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The Degradation of Polysorbates 20 and 80 and its Potential Impact on the Stability of Biotherapeutics

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ABSTRACT

Purpose

To study the potential impact of the degradation of Polysorbates (PS) 20 and 80 on the stability of therapeutic proteins in parenteral formulations.

Method

First, degradation products of PS20 and 80 were identified. Subsequently, the effect of degraded polysorbate on physical characteristics and long-term stability of protein formulations was assessed. Further, the impact of polysorbate degradation on protein stability was evaluated via shaking stress studies on formulations spiked with artificially degraded polysorbate or degradants like fatty acids. Additionally, aged formulations with reduced polysorbate content were shaken.

Results

The degradation of polysorbate leads to a buildup of various molecules, some of which are poorly soluble, including fatty acids and polyoxyethylene (POE) esters of fatty acids. Spiking studies showed that the insoluble degradants could potentially impact protein stability and that the presence of sufficient intact polysorbate was crucial to prevent this. End-of-shelf-life shaking of protein formulations showed that the stability of various monoclonal antibodies was, however, not affected.

Conclusions

Although some degradants can potentially influence the stability of the protein (as discerned from spiking studies), degradation of polysorbates did not impact the stability of the different proteins tested in pharmaceutically relevant temperature and storage conditions.

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ACKNOWLEDGMENTS

The authors wish to thank Dr. Balz Fischer and B. Gessier for SBSE-GC-MS measurements, Dr. Heribert Dolt and Dr. Siegfred Stolz for FT-MS measurements, Dr. Alfred Ross for NMR measurements, Dr. Monira Siam for FT-IR measurements, Dr. Andreas Staempfli for GC-MS measurements, and Christian Lehrmayer, Thomas Steffen and Martin Weiss for their help in the experimental work.

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Authors and Affiliations

  1. Pharmaceutical & Device Development, Pharma Technical Development, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Bldg 9/666, CH-4070, Basel, Switzerland

    Ravuri S. K. Kishore, Ulla Grauschopf & Hanns-Christian Mahler

  2. Formulation Research, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Sylvia Kiese, Stefan Fischer & Astrid Pappenberger

Authors
  1. Ravuri S. K. Kishore
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  2. Sylvia Kiese
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  3. Stefan Fischer
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  4. Astrid Pappenberger
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  5. Ulla Grauschopf
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  6. Hanns-Christian Mahler
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Correspondence to Hanns-Christian Mahler.

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Kishore, R.S.K., Kiese, S., Fischer, S. et al. The Degradation of Polysorbates 20 and 80 and its Potential Impact on the Stability of Biotherapeutics. Pharm Res 28, 1194–1210 (2011). https://doi.org/10.1007/s11095-011-0385-x

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  • DOI: https://doi.org/10.1007/s11095-011-0385-x

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