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Factors Governing the Precision of Subvisible Particle Measurement Methods – A Case Study with a Low-Concentration Therapeutic Protein Product in a Prefilled Syringe

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Abstract

Purpose

The current study was performed to assess the precision of the principal subvisible particle measurement methods available today. Special attention was given to identifying the sources of error and the factors governing analytical performance.

Methods

The performance of individual techniques was evaluated using a commercial biologic drug product in a prefilled syringe container. In control experiments, latex spheres were used as standards and instrument calibration suspensions.

Results

The results reported in this manuscript clearly demonstrated that the particle measurement techniques operating in the submicrometer range have much lower precision than the micrometer size-range methods. It was established that the main factor governing the relatively poor precision of submicrometer methods in general and inherently, is their low sampling volume and the corresponding large extrapolation factors for calculating final results.

Conclusions

The variety of new methods for submicrometer particle analysis may in the future support product characterization; however, the performance of the existing methods does not yet allow for their use in routine practice and quality control.

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Abbreviations

CC:

Coulter counter

CV:

Coefficient of variance

ECD:

Equivalent circular diameter

MFI:

Micro flow imaging

LO:

Light obscuration

NTA:

Nanoparticle tracking analysis

PFS:

Pre-filled syringe

r.h.:

Relative humidity

RMM:

Resonant mass measurement

RMM (+):

Positively buoyant particles detected by RMM

RMM (−):

Negatively buoyant particles detected by RMM

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ACKNOWLEDGEMENTS AND DISCLOSURES

The authors report no conflict of interest and would like to thank Rita Gruebel for technical support and Felix Heise for helpful discussions.

Author information

Authors and Affiliations

  1. Pharmaceutical Development & Supplies, Pharma Technical Development Biologics Europe, F. Hoffman-La Roche Ltd., Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Anacelia Ríos Quiroz, Adeline Boillon, Michael Adler, Roland Schmidt & Hanns-Christian Mahler

  2. Analytical Development & Quality Control, Pharma Technical Development Biologics Europe, F. Hoffman-La Roche Ltd., Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Anacelia Ríos Quiroz, Thierry Da Cunha, Christof Finkler & Atanas V. Koulov

  3. Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, 4056, Basel, Switzerland

    Anacelia Ríos Quiroz & Joerg Huwyler

  4. Pharma Development, Biometry, NonClinical Biostatistics, F. Hoffmann - La Roche Ltd, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Jens Lamerz

Authors
  1. Anacelia Ríos Quiroz
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  2. Jens Lamerz
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  3. Thierry Da Cunha
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  4. Adeline Boillon
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  5. Michael Adler
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  6. Christof Finkler
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  7. Joerg Huwyler
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  8. Roland Schmidt
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  9. Hanns-Christian Mahler
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  10. Atanas V. Koulov
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Corresponding author

Correspondence to Atanas V. Koulov.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

Boxplot of CV%, each estimated from 3 random values based on a Poisson distribution with expected number of particles λ and originating number of particles n1. (GIF 71 kb)

High Resolution Image (TIFF 107 kb)

Fig. S2

Pool variability in HIAC and CC. Variability of six independent and identically prepared pools of 10 units of PFS measured in HIAC (a) and CC (b). The large pool size originates low variability in the measurements. (GIF 17 kb)

High Resolution Image (TIFF 25 kb)

Fig. S3

Collage of randomly selected MFI image and larger than 5 μm of the protein product used in this study. Mainly silicon oil-like particles can be observed. (DOCX 407 kb)

Table S1

(DOCX 52 kb)

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Ríos Quiroz, A., Lamerz, J., Da Cunha, T. et al. Factors Governing the Precision of Subvisible Particle Measurement Methods – A Case Study with a Low-Concentration Therapeutic Protein Product in a Prefilled Syringe. Pharm Res 33, 450–461 (2016). https://doi.org/10.1007/s11095-015-1801-4

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  • DOI: https://doi.org/10.1007/s11095-015-1801-4

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