A critical review of methods for size characterization of non-particulate protein aggregates
Abstract
Although size exclusion chromatography (SEC) has been, and will continue to be, the primary analytical tool for characterization of the content and size distribution of non-particulate aggregates in protein pharmaceuticals, regulatory concerns are driving increased use of alternative and complementary methods such as analytical ultracentrifugation and light scattering techniques. This review will highlight and critically review the capabilities, advantages, and drawbacks of SEC, analytical ultracentrifugation, and light scattering methods for characterizing aggregates with sizes below about 0.3 microns. The physical principles of the biophysical methods are briefly described and examples of data for real samples and how that data is interpreted are given to help clarify capabilities and weaknesses.
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SEC is the primary method to assess aggregates in the biopharmaceutical industry due to simplicity, throughput, and speed.
“Used on HPLC systems with UV, FS, or differential refractive index (dRI) detectors to quantify the eluting species, it is the primary method to assess aggregates in the biopharmaceutical industry due to its simplicity, throughput, and speed.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [92]
SLS/DLS accuracy and precision are challenged by high sensitivity to refractive index of the sample that must be known a priori.
“A major challenge for accuracy and precision of SLS/DLS remains high sensitivity to the refractive index of the sample that must be known a priori.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [92]
SLS/DLS reliability is especially poor due to refractive index difference between empty and full capsids, leading to errors up to 33% if refractive index is incorrectly assigned.
“Reliability is especially poor due to the difference in refractive index between samples of empty and full capsids, leading to errors of up to 33% if the refractive index is incorrectly assigned.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [92]
DLS quantifies aggregate content and estimates capsid titer of purified rAAV samples without prior sample preparation within <5 min.
“DLS quantifies aggregate content and estimates the capsid titer of purified rAAV samples without prior sample preparation, within <5 min.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [92]
SEC-based methods are generally more accurate and precise than orthogonal methods such as AUC or DLS, but accuracy for large aggregates is limited by filtration, nonspecific interactions, and dissociation of reversible aggregates.
“They are generally more accurate and precise than orthogonal methods, e.g., AUC or DLS, but accuracy for large aggregates is limited by the SEC separation mechanism: filtration of aggregates by the stationary phase, nonspecific interactions between aggregates and the column frit, and dissociation of reversible aggregates due to dilution in the mobile phase are common.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [92]
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Analysis of nonideality: insights from high concentration simulations of sedimentation velocity data
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- Authors
- Philo, J.
- Affiliations
- Alliance Protein Laboratories (United States) (US)
- Corresponding author
- Philo, John
- ORCID
- Philo, John
- Venue
- Current Pharmaceutical Biotechnology
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2009-06-01
- Volume
- 10
- Issue
- 4
- Pages
- 359-372
- ISSN
- 1389-2010 (ISSN-L)
- OpenAlex
- W2007228224
- Cited by
- 196
- References
- 1
- Citations by year
- 2025: 4 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 14 · 2018: 12 · 2017: 11 · 2016: 13 · 2015: 22 · 2014: 19 · 2013: 13 · 2012: 24
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Pharmaceutical Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Keywords
- protein aggregates, size exclusion chromatography, analytical ultracentrifugation, light scattering, pharmaceutical proteins, regulatory compliance, biophysical characterization
- MeSH terms
- Biopharmaceutics, Chromatography, Gel, Chemical Fractionation, Nephelometry and Turbidimetry, Particle Size, Proteins, Technology, Pharmaceutical, Ultracentrifugation, Multiprotein Complexes
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