Reaching the breaking point: Effect of tubing characteristics on protein particle formation during peristaltic pumping

Deiringer, Natalie; Frieß, Wolfgang

doi:10.1016/j.ijpharm.2022.122216

Cited by 6 publications

(7 citation statements)

References 55 publications

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“…Our study was motivated by previous research, which suggests that a protein film initially forms and, through roller movement, compacts into aggregates that eventually enter the bulk solution. , In the first step, we therefore aimed to simulate this phenomenon (Figure ). To improve time efficiency and to allow us to simulate larger system sizes and time scales, a coarse-grained modeling approach was chosen.…”

Section: Resultsmentioning

confidence: 99%

“…9,40 An increasing compression factor correlates with an increase in the SVP count (Figure 2) as well as in turbidity (Figure S1), which agrees with previous studies on tubing interfaces. 15 For air−liquid interfaces, particle formation also increased with more compression. 8,13 In our simulations, the system was compressed once, and the average number of monomers per cluster at the interface was determined.…”

Section: Setup To Study Protein Aggregation At Dynamicmentioning

confidence: 99%

“…This is confirmed experimentally. 9,15 Simulations show that clusters form at the interface during compression but break up during relaxation. This suggests that particles in the bulk solution originate from detachment from tubing interfaces in the compressed state, where protein aggregation is more likely to occur.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…8,12,13 Solid interfaces in the form of tubing during peristaltic pumping are widely used in industry for transfer and filling operations. 9,14,15 It has been found that the particles observed in peristaltic pumping are the result of a similar mechanism: the formation of a protein film on the tubing surface, stretching and compression of the film during roller movement, and the subsequent entry of film fragments into the bulk solution. 9 To further elucidate the mechanism, isolate it from competing phenomena, and dissect the influence of individual factors on protein aggregation at interfaces, computational tools can be employed.…”

Section: ■ Introductionmentioning

confidence: 99%

“…It can result in the loss of active protein, noncompliance with regulatory standards, and an elevated risk of immunogenicity. − Interfaces are known to be major stress factors that promote protein aggregation during the processing of protein solutions. , Proteins are amphiphilic molecules and, therefore, adsorb to interfaces and form a protein film. − Interfaces include, for example, air–liquid interfaces in form of vial headspace or air bubbles . Compression and dilation cycles of said film formed at the air–liquid interface then lead to protein aggregation, layer collapse, and detachment of fragments into the bulk. ,, Solid interfaces in the form of tubing during peristaltic pumping are widely used in industry for transfer and filling operations. ,, It has been found that the particles observed in peristaltic pumping are the result of a similar mechanism: the formation of a protein film on the tubing surface, stretching and compression of the film during roller movement, and the subsequent entry of film fragments into the bulk solution …”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Study of Protein Aggregation at Moving Interfaces

Sarter,

Friess

2024

Mol. Pharmaceutics

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Repeated compression and dilation of a protein film adsorbed to an interface lead to aggregation and entry of film fragments into the bulk. This is a major mechanism for protein aggregate formation in drug products upon mechanical stress, such as shaking or pumping. To gain a better understanding of these events, we developed a molecular dynamics (MD) setup, which would, in a later stage, allow for in silico formulation optimization. In contrast to previous approaches, the molecules of our model protein human growth hormone displayed realistic shapes, surfaces, and interactions with each other and the interface. This enabled quantitative assessment of protein cluster formation. Simulation outcomes aligned with experimental data on subvisible particles and turbidity, thereby validating the model. Computational and experimental results indicated that compression speed does not affect the aggregation behavior of preformed protein films but rather their regeneration. Protein clusters that formed during compression disassembled upon relaxation, suggesting that the particles originate from a partly compressed state. Desorption studies via steered MD revealed that proteins from compressed systems are more likely to detach as clusters, implying that compression effects at the interface translate into aggregates present in the bulk solution. With the possibility of studying the impact of different variables upon compression and dilation at the interface on a molecular level, our model contributes to the understanding of the mechanisms of protein aggregation at moving interfaces. It also enables further studies to change formulation parameters, interfaces, or proteins.

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Section: Resultsmentioning

confidence: 99%