Bingquan wang - Academia.edu (original) (raw)

Papers by Bingquan wang

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze Dried Amorphous Pharmaceuticals: I. Dimer Formation in Sodium Ethacrynate

Journal of Pharmaceutical Sciences, Feb 1, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.

Research paper thumbnail of High-Precision Absolute (True) Density Measurements on Hygroscopic Powders by Gas Pycnometry: Application to Determining Effects of Formulation and Process on Free Volume of Lyophilized Products

Journal of Pharmaceutical Sciences, Jul 1, 2011

As density (free volume) of the amorphous solids should be related to mobility and stability, an ... more As density (free volume) of the amorphous solids should be related to mobility and stability, an attempt was made to develop a simple, sensitive, and reproducible method to evaluate free volume via high-precision gas pycnometry density measurements, and to apply this methodology to study the variation of free volume with formulation and thermal history (i.e., annealing). Annealed samples were prepared either by heating the product after freeze drying (postannealing) or drying at higher temperature in secondary drying than normal (in-process annealing). Density was measured using a gas pycnometer. We find that the key to high-precision density measurements is isolation of the instrument from atmospheric moisture; accordingly, all operations were carried out in a dry box. With suitable care, densities of amorphous freeze-dried products can be measured with a precision of better than 0.5% in a series of independent but nominally identical samples. Density decreased with increasing molecular weight of dextran, but density of proteins was independent of molecular weight. Small but significant increases in density upon annealing were observed for several formulations. Thus, we conclude that accurate density measurements may be made by carefully controlling residual moisture. Density may be a useful parameter to predict long-term stability.

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze-Dried Amorphous Pharmaceuticals: II. Aggregation in an IgG1 Fusion Protein

Journal of Pharmaceutical Sciences, Feb 1, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.

Research paper thumbnail of Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design

Lyophilized Biologics and Vaccines, 2015

The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle i... more The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle in an effective manner where deep understanding is gained through building a scalable freezing step in terms of ice nucleation along with the generation of a primary drying design space. Applying QbD to the design of the cycle allows for the consideration of scalability up front, removing the traditional “trial-and-error” approach, while understanding the performance of the large-scale freeze-dryer. To achieve this, the heat transfer coefficient (K v) of the vial and the product cake resistance (R p) are needed for the mathematical modeling in order to obtain an accurate design space. This chapter explores the latest development and scale-up of the lyophilization process for protein therapeutics in the vial using a QbD approach. Ice nucleation, heat and mass transfer, lyophilization cycle design, and scalability are discussed. A case study is presented for a protein product using both theoretical modeling and experimental scale-down model approach to obtain a wide design space.

Research paper thumbnail of Advances in Process Analytical Technology in Freeze-Drying

Lyophilized Biologics and Vaccines, 2015

Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows... more Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows the online monitoring of critical process parameters to ensure acceptable product quality attributes. This chapter provides a systematic review of latest PAT tools for freeze-drying, with emphasis on suitability for large-scale manufacturing process. Common process monitoring devices such as product temperature sensors (including wireless sensors), Pirani gauge, manometric temperature measurement (MTM), tunable diode laser adsorption spectroscopy (TDLAS), plasma emission spectroscopy (Lyotrack), near-infrared (NIR), and Raman et al. are reviewed in terms of the operation mechanism, major applications, and limitations. These PAT tools are then compared based on their capabilities, practical advantages, and scalability to a large-scale freeze dryer. The criteria of an “ideal” future PAT tool for freeze-drying are then proposed in order to be compliant with the QbD requirements. Finally, the current status of PAT implementation in both development scale and manufacturing scale lyophilizer is discussed, and future implementation of promising PAT tools is proposed.

Research paper thumbnail of Solid state chemistry of proteins: II. The correlation of storage stability of freeze‐dried human growth hormone (hGH) with structure and dynamics in the glassy solid

Journal of Pharmaceutical Sciences, 2008

Research paper thumbnail of High-Precision Absolute (True) Density Measurements on Hygroscopic Powders by Gas Pycnometry: Application to Determining Effects of Formulation and Process on Free Volume of Lyophilized Products

Journal of Pharmaceutical Sciences, 2011

As density (free volume) of the amorphous solids should be related to mobility and stability, an ... more As density (free volume) of the amorphous solids should be related to mobility and stability, an attempt was made to develop a simple, sensitive, and reproducible method to evaluate free volume via high-precision gas pycnometry density measurements, and to apply this methodology to study the variation of free volume with formulation and thermal history (i.e., annealing). Annealed samples were prepared either by heating the product after freeze drying (postannealing) or drying at higher temperature in secondary drying than normal (in-process annealing). Density was measured using a gas pycnometer. We find that the key to high-precision density measurements is isolation of the instrument from atmospheric moisture; accordingly, all operations were carried out in a dry box. With suitable care, densities of amorphous freeze-dried products can be measured with a precision of better than 0.5% in a series of independent but nominally identical samples. Density decreased with increasing molecular weight of dextran, but density of proteins was independent of molecular weight. Small but significant increases in density upon annealing were observed for several formulations. Thus, we conclude that accurate density measurements may be made by carefully controlling residual moisture. Density may be a useful parameter to predict long-term stability.

Research paper thumbnail of Impact of sucrose level on storage stability of proteins in freeze-dried solids: II. Correlation of aggregation rate with protein structure and molecular mobility**This work is a product of the U.S. Government and is not subject to copyright in the United States

Journal of Pharmaceutical Sciences, 2009

The purpose of this study is to investigate the impact of sucrose level on storage stability of d... more The purpose of this study is to investigate the impact of sucrose level on storage stability of dried proteins and thus better understand the mechanism of protein stabilization by disaccharides in lyophilized protein products. Five proteins were freeze dried with different amounts of sucrose, and protein aggregation was quantified using Size Exclusion Chromatography. Protein secondary structure was monitored by FTIR. The global mobility was studied using Thermal Activity Monitor (TAM), and fast local dynamics with a timescale of nanoseconds was characterized by neutron backscattering. The density of the protein formulations was measured with a gas pycnometer. The physical stability of the proteins increased monotonically with an increasing content of sucrose over the entire range of compositions studied. Both FTIR structure and structural relaxation time from TAM achieved maxima at about 1:1 mass ratio for most proteins studied. Therefore, protein stabilization by sugar cannot be completely explained by global dynamics and FTIR structure throughout the whole range of compositions. On the other hand, both the fast local mobility and free volume obtained from density decreased monotonically with an increased level of sucrose in the formulations, and thus the local dynamics and free volume correlate well with protein storage stability.

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze Dried Amorphous Pharmaceuticals: I. Dimer Formation in Sodium Ethacrynate

Journal of Pharmaceutical Sciences, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze Dried Amorphous Pharmaceuticals: I. Dimer Formation in Sodium Ethacrynate

Journal of Pharmaceutical Sciences, Feb 1, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.

Research paper thumbnail of High-Precision Absolute (True) Density Measurements on Hygroscopic Powders by Gas Pycnometry: Application to Determining Effects of Formulation and Process on Free Volume of Lyophilized Products

Journal of Pharmaceutical Sciences, Jul 1, 2011

As density (free volume) of the amorphous solids should be related to mobility and stability, an ... more As density (free volume) of the amorphous solids should be related to mobility and stability, an attempt was made to develop a simple, sensitive, and reproducible method to evaluate free volume via high-precision gas pycnometry density measurements, and to apply this methodology to study the variation of free volume with formulation and thermal history (i.e., annealing). Annealed samples were prepared either by heating the product after freeze drying (postannealing) or drying at higher temperature in secondary drying than normal (in-process annealing). Density was measured using a gas pycnometer. We find that the key to high-precision density measurements is isolation of the instrument from atmospheric moisture; accordingly, all operations were carried out in a dry box. With suitable care, densities of amorphous freeze-dried products can be measured with a precision of better than 0.5% in a series of independent but nominally identical samples. Density decreased with increasing molecular weight of dextran, but density of proteins was independent of molecular weight. Small but significant increases in density upon annealing were observed for several formulations. Thus, we conclude that accurate density measurements may be made by carefully controlling residual moisture. Density may be a useful parameter to predict long-term stability.

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze-Dried Amorphous Pharmaceuticals: II. Aggregation in an IgG1 Fusion Protein

Journal of Pharmaceutical Sciences, Feb 1, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.

Research paper thumbnail of Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design

Lyophilized Biologics and Vaccines, 2015

The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle i... more The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle in an effective manner where deep understanding is gained through building a scalable freezing step in terms of ice nucleation along with the generation of a primary drying design space. Applying QbD to the design of the cycle allows for the consideration of scalability up front, removing the traditional “trial-and-error” approach, while understanding the performance of the large-scale freeze-dryer. To achieve this, the heat transfer coefficient (K v) of the vial and the product cake resistance (R p) are needed for the mathematical modeling in order to obtain an accurate design space. This chapter explores the latest development and scale-up of the lyophilization process for protein therapeutics in the vial using a QbD approach. Ice nucleation, heat and mass transfer, lyophilization cycle design, and scalability are discussed. A case study is presented for a protein product using both theoretical modeling and experimental scale-down model approach to obtain a wide design space.

Research paper thumbnail of Advances in Process Analytical Technology in Freeze-Drying

Lyophilized Biologics and Vaccines, 2015

Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows... more Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows the online monitoring of critical process parameters to ensure acceptable product quality attributes. This chapter provides a systematic review of latest PAT tools for freeze-drying, with emphasis on suitability for large-scale manufacturing process. Common process monitoring devices such as product temperature sensors (including wireless sensors), Pirani gauge, manometric temperature measurement (MTM), tunable diode laser adsorption spectroscopy (TDLAS), plasma emission spectroscopy (Lyotrack), near-infrared (NIR), and Raman et al. are reviewed in terms of the operation mechanism, major applications, and limitations. These PAT tools are then compared based on their capabilities, practical advantages, and scalability to a large-scale freeze dryer. The criteria of an “ideal” future PAT tool for freeze-drying are then proposed in order to be compliant with the QbD requirements. Finally, the current status of PAT implementation in both development scale and manufacturing scale lyophilizer is discussed, and future implementation of promising PAT tools is proposed.

Research paper thumbnail of Solid state chemistry of proteins: II. The correlation of storage stability of freeze‐dried human growth hormone (hGH) with structure and dynamics in the glassy solid

Journal of Pharmaceutical Sciences, 2008

Research paper thumbnail of High-Precision Absolute (True) Density Measurements on Hygroscopic Powders by Gas Pycnometry: Application to Determining Effects of Formulation and Process on Free Volume of Lyophilized Products

Journal of Pharmaceutical Sciences, 2011

As density (free volume) of the amorphous solids should be related to mobility and stability, an ... more As density (free volume) of the amorphous solids should be related to mobility and stability, an attempt was made to develop a simple, sensitive, and reproducible method to evaluate free volume via high-precision gas pycnometry density measurements, and to apply this methodology to study the variation of free volume with formulation and thermal history (i.e., annealing). Annealed samples were prepared either by heating the product after freeze drying (postannealing) or drying at higher temperature in secondary drying than normal (in-process annealing). Density was measured using a gas pycnometer. We find that the key to high-precision density measurements is isolation of the instrument from atmospheric moisture; accordingly, all operations were carried out in a dry box. With suitable care, densities of amorphous freeze-dried products can be measured with a precision of better than 0.5% in a series of independent but nominally identical samples. Density decreased with increasing molecular weight of dextran, but density of proteins was independent of molecular weight. Small but significant increases in density upon annealing were observed for several formulations. Thus, we conclude that accurate density measurements may be made by carefully controlling residual moisture. Density may be a useful parameter to predict long-term stability.

Research paper thumbnail of Impact of sucrose level on storage stability of proteins in freeze-dried solids: II. Correlation of aggregation rate with protein structure and molecular mobility**This work is a product of the U.S. Government and is not subject to copyright in the United States

Journal of Pharmaceutical Sciences, 2009

The purpose of this study is to investigate the impact of sucrose level on storage stability of d... more The purpose of this study is to investigate the impact of sucrose level on storage stability of dried proteins and thus better understand the mechanism of protein stabilization by disaccharides in lyophilized protein products. Five proteins were freeze dried with different amounts of sucrose, and protein aggregation was quantified using Size Exclusion Chromatography. Protein secondary structure was monitored by FTIR. The global mobility was studied using Thermal Activity Monitor (TAM), and fast local dynamics with a timescale of nanoseconds was characterized by neutron backscattering. The density of the protein formulations was measured with a gas pycnometer. The physical stability of the proteins increased monotonically with an increasing content of sucrose over the entire range of compositions studied. Both FTIR structure and structural relaxation time from TAM achieved maxima at about 1:1 mass ratio for most proteins studied. Therefore, protein stabilization by sugar cannot be completely explained by global dynamics and FTIR structure throughout the whole range of compositions. On the other hand, both the fast local mobility and free volume obtained from density decreased monotonically with an increased level of sucrose in the formulations, and thus the local dynamics and free volume correlate well with protein storage stability.

Research paper thumbnail of The Impact of Thermal Treatment on the Stability of Freeze Dried Amorphous Pharmaceuticals: I. Dimer Formation in Sodium Ethacrynate

Journal of Pharmaceutical Sciences, 2010

The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.