The Effect of Container Surface Passivation on Aggregation of Intravenous Immunoglobulin Induced by Mechanical Shock

Abstract

Aggregation of therapeutic proteins can result from a number of stress conditions encountered during their manufacture, transportation, and storage. This work shows the effects of two interrelated sources of protein aggregation: the chemistry and structure of the surface of the container in which the protein is stored, and mechanical shocks that may result from handling of the formulation. How different mechanical stress conditions (dropping, tumbling, and agitation) and container surface passivation affect the stability of solutions of intravenous immunoglobulin are investigated. Application of mechanical shock causes cavitation to occur in the protein solution, followed by bubble collapse and the formation of high‐velocity fluid microjets that impinged on container surfaces, leading to particle formation. Cavitation was observed after dropping of vials from heights as low as 5 cm, but polyethylene glycol (PEG) grafting provided temporary protection against drop‐induced cavitation. PEG treatment of the vial surface reduced the formation of protein aggregates after repeated dropping events, most likely by reducing protein adsorption to container surfaces. These studies enable the development of new coatings and surface chemistries that can reduce the particulate formation induced by surface adsorption and/or mechanical shock.

Toward Isolation of Palytoxins: Liquid Chromatography Coupled to Low- or High-Resolution Mass Spectrometry for the Study on the Impact of Drying Techniques, Solvents and Materials

“…Actually, proteins can aggregate into particles because of conformational changes caused by different mechanical and chemical–physical stress conditions (pH, temperature, pressure, vortexing, etc.) including surface adsorption, which, in turn, can promote aggregate formation [ 27 , 28 ]. This resulted in a higher recovery than that obtained after complete drying ( Figure 4 ).…”

“…Toxins 2021, 13, x FOR PEER REVIEW 9 of 18 surface adsorption, which, in turn, can promote aggregate formation [27,28]. This resulted in a higher recovery than that obtained after complete drying (Figure 4).…”

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

“…Moreover, collapse of cavitation bubbles releases enormous amounts of energy 133 and heat [133][134][135] , which decomposes water molecules into reactive hydrogen atoms and hydroxyl radicals 65,130,136 . Radical-mediated protein oxidation can also lead to protein degradation and particle formation for molecules that are sensitive to oxidation 47,49,65,137 .…”

“…Also, with a more rigid PO material, perhaps more mechanical disruption of adsorbed protein films than with protein films formed on PVC. Moreover, proteins adsorb differently to different materials 47,143 . Perhaps more protein molecules adsorb to solid-liquid interfaces in PO bags compared to in PVC bags, ultimately resulting in more particle formation.…”

“…There are limited published studies on the effects of PTS transportation on protein products 56,57 , with one study documenting reduction in protein concentration in a transported insulin product 57 . However it is well known that mechanical shock for example, due to dropping or shipping of containers with therapeutic proteins --can cause cavitation that results in protein particle formation and aggregation, as well as oxidation [47][48][49][64][65][66] . Furthermore, dilution of protein products in IV solution typically results in concentrations of excipients (e.g., surfactants) to levels below those that are needed to stabilize proteins [67][68][69] .…”