Untargeted LC-MS/MS Profiling of Cell Culture Media Formulations for Evaluation of High Temperature Short Time Treatment Effects

Floris, Patrick; McGillicuddy, Nicola; Albrecht, Simone; Morrissey, Brian M.; Kaisermayer, Christian; Lindeberg, Anna; Bones, Jonathan

doi:10.1021/acs.analchem.7b02290

Cited by 13 publications

(7 citation statements)

References 37 publications

(55 reference statements)

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“…Floris et al . used nontarget MS to investigate the thermal stability of media during high‐temperature short‐term (HTST) sterilization, focusing particularly on Maillard products …”

Section: Introductionmentioning

confidence: 99%

“…32 Floris et al used nontarget MS to investigate the thermal stability of media during high-temperature short-term (HTST) sterilization, focusing particularly on Maillard products. 33 Among the multiple factors that are critical for CDM component stability, experience from 12 000-L scale manufacturing showed that preparation temperature is one of the main factors contributing to interbatch variability (unpublished data). This is based on the lack of temperature control in qualified medium preparation tanks.…”

Section: Introductionmentioning

confidence: 99%

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Effect of manufacturing temperature and storage duration on stability of chemically defined media measured with LC‐MS/MS

Krattenmacher

Heermann

Calvet

et al. 2018

J of Chemical Tech & Biotech

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BACKGROUND Chemically defined media (CDM) are used routinely in industrial settings for the production of biopharmaceuticals from mammalian cells, so attention has shifted to understanding their chemical behavior and impact on process robustness. In this context, one particular problem is the risk of cross reactivity and instability in complex mixtures of chemicals at high concentrations. RESULTS In order to characterize potentially unstable medium compounds in feed media, we developed and validated a novel liquid chromatography tandem mass spectrometry (LC‐MS/MS) method to simultaneously quantify the majority of medium compounds. We used this application advantage to provide the following insights into molecular processes occurring in CDM prepared at different temperatures and during storage: Concentration profiles of critical compounds in CDM are independent of preparation temperature and storage material but show significant alterations over time. In particular l‐cysteine, l‐proline, vitamin B6, thiamine and cyanocobalamin were found to be rather unstable. Using mixed mode chromatography allows expansion of the method to cover additional analytes of interest, as demonstrated by inclusion of seven additional CDM reaction products. CONCLUSION The successful development of a new LC‐MS/MS method allowed us to show the impact of storage duration on the stability of CDM compounds. Furthermore, the results suggest that essential parameters for medium preparation (e.g. temperature) and storage upscaling (e.g. vessel material) are not impacting upon the chemical composition of CDM. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…Floris et al . used nontarget MS to investigate the thermal stability of media during high‐temperature short‐term (HTST) sterilization, focusing particularly on Maillard products …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of manufacturing temperature and storage duration on stability of chemically defined media measured with LC‐MS/MS

Krattenmacher

Heermann

Calvet

et al. 2018

J of Chemical Tech & Biotech

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“…25,31,32 Floris et al reported that heat treatment of CHO media formulations was associated with increased presence of Maillard products, particularly for hydrolysate-supplemented formulations, which introduce more carbohydrates and amino-acids. 33 Furthermore, Weaver and Rosenthal observed that a medium containing fetal bovine serum was not compatible with heat treatment. 34 However, as HTST was not performed on the same medium without serum, it cannot be assessed whether this incompatibility came from the serum itself or another component of the basal medium.…”

Section: Impact On Culture Mediamentioning

confidence: 99%

“…35 Among them, some are known to be owned by Amgen, and Biomarin. 26,29,33,34,36 Eli Lilly also showed interest in this technology with a study at small-scale. 24 The Life Science business of Merck KGaA offers the opportunity for outsourcing HTST treatment of high-risk raw materials such as glucose at their two redundant large-scale production sites.…”

Section: High Temperature Short Time Treatment In the Biopharmaceutical Industrymentioning

confidence: 99%

Review: High temperature short time treatment of cell culture media and feed solutions to mitigate adventitious viral contamination in the biopharmaceutical industry

Djemal

Fournier

Hagen

et al. 2021

Biotechnology Progress

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Events of viral contaminations occurring during the production of biopharmaceuticals have been publicly reported by the biopharmaceutical industry. Upstream raw materials were often identified as the potential source of contamination. Viral contamination risk can be mitigated by inactivating or eliminating potential viruses of cell culture media and feed solutions. Different methods can be used alone or in combination on raw materials, cell culture media, or feed solutions such as viral inactivation technologies consisting mainly of high temperature short time, ultraviolet irradiation, and gamma radiation technologies or such as viral removal technology for instance nanofiltration. The aim of this review is to present the principle, the advantages, and the challenges of high temperature short time (HTST) technology. Here, we reviewed effectiveness of HTST treatment and its impact on media (filterability of media, degradation of components), on process performance (cell growth, cell metabolism, productivity), and product quality based on knowledge shared in the literature. K E Y W O R D S contamination, flash pasteurization, high temperature short time, precipitation, virus 1 | INTRODUCTION Viral contaminations are a severe issue in the frame of the production of biopharmaceuticals by mammalian cells. The production of therapeutic proteins from living organisms, such as mammalian cells, requires a set of components essential for cell survival and cell growth. Those components are provided by cell culture media. Formerly, bovine serum was widely used in cell culture media as a source of amino acids, proteins, vitamins, carbohydrates, lipids, hormones, growth factors, inorganic salts, trace elements, and other compounds. The use of serum or in general of any animal or animal derived raw materials is associated with a higher risk of viral contaminations. For safety and economic reasons, serum-free media, sometimes supplemented with protein hydrolysates, have been developed to replace the use of serum. 1 However, animal component free raw materials also carry a viral contamination risk if they were in contact with animal or animal-derived material during cultivation, manufacturing process, storage, or shipment. This risk of viral contamination by cell culture media raw materials was pointed out early in 1977 by Nuttall and al. 2 They reported the high risk of occurrence of bovine viral diarrhea virus (BVDV) contamination in untreated fetal bovine serum. Some examples of viral contamination in the pharmaceutical industry were publicly reported and are presented in Table 1. Those virus contamination events become rare as only 26 virus contaminations were reported over the past 36 years. 3 Raw materials were the likely source of contamination in most cases. In 11 of the 12 reported

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“…It is standard practice to maintain CCM at 4 • C prior to use, but the design of hydrated CCM that are stable at room temperature (RT) may decrease the energy consumption by eliminating the need for refrigeration. This optimization of CCM stability involves both developing methods to detect critical changes to CCM that can negatively impact cell culture [3,4] and using this information to discover strategies to mitigate such changes.…”

Section: Introductionmentioning

confidence: 99%

Degradation Products of Tryptophan in Cell Culture Media: Contribution to Color and Toxicity

Schnellbaecher

Lindig

Mignon

et al. 2021

IJMS

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Biomanufacturing processes may be optimized by storing cell culture media at room temperature, but this is currently limited by their instability and change in color upon long-term storage. This study demonstrates that one of the critical contributing factors toward media browning is tryptophan. LC-MS technology was utilized to identify tryptophan degradation products, which are likely formed primarily from oxidation reactions. Several of the identified compounds were shown to contribute significantly to color in solutions but also to exhibit toxicity against CHO cells. A cell-culture-compatible antioxidant, a-ketoglutaric acid, was found to be an efficient cell culture media additive for stabilizing components against degradation, inhibiting the browning of media formulations, and decreasing ammonia production, thus providing a viable method for developing room-temperature stable cell culture media.

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Untargeted LC-MS/MS Profiling of Cell Culture Media Formulations for Evaluation of High Temperature Short Time Treatment Effects

Cited by 13 publications

References 37 publications

Effect of manufacturing temperature and storage duration on stability of chemically defined media measured with LC‐MS/MS

Effect of manufacturing temperature and storage duration on stability of chemically defined media measured with LC‐MS/MS

Review: High temperature short time treatment of cell culture media and feed solutions to mitigate adventitious viral contamination in the biopharmaceutical industry

Degradation Products of Tryptophan in Cell Culture Media: Contribution to Color and Toxicity

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