Solid-State mAbs and ADCs Subjected to Heat-Stress Stability Conditions can be Covalently Modified with Buffer and Excipient Molecules

Valliere-Douglass, John; Lewis, P. R.; Salas‐Solano, Oscar; Jiang, Shan

doi:10.1002/jps.24276

Cited by 16 publications

(5 citation statements)

References 58 publications

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“…The same trend was observed for the isolated mAb used to formulate one of the ADCs, but in this case, an increase of the acidic variants with storage time also took place. This study proved the usefulness of iCIEF to control changes in therapeutic drugs, namely ADCs, happening even in lyophilized form, to ensure their stability and safety [133].…”

Section: Ji Et Al Illustrated the Use Of Icief To Characterize The Hy...supporting

confidence: 53%

Capillary electrophoresis of glycoproteins

Puerta

Gomez-Ruiz

Diez-Masa

et al. 2021

Carbohydrate Analysis by Modern Liquid Phase Separation Techniques

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Section: Ji Et Al Illustrated the Use Of Icief To Characterize The Hy...supporting

confidence: 53%

Capillary electrophoresis of glycoproteins

Puerta

Gomez-Ruiz

Diez-Masa

et al. 2021

Carbohydrate Analysis by Modern Liquid Phase Separation Techniques

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“…Glucose can eventually lead to glycation of the protein. 43,44 We confirmed mAb glycation by mass spectrometry showing an increased peak with a mass shift of þ162 Da (Fig. S5 in the Supporting Information).…”

Section: Discussionmentioning

confidence: 58%

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Haeuser

Goldbach

Huwyler

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tSucrose is a common cryoprotectant and lyoprotectant to stabilize labile biopharmaceuticals during freezedrying and storage. Sucrose-based formulations require low primary drying temperatures to avoid collapse and monoclonal antibody (mAb) containing products need to be stored refrigerated. The objective of this study is to investigate different excipients enabling storage at room temperature and aggressive, shorter lyophilization cycles. We studied combinations of 2-hydroxypropyl-beta-cyclodextrin (CD), recombinant human albumin, polyvinylpyrroldione (PVP), dextran 40 kDa (Dex), and sucrose (Suc) using 2 mAbs. Samples were characterized for collapse temperature (T c ), glass transition temperature of the liquid (T g 0 ) and freeze-dried formulation (T g ), cake appearance, residual moisture, and reconstitution time. Freezedried formulations were stored at 5 C, 25 C, and 40 C for up to 9 months and mAb stability was analyzed for color, turbidity, visible and sub-visible particles, and monomer content. Formulations with CD/ Suc or CD/PVP/Suc were superior to pure Suc formulations for long-term storage at 40 C. When using aggressive freeze-drying cycles, these formulations were characterized by pharmaceutically elegant cakes, short reconstitution times, higher T g 0 , T c , and T g . We conclude that the addition of CD allows for shorter freeze-drying cycles with improved cake appearance and enables storage at room temperature, which might reduce costs of goods substantially.

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“…Recently, solid state mAb formulations were also shown to exhibit covalent modifications of the mAb with buffer and excipient molecules on heat-stress stability. 27 Evidently, further investigation of different buffer and excipient species, as well as testing over a broad pH range, are needed to determine their impact on the correlation between D 2 O uptake and the corresponding increase in charged variants on stability (and chemical degradation in general), and is the subject of ongoing research.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The observed correlation suggests that some chemical and physical degradation mechanisms, perhaps related to protein conformation and/or the local accessibility of the protein to residual moisture, are captured adequately by exposure to D 2 O vapor in the ssHDX-MS technique. Recently, solid state mAb formulations were also shown to exhibit covalent modifications of the mAb with buffer and excipient molecules on heat-stress stability . Evidently, further investigation of different buffer and excipient species, as well as testing over a broad pH range, are needed to determine their impact on the correlation between D 2 O uptake and the corresponding increase in charged variants on stability (and chemical degradation in general), and is the subject of ongoing research.…”

Section: Discussionmentioning

confidence: 99%

Solid-State Hydrogen–Deuterium Exchange Mass Spectrometry: Correlation of Deuterium Uptake and Long-Term Stability of Lyophilized Monoclonal Antibody Formulations

et al. 2017

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Solid state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) has been used to assess protein conformation and matrix interactions in lyophilized solids. ssHDX-MS metrics have been previously correlated to the formation of aggregates of lyophilized myoglobin on storage. Here, ssHDX-MS was applied to lyophilized monoclonal antibody (mAb) formulations and correlated to their long-term stability. After exposing lyophilized samples to DO(g), the amount of deuterium incorporated at various time points was determined by mass spectrometry for four different lyophilized mAb formulations. Hydrogen-deuterium exchange data were then correlated with mAb aggregation and chemical degradation, which was obtained in stability studies of >2.5 years. Deuterium uptake on ssHDX-MS of four lyophilized mAb formulations determined at the initial time point prior to storage in the dry state was directly and strongly correlated with the extent of aggregation and chemical degradation during storage. Other measures of physical and chemical properties of the solids were weakly or poorly correlated with stability. The data demonstrate, for the first time, that ssHDX-MS results are highly correlated with the stability of lyophilized mAb formulations. The findings thus suggest that ssHDX-MS can be used as an early read-out of differences in long-term stability between formulations helping to accelerate formulation screening and selection.

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Solid-State mAbs and ADCs Subjected to Heat-Stress Stability Conditions can be Covalently Modified with Buffer and Excipient Molecules

Cited by 16 publications

References 58 publications

Capillary electrophoresis of glycoproteins

Capillary electrophoresis of glycoproteins

Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Solid-State Hydrogen–Deuterium Exchange Mass Spectrometry: Correlation of Deuterium Uptake and Long-Term Stability of Lyophilized Monoclonal Antibody Formulations

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