Unexplored benefits of controlled ice nucleation: Lyophilization of a highly concentrated monoclonal antibody solution

Singh, Shubhadra N.; Kumar, Swati; Bondar, V. V.; Wang, Ning; Forcino, Rachel; Colandene, James D.; Nesta, Doug P.

doi:10.1016/j.ijpharm.2018.09.057

Cited by 18 publications

(14 citation statements)

References 27 publications

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“…Geidobler et al 26 evidenced that controlled ice nucleation may be applied to reduce reconstitution time of highly concentrated lyophilized protein product, and it was reported that it also helped to suppress glass fogging, that is, the undesired migration of protein solutions up on the inner walls of glass vials during the freezing step of lyophilization. 27 Moreover, Fang et al 28 studied the effect of controlled nucleation on the stability of lactate dehydrogenase (LDH) during both freezing and freeze-drying, but their results were not conclusive. In fact, they found that controlled nucleation remarkably improved LDH recovery after freeze-thawing and also increased batch homogeneity.…”

Section: Introductionmentioning

confidence: 99%

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

Oddone

Arsiccio

Duru

et al. 2020

Journal of Pharmaceutical Sciences

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In the present work, the effect of controlled nucleation on the stability of human growth hormone (hGH) during freeze-drying has been investigated. More specifically, the vacuum-induced surface freezing technique has been compared to conventional freezing, both with and without an annealing step. Size exclusion chromatography and cell-based potency assays have been used to characterize the formation of soluble aggregates and the biological activity of hGH, respectively. The results obtained indicate that controlled nucleation has a positive effect on both cycle performance and product homogeneity because of the formation of bigger ice crystals, and characterized by a narrower dimensional distribution. From the point of view of hGH stability, we observed that vacuum-induced surface freezing is not detrimental to the biological activity of the protein, or aggregate formation. In addition, the effect of 2 different formulations, including trehalose or cellobiose, on protein preservation was also considered for this study.

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Section: Introductionmentioning

confidence: 99%

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

Oddone

Arsiccio

Duru

et al. 2020

Journal of Pharmaceutical Sciences

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“…In previous studies, application of the depressurization technique to lactate dehydrogenase (Fang et al, 2018) reduced the degradation of LDH during the freezing process, but did not markedly improve protein stability during the entire freeze-drying process. Controlled nucleation by depressurization was also reported to suppress glass fogging, i.e., the undesired migration of protein solutions up on the inner walls of glass vials during the freezing step of lyophilization, and to result in higher stability against shaking stress (Singh et al, 2018). Application of the ice-fog technique (Vollrath et al, 2018) to lyophilized monoclonal antibody formulations stored at different temperatures reduced particle formation in highly concentrated systems.…”

Section: Discussionmentioning

confidence: 99%

Impact of controlled vacuum induced surface freezing on the freeze drying of human plasma

Arsiccio

Matejtschuk

Ezeajughi

et al. 2020

International Journal of Pharmaceutics

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During the freezing step of a typical freeze drying process, the temperature at which nucleation is induced is generally stochastically distributed, resulting in undesired within-batch heterogeneity. Controlled nucleation techniques have been developed to address this problem; these make it possible to trigger the formation of ice crystals at the same time and temperature in all the batch. Here, the controlled nucleation technique known as vacuum induced surface freezing is compared to spontaneous freezing for the freeze drying of human plasma, a highly concentrated system commonly stored in a dried state. The potency of Factor VIII (FVIII), a sensitive, labile protein present in plasma, and the reconstitution time of the dried cakes are evaluated immediately after freeze drying, and after 1, 3, 6 or 9 months storage at different degradation temperatures. We show that the application of controlled nucleation significantly reduces the reconstitution time and in addition helps to improve FVIII stability.

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“…As another example, lyophilization processes with a high freezing temperatures (i.e., near the equilibrium freezing point) seem to have a protective effect against further stresses when compared to lower freezing temperature, as the cooling rate is decreased. 82…”

Section: Protein Structurementioning

confidence: 99%

“…This may be why it has been shown that lyophilized powders may be more sensitive to mechanical stress than liquid states of mAb formulations, with an increased number of subvisible particles (size over 1 mm). 82,174 Shearing occurs from the differences of fluid velocity (velocity gradients) in moving liquids, for example, between solution and surface (e.g., solution going through syringes and infusion tubes). It has been demonstrated that shearing does not lead to aggregation by itself (even though believed otherwise before), but rather through shear-related effects.…”

Section: Mechanical Stressmentioning

confidence: 99%

Physicochemical Stability of Monoclonal Antibodies: A Review

Basle

Chennell

Tokhadzé

et al. 2020

Journal of Pharmaceutical Sciences

294

162

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Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters, and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation, and primary, secondary, and tertiary structure analysis), chemical stability assays and quantitative assays. Finally, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment, and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested. Several stability studies have been published, some of them showing possibilities of extended stability. However, those data should be questioned due to potential lacks in study methodology.

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Unexplored benefits of controlled ice nucleation: Lyophilization of a highly concentrated monoclonal antibody solution

Cited by 18 publications

References 27 publications

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

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

Impact of controlled vacuum induced surface freezing on the freeze drying of human plasma

Physicochemical Stability of Monoclonal Antibodies: A Review

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