scholarly journals Antibody Disulfide Bond Reduction and Recovery during Biopharmaceutical Process Development - A Review

2020 ◽  
Author(s):  
Tingwei Ren ◽  
Zhijun Tan ◽  
Vivekh Ehamparanathan ◽  
Angela Lewandowski ◽  
Sanchayita Ghose ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Process Development ◽  
High Titer ◽  
Mammalian Cell Culture ◽  
Mitigation Strategy ◽  
Mitigation Strategies ◽  
Molecular Heterogeneity ◽  
Root Cause ◽  
Disulfide Reduction ◽  
Disulfide Bond Reduction

Disulfide bond reduction has been a challenging issue in antibody manufacturing, as it leads to reduced product purity, failed product specifications and more importantly, impacting drug safety and efficacy. Scientists across industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high-titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategy and development of novel approaches to achieve high product quality. Additionally, in recent years as more complex molecules emerge such as bispecific and trispecific antibodies, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative issue. Given the disulfide reduction challenges that our industry are facing, in this review, we provide a comprehensive contemporary scientific insight into the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and recovery based on our expertise in commercial and clinical manufacturing of biologics. First, this paper intended to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discussed disulfide bond reduction impact to product stability and process performance, analytical methods for detection and characterization, process control strategies and their manufacturing implementation. In addition, brief perspectives on development of future mitigation strategies will also be reviewed, including platform alignment, mitigation strategy application for bi- and tri-specific antibodies and using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from both the published papers and our internal development work.

scholarly journals Antibody disulfide bond reduction during process development: Insights using a scale-down model process

2015 ◽  
Vol 9 (S9) ◽  
Author(s):  
Julie Ruaudel ◽  
Martin Bertschinger ◽  
Sonia Letestu ◽  
Roberto Giovannini ◽  
Paul Wassmann ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Process Development ◽  
Scale Down ◽  
Disulfide Bond Reduction

scholarly journals Antibody Disulfide Bond Reduction and Recovery during Biopharmaceutical Process Development ‐ A Review

2021 ◽  
Author(s):  
Tingwei Ren ◽  
Zhijun Tan ◽  
Vivekh Ehamparanathan ◽  
Angela Lewandowski ◽  
Sanchayita Ghose ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Process Development ◽  
Disulfide Bond Reduction

Miniature Bioreactors for Rapid Bioprocess Development of Mammalian Cell Culture

2012 ◽  
Vol 59 (1) ◽  
Author(s):  
Mohd Helmi Sani ◽  
Frank Baganz
Keyword(s):  
Cell Culture ◽  
Mammalian Cell ◽  
Process Development ◽  
Mammalian Cell Culture ◽  
Small Scale ◽  
Cell Culture Process ◽  
Deep Wells ◽  
Working Volume ◽  
Culture Process ◽  
And Control

At present, there are a number of commercial small scale shaken systems available on the market with instrumented controllable microbioreactors such as Micro–24 Microreactor System (Pall Corporation, Port Washington, NY) and M2P Biolector, (M2P Labs GmbH, Aachen, Germany). The Micro–24 system is basically an orbital shaken 24–well plate that operates at working volume 3 – 7 mL with 24 independent reactors (deep wells, shaken and sparged) running simultaneously. Each reactor is designed as single use reactor that has the ability to continuously monitor and control the pH, DO and temperature. The reactor aeration is supplied by sparging air from gas feeds that can be controlled individually. Furthermore, pH can be controlled by gas sparging using either dilute ammonia or carbon dioxide directly into the culture medium through a membrane at the bottom of each reactor. Chen et al., (2009) evaluated the Micro–24 system for the mammalian cell culture process development and found the Micro–24 system is suitable as scaledown tool for cell culture application. The result showed that intra-well reproducibility, cell growth, metabolites profiles and protein titres were scalable with 2 L bioreactors.

scholarly journals Modelling the impact of COVID-19-related control programme interruptions on progress towards the WHO 2030 target for soil-transmitted helminths

2020 ◽  
Author(s):  
Veronica Malizia ◽  
Federica Giardina ◽  
Carolin Vegvari ◽  
Sumali Bajaj ◽  
Kevin McRae-McKee ◽  
...  
Keyword(s):  
Neglected Tropical Diseases ◽  
Control Programme ◽  
Mitigation Strategy ◽  
Mitigation Strategies ◽  
Preventive Chemotherapy ◽  
Soil Transmitted Helminths ◽  
Individual Based Models ◽  
Control Programmes ◽  
Catch Up ◽  
The Impact

Abstract Background On 1 April 2020, the WHO recommended an interruption of all activities for the control of neglected tropical diseases, including soil-transmitted helminths (STH), in response to the COVID-19 pandemic. This paper investigates the impact of this disruption on the progress towards the WHO 2030 target for STH. Methods We used two stochastic individual-based models to simulate the impact of missing one or more preventive chemotherapy (PC) rounds in different endemicity settings. We also investigated the extent to which this impact can be lessened by mitigation strategies, such as semiannual or community-wide PC. Results Both models show that without a mitigation strategy, control programmes will catch up by 2030, assuming that coverage is maintained. The catch-up time can be up to 4.5 y after the start of the interruption. Mitigation strategies may reduce this time by up to 2 y and increase the probability of achieving the 2030 target. Conclusions Although a PC interruption will only temporarily impact the progress towards the WHO 2030 target, programmes are encouraged to restart as soon as possible to minimise the impact on morbidity. The implementation of suitable mitigation strategies can turn the interruption into an opportunity to accelerate progress towards reaching the target.

The Paradox of Climate Change Mitigation and Adaptation in Danish Housing

2012 ◽  
Vol 37 (4) ◽  
pp. 19-28
Author(s):  
Rob Marsh
Keyword(s):  
Climate Change ◽  
Energy Consumption ◽  
Solar Energy ◽  
Theoretical Study ◽  
Climate Adaptation ◽  
Mitigation Strategy ◽  
Mitigation Strategies ◽  
Space Heating ◽  
Climate Mitigation ◽  
Passive Solar

Climate change means that buildings must greatly reduce their energy consumption. It is however paradoxical that climate mitigation in Denmark has created negative energy and indoor climate problems in housing that may be made worse by climate change. A literature review has been carried out of housing schemes where climate mitigation was sought through reduced space heating demand, and it is shown that extensive problems with overheating exist. A theoretical study of regulative and design strategies for climate mitigation in new build housing has therefore been carried out, and it is shown that reducing space heating with high levels of thermal insulation and passive solar energy results in overheating and a growing demand for cooling. Climate change is expected to reduce space heating and increase cooling demand in housing. An analysis of new build housing using passive solar energy as a climate mitigation strategy has therefore been carried out in relation to future climate change scenarios. It is shown that severe indoor comfort problems can occur, questioning the relevance of passive solar energy as a climate mitigation strategy. In conclusion, a theoretical study of the interplay between climate adaptation and mitigation strategies is carried out, with a cross-disciplinary focus on users, passive design and active technologies. It is shown that the cumulative use of these strategies can create an adaptation buffer, thus eliminating problems with overheating and reducing energy consumption. New build housing should therefore be designed in relation to both current and future climate scenarios to show that the climate mitigation strategies ensure climate adaptation.

scholarly journals Quantitative Risk assessment of product disulfide bond reduction in a recombinant protein manufacturing

2021 ◽  
Author(s):  
Yi Qing cui ◽  
rujie meng ◽  
yutong Li
Keyword(s):  
Risk Assessment ◽  
Cell Culture ◽  
Recombinant Protein ◽  
Disulfide Bond ◽  
Culture Fluid ◽  
Culture Conditions ◽  
Quantitative Risk Assessment ◽  
Prevention Measures ◽  
Recombinant Molecule ◽  
Disulfide Bond Reduction

Disulfide bond reduction occurred now and then during a recombinant protein manufacturing. Their reduction often led in the loss of batches. Various prevention measures were developed. Their implementation in a manufacturing inevitably increases its operation complexity and even might impact its product qualities and process performances. It is highly desirable to apply a reduction measure only if necessary and to apply no strong measure if a moderate one works. The reduction occurrence is determined both by the reduction sensitivity of a recombinant molecule and by the reduction power of harvested cell culture fluids. The reduction power of harvested cell culture fluids varies largely and depends on cells, lysis level, growth stage, and culture conditions. The method of the quantitative risk assessment of disulfide bond reduction was reported here. The quantitative assessment is realized by comparing the reduction sensitivity of a recombinant molecule with the reduction power of its harvested cell culture fluid.

Asphaltene Mitigation in Giant Carbonate Abu Dhabi Fields: A Techno-Economic Comparison Between Continuous Injection and Formation Squeeze

2021 ◽  
Author(s):  
Mark Grutters ◽  
Sameer Punnapala ◽  
Dalia Salem Abdallah ◽  
Zaharia Cristea ◽  
Hossam El Din Mohamed El Nagger ◽  
...  
Keyword(s):  
Cost Effective ◽  
Threshold Value ◽  
Field Trials ◽  
Mitigation Strategy ◽  
Operating Conditions ◽  
Mitigation Strategies ◽  
Production Cycle ◽  
Asphaltene Precipitation ◽  
Coiled Tubing ◽  
Continuous Injection

Abstract Asphaltene deposition is a serious and re-occurring flow assurance problem in several of the ADNOC onshore oilfields. Fluids are intrinsically unstable with respect to asphaltene precipitation, and operating conditions are such that severe deposition occurs in the wellbore. Wells in ADNOC are generally not equipped with downhole chemical injection lines for continuous inhibition, and protection of the wells require frequent shut-in and intervention by wireline and coiled tubing to inspect and clean up. Since some of the mature fields are under EOR recovery strategies, like miscible hydrocarbon WAG and CO2 flood, which exacerbates the asphaltene precipitation and deposition problems, a more robust mitigation strategy is required. In this paper the results of two different mitigation strategies will be discussed; continuous injection of asphaltene inhibitor via a capillary line in the tubular and asphaltene inhibitor formation squeeze. Three asphaltene inhibitors from different suppliers were pre-qualified and selected for field trial. Each inhibitor was selected for a formation squeeze in both one horizontal and one vertical well, and one of the inhibitors was applied via thru-tubing capillary string. The field trials showed that continuous injection in remote wells with no real-time surveillance options (e.g. gauges, flow meters) is technically challenging. The continuous injection trial via the capillary string was stopped due to technical challenges. From the six formation squeezes four were confirmed to be effective. Three out of fours squeezes significantly extended the production cycle, from approximately 1.4 to 6 times the normal uninhibited flow period. The most successful squeezes were in the vertical wells. The results of the trial were used to model the economic benefit of formation squeeze, compared to a ‘do-nothing’ approach where the wells are subject to shut-in and cleanup once the production rates drop below a threshold value. The model clearly indicates that the squeezes applied in ADNOC Onshore are only cost-effective if it extends the normal flow period by approximately three times. However, a net gain can be achieved already if the formation squeeze extends the flow cycle by 15 to 20%, due to reduction of shut-in days required for intervention. Therefore, the results in this paper illustrate that an asphaltene inhibitor formation squeeze can be an attractive mitigation strategy, both technically and economically.

scholarly journals Impacts of climate mitigation strategies in the energy sector on global land use and carbon balance

2016 ◽  
Author(s):  
Kerstin Engström ◽  
Mats Lindeskog ◽  
Stefan Olin ◽  
John Hassler ◽  
Benjamin Smith
Keyword(s):  
Climate Change ◽  
Land Use ◽  
Carbon Balance ◽  
Global Economy ◽  
Fossil Fuels ◽  
Carbon Tax ◽  
Mitigation Strategy ◽  
Mitigation Strategies ◽  
Terrestrial Biosphere ◽  
Global Carbon

Abstract. Reducing greenhouse gas emissions to limit climate change-induced damage to the global economy and secure the livelihoods of future generations requires ambitious mitigation strategies. The introduction of a global carbon tax on fossil fuels is tested here as a mitigation strategy to reduce atmospheric CO2 concentrations and radiative forcing. Taxation of fossil fuels potentially leads to changed composition of energy sources, including a larger relative contribution from bioenergy. Further, the introduction of a mitigation strategy reduces climate change-induced damage to the global economy, and thus can indirectly affect consumption patterns and investments in agricultural technologies and yield enhancement. Here we assess the implications of changes in bioenergy demand as well as the indirectly caused changes in consumption and crop yields for global and national cropland area and terrestrial biosphere carbon balance. We apply a novel integrated assessment modelling framework, combining a climate-economy model, a socio-economic land-use model and an ecosystem model. We develop reference and mitigation scenarios based on the Shared Socio-economic Pathways (SSPs) framework. Taking emissions from the land-use sector into account, we find that the introduction of a global carbon tax on the fossil fuel sector is an effective mitigation strategy only for scenarios with low population development and strong sustainability criteria (SSP1 "Taking the green road"). For scenarios with high population growth, low technological development and bioenergy production the high demand for cropland causes the terrestrial biosphere to switch from being a carbon sink to a source by the end of the 21st century.

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