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Assessment of Imaging Flow Cytometry for the Simultaneous Discrimination of Protein Particles and Silicone Oil Droplets in Biologicals

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Abstract

Purpose

Silicone oil droplets in biopharmaceutical products can originate from sources such as siliconized surfaces of primary packaging materials, potentially triggering the formation of protein–silicone oil particles. To better understand this phenomenon, there is a need for particle detection devices that cannot only distinguish between protein particles and silicone oil droplets but also determine particle sizes ranging from nanometers to micrometers.

Method

In this study, we conducted a systematic assessment of imaging flow cytometry (IFC) using the FlowSight® instrument. Our first step was to investigate specific instrument settings using protein particle samples spiked with silicone oil for particle classification. Based on these findings, we established suitable, harmonized working templates. Next, we evaluated the instrument’s accuracy and precision for particle sizes within the range of 0.5 to 100 µm and their respective concentrations. Finally, we investigated any constraints in particle concentration within this size range.

Results

This study demonstrates that IFC can effectively distinguish protein particles from silicone oil droplets when the latter is labeled with a specific fluorescent dye. Our findings suggest that fluorescently labeled particles ≥ 0.5 µm can be reliably detected. Through our research, we determined the particle concentration limits for each particle size in the range of 0.5 to 10 µm, with a precision deviation of less than 15%. However, our study also revealed that IFC exhibited insufficient accuracy for the tested particle concentrations within this size range. Additionally, we showed that the measurements were significantly influenced by the instrument settings.

Conclusion

Although we addressed numerous new aspects to enhance the experimental procedure of IFC measurements, we conclude that IFC is not an ideal technique for quantifying sub-visible particles. Instead, it should be employed to provide supportive characterization data in conjunction with commonly used sub-visible particle detection methods. If distinguishing between protein particles and silicone oil droplets is essential, IFC is an option, as long as the fluorescent dye is carefully selected.

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Data Availability

The datasets generated during and/or analyzed during the current study are avalaible from the corresponding author on reasonable request.

Abbreviations

BF:

Brightfield

FL:

Fluorescence

SO:

Silicone oil

IFC:

Imaging flow cytometry

PFS:

Pre-filled syringe

SSC:

Side scatter

TDI:

Time delay integration

CCD:

Charge-coupled device

Ch:

Channel

CV:

Coefficient of variation

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Acknowledgements

We acknowledge Dr. Julia Groß-Rother and Dr. Eric Frotscher for their excellent support and helpful discussions and Holger Thie for project management.

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Authors and Affiliations

  1. Department of Pharmaceutics and Biopharmaceutics, University of Marburg, Robert-Koch-Str. 4, 35037, Marburg, Germany

    Ibrahim Fawaz & Udo Bakowsky

  2. Boehringer Ingelheim Pharma GmbH & Co. KG, Innovation Unit, Birkendorfer Strasse 65, 88397, Biberach/Riss, Germany

    Simone Helene Schaz, Patrick Garidel & Michaela Blech

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  1. Ibrahim Fawaz
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Contributions

All auhtors contributed to the study concept and design. Material preparation, data collection, and analysis were performed by IF and SS. The first draft of the manuscript was written by IF and MB. All authors read and approved the final manuscript. PG and MB supervised the study and MB was responsible for funding acquisition and resources.

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Correspondence to Michaela Blech.

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Fawaz, I., Schaz, S., Garidel, P. et al. Assessment of Imaging Flow Cytometry for the Simultaneous Discrimination of Protein Particles and Silicone Oil Droplets in Biologicals. J Pharm Innov 19, 11 (2024). https://doi.org/10.1007/s12247-024-09810-4

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