Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events

Kotarek, Joseph A.; Stuart, Christine; Paoli, Silvia H. De; Šimák, Jan; Lin, Tsai-Lien; Gao, Yamei; Ovanesov, Mikhail V.; Liang, Yideng; Scott, Dorothy E.; Brown, Janice; Bai, Yun; Metcalfe, Dean D.; Marszal, Ewa; Ragheb, Jack A.

doi:10.1016/s0022-3549(15)00180-x

Cited by 93 publications

(72 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 Despite the general stability benefits of freeze-dried formulations, some degree of protein aggregation and particle formation may still be detected in reconstituted, lyophilized formulations. [5][6][7] On account of the potential of particulate matter in therapeutic protein formulations to induce unwanted immune responses, [8][9][10][11] quantification and characterization of aggregates and particles within these formulations has become a major area of research focus. In the present study, we report the discovery and characterization of NBs in reconstituted lyophilized formulations, examine their stability and investigate the effects of excipients on their formation during reconstitution.…”

Section: Introductionmentioning

confidence: 99%

Formation of Stable Nanobubbles on Reconstituting Lyophilized Formulations Containing Trehalose

Zhou

Cleland

Snell

et al. 2016

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Formation of Stable Nanobubbles on Reconstituting Lyophilized Formulations Containing Trehalose

Zhou

Cleland

Snell

et al. 2016

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“…Recent work by both Barnard et al and Kotarek et al has identified a correlation between increased concentrations of sub-visible particles and immune responses to marketed therapeutic protein products. 5, 30 In addition, Rosenberg et al highlighted the importance of investigating and characterizing sub-visible particles in formulations to develop strategies to mitigate risk and ensure the safety of protein therapeutic products. 2 As a newly identified source of sub-visible particles likely present upon reconstitution of lyophilized protein products, nanobubbles pose an unknown risk to the safety of protein therapeutic formulations requiring additional research to investigate if nanobubbles could alter the efficacy and immunogenicity of protein therapeutic products.…”

Section: Discussionmentioning

confidence: 99%

“…2–5 This focus has led to significant efforts within the biopharmaceutical industry to count and characterize populations of sub-visible particles within formulations. Recently, a new source of particles in therapeutic formulations was identified by Zhou et al, who showed that large numbers of stable nanobubbles were generated following reconstitution of lyophilized trehalose formulations.…”

Section: Introductionmentioning

confidence: 99%

Particle Formation and Aggregation of a Therapeutic Protein in Nanobubble Suspensions

Snell

Zhou

Carpenter

et al. 2016

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

The generation of nanobubbles following reconstitution of lyophilized trehalose formulations has recently been reported.1 Here, we characterize particle formation and aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in reconstituted formulations of lyophilized trehalose. Particle characterization methods including resonant mass measurement and nanoparticle tracking analysis were used to count and size particles generated upon reconstitution of lyophilized trehalose formulations. In addition, accelerated degradation studies were conducted to monitor rhIL-1ra aggregation in solutions containing various concentrations of suspended nanobubbles. Reconstitution of lyophilized trehalose formulations with solutions containing rhIL-1ra reduced nanobubble concentrations and generated negatively buoyant particles attributed to aggregated rhIL-1ra. Furthermore, levels of rhIL-1ra aggregation following incubation in aqueous solution correlated with concentrations of suspended nanobubbles. The results of this study suggest nanobubbles may be a contributor to protein aggregation and particle formation in reconstituted, lyophilized therapeutic protein formulations.

show abstract

“…Nanoparticle tracking analysis (NTA) and resistive pulse sensing (RPS) are also potentially useful techniques for measuring nanoparticle size in solution and monitoring aggregation and agglomeration. NTA has been used recently to detect subvisible particulates in Peginesatide (Omontys; Affymax, Inc.) after it was voluntarily withdrawn from the market following an unexpected rise in severe adverse events (including anaphylaxis) upon exposure (28). The underlying biological mechanism for the hypersensitivity events remains under investigation (29).…”

Section: Drug and Nanoparticulate Stabilitymentioning

confidence: 99%

Early Development Challenges for Drug Products Containing Nanomaterials

Grossman

Crist

Clogston

2016

AAPS J

View full text Add to dashboard Cite

The vast majority of drug product candidates in early development fail to progress to clinics. This is true for products containing nanomaterials just as for other types of pharmaceuticals. Early development pathways should therefore place high priority on experiments that help candidates fail faster and less expensively. Nanomedicines fail for many reasons, but some are more avoidable than others. Some of the points of failure are not considerations in the development of small molecules or biopharmaceuticals, and so may be unexpected, even to those with previous experience bringing drug products to the clinic. This article reviews experiments that have proven useful in providing "go/no-go" decision-making data for nanomedicines in early preclinical development. Of course, the specifics depend on the particulars of the drug product and the nanomaterial type, and not every product shares the same development pathway or the same potential points of failure. Here, we focus on challenges that differ from those in the development of traditional small molecule therapeutics, and on experiments that reveal deficiencies that can only be corrected by essentially starting over-altering the nanomedicine to an extent that all previous characterization and proof-of-concept testing must be repeated. Conducting these experiments early in the development process can save significant resources and time and allow developers to focus on derisked candidates with a greater likelihood of ultimate success.

show abstract

Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events

Cited by 93 publications

References 18 publications

Formation of Stable Nanobubbles on Reconstituting Lyophilized Formulations Containing Trehalose

Formation of Stable Nanobubbles on Reconstituting Lyophilized Formulations Containing Trehalose

Particle Formation and Aggregation of a Therapeutic Protein in Nanobubble Suspensions

Early Development Challenges for Drug Products Containing Nanomaterials

Contact Info

Product

Resources

About