IgG particle formation during filling pump operation: A case study of heterogeneous nucleation on stainless steel nanoparticles

Tyagi, Anil K.; Randolph, Theodore W.; Dong, Aichun; Maloney, Kevin M.; Hitscherich, Carl; Carpenter, John F.

doi:10.1002/jps.21419

Cited by 181 publications

(155 citation statements)

References 20 publications

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“…during vial filling. Stainless-steel piston pumps are known to shed nanoparticles during operation that can lead to adsorption and subsequent aggregation of an IgG monoclonal antibody (Tyagi et al 2009;Bee et al 2009b) and indeed this may be a consequence of the micro-cavitation reported by van Reis and Zydney (2007). A key outcome of these studies was that particulates thought to provide substrates for aggregation in protein drug products were below the current particle size thresholds for which there is routine testing (e.g.…”

Section: Figure 2 Herementioning

confidence: 75%

Effects of shear on proteins in solution

2010

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The effects of "shear" on proteins in solution are described and discussed. Research on this topic covers many decades, beginning with investigations of possible denaturation of enzymes during processing, whilst more recent concerns are how the quality of therapeutic proteins might be affected by shear or shear related effects.The paradigm that emerges from most studies is that shear in the fluid mechanical sense is unlikely by itself to damage most proteins and that interfacial phenomena are critically important. In particular, moving gas-liquid interfaces can be very deleterious. Aggregation of therapeutic proteins on nanoparticles shed from solid surfaces is a recent concern because of potential consequences on patient safety. It is clear that labeling such damage as "shear" is a mistake as this inhibits clear investigations of, and thinking about, the true causes of damage to proteins in solution during processing.

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Section: Figure 2 Herementioning

confidence: 75%

Effects of shear on proteins in solution

2010

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“…[18][19][20][21] However, the Al-phosphate complex formation in other injectable drugs is unacceptable because these insoluble particles have the ability to harm the patient's veins. In particular, for development of antibody drugs, particles are a concern for biopharmaceutical manufacturers and regulatory officers 22) based on reports that particles in protein drugs may serve as nuclei triggering the aggregation of the protein, increasing the risk of immunogenicity, [23][24][25] and that particles may also enhance the immunogenicity of the protein drug by themselves. 26) Therefore, the phenomenon of particle formation from the storage of phosphate buffer solution in glass vials induced by interactions of the phosphate ions with Al eluted from the vial should be completely prevented in the field of injectable drug products.…”

Section: Resultsmentioning

confidence: 99%

Effects of Phosphate Buffer in Parenteral Drugs on Particle Formation from Glass Vials

Ogawa

Miyajima

Wakiyama

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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The characteristics of inorganic particles generated in glass vials filled with phosphate buffer solutions were investigated. During storage, particles were visually detected in the phosphate buffer solution in particular glass vials which pass compendial tests of containers for injectable drugs. These particles were considered to be different from ordinal glass delamination, which has been reported in a number of papers because the particles were mainly composed of Al, P and O, but not Si. The formation of the particles accelerated at higher storage temperatures. Among the surface treatments tested for the glass vials, sulfur treatment showed a protective effect on the particle formation in the vials, whereas the SiO 2 coating did not have any protective effects. It was found that the elution ratio of Al and Si in the solution stored in the glass vials after the heating was similar to the ratio of Al and Si in borosilicate glass. However, the Al concentration decreased during storage (5°C, 6 months), and consequently, particle formation was observed in the solution. Adding citrate, which is a chelating agent for Al, effectively suppressed the particle formation in the heated solution. When 50 ppb and higher concentrations of Al ion were added to the phosphate buffer solution, the formation of white particles containing Al, P and O was detected. It is suggested that a phosphate buffer solution in a borosilicate glass vial has the ability to form particles due to interactions with the Al that is eluted from the glass during storage.Key words aluminum; borosilicate glass; tubing vial; aluminum phosphate complex The primary packaging system for a sterile drug product should provide adequate protection against any contamination from the external environment, and this protection should be assured during the entire shelf life of the product. In contrast, particularly for liquid, injectable drugs, components of the drugs are always in contact with the surface of the packaging component during storage. Therefore, during the course of formulation development of injectable drugs, it is essential to evaluate the physicochemical compatibility between the drug formulation and the packaging components to select appropriate primary packaging systems. 1,2) Among the packaging materials that are compatible with injectable drug solutions, glass containers, such as vials or ampoules, have been widely chosen and used. For parenteral drug products, borosilicate glasses (Type I) composed principally of silicon dioxide and boric oxides and soda-lime glasses composed of relatively high levels of sodium oxide and calcium oxide are used. Borosilicate glasses in particular are known to have a good chemical durability and are used commonly in the pharmaceutical industry as the primary container. However, these glass containers, even when made from borosilicate glasses, will unavoidably suffer some undesirable events from being in contact with the drug solutions in longterm storage. In certain cases, insoluble particle formation occurs in g...

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“…13) They reached this conclusion because the proteinfree buffer, which was pumped with a positive displacement piston pump having a stainless steel head, induced the formation of protein aggregates when added to unpumped antibody solutions. In addition, they noted that the number of microparticles in the added protein solution was 20 times higher than that in the pumped protein-free buffer.…”

Section: Discussionmentioning

confidence: 99%

“…4) Tyagi et al postulated that the stainless steel nanoparticles shed from the pump-solution contact surface induced heterogeneous nucleation of immunoglobulin G (IgG) particles. 13) There have been very few studies discussing aggregate formation during the formulated bulk preparation process of antibody solution manufacture, in which various excipients such as sodium chloride, phosphate, amino acids, and detergents are added. This process inevitably entails the stirring of antibody solutions.…”

mentioning

confidence: 99%

Prevention of Stirring-Induced Microparticle Formation in Monoclonal Antibody Solutions

Ishikawa

Kobayashi

Osawa

et al. 2010

Biological & Pharmaceutical Bulletin

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Monoclonal antibodies are being widely used for the treatment of various diseases. Microparticle formation in high-concentration protein solutions is a major problem during the manufacture of therapeutic monoclonal antibodies, because aggregation leads to fouling of aseptic filters and may lead to an immunogenic reaction in patients. We found that stirring using a traditional bottom-magnetic type stirrer results in extensive and sustained formation of 500-nm diameter protein microparticles arising from shear stress on protein molecules. The antibody solution stirred for only 5 min using this type of stirrer exhibited significant fouling of aseptic filter membranes. In contrast, a top-entering type stirrer did not lead to the formation of microparticles, and the solution did not exhibit membrane fouling even after 30 min of stirring. We conclude that a top-entering type stirrer is more suited for the manufacture of concentrated therapeutic monoclonal antibody solutions.

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IgG particle formation during filling pump operation: A case study of heterogeneous nucleation on stainless steel nanoparticles

Cited by 181 publications

References 20 publications

Effects of shear on proteins in solution

Effects of shear on proteins in solution

Effects of Phosphate Buffer in Parenteral Drugs on Particle Formation from Glass Vials

Prevention of Stirring-Induced Microparticle Formation in Monoclonal Antibody Solutions

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