Freeze-Drying of Pharmaceutical Proteins in Vials: Modeling of Freezing and Sublimation Steps

Hottot, Aurélie; Peczalski, Roman; Vessot, Séverine; Andrieu, Julien

doi:10.1080/07373930600626388

Cited by 71 publications

(43 citation statements)

References 14 publications

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“…In most of the studies [19,20,22,25], the heat transfer by radiation from the door and walls of the drying chamber was considered completely responsible of the higher product temperature observed in edge vials. However, Gan et al [18] and Rambhatla et al [7] showed that the presence of the metallic rail surrounding vials also contributes to the heat transfer by means of contact conduction and radiation.…”

Section: Introductionmentioning

confidence: 99%

“…Several mono-and multi-dimensional mathematical models of freeze-drying were developed in the past years [16][17][18][19][20][21][22][23][24][25], but only few of them explore the sources of the atypical heat flow rate in edge vials. In most of the studies [19,20,22,25], the heat transfer by radiation from the door and walls of the drying chamber was considered completely responsible of the higher product temperature observed in edge vials.…”

Section: Introductionmentioning

confidence: 99%

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3D mathematical modelling to understand atypical heat transfer observed in vial freeze-drying

Scutellà

Plana-Fattori

Passot

et al. 2017

Applied Thermal Engineering

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In pharmaceutical freeze-drying, the position of the product container (vial) on the shelf of the equipment constitutes a major issue for the final product quality. Vials located at the shelf edges exhibit higher product temperature than vials located at the centre, which in turn often results in collapsed product. A physics-based model was developed to represent heat transfer phenomena and to study their variation with the distance from the periphery of the shelf. Radiation, conduction between solids, and conduction through low-pressure water vapour were considered. The modelling software package COMSOL Multiphysics was employed in representing these phenomena for a set of five vials located at the border of the shelf, close to the metallic guardrail. Model predictions of heat fluxes were validated against experimental measurements conducted over a broad range of shelf temperatures and chamber pressures representative for pharmaceutical freeze-drying. Conduction through low-pressure water vapour appeared as the dominant mechanism explaining the additional heat transfer to border vials compared to central ones. The developed model constitutes a powerful tool for studying heterogeneity in freeze-drying while reducing experimental costs. Highlights:• A 3D mathematical model of heat transfer in freeze-drying is proposed.• The role of several heat transfer mechanisms is explored.• Knudsen effect is considered for conduction inside low-pressure water vapour.• Radiation heat transfer is evaluated using the surface-to-surface model.• Atypical heat transfer is explained mainly by gas conduction rather than radiation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3D mathematical modelling to understand atypical heat transfer observed in vial freeze-drying

Scutellà

Plana-Fattori

Passot

et al. 2017

Applied Thermal Engineering

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show abstract

“…In order to assess the effect of Tfluid and Pc on product temperature in the primary drying stage a one-dimensional model can be used [16][17][18][19][20][21]. The heat flux to the product (Jq) is proportional to the temperature difference between the heating fluid and the product at the bottom of the container (TB):…”

Section: Introductionmentioning

confidence: 99%

Computer-Aided Framework for the Design of Freeze-Drying Cycles: Optimization of the Operating Conditions of the Primary Drying Stage

Fissore

Pisano

2015

Processes

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This paper deals with the freeze-drying process and, in particular, with the optimization of the operating conditions of the primary drying stage. When designing a freeze-drying cycle, process control aims at obtaining the values of the operating conditions (temperature of the heating fluid and pressure in the drying chamber) resulting in a product temperature lower than the limit value of the product, and in the shortest drying time. This is particularly challenging, mainly due to the intrinsic nonlinearity of the system. In this framework, deep process knowledge is required for deriving a suitable process dynamic model that can be used to calculate the design space for the primary drying stage. The design space can then be used to properly design (and optimize) the process, preserving product quality. The case of a product whose dried layer resistance, one of the key model parameters, is affected by the operating conditions is addressed in this paper, and a simple and effective method to calculate the design space in this case is presented and discussed.

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“…Tang et al 23 and Liapis and Bruttini 24 proposed a model based on a bi-dimensional axial-symmetric description of the geometry of the system: the main objective of the work was to derive some qualitative features of the process and, in particular, to show that the sublimating interface temperature can vary in the radial direction when radiant flux at the vial side is taken into account, and that the slope of the free surface at the edge of the vial is always curved downward. A finite element formulation was used by Mascarenhas et al 25 , by Lombrañ a et al 26 , by Hottot et al 27 , and by Brü lls and Rasmuson 28 to solve the bi-dimensional model, while the orthogonal collocation method was used by Sheehan and Liapis 29 . Numerical simulations showed that when there is no heat input from the vial sides, no physical stimulus exists to induce radial effects, and the geometry of the moving interface is flat: this situation is representative for the vast majority of the vials undergoing freeze-drying, that is, the vials located at the center of the shelf.…”

Section: Governing Equations and Mathematical Modelingmentioning

confidence: 99%

On the Use of a Dual-Scale Model to Improve Understanding of a Pharmaceutical Freeze-Drying Process

Rasetto

Marchisio

Fissore

2010

Journal of Pharmaceutical Sciences

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Freeze-Drying of Pharmaceutical Proteins in Vials: Modeling of Freezing and Sublimation Steps

Cited by 71 publications

References 14 publications

3D mathematical modelling to understand atypical heat transfer observed in vial freeze-drying

3D mathematical modelling to understand atypical heat transfer observed in vial freeze-drying

Computer-Aided Framework for the Design of Freeze-Drying Cycles: Optimization of the Operating Conditions of the Primary Drying Stage

On the Use of a Dual-Scale Model to Improve Understanding of a Pharmaceutical Freeze-Drying Process

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