Vacuum-Induced Surface Freezing for the Freeze-Drying of the Human Growth Hormone: How Does Nucleation Control Affect Protein Stability?

Oddone, Irene; Arsiccio, Andrea; Duru, Chinwe; Malik, Kiran; Ferguson, Jackie; Pisano, Roberto; Matejtschuk, Paul

doi:10.1016/j.xphs.2019.04.014

Cited by 15 publications

(13 citation statements)

References 52 publications

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“…The freezing step has been recently studied in detail as it was proven to substantially influence the product structure [ 4 , 5 , 6 ] and the drug residual activity [ 7 , 8 , 9 , 10 ]. When water is cooled below its equilibrium temperature, it can remain in the liquid state for a relatively long time before the occurrence of the phase transition into solid ice.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera

et al. 2021

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The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental observations of the freezing phenomenon in vials in the literature. Thus, the present work offers new experimental observations of the freezing phenomenon in vials by infrared (IR) thermography. IR imaging allowed each vial’s whole axial temperature profile to be collected during freezing, providing significant insights into the process. Spontaneous nucleation and vacuum-induced surface freezing (VISF), as a controlled nucleation technique, are investigated. Batches having vials in direct contact with the shelf (exchanging heat mainly through conduction) as well as suspended (exchanging heat mainly through natural convection and radiation) were tested. The study used three solutions: sucrose 5%, mannitol 5%, and dextran 10%. SEM images coupled with an automated image segmentation technique were also performed to examine possible correlations between the freezing observations and the resulting pore size distributions. IR thermography was found to be a promising tool for experimentally predicting the resulting product morphology in-line.

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Section: Introductionmentioning

confidence: 99%

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera

et al. 2021

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“…Moreover, even though economic evaluations have been presented in the past [9][10][11], they are often too broad or too specific to be used for making comparisons between different process strategies. Whereas little effort has been made in this field to determine the economic impact of freeze-drying quantitatively, the optimization of the process has usually remained product-or quality-specific [12][13][14][15][16][17][18], with no considerations of possible bottlenecks in the expenses. In this work, we aim to create a model to evaluate the actual economic impact of a freeze-drying cycle, and evaluate the impact of process parameters on processing costs and, finally, the benefits of process optimization.…”

Section: Introductionmentioning

confidence: 99%

Economic Analysis of a Freeze-Drying Cycle

et al. 2020

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Freeze-drying has always been considered an extremely expensive procedure to dehydrate food or pharmaceutical products, and for this reason, it has been employed only if strictly necessary or when the high added value of the final product could justify the costs. However, little effort has been made to analyze the factors that make this technology so unaffordable. In this work, a model was proposed to calculate in detail the operational (OC) and capital costs (CC) of a freeze-drying cycle and an evaluation of the process bottlenecks was made. The main result is that the process itself, contrary to the classic belief, is not the most expensive part of freeze-drying, while the initial investment is the real limiting factor. Under this consideration, the optimization of a freeze-drying cycle should be formulated in order to fit more cycles in the lifespan of the apparatus, instead of merely reducing the power consumption of the machine.

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“…Although solid-state properties differed slightly, they concluded that controlled ice nucleation had neither a positive nor negative impact on protein stability compared to stochastically nucleated samples. Oddone et al reported no difference in stability of stochastic versus controlled nucleation vials by the "partial vacuum" method investigated for different formulations of human growth hormone [22]. The current study focused on investigating and comparing the impact of three mechanistically different nucleation techniques on protein stability and included challenging protein configurations.…”

Section: Comparability Of Product Attributesmentioning

confidence: 96%

Comparison of Techniques to Control Ice Nucleation during Lyophilization

Luoma¹,

Ingham²,

Martinez

et al. 2020

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Controlling ice nucleation during lyophilization of parenteral drug products increases the homogeneity of critical quality attributes, such as residual moisture, across drug product batches and shortens lyophilization cycle time. In the present study, we compare three mechanistically different techniques to control ice nucleation during the freezing step of lyophilization, which are referred to as “depressurization”, “partial vacuum”, and “ice fog” techniques. The techniques are compared with respect to their operational limitations and challenges. Installation considerations are also discussed. Using the aforementioned nucleation techniques, we investigated a monoclonal antibody formulation and an enzyme formulation at different protein concentrations using feasible nucleation temperatures and different vial formats and fill volumes. Samples were compared for solid state properties and other critical quality attributes on stability. When nucleated at the same temperature, the three techniques produced products with the same quality attributes and stability behavior. Under conditions resulting in micro-collapse, stability behavior can be different. We found that each technology had considerations for achieving robust nucleation. The present comparison may serve as guidance in selecting a nucleation method.

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Vacuum-Induced Surface Freezing for the Freeze-Drying of the Human Growth Hormone: How Does Nucleation Control Affect Protein Stability?

Cited by 15 publications

References 52 publications

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera

Economic Analysis of a Freeze-Drying Cycle

Comparison of Techniques to Control Ice Nucleation during Lyophilization

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