Should charge variants of monoclonal antibody therapeutics be considered critical quality attributes?

Singh, Sumit; Narula, G. K.; Rathore, Anurag S.

doi:10.1002/elps.201600078

Cited by 42 publications

(28 citation statements)

References 27 publications

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“…. Not all charge variants are generally resolved using a salt gradient in IEC mode, especially the acidic variants . As the pH remained constant during the elution process, proteins with the same effective charge will be eluting with poor resolution.…”

Section: Native Lc Modesmentioning

confidence: 99%

Advances in native high‐performance liquid chromatography and intact mass spectrometry for the characterization of biopharmaceutical products

Tassi

Vos

Chatterjee

et al. 2017

J of Separation Science

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The characterization of biotherapeutics represents a major analytical challenge. This review discusses the current state‐of‐the‐art in analytical technologies to profile biopharma products under native conditions, i.e., the protein three dimensional conformation is maintained during liquid chromatographic analysis. Native liquid‐chromatographic modes that are discussed include aqueous size‐exclusion chromatography, hydrophobic interaction chromatography, and ion‐exchange chromatography. Infusion conditions and the possibilities and limitations to hyphenate native liquid chromatography to mass spectrometry are discussed. Furthermore, the applicability of native liquid‐chromatography methods and intact mass spectrometry analysis for the characterization of monoclonal antibodies and antibody–drug conjugates is discussed.

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Section: Native Lc Modesmentioning

confidence: 99%

Advances in native high‐performance liquid chromatography and intact mass spectrometry for the characterization of biopharmaceutical products

Tassi

Vos

Chatterjee

et al. 2017

J of Separation Science

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show abstract

“…In the case of mAbs, heterogeneities primarily arise due to differences in charge distribution (charge variants) and size (dimers and multimers) . With the emergence of mAb biosimilars, control of product heterogeneity has emerged as a key challenge as charge variants are regarded as a critical quality attribute (CQA) . Cation exchange chromatography (CEX) is the primary unit operation for removal and control of these heterogeneities …”

Section: Introductionmentioning

confidence: 99%

Mechanistic Modeling Based PAT Implementation for Ion‐Exchange Process Chromatography of Charge Variants of Monoclonal Antibody Products

Kumar

Rathore

2017

Biotechnology Journal

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Process chromatography is typically used to remove product related impurities and variants that have very similar physicochemical properties to the product. Baseline separation may not be achieved in most cases due to high protein loading and thus, pooling of the elution peak can be challenging for maximizing yield and achieving consistency in product quality. Batch-to-batch variability in quality of the feed material also occurs in commercial manufacturing. Mechanistic modeling of process chromatography, though non-trivial, can be an enabler for implementation of Process Analytical Technology. This paper presents one such application involving prediction of the impact of variability in feed quality and in gradient shape on separation of charge variants by cation exchange process chromatography and thereby facilitating feed forward control. Five batches having different compositions of charge variants have been used to demonstrate the proposed pooling strategy based on simulated chromatograms and the outcome has been compared to offline pooling based on fractionation. For all the conditions examined and for the desired target of main product (67%), the proposed approach resulted in remarkable consistency in product quality (67 ± 2%) while delivering a yield of greater than 90%.

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“…Charge variants are a critical quality attribute of therapeutic proteins . Charge heterogeneity can be triggered by many posttranslational modifications such as deamidation and C‐terminal lysine variants , for example.…”

Section: Introductionmentioning

confidence: 99%

Determination of protein charge variants with (imaged) capillary isoelectric focusing and capillary zone electrophoresis

Kahle

Wätzig

2018

Electrophoresis

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Biopharmaceuticals are increasingly present in pharmaceutical therapy. These highly complex molecules are still challenging for development and quality control. Charge heterogeneity is next to size heterogeneity, glycan analysis, or peptide mapping one main aspect of their thorough characterization. This review focuses on the charge-based analysis of biopharmaceuticals through CE. An overview is given about the three separation techniques cIEF, imaged cIEF and CZE for the analyses of charge variants, emphasizing assays and their precision. Especially the developments in the experimental conditions have been given a high priority: sample preparation, capillary properties, anolytes and catholytes, carrier ampholytes, sacrificing agents, solubility enhancement, isoelectric point marker, mobilization techniques, and detection modes have been discussed. CIEF shows a particularly high heterogeneity in its methods. Therefore, a design space is suggested that states the most important adjustable parameters and their range. This enables an adequate design of experiments for individual sample separations, in order to accelerate and simplify method developments.

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Should charge variants of monoclonal antibody therapeutics be considered critical quality attributes?

Cited by 42 publications

References 27 publications

Advances in native high‐performance liquid chromatography and intact mass spectrometry for the characterization of biopharmaceutical products

Advances in native high‐performance liquid chromatography and intact mass spectrometry for the characterization of biopharmaceutical products

Mechanistic Modeling Based PAT Implementation for Ion‐Exchange Process Chromatography of Charge Variants of Monoclonal Antibody Products

Determination of protein charge variants with (imaged) capillary isoelectric focusing and capillary zone electrophoresis

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