Impact of fast and conservative freeze-drying on product quality of protein-mannitol-sucrose-glycerol lyophilizates

Horn, Jacqueline; Schanda, Julia; Frieß, Wolfgang

doi:10.1016/j.ejpb.2018.03.003

Cited by 38 publications

(19 citation statements)

References 62 publications

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“…Typically, ramp rates of less than 1.0 °C/min are applied, but faster ramp rates of e.g., 1 °C/min are also suitable. Horn et al found no negative impact when increasing the ramp rate into primary drying from 0.5 °C to 1 °C/min [14]. Ohio et al demonstrated that faster ramp rates might result in even better cake appearance for high T s conditions during primary drying compared to very slow ramp rates [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…To this end, crystalline excipients can be included as bulking agents in combination with amorphous sucrose as stabilizer. Recent publications by Horn et al and Pansare et al showed that combinations of crystalline and amorphous excipients allow for aggressive freeze-drying of low concentration protein formulations, while maintaining elegant lyophilisates [14,15]. The ideal ratio of crystalline and amorphous excipients has to be chosen carefully.…”

Section: Introductionmentioning

confidence: 99%

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Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

et al. 2019

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Short freeze-drying cycles for biopharmaceuticals are desirable. Formulations containing an amorphous disaccharide, such as sucrose, are prone to collapse upon aggressive primary drying at higher shelf temperature. We used 2-hydroxypropyl-betacyclodextrin (HPBCD) in combination with sucrose and polyvinylpyrrolidone (PVP) to develop an aggressive lyophilization cycle for low concentration monoclonal antibody (mAb) formulations. Glass transition temperature and collapse temperature of the formulations were determined, and increasingly aggressive cycle parameters were applied. Using a shelf temperature of +30 °C during primary drying, the concept of combining sublimation and desorption of water in a single drying step was investigated. Cake appearance was evaluated visually and by micro-computed tomography. Lyophilisates were further analyzed for reconstitution time, specific surface area, residual moisture, and glass transition temperature. We demonstrated the applicability of single-step freeze-drying, shortening the total cycle time by 50% and providing elegant lyophilisates for pure HPBCD and HPBCD/sucrose formulations. HPBCD/PVP/sucrose showed minor dents, while good mAb stability at 10 mg/mL was obtained for HPBCD/sucrose and HPBCD/PVP/sucrose when stored at 40 °C for 3 months. We conclude that HPBCD-based formulations in combination with sucrose are highly attractive, enabling aggressive, single-step freeze-drying of low concentration mAb formulations, while maintaining elegant lyophilisates and ensuring protein stability at the same time.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

et al. 2019

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“…It is important to inhibit denaturation and deactivation of proteins in cell‐based biomaterials during freeze drying. Nonreducing disaccharides (e.g., sucrose and trehalose) (Frank, ; Horn, Schanda, & Friess, ; Kawai, Hagiwara, Takai, & Suzuki, ) and amino acids (e.g., L‐arginine and L‐histidine) (Jensen et al, ; Mattern, Winter, Kohnert, & Lee, ) are used as protein protectants for pharmaceutical products and research materials. It is known that protein protectants form hydrogen bonds with proteins during freeze drying and suppress deformation of the protein conformation (Carpenter, Arakawa, & Crowe, ; Carpenter & Crowe, ).…”

Section: Discussionmentioning

confidence: 99%

Freeze‐dry processing of three‐dimensional cell constructs for bone graft materials

et al. 2019

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Freeze‐dry processing improves the operability and stability of cell‐based biomaterials and facilitates sterilization for clinical application. However, there is no established freeze‐drying protocol for engineered tissues. Recently, we reported that biomimetic bone tissues can be fabricated using scaffold‐free three‐dimensional (3D) cell constructs with potential applications as bone graft materials. The purpose of this study was to assess the influence of freeze drying on the morphology and components of 3D cell constructs. Cell constructs freeze dried in phosphate buffered saline (PBS) maintained organic and inorganic components; whereas sodium citrate buffer (SCB)‐treated constructs had significantly lower amounts of calcium and bone‐related proteins. Alkaline phosphatase (ALP) activity in cell constructs was maintained by freeze drying in 10% sucrose‐containing PBS, whereas cell constructs treated with PBS without sucrose or with sucrose‐containing SCB showed significant reductions of ALP activity. In this study, we found that sucrose‐containing phosphate buffer was suitable for freeze drying to maintain minerals and protein functions within 3D cell constructs, whereas citrate buffer was inappropriate. The insights gained by this study may facilitate the development of novel cell‐based biomaterials fabricated by tissue engineering approaches and bone graft biomaterials.

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“…29 Low temperatures can also induce protein denaturation, especially during freezing and freeze-thawing cycles, linked to the combination of multiple stress factors (drop of buffer pH due to crystallization, solute molecules cryoconcentration, water-ice interface formation…), affecting both colloidal and conformational stability of proteins. 73 Freezing mAbs solutions may happen willingly, for example, for freeze-drying 74 or bulk storage, 75 or accidently during refrigerated storage. Cold caused unfolding and aggregation is usually reversible, as the mAb mostly stays in a native conformation.…”

Section: Protein Structurementioning

confidence: 99%

“…Heating and cooling rates are also important factors, as extreme rates seeming to lead to instability. 74,79,81 However, mAbs have a good stability and resistance to moderate thermal stress, when compared to other proteins. 23,32 This fact is of crucial importance in case of accidental short-term temperature excursion, justifying a safe use of the exposed products.…”

Section: Protein Structurementioning

confidence: 99%

Physicochemical Stability of Monoclonal Antibodies: A Review

Basle

Chennell

Tokhadzé

et al. 2020

Journal of Pharmaceutical Sciences

255

152

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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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Impact of fast and conservative freeze-drying on product quality of protein-mannitol-sucrose-glycerol lyophilizates

Cited by 38 publications

References 62 publications

Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

Freeze‐dry processing of three‐dimensional cell constructs for bone graft materials

Physicochemical Stability of Monoclonal Antibodies: A Review

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