Advertisement

Application of Tunable Resistive Pulse Sensing for the Quantification of Submicron Particles in Pharmaceutical Monoclonal Antibody Preparations

  • Andreas Stelzl
    Correspondence
    Correspondence: Andreas Stelzl, Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Butenandtstraβe 5-13, 81377 Munich, Germany
    Affiliations
    Ludwig-Maximilians Universität München, Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Butenandtstraße 5-13, 81377 Munich, Germany
    Search for articles by this author
  • Stefan Schneid
    Affiliations
    Bayer AG, Pharmaceuticals, Formulation Development Parenterals, Friedrich-Ebert-Str. 475, 42096 Wuppertal, Germany
    Search for articles by this author
  • Gerhard Winter
    Affiliations
    Ludwig-Maximilians Universität München, Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Butenandtstraße 5-13, 81377 Munich, Germany
    Search for articles by this author

      Abstract

      Tunable resistive pulse sensing (TRPS, qNano Gold, IZON Ltd.) was investigated as a method to quantify submicron particles (SMPs) between 0.1 and 1 µm in solutions of biopharmaceuticals. To reduce sample dilution, a spiking-in approach was used to add the appropriate amount of electrolytes required for the measurement. For correct particle quantification, an electrolyte concentration of at least 50 mM sodium chloride was needed. Intra- and inter-nanopore variability were below 5% for size and below 10% for concentration measurements when analyzing polystyrene standard beads. Submicron particle counts in a stir stressed IgG1 monoclonal antibody formulation resulted in a non-symmetrical, almost bell-shaped size distribution with a maximum at 250 nm when using a NP300 nanopore (IZON Ltd.). It was shown that particle counts are heavily underestimated below 250 nm, and therefore it is recommended to quantify particle counts by TRPS in samples with heterogeneous particle size distributions (e.g., biopharmaceuticals) only starting from the maximum of the histogram towards the upper limit of detection.

      Key words

      To read this article in full you will need to make a payment
      APhA Member Login
      APhA Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • U.S. Department of health and human services FDA (Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research)
        Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products.
        Food and Drug Administration, Silver Spring, MD, USA2014
        • Hawe A
        • Zölls S
        • Freitag A
        • Carpenter JF.
        Subvisible and visible particle analysis in biopharmaceutical research and development.
        Biophysical Characterization of Proteins in Developing Biopharmaceuticals. Susan Dennis, Amsterdam, Netherlands2015: 261-286
        • Anderson W
        • Lane R
        • Korbie D
        • Trau M
        Observations of tunable resistive pulse sensing for exosome analysis: improving system sensitivity and stability.
        Langmuir. 2015; 31: 6577-6587
        • Maas SL
        • De Vrij J
        • Broekman ML
        Quantification and size-profiling of extracellular vesicles using tunable resistive pulse sensing.
        J Vis Exp. 2014; : e51623
        • Vogel R
        • Coumans FA
        • Maltesen RG
        • et al.
        A standardized method to determine the concentration of extracellular vesicles using tunable resistive pulse sensing.
        J Extracell Vesicles. 2016; 5: 31242
        • Anderson W
        • Kozak D
        • Coleman VA
        • Jamting AK
        • Trau M
        A comparative study of submicron particle sizing platforms: accuracy, precision and resolution analysis of polydisperse particle size distributions.
        J Colloid Interface Sci. 2013; 405: 322-330
        • Weatherall E
        • Willmott GR
        Applications of tunable resistive pulse sensing.
        Analyst. 2015; 140: 3318-3334
        • Scherer TM
        • Leung S
        • Owyang L
        • Shire SJ
        Issues and challenges of subvisible and submicron particulate analysis in protein solutions.
        AAPS J. 2012; 14: 236-243
        • Roberts GS
        • Yu S
        • Zeng Q
        • et al.
        Tunable pores for measuring concentrations of synthetic and biological nanoparticle dispersions.
        Biosens Bioelectron. 2012; 31: 17-25
        • Vogel R
        • Willmott G
        • Kozak D
        • et al.
        Quantitative sizing of nano/microparticles with a tunable elastomeric pore sensor.
        Anal Chem. 2011; 83: 3499-3506
      1. Izon Science Support Centre. Video: Maintaining a stable baseline current. Available at: https://support.izon.com/video-maintaining-a-stable-baseline. Accessed February 7, 2021.

        • Grabarek AD
        • Weinbuch D
        • Jiskoot W
        • Hawe A
        Critical evaluation of microfluidic resistive pulse sensing for quantification and sizing of nanometer- and micrometer-sized particles in biopharmaceutical products.
        J Pharm Sci. 2019; 108: 563-573
        • Zolls S
        • Tantipolphan R
        • Wiggenhorn M
        • et al.
        Particles in therapeutic protein formulations, part 1: overview of analytical methods.
        J Pharm Sci. 2012; 101: 914-935
        • Roberts CJ
        Therapeutic protein aggregation: mechanisms, design, and control.
        Trends Biotechnol. 2014; 32: 372-380
        • Yoneda S
        • Niederleitner B
        • Wiggenhorn M
        • et al.
        Quantitative laser diffraction for quantification of protein aggregates: comparison with resonant mass measurement, nanoparticle tracking analysis, flow imaging, and light obscuration.
        J Pharm Sci. 2019; 108: 755-762
        • Zidar M
        • Kuzman D
        • Ravnik M
        Characterisation of protein aggregation with the Smoluchowski coagulation approach for use in biopharmaceuticals.
        Soft Matter. 2018; 14: 6001-6012
        • Hubert M
        • Yang DT
        • Kwok SC
        • et al.
        A multicompany assessment of submicron particle levels by NTA and RMM in a wide range of late-phase clinical and commercial biotechnology-derived protein products.
        J Pharm Sci. 2019; 109: 830-844
        • Barnett GV
        • Perhacs JM
        • Das TK
        • Kar SR
        Submicron protein particle characterization using resistive pulse sensing and conventional light scattering based approaches.
        Pharm Res. 2018; 35: 58