Effects of Tubing Type, Formulation, and Postpumping Agitation on Nanoparticle and Microparticle Formation in Intravenous Immunoglobulin Solutions Processed With a Peristaltic Filling Pump

Abstract

The main goal of this study was to use state-of-the-art instruments for nanoparticle (nanoparticle tracking analysis and resonant mass measurement) and microparticle counting (flow imaging) to assess the effects of peristaltic filling pump operation on particle formation in formulations of intravenous immunoglobulin. Microparticle levels were also measured with light obscuration. Postpumping agitation was studied as an accelerated degradation method, 3 different commercial peristaltic tubing types were tested, and the effects of formulation pH and inclusion of polysorbate 80 were determined. Overall, the results documented that nanoparticle measurements, as well as microparticle determinations with flow imaging, were essential to gain rigorous insights into impacts of processing and formulation parameters on pumping-and agitation-induced particle formation. In addition, light obscuration was a relatively insensitive method and failed to detect large increases in protein particles caused by pumping and postpumping agitation. Formulation studies showed that the presence of polysorbate 80 or increasing protein colloidal stability with appropriate choice of buffer generally reduced particle formation. The results highlight the need for filling pump assessments in formulation development studies. Combining such assessments with appropriate analytical methods should help assure that particle levels are controlled during filling pump operation and that the highest quality products are manufactured.

Finding the Needle in the Haystack: High-Resolution Techniques for Characterization of Mixed Protein Particles Containing Shed Silicone Rubber Particles Generated During Pumping

“…Previous studies highlighted that upon peristaltic pumping, tubing material sheds 27 and protein aggregates can be formed. 21 Hence, potential formation of particles and aggregates is critical, as different size species may enter the final product in an unobstructed way.…”

“…With higher surface roughness on the nano-and micrometer scale, protein adsorption is enhanced beyond the corresponding increase in specific surface area, [56][57][58] which again may lead to increased protein aggregation and particle formation. It is assumed that protein particle formation is based on the detachment of the protein film from the tubing surface by roller movements 21 similar to effects known from piston pumps. 18 We speculate that, based on their morphology, the protein particles resemble fragmented protein film.…”

“…Her and Carpenter showed that protein aggregation in peristaltic pumps depends on tubing type and formulation. 21 It is assumed that the aggregation is more likely driven by interfacial stress 20,22 than by shear stress. 23 Peristaltic pumps are mostly equipped with silicone tubings due to cost and availability, but these tubings shed particles.…”

Physicochemical Stability of Monoclonal Antibodies: A Review

“…Pumping provokes shearing and cavitation in tubing and has been shown to decrease bioactivity and increase particle count. 178,181,182 Filtration can also be associated to shearing. Shear-thinning behavior (decrease of viscosity under shear strain) has been reported for high concentration mAb solutions, perhaps linked to the dissociation of selfassociating of mAb clusters, 183 but it is unclear if shear forces during by filtration induced other modifications.…”

Effects of Transportation of IV Bags Containing Protein Formulations Via Hospital Pneumatic Tube System: Particle Characterization by Multiple Methods

“…Moreover, with inadequate surfactant levels in the IV solution, proteins can form films at the air-liquid interface and at solid-liquid interface of the bag walls [71][72][73][74][75][76] . These films can be ruptured by mechanical stress and contribute to aggregate and particulate released into to the bulk solution 71,72,74,75,[77][78][79][80][81][82][83][84][85][86][87] . The extreme mechanical shock occurring during transportation in the PTS system would be expected to cause rupture of adsorbed protein films.…”