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

Christina Haeuser,Pierre Goldbach,Wolfgang Friess,Joerg Huwyler,Andrea Allmendinger

doi:10.3390/pharmaceutics11110616

Christina Haeuser, Pierre Goldbach + Show 3 more

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https://doi.org/10.3390/pharmaceutics11110616

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Abstract

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.

Highlights

Freeze-drying is frequently used to manufacture drug products of proteins which are unstable as liquids
The impact of protein concentration on Tg’ was more pronounced the lower the Tg’ of the formulations compared to each other. This means that the Tg’ of FS increased by 4.1 ◦C from −29.5 to −25.4 ◦C when increasing the monoclonal antibody (mAb) concentration from 10 to 50 mg/mL compared to an increase of only 2.6 ◦C for FCD for example
Within the present study we demonstrated that scientists can be very aggressive during freeze-drying, using HPBCD-based formulations in combination with sucrose or PVP/sucrose

Summary

Introduction

Freeze-drying is frequently used to manufacture drug products of proteins which are unstable as liquids. Around 40% of all biopharmaceuticals are freeze-dried, liquid formulations are often preferred due to a significantly less complex manufacturing process [1,2]. Freeze-drying is a time-consuming low throughput batch process which usually takes several days up to weeks [3], requires much energy, and is costly. Freeze-drying consists of three process steps, (i) freezing, (ii) primary drying, where crystallized water is removed under vacuum by sublimation, and (iii) secondary drying, where desorption of the bound water takes place. Primary drying is the most time consuming of the three steps. Efforts to optimize the lyophilization cycle time often focus on the primary drying step

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