Effects of Tubing Type, Operating Parameters, and Surfactants on Particle Formation During Peristaltic Filling Pump Processing of a mAb Formulation

Her, Cheng; Tanenbaum, Laura M.; Bandi, Swati; Randolph, Theodore W.; Thirumangalathu, Renuka; Mallela, Krishna; Carpenter, John F.; Elias, Yannick

doi:10.1016/j.xphs.2020.01.009

Cited by 19 publications

(8 citation statements)

References 20 publications

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“…42 Although k D values were comparable to the bulk formulation, adding PS20 to the formulation completely supressed protein particle formation. This latter result is in perfect agreement with the studies from Her et al 19,20 In this study, we used k D as a simplistic approach for colloidal stability estimation. Although k D is used as a descriptor for interparticle interaction in protein solutions 43 , this parameter does not provide a full picture of colloidal stability.…”

Section: Discussionsupporting

confidence: 90%

“…The particle formation propensity upon peristaltic pumping depends on formulation conditions and tubing type. 19,20 As peristaltic pumping is a complex combination of different mechanical stresses which potentially overlap with chemical stress the following factors are seen as potential drivers: temperature, exposure to interfaces, shear, and contaminants as nucleation sites. 21 Silicone tubing sheds particles into the product during pumping due to abrasion of the tubing piece in the pump head.…”

Section: Introductionmentioning

confidence: 99%

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Proteins on the Rack: Mechanistic Studies on Protein Particle Formation During Peristaltic Pumping

Deiringer¹,

Frieß²

2022

Journal of Pharmaceutical Sciences

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Peristaltic pumping can cause protein particle formation. The expected causes were unfolding by heat in the pump head, oxidative stress by cavitation generated during roller movement, interfacial adsorption to the tubing wall and mechanical stress by stretching of the tubing itself. The pump head reached 28°C during experiments stayed well below the onset of the melting point of the proteins. Thus, heat may only be a relevant root cause for proteins containing domains with very low unfolding temperature. Analysis by terephthalic acid dosimetry and protein oxidation via RP-HPLC ruled out major induction of reactive hydroxyl radicals by pumping, indicating that cavitation does not play a significant role in particle generation. Addition of surfactants suppresses protein adsorption to the tubing wall and drastically reduced protein particle formation. This indicates that interfacial protein adsorption is a key element. Repeated stretching of tubing filled with protein solution led to the formation of protein particles, demonstrating that expansion and compression of the protein film on the tubing surface is the second key component for particle formation. Thus, protein particle generation during peristaltic pumping originates from the formation of a protein film on the tubing surface which gets stretched and compressed, leading to film fragments entering the bulk solution. This interplay of protein film formation and its rupture has been also observed at liquid/liquid or liquid/air interfaces.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Proteins on the Rack: Mechanistic Studies on Protein Particle Formation During Peristaltic Pumping

Deiringer¹,

Frieß²

2022

Journal of Pharmaceutical Sciences

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“…A potential drawback of this system is that the additional wear and tear of the silicone tubing has a higher potential to generate intrinsic particles from tubing materials that could enter the DP solution. 63 During peristaltic filling pump processing, unfolded protein that is adsorbed to the silicone tubing may become dislodged during pump operation and become nucleation sites for protein aggregation and particle formation. 38,63,64 The use of a longer silicone hose leads to potential increase in the amount of leachables that may compromise product quality.…”

Section: Fillingmentioning

confidence: 99%

“…63 During peristaltic filling pump processing, unfolded protein that is adsorbed to the silicone tubing may become dislodged during pump operation and become nucleation sites for protein aggregation and particle formation. 38,63,64 The use of a longer silicone hose leads to potential increase in the amount of leachables that may compromise product quality. Additionally, for high protein concentration formulations, the suck-back (pump-reversal) on peristaltic pumps must be carefully controlled to avoid droplet formation on the end of the filling needle, which is prone to rapid drying and clogging of the filling needles during the process.…”

Section: Fillingmentioning

confidence: 99%

“…The impact assessment can be enhanced by in-depth understanding with any type of filling system, tubing type (including brand and size), operating parameters (e.g., pumping velocity), and formulation (e.g., amount of surfactant) -all of which can contribute to particle formation. 63,64 The assessment should be conducted in a cross functional manner that integrates all process and product knowledge of the DP and formulation to ensure manufacturing process robustness and selection of suitable process parameters and product contact materials for the filling operation. Ideally, filling evaluations should be performed at both early stage and late stage development to identify potential product quality issues resulting from the use of different filling systems.…”

Section: Risk Mitigation and Control Strategy For Fillingmentioning

confidence: 99%

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Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality

Das

Sreedhara²,

Colandene

et al. 2022

Journal of Pharmaceutical Sciences

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Machine learning approaches to root cause analysis, characterization, and monitoring of subvisible particles in monoclonal antibody formulations

Greenblott

Zhang

Calderon

et al. 2022

Biotech & Bioengineering

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Processing stresses on therapeutic proteins may cause formation of subvisible particles. Different stress mechanisms generate particle populations with characteristic morphological "fingerprints," and machine learning techniques like convolutional neural networks (CNNs) allow classification of microscopy images of these particles according to known stresses at their root cause. Using CNNs to classify novel particle types not included during network training may lead to inaccurate classification, however, using CNNs to monitor the presence of particulate matter not explicitly used in training could serve as a useful process analytical technology.We used CNNs to classify and identify the root cause of particles generated by subjecting three monoclonal antibodies (mAbs) to various common manufacturing stresses. We probed the generality of particles generated by stressing different mAbs in different formulations and showed that CNN analyses were sensitive not only to the applied stress, but also the buffer conditions and the particular mAb that generated particle populations. Thus, models trained on images of particles created with one mAb and buffer system may not provide accurate root cause analysis when applied to particles generated by other mAb and buffer systems. A lever-rule analysis of CNN-derived fingerprints was used to characterize the composition of mixtures of particle types. Finally, we monitored the temporal evolution of CNN-derived fingerprints when novel populations of particles, which were not included during training, were generated by pumping mAb solutions through a peristaltic pump.

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Effects of Tubing Type, Operating Parameters, and Surfactants on Particle Formation During Peristaltic Filling Pump Processing of a mAb Formulation

Cited by 19 publications

References 20 publications

Proteins on the Rack: Mechanistic Studies on Protein Particle Formation During Peristaltic Pumping

Proteins on the Rack: Mechanistic Studies on Protein Particle Formation During Peristaltic Pumping

Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality

Machine learning approaches to root cause analysis, characterization, and monitoring of subvisible particles in monoclonal antibody formulations

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