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Freeze-Dried Biopharmaceutical Formulations are Surprisingly Less Stable than Liquid Formulations during Drop**

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Abstract

Purposes

This article describes an interesting phenomenon in which optimized freeze-dried (FD) biopharmaceutical formulations are generally more prone to degradation than their liquid counterparts during drop** and proposes an underlying cause for this surprising phenomenon.

Methods

Two monoclonal antibodies (mAbs) and a fusion protein (FP) were used as model biopharmaceuticals. The stability after drop** stress was determined by ultraviolet–visible (UV–Vis), size exclusion high-performance liquid chromatography (SE–HPLC), micro-flow imaging (MFI), and dynamic light scattering (DLS).

Results

Contrary to what we would normally assume, the FD formulations of the three biopharmaceuticals studied here generally showed much higher amounts of protein sub-visible particles (SbVPs) than liquid formulations after applying the same drop** stress as determined by MFI and DLS. Traditional techniques, such as UV–Vis and SE–HPLC, could hardly detect such degradation.

Conclusions

We propose that the higher temperature caused by drop** for the FD powders than the liquid formulations was probably one of the root causes for the higher amount of particles formed for the FD powders. We also recommend that drop** stress should be included for early-stage screening and choosing liquid versus FD biopharmaceutical formulations.

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Abbreviations

ASTM:

American Society for Testing and Materials

CHO:

Chinese Hamster Ovary

C p :

Specific heat capacity

EC280 :

Extinction coefficient at 280 nm

FD:

Freeze-dried

FP:

Fusion protein

IgG:

Immunoglobulin G

IR:

Infrared

mAb:

Monoclonal antibody

MFI:

Micro-flow imaging

NMPA:

National Medicinal Products Administration of China

SbVP:

Sub-visible particle

SE–HPLC:

Size exclusion high-performance liquid chromatography

UV–Vis:

Ultraviolet–visible

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ACKNOWLEDGMENTS AND DISCLOSURES

We greatly appreciate Zhejiang Bioray Biopharmaceuticals for providing mAb-A, mAb-B, and FP-A for this study. The authors have no conflicts of interest to declare.

Funding

Funding was kindly provided by the Ministry of Science and Technology of China (Grant No. 2018ZX09J18107-002), the National Natural Science Foundation of China (Grant No. 81741144), and Experimental Technology Project of Zhejiang University (Grant No. SJS202003).

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Authors and Affiliations

  1. Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Wei-Jie Fang, Meng-Juan Pang, Jia-Wei Liu & Min-Fei Sun

  2. Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310016, China

    Wei-Jie Fang, Meng-Juan Pang, Jia-Wei Liu & Min-Fei Sun

  3. Department of Chemistry, Zhejiang University, Hangzhou, 310013, China

    **nyu Wang

  4. Zhejiang Bioray Biopharmaceutical Co, Taizhou, 317000, China

    Haibin Wang

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  1. Wei-Jie Fang
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  2. Meng-Juan Pang
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Correspondence to Wei-Jie Fang.

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Fang, WJ., Pang, MJ., Liu, JW. et al. Freeze-Dried Biopharmaceutical Formulations are Surprisingly Less Stable than Liquid Formulations during Drop**. Pharm Res 39, 795–803 (2022). https://doi.org/10.1007/s11095-022-03235-9

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  • DOI: https://doi.org/10.1007/s11095-022-03235-9

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