Downstream processing of monoclonal antibodies—Application of platform approaches

Shukla, Abhinav A.; Hubbard, Brian; Tressel, Tim; Guhan, Sam; Low, Duncan

doi:10.1016/j.jchromb.2006.09.026

Cited by 786 publications

(609 citation statements)

References 29 publications

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“…When antibodies are derived from a single subclass such as IgG 2 , then the homology is even higher. However, when compared following the major purification step, Protein A affinity chromatography, there is a surprisingly wide range of HCP levels (Shukla et al, 2007). These findings show that the (relatively) minor structural differences between otherwise biochemically similar (conserved sequence) IgG's can have a significant impact on HCP clearance.…”

Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 94%

“…It is therefore not surprising that a large number of reports on process development have chosen HCP clearance as one of the benchmarks to demonstrate a robust and well-controlled bioprocess (Follman and Fahrner, 2004;Rathore et al, 2003;Shukla et al, 2007Venkiteshwaran et al, 2007). Furthermore, much of our knowledge regarding HCPs in biologics was obtained through process development studies.…”

Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 99%

“…In a recent study, Shukla et al (2007) has demonstrated that the level of HCPs in a monoclonal antibody purification process depends on the antibody itself. Human IgGs are highly conserved with most differences in the complementarity determining regions (CDRs) being responsible for antigen recognition (Janeway et al, 2005).…”

Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 99%

“…The advantages of specific, high affinity purification techniques (e.g., Protein A capture for monoclonal antibodies) are well known, as they typically enable the removal of a vast majority of HCPs. Finally, the composition of HCPs depends on the biologic molecule being expressed (Hunter et al, 2009;Shukla et al, 2007. The physiochemical properties of the intended recombinant protein (charge, hydrophobicity, structure, etc.)…”

Section: Introductionmentioning

confidence: 99%

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Host cell proteins in biologics development: Identification, quantitation and risk assessment

Wang

Hunter

Mozier

2009

Biotech & Bioengineering

201

184

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Host cell proteins (HCPs) are those produced or encoded by the organisms and unrelated to the intended recombinant product. Some are necessary for growth, survival, and normal cellular processing whereas others may be non-essential, simply carried along as baggage. Like the recombinant product, HCPs may also be modified by the host with a number of post-translational modifications. Regardless of the utility, or lack thereof, HCPs are undesirable in the final drug substance. Though commonly present in small quantities (parts per million expressed as nanograms per milligrams of the intended recombinant protein) much effort and cost is expended by industry to remove them. The purpose of this review is to summarize what is of relevance in regards to the biology, the impact of genomics and proteomics on HCP evaluation, the regulatory expectations, analytical approaches, and various methodologies to remove HCPs with bioprocessing. Historical data, bioinformatics approaches and industrial case study examples are provided. Finally, a proposal for a risk assessment tool is provided which brings these facets together and proposes a means for manufacturers to classify and organize a control strategy leading to meaningful product specifications.

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Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 94%

Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 99%

Section: Impacts Of Host Cell Protein Analysis In Bioprocess Developmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Host cell proteins in biologics development: Identification, quantitation and risk assessment

Wang

Hunter

Mozier

2009

Biotech & Bioengineering

201

184

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“…Peak cutting or loading is often kept conservative to minimize the risk of aggregate breakthrough in the effluent. 7,8 …”

mentioning

confidence: 99%

Multi-angle light scattering as a process analytical technology measuring real-time molecular weight for downstream process control

Patel

Gospodarek

Larkin³

et al. 2018

mAbs

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For many protein therapeutics including monoclonal antibodies, aggregate removal process can be complex and challenging. We evaluated two different process analytical technology (PAT) applications that couple a purification unit performing preparative hydrophobic interaction chromatography (HIC) to a multi-angle light scattering (MALS) system. Using first principle measurements, the MALS detector calculates weight-average molar mass, Mw and can control aggregate levels in purification. The first application uses an in-line MALS to send start/stop fractionation trigger signals directly to the purification unit when preset Mw criteria are met or unmet. This occurs in real-time and eliminates the need for analysis after purification. The second application uses on-line ultra-high performance size-exclusion liquid chromatography to sample from the purification stream, separating the mAb species and confirming their Mw using a µMALS detector. The percent dimer (1.5%) determined by the on-line method is in agreement with the data from the in-line application (Mw increase of approximately 2750 Da). The novel HIC-MALS systems demonstrated here can be used as a powerful tool for real-time aggregate monitoring and control during biologics purification enabling future real time release of biotherapeutics.

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Process Development of Protein Therapeutics

Thomas

Guhan

Pettit

2010

Burger's Medicinal Chemistry and Drug Discovery

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The application of recombinant DNA technology to the production of protein therapeutics has undergone considerable progress since first introduced 30 years ago. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This chapter will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented.

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Downstream processing of monoclonal antibodies—Application of platform approaches

Cited by 786 publications

References 29 publications

Host cell proteins in biologics development: Identification, quantitation and risk assessment

Host cell proteins in biologics development: Identification, quantitation and risk assessment

Multi-angle light scattering as a process analytical technology measuring real-time molecular weight for downstream process control

Process Development of Protein Therapeutics

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