Gelation of a Monoclonal Antibody at the Silicone Oil–Water Interface and Subsequent Rupture of the Interfacial Gel Results in Aggregation and Particle Formation

Mehta, Smita; Lewus, Rachael A.; Bee, Jared S.; Randolph, Theodore W.; Carpenter, John F.

doi:10.1002/jps.24358

Cited by 85 publications

(69 citation statements)

References 47 publications

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“…The sloughing off and/or mechanical rupture of such films leads to subvisible particles in solution. 21,22 Protein particle formation in IV bags due to protein adsorption to interfaces was also suggested by Kumru, et al , and they observed a reduction in protein particles in the presence of polysorbate 20, an effect attributed to inhibition of protein adsorption to the bag walls and to the air-water interface. 14 …”

Section: Introductionmentioning

confidence: 56%

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Pardeshi

Wei²,

Dahl³

et al. 2017

Journal of Pharmaceutical Sciences

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Intravenous (IV) infusion is used for administration of a large proportion of biologic therapeutics, including most monoclonal antibody (mAb) products. In this study, we determined the sub-visible particle levels in IV solutions and after the solutions were processed with an IV administration setup that mimicked the typical clinical method of administration. IV saline in bags manufactured by both Hospira and Baxter contained 1,600–8,000 microparticles/mL and 4–73×106 nanoparticles/mL in solution. When intravenous immunoglobulin (IVIG) was diluted into the IV saline, 3,700–23,000 microparticles/mL and 18–240×106 nanoparticles/mL were detected. During processing of the solution through the IV system, in-line filters removed most microparticles. However, there were still 1–21×106 nanoparticles/mL in IV saline and 7–83×106 nanoparticles/mL in IVIG diluted in saline. Finally, in samples processed through in-line filters, we found relatively large microparticles (20–60 μm) that were composed of protein or polycarbonate. These particles resulted from shedding of polycarbonate and sloughing off of protein films downstream from the filter membrane. Overall, the results document that even with in-line filters in place, high levels of subvisible particles are delivered to patients and there is a need for improved, more effective filters and IV solutions with lower particle levels.

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Section: Introductionmentioning

confidence: 56%

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Pardeshi

Wei²,

Dahl³

et al. 2017

Journal of Pharmaceutical Sciences

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“…At the protein concentration used in this work, the adsorbed protein layer should form a gel within seconds (Fig. ) . Because an air bubble is introduced into the syringe during the filling and stoppering process, a three‐phase contact line is created where the air–water interface, the silicone oil–water interface, and the silicone oil–air interface meet (Fig.…”

Section: Discussionmentioning

confidence: 99%

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

Gerhardt

Mcgraw

Schwartz

et al. 2014

Journal of Pharmaceutical Sciences

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153

124

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“…It has been proposed that accounting for both exposure to interfaces and hydrodynamic stresses may better explain protein aggregation than shear exposure alone (Bee, Stevenson et al, ; Kalonia et al, ; Sediq, van Duijvenvoorde, Jiskoot, & Nejadnik, ; Thomas & Geer, ). In fact, it is now established that air–liquid, liquid‐liquid, and solid–liquid interfaces can significantly promote and amplify protein aggregation (Bee et al, ; Bee, Stevenson et al, ; Jones, Kaufmann, & Middaugh, ; Kalonia et al, ; Maa & Hsu, ; Mahler et al, ; Mehta, Lewus, Bee, Randolph, & Carpenter, ; Perevozchikova, Nanda, Nesta, & Roberts, ; Sediq et al, ; Thirumangalathu et al, ). For instance, shaking or foaming of protein solutions potentially leads to considerable aggregation and precipitation phenomena (Bee et al, ; Maa & Hsu, ; Mahler et al, ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of flow and interfaces on antibody aggregation

Grigolato

Arosio

2019

Biotech & Bioengineering

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During the manufacturing process, solutions of protein‐based drugs are exposed to hydrodynamic forces, which can potentially affect protein stability and aggregation. Despite being an area of extensive investigation, the effect of hydrodynamic flow on protein aggregation is still controversial. In this study, we designed an experimental setup that allowed us to investigate flow‐ and interface‐induced protein aggregation of two model immunoglobulins in the presence of well‐defined flow stresses and solid–liquid interfaces. Within the range of shear rates typically encountered in bioprocessing ( γ ̇ = 10 – 10 3 normals − 1), we observed that increasing the shear rate by three orders of magnitude had a negligible effect on protein aggregation. By contrast, changes in the materials of the syringe barrels had a dramatic effect on the monomer loss, demonstrating the key role of solid–liquid interfaces in flow‐induced aggregation. This finding was confirmed by the observed inverse dependence of the aggregation rate on the initial protein concentration, which is inconsistent with mechanisms of protein aggregation in bulk solution. Overall, our results reveal the presence of a synergistic effect of interfaces and hydrodynamic flow in flow‐induced protein aggregation, which arises from the formation of protein particles or films on interfaces followed by displacement by flow or mechanical scraping.

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Gelation of a Monoclonal Antibody at the Silicone Oil–Water Interface and Subsequent Rupture of the Interfacial Gel Results in Aggregation and Particle Formation

Cited by 85 publications

References 47 publications

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

Synergistic effects of flow and interfaces on antibody aggregation

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