combining axis length distributions (ALDs) with a kernel-density estimator was used for evaluation. This approach was extended with a quantification of the center of mass of the density-weighted ALDs, providing a measure to analyze the preservation of the inlet PSD statistically. Moreover, a targeted residual moisture below 1% could be achieved by adding a drying module (Tdry = 60 °C) to the modular setup of the CVSF.

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“…16 Multiple linear regression was used to approximate the boundary of the probabilistic design space to find the optimal operation of an integrated filtration−washing−drying model. 17 Kriging, adaptive sampling, and a proposed feasibilitydriven surrogate-based optimization were also used for various global optimization test problems with the intention of furthering pharmaceutical manufacturing modeling capabilities. 18 A recent review of surrogate-based modeling and optimization strategies in chemical process engineering was given by McBride and Sundmacher, 19 where it was noted that pharmaceutical processes constitute an important application space for surrogate-based modeling.…”

Section: Introductionmentioning

confidence: 99%

“…Some recent examples include Bayesian optimization to reduce the number of experiments required to model tablet properties via a wet molding procedure and Kriging-based approximation of objective and constraints on several global optimization test problems . Multiple linear regression was used to approximate the boundary of the probabilistic design space to find the optimal operation of an integrated filtration–washing–drying model . Kriging, adaptive sampling, and a proposed feasibility-driven surrogate-based optimization were also used for various global optimization test problems with the intention of furthering pharmaceutical manufacturing modeling capabilities .…”

Section: Introductionmentioning

confidence: 99%

Simulation–Optimization Framework for the Digital Design of Pharmaceutical Processes Using Pyomo and PharmaPy

Laky

Casas-Orozco

Laird

et al. 2022

Ind. Eng. Chem. Res.

Self Cite

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The problem of performing model-based process design and optimization in the pharmaceutical industry is an important and challenging one both computationally and in the choice of solution implementation. In this work, a framework is presented to directly utilize a process simulator via callbacks during derivative-based optimization. The framework allows users with little experience in translating mechanistic ordinary differential equations and partial differential equations to robust and fully discretized algebraic formulations, required for executing simultaneous equation-oriented optimization and to obtain mathematically guaranteed optima at a competitive solution time when compared with the existing derivative-free and derivative-based frameworks. The effectiveness of the framework in the accuracy of the optimal solution as well as the computational efficiency is analyzed in two case studies: (i) an integrated 2-unit reaction synthesis train used for the synthesis of an anti-cancer active pharmaceutical ingredient and (ii) a more complex flowsheet representing a common synthesis–purification–isolation train of a pharmaceutical manufacturing process.

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Mathematical modeling and digital design of an intensified filtration-washing-drying unit for pharmaceutical continuous manufacturing

Cited by 22 publications

References 31 publications

Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter

Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Simulation–Optimization Framework for the Digital Design of Pharmaceutical Processes Using Pyomo and PharmaPy

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