A Comparison of Controlled Ice Nucleation Techniques for Freeze-Drying of a Therapeutic Antibody

Gitter, Julian Hendryk; Geidobler, Raimund; Presser, Ingo; Winter, Gerhard

doi:10.1016/j.xphs.2018.07.019

Cited by 17 publications

(7 citation statements)

References 15 publications

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“…In particular, CN is used to control ice nucleation and the ice crystal size. After the water sublimates, the remaining pores in samples generated by CN are larger and the sample overall possesses a smaller specific surface area, which often leads to products with higher residual moisture [ 105 ].…”

Section: Application Of α -Relaxation Analysismentioning

confidence: 99%

Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids

Groёl

Menzen²,

Winter

2021

Pharmaceutics

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Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant today, as the application of new process techniques in freeze-drying (which strongly influence the thermal history of the products) has recently gained more interest. To revive the application of calorimetric methods, the widely scattered knowledge on this matter is condensed into a review and completed with new experimental data. The calorimetric methods are applied to recent techniques in lyophilization, such as controlled nucleation and aggressive/collapse drying. Phenomena such as pre-Tg events in differential scanning calorimetry and aging shoulders in isothermal microcalorimetry are critically reviewed and supplemented with data of freeze-dried products that have not been characterized with these methods before.

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Section: Application Of α -Relaxation Analysismentioning

confidence: 99%

Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids

Groёl

Menzen²,

Winter

2021

Pharmaceutics

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“…In general, freeze-drying comprises three steps: freezing, primary drying (= sublimation drying), and secondary drying (= desorption drying). Typically, the sublimation step is widely described to be the most time-consuming, and conventional freeze-drying is associated with lengthy process times [2,[9][10][11][12]. One alternative drying method utilizing microwaves is known from the food industry: microwave-assisted freeze-drying (MFD) [13].…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Freeze-Drying of Monoclonal Antibodies: Product Quality Aspects and Storage Stability

et al. 2019

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In order to overcome the downside of long conventional freeze-drying (CFD) process times for monoclonal antibody formulations, microwave-assisted freeze-drying (MFD) was introduced. Recently, the general applicability and potential shortening of drying times were shown. However, little is known about the storage stability of MFD products compared to CFD references. Additionally, batch homogeneity issues were seen within MFD in the past. In this study, we examined four different formulations of two different monoclonal antibodies using three different glass-forming excipients: sucrose, trehalose, and arginine phosphate. These formulations were freeze-dried with two different drying protocols (CFD and MFD), stored for 24 weeks, and analyzed for solid-state and protein-related quality attributes. Moreover, a new microwave generator setup was investigated for its potential to improve batch homogeneity. In all investigated formulations, comparable stability profiles were found, although the classical magnetron generator led to inferior batch homogeneity with respect to residual moisture distribution. In contrast, the new MFD setup indicated the potential to approximate batch homogeneity to the level of CFD. However, for future applications, there is an unabated need for new machine designs to comply with pharmaceutical manufacturing requirements.Pharmaceutics 2019, 11, 674 2 of 21 be frozen. In a second step, the drying itself takes place. In contrast to CFD, the main heat transfer mechanism is radiation rather than convection and conduction. Especially polar substances, e.g., water, sugars, and amino acids, show good absorption of electromagnetic waves of wavelengths of 12.2 cm and frequencies of 2.45 GHz [15,16]. In brief, the heating mechanism in pharmaceutics occurs due to dipolar and ionic mechanisms. When such a polar compound is placed in an oscillating field, dipoles or ions try to realign in the direction of the electric field. Due to the ultra-rapid change in the direction of the electric field, internal friction of the molecules is caused, leading to heating within the material, i.e., volumetric heating. In the case of ions, a charge-driven migration is discussed [16][17][18]. MFD has clear advantages over conventional drying processes, like significantly shorter process times [19,20], and in the field of food processing, in the maintenance of shape, color, taste, odor, and texture [14,[21][22][23]. In the transition area between food and pharmaceutical technology, MFD was used for the gentle drying of bacteria suspensions. Ambros et al. [19] investigated the survival rate and viability of different bacterial cultures. They found comparable survival rates of the investigated cultures produced by MFD compared to conventional freeze-drying but were able to shorten process times by up to 80%. The first usage in pharmaceutical freeze-drying was presented by Evans et al. [24] at the CPPR Freeze Drying of Pharmaceuticals & Biologics Conference in 2014, showing the general applicability to monoclonal antibodies a...

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“…Evaluating this technology at a laboratory scale is advisable as an alternative to annealing. Different methods of CIN were utilized to compare dried product attributes when nucleated at the same temperature [19][20][21][22]. Gitter et al [19] conducted ice nucleation was achieved at -5°C using ice fog or depressurization methods in systems containing excipients (sucrose, trehalose) or their mixtures (mannitol and sucrose at a 4:1 ratio) and in monoclonal antibodies containing formulation (in sucrose, or trehalose, or mannitol-sucrose and 10 mM histidine buffer and 0.02% w/v polysorbate 80).…”

Section: Overviewmentioning

confidence: 99%

Practical Advice on Scientific Design of Freeze-Drying Process: 2023 Update

Tchessalov,

Maglio,

Kazarin

et al. 2023

Pharm Res

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Objective The purpose of this paper is to re-visit the design of three steps in the freeze-drying process, namely freezing, primary drying, and secondary drying steps. Specifically, up-to-date recommendations for selecting freeze-drying conditions are provided based on the physical–chemical properties of formulations and engineering considerations. Methods and Results This paper discusses the fundamental factors to consider when selecting freezing, primary drying, and secondary drying conditions, and offers mathematical models for predicting the duration of each segment and product temperature during primary drying. Three simple heat/mass transfer primary drying (PD) models were tested, and their ability to predict product temperature and sublimation time showed good agreement. The PD models were validated based on the experimental data and utilized to tabulate the primary drying conditions for common pharmaceutical formulations, including amorphous and partially crystalline products. Examples of calculated drying cycles, including all steps, for typical amorphous and crystalline formulations are provided. Conclusions The authors revisited advice from a seminal paper by Tang and Pikal (Pharm Res. 21(2):191-200, 2004) on selecting freeze-drying process conditions and found that the majority of recommendations are still applicable today. There have been a number of advancements, including methods to promote ice nucleation and computer modeling for all steps of freeze-drying process. The authors created a database for primary drying and provided examples of complete freeze-drying cycles design. The paper may supplement the knowledge of scientists and formulators and serve as a user-friendly tool for quickly estimating the design space.

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A Comparison of Controlled Ice Nucleation Techniques for Freeze-Drying of a Therapeutic Antibody

Cited by 17 publications

References 15 publications

Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids

Calorimetric Investigation of the Relaxation Phenomena in Amorphous Lyophilized Solids

Microwave-Assisted Freeze-Drying of Monoclonal Antibodies: Product Quality Aspects and Storage Stability

Practical Advice on Scientific Design of Freeze-Drying Process: 2023 Update

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