A benchmark simulator for quality-by-design and quality-by-control studies in continuous pharmaceutical manufacturing ‒ Intensified filtration-drying of crystallization slurries

Destro, Francesco; Nagy, Zoltán K.; Barolo, Massimiliano

doi:10.1016/j.compchemeng.2022.107809

Cited by 12 publications

(12 citation statements)

References 43 publications

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“…We develop an in silico case study with ContCarSim, based on challenges 1, 2, 4, and 5 proposed in the article accompanying the release of the simulator. 36 We design and implement a closed-loop control system, acting on the CPPs (V sp slurry and Δt sp cycle ) to maximize the production of cakes meeting the target quality discharged by the carousel in a given time window. We compare the control system performance with open-loop operation and with simpler control systems, including only a subset of the elements of the complete approach, under the reference scenario proposed in challenge #5 (Table 4).…”

Section: Case Study Definitionmentioning

confidence: 99%

“…elements of ϕ are sampled from the respective probability distributions implemented in ContCarsim. 36 A single value is sampled for all the filter mesh resistances (R m,1 , R m,2 , R m,3 , and R m,4 ), since the carousel rotation mechanism (Section 2) causes a fouling lag among stations; hence, a given cake will encounter filters of approximately the same resistance while progressing in the carousel stations. Finally, w final (i.e., the product CQA) is calculated for the given set of grid point conditions and disturbances using the input/output carousel model.…”

Section: Ds Descriptionmentioning

confidence: 99%

“…While c slurry and V sp slurry are inputs of the input/output model, α and ϵ are fixed parameters, taken as in ContCarSim. 36 Within the SS framework, instead, the available measurements of c slurry and V slurry (respectively, y cslurry and y Vslurry ) and the estimation of α and ϵ (respectively, b α and b ϵ) are directly used.…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…Previous studies involved experimental and digital design of the carousel technology and its operation, 30,32–34 and experimental and modeling results that successfully integrated carousels, in filtration‐only mode, with upstream continuous crystallization systems 25,31,35 . Recently, a comprehensive benchmark simulator (ContCarSim 36 ) has been proposed for the digital design and testing of control strategies for this type of units. ContCarSim, implemented in MATLAB, reproduces the operation of physical carousels and their sensors and actuators network, 33 and it allows the implementation of control loops by the user.…”

Section: Introductionmentioning

confidence: 99%

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Quality‐by‐control of intensified continuous filtration‐drying of active pharmaceutical ingredients

2022

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Continuous manufacturing and closed‐loop quality control are emerging technologies that are pivotal for next‐generation pharmaceutical modernization. We develop a process control framework for a continuous carousel for integrated filtration‐drying of crystallization slurries. The proposed control system includes model‐based monitoring and control routines, such as state estimation and real‐time optimization, implemented in a hierarchical, three‐layer quality‐by‐control (QbC) framework. We implement the control system in ContCarSim, a publicly available carousel simulator. We benchmark the proposed control system against simpler methods, comprising a reduced subset of the elements of the overall control system, and against open‐loop operation (the current standard in pharmaceutical manufacturing). The proposed control system demonstrates superior performance in terms of higher consistency in product quality and increased productivity, proving the benefits of closed‐loop control and of model‐based techniques in pharmaceutical manufacturing. This study represents a step forward toward end‐to‐end continuous pharmaceutical processing, and in the evolution of quality‐by‐design toward quality‐by‐control.

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Section: Case Study Definitionmentioning

confidence: 99%

Section: Ds Descriptionmentioning

confidence: 99%

Section: Acknowledgmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quality‐by‐control of intensified continuous filtration‐drying of active pharmaceutical ingredients

2022

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“…18 Conventional filtration theory describes the relevant continuity equations, the closing relationship, and the appropriate initial boundary conditions and moving boundary conditions 19,20 of a filtration process. A further detailed description of the existing filtration models was reviewed by Ottoboni et al 21 Nagy et al, 22 Other filtration models were reported by Benyahia et al 23 and Destro et al 24,25 In general, these models are based on Darcy's law, but different theories are used to calculate cake porosity and cake resistance, such as the Yu et al 26 approaches proposed by Destro et al 24 or the Endo Alonso theory proposed by Nagy et al 22 One of the first washing models developed was proposed by Rhodes, 27,28 used to describe the variables affecting the washing curve. This is further described in Section 3.1.…”

Section: Introductionmentioning

confidence: 99%

Digital Design of Filtration and Washing of Active Pharmaceutical Ingredients via Mechanistic Modeling

Ottoboni

Brown

Mehta

et al. 2022

Org. Process Res. Dev.

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To facilitate integrated end-to-end pharmaceutical manufacturing using digital design, a model capable of transferring material property information between operations to predict product attributes in integrated purification processes has been developed. The focus of the work reported here combines filtration and washing operations used in active pharmaceutical ingredient (API) purification and isolation to predict isolation performance without the need of extensive experimental work. A fixed Carman–Kozeny filtration model is integrated with several washing mechanisms (displacement, dilution, and axial dispersion). Two limiting cases are considered: case 1 where there is no change in the solid phase during isolation (no particle dissolution and/or growth), and case 2 where the liquid and solid phases are equilibrated over the course of isolation. In reality, all actual manufacturing conditions would be bracketed by these two limiting cases, so consideration of these two scenarios provides rigorous theoretical bounds for assessing isolation performance. This modeling approach aims to facilitate the selection of most appropriate models suitable for different isolation scenarios, without the requirement to use overly complex models for straightforward isolation processes. Mefenamic acid and paracetamol were selected as representative model compounds to assess a range of isolation scenarios. In each case, the objective of the models was to identify the purity of the product reached with a fixed wash ratio and minimize the changes to the crystalline particle attributes that occur during the isolation process. This was undertaken with the aim of identifying suitable criteria for the selection of appropriate filtration and washing models corresponding to relevant processing conditions, and ultimately developing guidelines for the digital design of filtration and washing processes.

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A general procedure for the evaluation of the prediction fidelity of pharmaceutical systems models

Geremia

Diab

Christodoulou

et al. 2023

Chemical Engineering Science

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A benchmark simulator for quality-by-design and quality-by-control studies in continuous pharmaceutical manufacturing ‒ Intensified filtration-drying of crystallization slurries

Cited by 12 publications

References 43 publications

Quality‐by‐control of intensified continuous filtration‐drying of active pharmaceutical ingredients

Quality‐by‐control of intensified continuous filtration‐drying of active pharmaceutical ingredients

Digital Design of Filtration and Washing of Active Pharmaceutical Ingredients via Mechanistic Modeling

A general procedure for the evaluation of the prediction fidelity of pharmaceutical systems models

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