Search results for: Theodore W. Randolph

Items from 1 to 20 out of 94 results

article

Supervised and unsupervised machine learning approaches for monitoring subvisible particles within an aluminum‐salt adjuvanted vaccine formulation

David N. Greenblott, Caitlin V. Wood, Jingtao Zhang, Nelia Viza, more

Biotechnology and Bioengineering > 121 > 5 > 1626 - 1641

Suspensions of protein antigens adsorbed to aluminum‐salt adjuvants are used in many vaccines and require mixing during vial filling operations to prevent sedimentation. However, the mixing of vaccine formulations may generate undesirable particles that are difficult to detect against the background of suspended adjuvant particles. We simulated the mixing of a suspension containing a protein antigen...

article

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

David N. Greenblott, Jingtao Zhang, Christopher P. Calderon, Theodore W. Randolph

Biotechnology and Bioengineering > 119 > 12 > 3596 - 3611

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...

article

Machine learning and statistical analyses for extracting and characterizing “fingerprints” of antibody aggregation at container interfaces from flow microscopy images

Austin L. Daniels, Christopher P. Calderon, Theodore W. Randolph

Biotechnology and Bioengineering > 117 > 11 > 3322 - 3335

Therapeutic proteins are exposed to numerous stresses during their manufacture, shipping, storage and administration to patients, causing them to aggregate and form particles through a variety of different mechanisms. These varied mechanisms generate particle populations with characteristic morphologies, creating “fingerprints” that are reflected in images recorded using flow imaging microscopy. Particle...

article

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

Sanli Movafaghi, Hao Wu, Irene M. Francino Urdániz, David S. Bull, more

Biotechnology Journal > 15 > 9 > n/a - n/a

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...

article

Protein–protein interactions controlling interfacial aggregation of rhIL‐1ra are not described by simple colloid models

Lea L. Sorret, Madison A. DeWinter, Daniel K. Schwartz, Theodore W. Randolph

Protein Science > 27 > 7 > 1191 - 1204

We investigated the effects of protein–protein interaction strength on interfacial viscoelastic properties and aggregation of recombinant human interleukin‐1 receptor antagonist (rhIL‐1ra) at silicone oil–water interfaces. Osmotic second virial coefficients determined by static light scattering were used to quantify protein–protein interactions in bulk solution. Attractive protein–protein interactions...

article

Challenges in Predicting Protein-Protein Interactions from Measurements of Molecular Diffusivity

Lea L. Sorret, Madison A. DeWinter, Daniel K. Schwartz, Theodore W. Randolph

Biophysical Journal > 2016 > 111 > 9 > 1831-1842

Dynamic light scattering can be used to measure the diffusivity of a protein within a formulation. The dependence of molecular diffusivity on protein concentration (traditionally expressed in terms of the interaction parameter k_D) is often used to infer whether protein-protein interactions are repulsive or attractive, resulting in solutions that are colloidally stable or unstable, respectively. However,...

article

Surfactant Effects on Particle Generation in Antibody Formulations in Pre‐filled Syringes

Alana Gerhardt, Aaron C. Mcumber, Bao H. Nguyen, Rachael Lewus, more

Journal of Pharmaceutical Sciences > 104 > 12 > 4056 - 4064

Protein aggregation and particle formation have been observed when protein solutions contact hydrophobic interfaces, and it has been suggested that this undesirable phenomenon may be initiated by interfacial adsorption and subsequent gelation of the protein. The addition of surfactants, such as polysorbate 20, to protein formulations has been proposed as a way to reduce protein adsorption at silicone...

article

The Role of Protein Excipient in Driving Antibody Responses to Erythropoietin

Merry Christie, David Peritt, Raul M. Torres, Theodore W. Randolph, more

Journal of Pharmaceutical Sciences > 104 > 12 > 4041 - 4055

Human serum albumin (HSA) is an excipient present in formulations of several recombinant protein products that are approved for clinical use. We investigated the relative contributions of HSA and HSA particles to the generation of antibody responses against recombinant human erythropoietin (rhEPO) and the excipient HSA itself. Protein samples were characterized before injection for quantities of monomeric...

article

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

Carly Fleagle Chisholm, Bao Han Nguyen, Kaitlin R. Soucie, Raul M. Torres, more

Journal of Pharmaceutical Sciences > 104 > 11 > 3681 - 3690

Subvisible particles in a therapeutic protein product may act as adjuvants to promote unwanted immune responses against the protein. Silicone oil is used as a lubricant in prefilled syringes, and microdroplets of silicone oil are often detected in protein formulations expelled from prefilled syringes. In order to test the adjuvant potency of silicone oil microdroplets, antibody responses in mice to...

article

Development of a highly thermostable, adjuvanted human papillomavirus vaccine

Kimberly J. Hassett, Natalie M. Meinerz, Florian Semmelmann, Megan C. Cousins, more

European Journal of Pharmaceutics and Biopharmaceutics > 2015 > 94 > Complete > 220-228

A major impediment to economical, worldwide vaccine distribution is the requirement for a “cold chain” to preserve antigenicity. We addressed this problem using a model human papillomavirus (HPV) vaccine stabilized by immobilizing HPV16 L1 capsomeres, i.e., pentameric subunits of the virus capsid, within organic glasses formed by lyophilization. Lyophilized glass and liquid vaccine formulations were...

article

Dose Levels in Particulate‐Containing Formulations Impact Anti‐drug Antibody Responses to Murine Monoclonal Antibody in Mice

Maliheh Shomali, Sultan Tanriverdi, Angelika J. Freitag, Julia Engert, more

Journal of Pharmaceutical Sciences > 104 > 5 > 1610 - 1621

Dosage levels and particulate contents of therapeutic protein formulations are potential factors that impact immunogenicity of protein therapeutics. Here, we evaluated the effect of dose levels on the immunogenicity of protein particulates formed by adsorbing a murine monoclonal IgG2c/κ antibody (mAb1) onto silicone oil microdroplets, glass, or aluminum hydroxide (Alhydrogel^®) microparticles. Immune...

article

Effect of the Siliconization Method on Particle Generation in a Monoclonal Antibody Formulation in Pre‐filled Syringes

Alana Gerhardt, Bao H. Nguyen, Rachael Lewus, John F. Carpenter, more

Journal of Pharmaceutical Sciences > 104 > 5 > 1601 - 1609

Silicone oil is used as a lubricant in glass pre‐filled syringes (PFS) but can contribute to the generation of particles within protein formulations in PFS. To mitigate the production of such particles, various silicone oil coating processes have been proposed. In this study, three siliconization methods (the “covalent” method, the “baked silicone oil” method, and the “liquid silicone oil” method)...

article

Gelation of a Monoclonal Antibody at the Silicone Oil–Water Interface and Subsequent Rupture of the Interfacial Gel Results in Aggregation and Particle Formation

Shyam B. Mehta, Rachael Lewus, Jared S. Bee, Theodore W. Randolph, more

Journal of Pharmaceutical Sciences > 104 > 4 > 1282 - 1290

The formation of viscoelastic gels by a monoclonal antibody (mAb) at the silicone oil–water interface was studied using interfacial shear rheology. At a concentration of 50 μg/mL, the mAb formed gels in less than 1 h, and the gelation time decreased with increasing protein concentration. To probe the effects of mechanical rupture of the interfacial gel layers, a layer of silicone oil was overlaid...

article

Glassy‐State Stabilization of a Dominant Negative Inhibitor Anthrax Vaccine Containing Aluminum Hydroxide and Glycopyranoside Lipid A Adjuvants

Kimberly J. Hassett, David J. Vance, Nishant K. Jain, Neha Sahni, more

Journal of Pharmaceutical Sciences > 104 > 2 > 627 - 639

During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, dominant negative inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide...

article

Do Not Drop: Mechanical Shock in Vials Causes Cavitation, Protein Aggregation, and Particle Formation

Theodore W. Randolph, Elise Schiltz, Donn Sederstrom, Daniel Steinmann, more

Journal of Pharmaceutical Sciences > 104 > 2 > 602 - 611

Industry experience suggests that g‐forces sustained when vials containing protein formulations are accidentally dropped can cause aggregation and particle formation. To study this phenomenon, a shock tower was used to apply controlled g‐forces to glass vials containing formulations of two monoclonal antibodies and recombinant human growth hormone (rhGH). High‐speed video analysis showed cavitation...

article

Investigation of the Immunogenicity of Different Types of Aggregates of a Murine Monoclonal Antibody in Mice

Angelika J. Freitag, Maliheh Shomali, Stylianos Michalakis, Martin Biel, more

Pharmaceutical Research > 2015 > 32 > 2 > 430-444

Purpose The potential contribution of protein aggregates to the unwanted immunogenicity of protein pharmaceuticals is a major concern. In the present study a murine monoclonal antibody was utilized to study the immunogenicity of different types of aggregates in mice. Samples containing defined types of aggregates were prepared by processes such as stirring, agitation, exposure to ultraviolet (UV)...

article

Storage stability of keratinocyte growth factor-2 in lyophilized formulations: Effects of formulation physical properties and protein fraction at the solid–air interface

Dilip Devineni, Christoph Gonschorek, Marcus T. Cicerone, Yemin Xu, more

European Journal of Pharmaceutics and Biopharmaceutics > 2014 > 88 > 2 > 332-341

Lyophilized formulations of keratinocyte growth factor-2 (KGF-2) were prepared with a range of disaccharide (sucrose or trehalose) and hydroxyethyl starch (HES) mass ratios. Protein degradation was assessed as a function of time of storage of the dried formulations at 40, 50 and 60°C. Lyophilized and stored samples were rehydrated, and protein degradation was quantified by measuring loss of monomeric...

article

The Effect of Protein PEGylation on Physical Stability in Liquid Formulation

Louise Stenstrup Holm, Aaron Mcumber, Jakob Ewald Rasmussen, Marc Obiols‐Rabasa, more

Journal of Pharmaceutical Sciences > 103 > 10 > 3043 - 3054

The presence of micron aggregates in protein formulations has recently attracted increased interest from regulatory authorities, industry, and academia because of the potential undesired side effects of their presence. In this study, we characterized the micron aggregate formation of hen egg‐white lysozyme (Lyz) and its diPEGylated (5 kDa) analog as a result of typical handling stress conditions....

article

Effects of Phenol and meta‐Cresol Depletion on Insulin Analog Stability at Physiological Temperature

Brandon M. Teska, Javier Alarcón, Ronald J. Pettis, Theodore W. Randolph, more

Journal of Pharmaceutical Sciences > 103 > 8 > 2255 - 2267

The stability of three commercial “fast‐acting” insulin analogs, insulin lispro, insulin aspart, and insulin glulisine, was studied at various concentrations of phenolic preservatives (phenol and/or meta‐cresol) during 9 days of incubation at 37°C. The analysis by both size‐exclusion and reversed‐phase chromatography showed degradation of lispro and aspart that was inversely dependent on the concentration...

article

UV photodegradation of murine growth hormone: Chemical analysis and immunogenicity consequences

Amber Haynes Fradkin, Olivier Mozziconacci, Christian Schöneich, John F. Carpenter, more

European Journal of Pharmaceutics and Biopharmaceutics > 2014 > 87 > 2 > 395-402

During manufacturing, therapeutic proteins may be exposed to ultraviolet (UV) radiation. Such exposure is of concern because UV radiation may cause photooxidative damage to proteins, which in turn could lead to physical changes such as aggregation and enhanced immunogenicity. We exposed murine growth hormone (mGH) to controlled doses of UV radiation, and examined the resulting chemical, physical and...

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INFONA - science communication portal

Search results for: Theodore W. Randolph

Supervised and unsupervised machine learning approaches for monitoring subvisible particles within an aluminum‐salt adjuvanted vaccine formulation

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

Machine learning and statistical analyses for extracting and characterizing “fingerprints” of antibody aggregation at container interfaces from flow microscopy images

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

Protein–protein interactions controlling interfacial aggregation of rhIL‐1ra are not described by simple colloid models

Challenges in Predicting Protein-Protein Interactions from Measurements of Molecular Diffusivity

Surfactant Effects on Particle Generation in Antibody Formulations in Pre‐filled Syringes

The Role of Protein Excipient in Driving Antibody Responses to Erythropoietin

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

Development of a highly thermostable, adjuvanted human papillomavirus vaccine

Dose Levels in Particulate‐Containing Formulations Impact Anti‐drug Antibody Responses to Murine Monoclonal Antibody in Mice

Effect of the Siliconization Method on Particle Generation in a Monoclonal Antibody Formulation in Pre‐filled Syringes

Gelation of a Monoclonal Antibody at the Silicone Oil–Water Interface and Subsequent Rupture of the Interfacial Gel Results in Aggregation and Particle Formation

Glassy‐State Stabilization of a Dominant Negative Inhibitor Anthrax Vaccine Containing Aluminum Hydroxide and Glycopyranoside Lipid A Adjuvants

Do Not Drop: Mechanical Shock in Vials Causes Cavitation, Protein Aggregation, and Particle Formation

Investigation of the Immunogenicity of Different Types of Aggregates of a Murine Monoclonal Antibody in Mice

Storage stability of keratinocyte growth factor-2 in lyophilized formulations: Effects of formulation physical properties and protein fraction at the solid–air interface

The Effect of Protein PEGylation on Physical Stability in Liquid Formulation

Effects of Phenol and meta‐Cresol Depletion on Insulin Analog Stability at Physiological Temperature

UV photodegradation of murine growth hormone: Chemical analysis and immunogenicity consequences

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