The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Tudor Arvinte - One of the best experts on this subject based on the ideXlab platform.
-
Influence of Protein Formulation and carrier solution on asymmetrical flow field-flow fractionation: a case study of the plant-produced recombinant anthrax protective antigen pp-PA83.
Journal of pharmaceutical sciences, 2014Co-Authors: Caroline Palais, Jessica A. Chichester, Slobodanka D. Manceva, Vidadi Yusibov, Tudor ArvinteAbstract:Asymmetrical flow field-flow fractionation (afFFF) was used to investigate the properties of a plant-produced anthrax toxin protective antigen, pp-PA83. The afFFF fractogram consisted of two main peaks with molar masses similar to the molecular mass of pp-PA83 monomer. afFFF carrier solutions strongly influenced the ratio and the intensity of the two main peaks. These differences indicate that conformation changes in the pp-PA83 molecule occurred during the afFFF analysis. Similar fractograms were obtained for different pp-PA83 Formulations when the afFFF carrier solution and the Protein Formulation were the same (or very similar). The data show that in specific cases, afFFF could be used to study Protein conformation and document the importance of studying the influence of the carrier solution on afFFF.
-
addressing new analytical challenges in Protein Formulation development
European Journal of Pharmaceutics and Biopharmaceutics, 2011Co-Authors: Henryk Mach, Tudor ArvinteAbstract:As the share of therapeutic Proteins in the arsenal of modern medicine continue increasing, relatively little progress has been made in the development of analytical methods that would address specific needs encountered during the development of these new drugs. Consequently, the researchers resort to adaptation of existing instrumentation to meet the demands of rigorous bioprocess and Formulation development. In this report, we present a number of such adaptations as well as new instruments that allow efficient and precise measurement of critical parameters throughout the development stage. The techniques include use of atomic force microscopy to visualize Proteinacious sub-visible particles, use of extrinsic fluorescent dyes to visualize Protein aggregates, particle tracking analysis, determination of the concentration of monoclonal antibodies by the analysis of second-derivative UV spectra, flow cytometry for the determination of subvisible particle counts, high-throughput fluorescence spectroscopy to study phase separation phenomena, an adaptation of a high-pressure liquid chromatography (HPLC) system for the measurement of solution viscosity and a variable-speed streamlined analytical ultracentrifugation method. An ex vivo model for understanding the factors that affect bioavailability after subcutaneous injections is also described. Most of these approaches allow not only a more precise insight into the nature of the formulated Proteins, but also offer increased throughput while minimizing sample requirements.
-
A high throughput Protein Formulation platform: case study of salmon calcitonin.
Pharmaceutical research, 2008Co-Authors: Martinus A.h. Capelle, Robert Gurny, Tudor ArvinteAbstract:Purpose The feasibility of using high throughput spectroscopy for characterization and selection of physically stable Protein Formulations was studied.
-
High throughput screening of Protein Formulation stability: practical considerations.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2006Co-Authors: Martinus A.h. Capelle, Robert Gurny, Tudor ArvinteAbstract:The Formulation of Protein drugs is a difficult and time-consuming process, mainly due to the complexity of Protein structure and the very specific physical and chemical properties involved. Understanding Protein degradation pathways is essential for the success of a biopharmaceutical drug. The present review concerns the application of high throughput screening techniques in Protein Formulation development. A Protein high throughput Formulation (HTF) platform is based on the use of microplates. Basically, the HTF platform consists of two parts: (i) sample preparation and (ii) sample analysis. Sample preparation involves automated systems for dispensing the drug and the Formulation ingredients in both liquid and powder form. The sample analysis involves specific methods developed for each Protein to investigate physical and chemical properties of the Formulations in microplates. Examples are presented of the use of Protein intrinsic fluorescence for the analysis of Protein aqueous properties (e.g., conformation and aggregation). Different techniques suitable for HTF analysis are discussed and some of the issues concerning implementation are presented with reference to the use of microplates.
-
where disease pathogenesis meets Protein Formulation renal deposition of immunoglobulin aggregates
European Journal of Pharmaceutics and Biopharmaceutics, 2006Co-Authors: Barthelemy Demeule, Robert Gurny, Tudor ArvinteAbstract:Aggregation is one of the important issues encountered during the development of immunoglobulin-based drugs. The aim of the current review is to discuss the causes and consequences of immunoglobulin aggregation as well as the relevance of immunoglobulin aggregation to disease pathogenesis. Extracellular deposition of immunoglobulins, either monoclonal light chains or intact polyclonal antibodies, induces renal failure in various nephropathies. The aggregates can present fibrillar or amorphous structures. In this review, factors known to influence Protein aggregation, such as the primary structure of the Protein, local environment and glycosylation are assessed, as well as the subsequent altered clearance, fibril formation and toxicity. The role of the Protein local environment is emphasized. Even if the local environment causes only minor perturbations in the Protein structure, these perturbations might be sufficient to trigger aggregate formation. This fact underlines the importance of choosing appropriate Formulations for Protein drugs. If the Formulation provides a slightly destabilizing environment to the Protein, the long-term stability of the drug may be compromised by aggregate formation.
Henning Gieseler - One of the best experts on this subject based on the ideXlab platform.
-
Predictive Screening Tools Used in High-Concentration Protein Formulation Development.
Journal of pharmaceutical sciences, 2017Co-Authors: Melanie Hofmann, Henning GieselerAbstract:This review examines the use of predictive screening approaches in high-concentration Protein Formulation development. In addition to the normal challenges associated with Protein Formulation development, for high-concentration Formulations, solubility, viscosity, and physical Protein degradation play major roles. To overcome these challenges, multiple Formulation conditions need to be evaluated such that it is desirable to have predictive but also low-volume and high-throughput methods in order to identify optimal Formulation conditions very early in development without time- and material-consuming setups. Many screening techniques have been reported for use in high-concentration Formulation development, but not all fulfill the requirements mentioned previously. This review summarizes the advantages and disadvantages of different screening approaches currently used in Formulation development and the correlation of predictive data to Protein solubility, viscosity, and stability at high Protein concentrations.
-
Low‐volume solubility assessment during high‐concentration Protein Formulation development
The Journal of pharmacy and pharmacology, 2016Co-Authors: Melanie Hofmann, Matthias Winzer, Christian Weber, Henning GieselerAbstract:Objective Solubility is often one of the limiting factors for high-concentration Protein Formulation (HCF) development. Determination of Protein solubility is challenging and requires high amount of material. Therefore, low-volume and predictive approaches are desired. Methods This work presents a simple and material-saving approach using static light scattering to describe non-ideal solution behaviour of HCF. Non-ideality can be related to Protein–Protein interactions in solution. The type and strength of these interactions indicate maximum Protein solubility at actual Formulation compositions. Interactions of four therapeutic model Proteins at multiple Formulation compositions were investigated, and deduced solubility was compared to apparent solubility behaviour determined by ether turbidity or content measurements. Key findings Protein–Protein interactions and deduced solubilities matched actual solubility data for all tested Formulations. Protein solubility was found to be lowest at pH values near the isoelectric point of each model Protein. Buffer salts and ionic strength were also found to strongly influence Protein solubility. In addition, sucrose and a combination of arginine and glycine enhanced Protein solubility, whereas surfactants such as polysorbate 20 did not influence Protein solubility. Conclusions The introduced screening procedure is a powerful tool during (early) Protein Formulation development. It meets several requirements of HCF development and enables reliable prediction of Protein solubility based on determination of Protein interactions. In addition, rare data about the influence of several common excipients on apparent solubility of therapeutic Proteins were shown.
-
Application of Process Analytical Technology for Monitoring Freeze-Drying of an Amorphous Protein Formulation: Use of Complementary Tools for Real-Time Product Temperature Measurements and Endpoint Detection
Journal of pharmaceutical sciences, 2015Co-Authors: Stefan C. Schneid, Robert E. Johnson, M. Laviniam Lewis, Peter Stärtzel, Henning GieselerAbstract:Process analytical technology (PAT) and quality by design have gained importance in all areas of pharmaceutical development and manufacturing. One important method for monitoring of critical product attributes and process optimization in laboratory scale freeze-drying is manometric temperature measurement (MTM). A drawback of this innovative technology is that problems are encountered when processing high-concentrated amorphous materials, particularly Protein Formulations. In this study, a model solution of bovine serum albumin and sucrose was lyophilized at both conservative and aggressive primary drying conditions. Different temperature sensors were employed to monitor product temperatures. The residual moisture content at primary drying endpoints as indicated by temperature sensors and batch PAT methods was quantified from extracted sample vials. The data from temperature probes were then used to recalculate critical product parameters, and the results were compared with MTM data. The drying endpoints indicated by the temperature sensors were not suitable for endpoint indication, in contrast to the batch methods endpoints. The accuracy of MTM Pice data was found to be influenced by water reabsorption. Recalculation of Rp and Pice values based on data from temperature sensors and weighed vials was possible. Overall, extensive information about critical product parameters could be obtained using data from complementary PAT tools.
Gerhard Winter - One of the best experts on this subject based on the ideXlab platform.
-
the refold assay for Protein Formulation studies and prediction of Protein aggregation during long term storage
European Journal of Pharmaceutics and Biopharmaceutics, 2019Co-Authors: Hristo Svilenov, Gerhard WinterAbstract:The Formulation of novel therapeutic Proteins is a challenging task which aims at finding Formulation conditions that will minimize Protein degradation during long-term storage. One particularly important and difficult-to-predict Protein degradation pathway is the so-called non-native aggregation. The qualitative and quantitative prediction of the latter has been a subject of extensive research over the past two decades. An increasing body of evidence shows that the widely-used short-term biophysical techniques cannot accurately rank Formulation conditions in order of their effect on the aggregation during long-term storage of some therapeutic Proteins, e.g. monoclonal antibodies. Here we suggest a novel approach for the selection of Formulation conditions that will suppress the formation of Protein aggregates during long-term storage. We postulate that conditions (i.e. pH, buffer type, ionic strength) that reduce the isothermal aggregation of various denaturant-induced partially folded Protein species will be conditions that impede Protein aggregation during long-term storage. To test our hypothesis, we developed an isothermal microdialysis-based unfolding/refolding assay, named ReFOLD, which we use to induce moderate aggregation of partially folded Proteins. Next, we assessed the relative monomer yield after isothermal unfolding/refolding of two monoclonal antibodies, each formulated in 12 different conditions. Using the proposed approach, we were able to accurately rank the Formulations in order of their effect on the amount of Protein aggregates detected after storage for 12 months at 4 °C and 25 °C, while widely-used stability-indicating parameters like Protein melting and aggregation onset temperatures failed to provide accurate predictive Formulation rankings.
-
CMC determination of nonionic surfactants in Protein Formulations using ultrasonic resonance technology
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2015Co-Authors: Shohei Horiuchi, Gerhard WinterAbstract:Biological products often contain surfactants as stabilizers in their Formulations to avoid surface adsorption, interfacial denaturation and aggregation of the Protein drug and thereby improve the overall pharmaceutical quality of the product. On the other hand, when the surfactant concentration exceeds the critical micelle concentration (CMC) in a Protein Formulation, Protein-loaded micelles could be formed which could potentially be the cause of immunogenicity. Therefore, the actual CMC and the presence of micelles generally need to be confirmed for each Protein Formulation because the CMC is affected by the presence of Protein and other Formulation factors. In this study, the ultrasonic resonance technology (URT) was applied to determine CMC of surfactants in pharmaceutical Protein solutions in comparison with surface tensiometry (TE) and dynamic light scattering (DLS). According to our results, the ultrasonic resonance technology can easily and precisely provide CMCs of surfactants in Protein Formulations while it is not working for Protein-free Formulations. This indicates that the signal we measure with ultrasonic velocity comes from complex micelles composed of surfactant and Protein molecules. DLS did not provide reliable data for Protein/surfactant systems. Interestingly, a Protein Formulation with arginine and polysorbate 20 behaved differently when studied with TE and URT allowing us to see that arginine is bound to Protein and that the complex interacts with the surfactant.
-
particles in therapeutic Protein Formulations part 1 overview of analytical methods
Journal of Pharmaceutical Sciences, 2012Co-Authors: Sarah Zolls, Ruedeeporn Tantipolphan, Michael Wiggenhorn, Gerhard Winter, Wim Jiskoot, Wolfgang Friess, Andrea HaweAbstract:The presence of particles is a major issue during therapeutic Protein Formulation development. Both Proteinaceous and nonProteinaceous particles need to be analyzed not only due to the requirements of the Pharmacopeias but also to monitor the stability of the Protein Formulation. Increasing concerns about the immunogenic potential together with new developments in particle analysis make a comparative description of established and novel analytical methods useful. Our review aims to provide a comprehensive overview on analytical methods for the detection and characterization of visible and subvisible particles in therapeutic Protein Formulations. We describe the underlying theory, benefits, shortcomings, and illustrative examples for quantification techniques, as well as characterization techniques for particle shape, morphology, structure, and identity.
Kentaro Shiraki - One of the best experts on this subject based on the ideXlab platform.
-
Protein–Poly(amino acid) Complex Precipitation for High-Concentration Protein Formulation
Journal of pharmaceutical sciences, 2014Co-Authors: Takaaki Kurinomaru, Takuya Maruyama, Izaki Shunsuke, Kenji Handa, Tomoaki Kimoto, Kentaro ShirakiAbstract:A method for concentration of Protein solutions is required for high-dosage Protein Formulation. Here, we present a precipitation–redissolution method by poly(amino acid) for Proteins, including therapeutic enzymes, antibodies, and hormones. The Proteins were fully precipitated by the addition of poly-l-lysine or poly-l-glutamic acid at low ionic strength, after which precipitate was dissolved at physiological ionic strength. The activities and secondary structures of redissolved Proteins, especially antibodies, were almost identical to the native state. The precipitation–redissolution method is a simple and rapid technique for concentration of Protein Formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2248–2254, 2014
Robert Gurny - One of the best experts on this subject based on the ideXlab platform.
-
A high throughput Protein Formulation platform: case study of salmon calcitonin.
Pharmaceutical research, 2008Co-Authors: Martinus A.h. Capelle, Robert Gurny, Tudor ArvinteAbstract:Purpose The feasibility of using high throughput spectroscopy for characterization and selection of physically stable Protein Formulations was studied.
-
High throughput screening of Protein Formulation stability: practical considerations.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2006Co-Authors: Martinus A.h. Capelle, Robert Gurny, Tudor ArvinteAbstract:The Formulation of Protein drugs is a difficult and time-consuming process, mainly due to the complexity of Protein structure and the very specific physical and chemical properties involved. Understanding Protein degradation pathways is essential for the success of a biopharmaceutical drug. The present review concerns the application of high throughput screening techniques in Protein Formulation development. A Protein high throughput Formulation (HTF) platform is based on the use of microplates. Basically, the HTF platform consists of two parts: (i) sample preparation and (ii) sample analysis. Sample preparation involves automated systems for dispensing the drug and the Formulation ingredients in both liquid and powder form. The sample analysis involves specific methods developed for each Protein to investigate physical and chemical properties of the Formulations in microplates. Examples are presented of the use of Protein intrinsic fluorescence for the analysis of Protein aqueous properties (e.g., conformation and aggregation). Different techniques suitable for HTF analysis are discussed and some of the issues concerning implementation are presented with reference to the use of microplates.
-
where disease pathogenesis meets Protein Formulation renal deposition of immunoglobulin aggregates
European Journal of Pharmaceutics and Biopharmaceutics, 2006Co-Authors: Barthelemy Demeule, Robert Gurny, Tudor ArvinteAbstract:Aggregation is one of the important issues encountered during the development of immunoglobulin-based drugs. The aim of the current review is to discuss the causes and consequences of immunoglobulin aggregation as well as the relevance of immunoglobulin aggregation to disease pathogenesis. Extracellular deposition of immunoglobulins, either monoclonal light chains or intact polyclonal antibodies, induces renal failure in various nephropathies. The aggregates can present fibrillar or amorphous structures. In this review, factors known to influence Protein aggregation, such as the primary structure of the Protein, local environment and glycosylation are assessed, as well as the subsequent altered clearance, fibril formation and toxicity. The role of the Protein local environment is emphasized. Even if the local environment causes only minor perturbations in the Protein structure, these perturbations might be sufficient to trigger aggregate formation. This fact underlines the importance of choosing appropriate Formulations for Protein drugs. If the Formulation provides a slightly destabilizing environment to the Protein, the long-term stability of the drug may be compromised by aggregate formation.
