Using X-ray fluorescence to measure inorganics in biopharmaceutical raw materials

Mondia, J. P.; Goh, F. C.; Bryngelson, Pete; MacPhee, James; Ali, Amr; Weiskopf, Andrew; Lanan, Maureen

doi:10.1039/c4ay02936d

Cited by 13 publications

(11 citation statements)

References 18 publications

(20 reference statements)

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“…The XRF spectra were collected using Bruker's software (S1PXRF 3.8) and analyzed using custom software written with Matlab's wavelet toolbox (MathWorks, Natick, MA ver. R2012a) …”

Section: Methodsmentioning

confidence: 99%

Effect of copper variation in yeast hydrolysate on C‐terminal lysine levels of a monoclonal antibody

Mitchelson

Mondia

Hughes

2017

Biotechnology Progress

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The ability to control charge heterogeneity in monoclonal antibodies is important to demonstrate product quality comparability and consistency. This article addresses the control of C-terminal lysine processing through copper supplementation to yeast hydrolysate powder, a raw material used in the cell culture process. Large-scale production of a murine cell line exhibited variation in the C-terminal lysine levels of the monoclonal antibody. Analysis of process data showed that this variation correlated well with shifts in cell lactate metabolism and pH levels of the production culture. Small-scale studies demonstrated sensitivity of the cells to copper, where a single low dose of copper to the culture impacted cell lactate metabolism and C-terminal lysine processing. Subsequent analytical tests indicated that the yeast hydrolysate powder, added to the basal media and nutrient feed in the process, contained varying levels of trace copper across lots. The measured copper concentrations in yeast hydrolysate lots correlated well with the variation in lactate and pH trends and C-terminal lysine levels of the batches in manufacturing. Small-scale studies further demonstrated that copper supplementation to yeast hydrolysate lots with low concentrations of copper can shift the metabolic performance and C-terminal lysine levels of these cultures to match the control, high copper cultures. Hence, a strategy of monitoring, and if necessary supplementing, copper in yeast-hydrolysate powders resulted in the ability to control and ensure product quality consistency. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:463-468, 2017.

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“…The XRF spectra were collected using Bruker's software (S1PXRF 3.8) and analyzed using custom software written with Matlab's wavelet toolbox (MathWorks, Natick, MA ver. R2012a) …”

Section: Methodsmentioning

confidence: 99%

Effect of copper variation in yeast hydrolysate on C‐terminal lysine levels of a monoclonal antibody

Mitchelson

Mondia

Hughes

2017

Biotechnology Progress

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“…An extension of this analysis also revealed that copper fluctuations from various lots of basal media were substantial enough to alter procaspase‐3 expression in Caco‐2 cells. A breakdown of copper content within 10 different lots of an undefined nutrient powder used in NS0 culture for mAb production showed similar fluctuations, offering a key avenue by which trace metals may be inadvertently introduced to culture media (Mondia et al, ).…”

Section: Vendor and Batch/lot Variability Of Metal Content In Culturementioning

confidence: 96%

Consequences of trace metal variability and supplementation on Chinese hamster ovary (CHO) cell culture performance: A review of key mechanisms and considerations

Graham

Bhatia

Yoon

2019

Biotech & Bioengineering

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Trace metals are supplied to chemically-defined media (CDM) for optimal Chinese hamster ovary (CHO) cell culture performance during the production of monoclonal antibodies and other therapeutic proteins. However, lot-to-lot and vendor-to-vendor variability in raw materials consequently leads to an imbalance of trace metals that are supplied to CDM. This imbalance can yield detrimental effects rooted in several primary mechanisms and pathways including oxidative stress, apoptosis, lactate accumulation, and unfavorable glycan synthesis. Recent research endeavors involve supplying zinc, copper, and manganese to CDM in excess to further maximize culture productivity and product quality. These treatments significantly impact critical quality attributes and furthermore highlight the degree to which trace metal availability can affect CHO cell culture performance. This review highlights the role of trace metal variability, supplementation, and interplay on key cellular mechanisms responsible for overall culture performance and the production and quality of therapeutic proteins. K E Y W O R D SCHO cell culture performance, raw material variability, therapeutic proteins, trace metal deficiency, trace metal supplementation, trace metals

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“…All samples were sent to Element Materials Technology (Santa Fe Springs, CA) for quantitation of Cu and Zn metal content via Inductively Coupled Plasma Mass Spectrometry (50). Briefly, a sample portion (0.05 g) was mixed with internal standards (In-Tb-Sc) and then diluted to a final mass of 5 g with a solution of 0.1% ammonium hydroxide, 0.05% EDTA, and 0.05% Triton X100.…”

Section: Determination Of Cu and Zn Metal Contentmentioning

confidence: 99%

Protein crosslinking as a therapeutic strategy for SOD1-related ALS

Sarin

et al. 2021

Preprint

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Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS). One effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers. Considerable research efforts have been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but these have not yet resulted in an approved drug. We demonstrate that a cyclic thiosulfinate cross-linker can stabilize prevalent disease-causing SOD1 variants. The degree of stabilization afforded by cyclic thiosulfinates (up to 24 degC) is unprecedented. We show this compound works rapidly in vivo with a half-life of ~3 days. The efficacy, low toxicity, and pharmacodynamics of cross-linker mediated stabilization make it a promising therapeutic approach for SOD1-related fALS.

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Using X-ray fluorescence to measure inorganics in biopharmaceutical raw materials

Abstract: XRF is used to measure metals in cell culture raw materials to provide consistency in cell performance and production.

Cited by 13 publications

References 18 publications

Effect of copper variation in yeast hydrolysate on C‐terminal lysine levels of a monoclonal antibody

Effect of copper variation in yeast hydrolysate on C‐terminal lysine levels of a monoclonal antibody

Consequences of trace metal variability and supplementation on Chinese hamster ovary (CHO) cell culture performance: A review of key mechanisms and considerations

Protein crosslinking as a therapeutic strategy for SOD1-related ALS

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