Emerging Challenges and Innovations in Surfactant-mediated Stabilization of Biologic Formulations

Katz, Joshua S.; Chou, Danny K.; Christian, Twinkle R.; Das, Tapan K.; Patel, Madhabhai M.; Singh, Shubhadra N.; Wen, Yi

doi:10.1016/j.xphs.2021.12.002

Cited by 21 publications

(12 citation statements)

References 153 publications

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“…5,6 Nonionic surfactants like polysorbates and poloxamers are typically used in biopharmaceutical formulations. 5,7 Surfactants appear to stabilize proteins by different mechanisms, for example, by directly binding to a protein or by occupying hydrophobic interfaces like the air/liquid interface to prevent protein adsorption and subsequent degradation due to structural changes. 7−9 The question of whether a surfactant binds directly to a particular protein is important for understanding the mechanisms of stabilization.…”

Section: Introductionmentioning

confidence: 99%

“…7−9 The question of whether a surfactant binds directly to a particular protein is important for understanding the mechanisms of stabilization. 7 However, proteinsurfactant interactions are typically weak and transient (K d > 1 mM), and therefore challenging to measure. 6 There are different approaches to study protein-surfactant interactions.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Stabilization of Interferon Alpha by Two Surfactants Revealed by STD-NMR Spectroscopy

Svilenov¹,

Kopp²,

Golovanov³

et al. 2023

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights into the Stabilization of Interferon Alpha by Two Surfactants Revealed by STD-NMR Spectroscopy

Svilenov¹,

Kopp²,

Golovanov³

et al. 2023

Journal of Pharmaceutical Sciences

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“…Polysorbates have been widely used in biologic drug products to stabilize protein formulations as they are considered safe. However, several stability challenges of polysorbates have been recently described in the literature . Degradation of polysorbates due to cleavage of the ester bond, resulting in the formation of free fatty acids over time, has been a subject of concern.…”

Section: Introductionmentioning

confidence: 99%

“…Oxidation pathways are similar to those found in PS80 and poloxamer due to the presence of polyether hydrophiles in all molecules, and oxidation mitigation strategies used for PS80 and poloxamer could similarly be leveraged for FM1000. 32 Initial studies on the ability of FM1000 to prevent protein aggregation have been reported by Hanson et al 43 and Katz et al 42,44 To examine this molecular hypothesis, we use pendant bubble tensiometry and X-ray reflectivity (XRR). Prior studies from our group 45 on PS80 applied similar tools to quantify the concentration of the surfactant required to protect proteins from interfaces as a function of different mAbs' surface activities.…”

Section: ■ Introductionmentioning

confidence: 99%

Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization

et al. 2022

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Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5–2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants.

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“…Surfactants are commonly added to protein formulations to mitigate interfacial-induced aggregation and surface adsorption experienced during commercial processing steps, transportation, and clinical administration [ 2 , 3 ]. Surfactants are thought to protect proteins against interfacial damage by competing with proteins for adsorption sites on different interfaces, such as air–water, solid–water, and oil–water interfaces [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Polysorbates versus Hydroxypropyl Beta-Cyclodextrin (HPβCD): Comparative Study on Excipient Stability and Stabilization Benefits on Monoclonal Antibodies

Zhang¹,

Hong²,

Tan³

et al. 2022

Molecules

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Polysorbates (PS 20 and PS 80) are the most widely used surfactants in biopharmaceutical formulations to protect proteins from denaturation, aggregation, and surface adsorption. To date, around 70% of marketed therapeutic antibodies contain either PS 20 or PS 80 in their formulations. However, polysorbates are chemically diverse mixtures, which are prone to degradation by oxidation and hydrolysis to produce peroxides and fatty acids, which, in turn, induce protein oxidation, aggregation, and insoluble particle formation. These will negatively impact protein quality and stability. Thus, polysorbate degradation has emerged as one of the major challenges in the development and commercialization of therapeutic protein products. KLEPTOSE® HPβCD (hydroxypropyl beta-cyclodextrin), a new multifunctional excipient, has been shown to provide protein stabilization functions in biopharmaceutical downstream processes and in their final formulations. This study aims to evaluate HPβCD, a new molecule of its class, against polysorbates as a stabilizer in biologics formulations. In this study, the chemical stability of KLEPTOSE® HPβCDs is compared with polysorbates (20 and 80) under various stress conditions. When subjected to heat stress, HPβCDs show little change in product recovery (90.7–100.7% recovery for different HPβCDs), while polysorbates 20 and 80 show significant degradation, with only 11.5% and 7.3% undegraded product remaining, respectively. When subjected to other chemical stressors, namely, autoclave, light, and oxidative stresses, HPβCD remains almost stable, while polysorbates show more severe degradation, with 95.5% to 98.8% remaining for polysorbate 20 and 85.5% to 97.4% remaining for polysorbate 80. Further, profiling characterization and degradation analysis reveal that chemical structures of HPβCDs remain intact, while polysorbates undergo significant hydrolytic degradation and oxidation. Lastly, the physicochemical stability of monoclonal antibodies in formulations is investigated. When subjected to light stress, adalimumab, as a model mAb, formulated in the presence of HPβCD, shows a significant decrease in protein aggregation, and superior monomer and total protein recovery compared to PS 80-containing formulations. HPβCD also reduces both agitation and thermal stress-induced protein aggregation and prevents subvisible particle formation compared to PS 80.

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Emerging Challenges and Innovations in Surfactant-mediated Stabilization of Biologic Formulations

Cited by 21 publications

References 153 publications

Insights into the Stabilization of Interferon Alpha by Two Surfactants Revealed by STD-NMR Spectroscopy

Insights into the Stabilization of Interferon Alpha by Two Surfactants Revealed by STD-NMR Spectroscopy

Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization

Polysorbates versus Hydroxypropyl Beta-Cyclodextrin (HPβCD): Comparative Study on Excipient Stability and Stabilization Benefits on Monoclonal Antibodies

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