Proteins behaving badly: emerging technologies in profiling biopharmaceutical aggregation

Hamrang, Zahra; Rattray, Nicholas A.; Pluen, Alain

doi:10.1016/j.tibtech.2013.05.004

Cited by 71 publications

(50 citation statements)

References 74 publications

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“…94 It is therefore very important to monitor the protein so as to ensure that no unwanted structural changes or aggregation have been induced. 129,188 Raman spectroscopy offers some useful characterization of the larger aggregates which can be analyzed using confocal microscopy-based instruments. For soluble oligomers and sub-visible aggregates, Raman can also be used as long as there is some discernible change in the spectra due to the aggregation process.…”

Section: Analysis Of Biopharmaceutical Productsmentioning

confidence: 99%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein-and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc.) and have spawned a large (>E35 billion sales annually in Europe) and growing biopharmaceutical industry (BioPharma). The structural and chemical complexity of biologics, combined with the intricacy of cell-based manufacturing, imposes a huge analytical burden to correctly characterize and quantify both processes (upstream) and products (downstream). In small molecule manufacturing, advances in analytical and computational methods have been extensively exploited to generate process analytical technologies (PAT) that are now used for routine process control, leading to more efficient processes and safer medicines. In the analytical domain, biologic manufacturing is considerably behind and there is both a huge scope and need to produce relevant PAT tools with which to better control processes, and better characterize product macromolecules. Raman spectroscopy, a vibrational spectroscopy with a number of useful properties (nondestructive, non-contact, robustness) has significant potential advantages in BioPharma. Key among them are intrinsically high molecular specificity, the ability to measure in water, the requirement for minimal (or no) sample pre-treatment, the flexibility of sampling configurations, and suitability for automation. Here, we review and discuss a representative selection of the more important Raman applications in BioPharma (with particular emphasis on mammalian cell culture). The review shows that the properties of Raman have been successfully exploited to deliver unique and useful analytical solutions, particularly for online process monitoring. However, it also shows that its inherent susceptibility to fluorescence interference and the weakness of the Raman effect mean that it can never be a panacea. In particular, Raman-based methods are intrinsically limited by the chemical complexity and wide analyte-concentration-profiles of cell culture media/bioprocessing broths which limit their use for quantitative analysis. Nevertheless, with appropriate foreknowledge of these limitations and good experimental design, robust analytical methods can be produced. In addition, new technological developments such as time-resolved detectors, advanced lasers, and plasmonics offer potential of new Raman-based methods to resolve existing limitations and/or provide new analytical insights.

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Section: Analysis Of Biopharmaceutical Productsmentioning

confidence: 99%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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“…Although the recent literature provides a good overview of the latest analytical developments in the field of particle analysis (11)(12)(13)(14)(15)(16)(17)(18), a systematic critical assessment and comparison of the individual methods is still missing. In particular, a detailed comparative evaluation of the analytical performance of the individual methods and most importantly -a qualitative understanding of the sources of error (both random and systematic) of these methods are not yet available.…”

Section: Viewing Of Single Particlesmentioning

confidence: 99%

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

et al. 2015

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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. ResultsThe 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. ConclusionsThe 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.KEY WORDS subvisible particles . precision . particle counting methods . protein particles 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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“…The detection of the full complement of proteins expressed by a cell is obtained by the combination of two-dimensional (2D) electrophoresis and mass spectrometry (MS). In this approach, a cell Hamrang et al ( 2013 ). The latest advances in MS have also allowed the emergence of the profi ling of more than 1,000 proteins in one study through Orbitrap technology (Scigelova and Makarov 2006 ;McAlister et al 2008 ).…”

Section: Protein Profi Lingmentioning

confidence: 99%

Functional Genomics

Gomes¹,

Alves-Ferreira²,

Carels³

2015

Plant Biology and Biotechnology

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Physiological responses, developmental programs, and cellular functions depend on complex networks of interactions at different scales and levels. Systems biology unites biochemical, genetic, and molecular approaches to generate omics data that can be analyzed and used in computational models to uncover these global networks. Various approaches, including genomics, transcriptomics, proteomics, interactomics, and metabolomics, have been employed to obtain these data at the cellular, tissue, organ, and whole organism levels.

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Proteins behaving badly: emerging technologies in profiling biopharmaceutical aggregation

Cited by 71 publications

References 74 publications

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

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

Functional Genomics

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