Parenteral protein formulations: An overview of approved products within the European Union

Gervasi, Valeria; Agnol, Rafaela Dall; Cullen, Sean P.; McCoy, Timothy R.; Vučen, Sonja; Crean, Abina M.

doi:10.1016/j.ejpb.2018.07.011

Cited by 121 publications

(54 citation statements)

References 80 publications

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“…To date, the majority of freezedried biopharmaceuticals on the market contain trehalose and more commonly sucrose as excipient, which are well known to be potent stabilizers, providing both lyoprotection and cryoprotection. 1 The excellent protein stabilization by sucrose is attributed to its ability (1) to form hydrogen bonds with protein molecules, which is described by the water replacement theory 2 and (2) to form a glassy matrix in the dried state in which protein molecules are immobilized as described by the vitrification theory. 3 Recent literature demonstrates that stabilization via vitrification holds true as long as the storage temperature is at least 10 C-20 C below the glass transition temperature (T g ) of the freeze-dried product.…”

Section: Introductionmentioning

confidence: 99%

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Haeuser

Goldbach

Huwyler

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tSucrose is a common cryoprotectant and lyoprotectant to stabilize labile biopharmaceuticals during freezedrying and storage. Sucrose-based formulations require low primary drying temperatures to avoid collapse and monoclonal antibody (mAb) containing products need to be stored refrigerated. The objective of this study is to investigate different excipients enabling storage at room temperature and aggressive, shorter lyophilization cycles. We studied combinations of 2-hydroxypropyl-beta-cyclodextrin (CD), recombinant human albumin, polyvinylpyrroldione (PVP), dextran 40 kDa (Dex), and sucrose (Suc) using 2 mAbs. Samples were characterized for collapse temperature (T c ), glass transition temperature of the liquid (T g 0 ) and freeze-dried formulation (T g ), cake appearance, residual moisture, and reconstitution time. Freezedried formulations were stored at 5 C, 25 C, and 40 C for up to 9 months and mAb stability was analyzed for color, turbidity, visible and sub-visible particles, and monomer content. Formulations with CD/ Suc or CD/PVP/Suc were superior to pure Suc formulations for long-term storage at 40 C. When using aggressive freeze-drying cycles, these formulations were characterized by pharmaceutically elegant cakes, short reconstitution times, higher T g 0 , T c , and T g . We conclude that the addition of CD allows for shorter freeze-drying cycles with improved cake appearance and enables storage at room temperature, which might reduce costs of goods substantially.

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Section: Introductionmentioning

confidence: 99%

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Haeuser

Goldbach

Huwyler

et al. 2020

Journal of Pharmaceutical Sciences

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“…The method has been used for pharmaceutical industrial purposes since World War II, for the preparation of human blood plasma [2], and the demand for freeze-drying (FD) remains high. By 2018, one-third of all parenteral protein formulations approved by the European Medicines Agency were freeze-dried products [3]. During lyophilization, the protein drug is immobilized in the solid-state, slowing down chemical and physical degradation reactions [2,[4][5][6][7].…”

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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“…This allows binding to hydrophobic sites of the protein to protect it from interacting with other Abs or surfaces[ 24 ]. Most commonly added surfactants are polysorbate 20, polysorbate 80, and poloxamer 188, regardless liquid or solid forms[ 25 ].…”

Section: Formulations and Excipients In Antibody-based Biopharmaceutimentioning

confidence: 99%

Formulation strategies in immunotherapeutic pharmaceutical products

Zhang¹,

Williams²,

Tucker³

2020

WJCO

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Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health. Antibodies are the leading entity in immunotherapy, while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area. In order to enable antibody candidates or cells available as products, formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life, storage and handling conditions. Here we provide a concise and contemporary review of ongoing formulation strategies and excipients used in approved antibodies and cellular therapeutic products. Excipients are categorized, and their function in formulations are discussed.

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Parenteral protein formulations: An overview of approved products within the European Union

Cited by 121 publications

References 80 publications

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

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

Formulation strategies in immunotherapeutic pharmaceutical products

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