Optimization of Reaction Selectivity Using CFD-Based Compartmental Modeling and Surrogate-Based Optimization

Mixing is considered as a critical process parameter (CPP) during process development due to its significant influence on reaction selectivity and process safety. Nevertheless, mixing issues are difficult to identify and solve owing to their complexity and dependence on knowledge of kinetics and hydrodynamics. In this paper, we proposed an optimization methodology using Computational Fluid Dynamics (CFD) based compartmental modelling to improve mixing and reaction selectivity. More importantly, we have demonstrated that through the implementation of surrogate-based optimization, the proposed methodology can be used as a computationally non-intensive way for rapid process development of reaction unit operations. For illustration purpose, reaction selectivity of a process with Bourne competitive reaction network is discussed. Results demonstrate that we can improve reaction selectivity by dynamically controlling rates and locations of feeding in the reactor. The proposed methodology incorporates mechanistic understanding of the reaction kinetics together with an efficient optimization algorithm to determine the optimal process operation and thus can serve as a tool for quality-by-design (QbD) during product development stage.

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Analysis and Model-Based Description of the Total Process of Periodic Deactivation and Regeneration of a VOx Catalyst for Selective Dehydrogenation of Propane

Catalysts ◽

10.3390/catal10121374 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1374

Author(s):

Andreas Brune ◽

Andreas Seidel-Morgenstern ◽

Christof Hamel

Keyword(s):

Catalyst Deactivation ◽

Process Development ◽

Coke Formation ◽

Fixed Bed ◽

Reaction Network ◽

Fixed Bed Reactor ◽

Side Reactions ◽

Model Based ◽

Total Process

This study intends to provide insights into various aspects related to the reaction kinetics of the VOx catalyzed propane dehydrogenation including main and side reactions and, in particular, catalyst deactivation and regeneration, which can be hardly found in combination in current literature. To kinetically describe the complex reaction network, a reduced model was fitted to lab scale experiments performed in a fixed bed reactor. Additionally, thermogravimetric analysis (TGA) was applied to investigate the coking behavior of the catalyst under defined conditions considering propane and propene as precursors for coke formation. Propene was identified to be the main coke precursor, which agrees with results of experiments using a segmented fixed bed reactor (FBR). A mechanistic multilayer-monolayer coke growth model was developed to mathematically describe the catalyst coking. Samples from long-term deactivation experiments in an FBR were used for regeneration experiments with oxygen to gasify the coke deposits in a TGA. A power law approach was able to describe the regeneration behavior well. Finally, the results of periodic experiments consisting of several deactivation and regeneration cycles verified the long-term stability of the catalyst and confirmed the validity of the derived and parametrized kinetic models for deactivation and regeneration, which will allow model-based process development and optimization.

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The Integration of Unit Operations for Bulk Product Manufacture by Continuous?Flow Fermentation Processes?Lessons from SCP Process Development

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1983.tb47908.x ◽

1983 ◽

Vol 413 (1 Biochemical E) ◽

pp. 322-331 ◽

Cited By ~ 2

Author(s):

GEOFFREY HAMER

Keyword(s):

Continuous Flow ◽

Process Development ◽

Fermentation Processes ◽

Unit Operations ◽

Product Manufacture

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Q-SA√ESS: a methodology to help solvent selection for pharmaceutical manufacture at the early process development stage

Green Chemistry ◽

10.1039/c6gc02440h ◽

2016 ◽

Vol 18 (24) ◽

pp. 6564-6572 ◽

Cited By ~ 11

Author(s):

Valerio Isoni ◽

Loretta L. Wong ◽

Hsien H. Khoo ◽

Iskandar Halim ◽

Paul Sharratt

Keyword(s):

Manufacturing Process ◽

Process Development ◽

Development Stage ◽

Solvent Selection ◽

Pharmaceutical Manufacture ◽

Selection For

A practicable, LCA based methodology has been developed to evaluate the sustainability implications of solvent selection during early process development for a batch manufacturing process for an API.

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Semi-Automated Glycoproteomic Data Analysis of LC-MS Data Using GlycopeptideGraphMS in Process Development of Monoclonal Antibody Biologics

Frontiers in Chemistry ◽

10.3389/fchem.2021.661406 ◽

2021 ◽

Vol 9 ◽

Author(s):

Kuin Tian Pang ◽

Shi Jie Tay ◽

Corrine Wan ◽

Ian Walsh ◽

Matthew S. F. Choo ◽

...

Keyword(s):

Data Analysis ◽

Method Development ◽

Process Development ◽

Glycosylation Pattern ◽

Mass Spectrometers ◽

Unit Operations ◽

Therapeutic Outcomes ◽

Analysis Workflow ◽

Fluorescent Tagging ◽

The Right

The glycosylation of antibody-based proteins is vital in translating the right therapeutic outcomes of the patient. Despite this, significant infrastructure is required to analyse biologic glycosylation in various unit operations from biologic development, process development to QA/QC in bio-manufacturing. Simplified mass spectrometers offer ease of operation as well as the portability of method development across various operations. Furthermore, data analysis would need to have a degree of automation to relay information back to the manufacturing line. We set out to investigate the applicability of using a semiautomated data analysis workflow to investigate glycosylation in different biologic development test cases. The workflow involves data acquisition using a BioAccord LC-MS system with a data-analytical tool called GlycopeptideGraphMS along with Progenesis QI to semi-automate glycoproteomic characterisation and quantitation with a LC-MS1 dataset of a glycopeptides and peptides. Data analysis which involved identifying glycopeptides and their quantitative glycosylation was performed in 30 min with minimal user intervention. To demonstrate the effectiveness of the antibody and biologic glycopeptide assignment in various scenarios akin to biologic development activities, we demonstrate the effectiveness in the filtering of IgG1 and IgG2 subclasses from human serum IgG as well as innovator drugs trastuzumab and adalimumab and glycoforms by virtue of their glycosylation pattern. We demonstrate a high correlation between conventional released glycan analysis with fluorescent tagging and glycopeptide assignment derived from GraphMS. GraphMS workflow was then used to monitor the glycoform of our in-house trastuzumab biosimilar produced in fed-batch cultures. The demonstrated utility of GraphMS to semi-automate quantitation and qualitative identification of glycopeptides proves to be an easy data analysis method that can complement emerging multi-attribute monitoring (MAM) analytical toolsets in bioprocess environments.

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Midstream unit operations: unsung heroes in AAV process development

Cell and Gene Therapy Insights ◽

10.18609/cgti.2021.173 ◽

2021 ◽

Vol 7 (10) ◽

pp. 1309-1321

Author(s):

Ratish Krishnan ◽

◽

Matthew Roach

Keyword(s):

Process Development ◽

Unit Operations

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Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable Without a Digital-Twin?

Processes ◽

10.3390/pr7020094 ◽

2019 ◽

Vol 7 (2) ◽

pp. 94 ◽

Cited By ~ 25

Author(s):

Steffen Zobel-Roos ◽

Axel Schmidt ◽

Fabian Mestmäcker ◽

Mourad Mouellef ◽

Maximilian Huter ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Process Development ◽

Process Analytical Technology ◽

Control Strategies ◽

Development Stage ◽

Point Of View ◽

Digital Twin ◽

Market Competitiveness ◽

Digital Twins ◽

Potential Methods

Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?

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An Alternative Process for Butanol Production: Continuous Flash Fermentation

Chemical Product and Process Modeling ◽

10.2202/1934-2659.1226 ◽

2008 ◽

Vol 3 (1) ◽

Cited By ~ 4

Author(s):

Adriano Pinto Mariano ◽

Dejanira de Franceschi de Angelis ◽

Francisco Maugeri Filho ◽

Daniel Ibraim Pires Atala ◽

Maria Regina Wolf Maciel ◽

...

Keyword(s):

Process Development ◽

Inhibitory Effect ◽

Development Stage ◽

Final Concentration ◽

Environmental Benefits ◽

Sugar Solution ◽

Butanol Production ◽

Retention System ◽

Butanol Concentration ◽

Sugar Conversion

The objective of this work is to introduce and demonstrate the technical feasibility of the continuous flash fermentation for the production of butanol. The evaluation was carried out through mathematical modeling and computer simulation which is a good approach in such a process development stage. The process consists of three interconnected units, as follows: the fermentor, the cell retention system (tangential microfiltration) and the vacuum flash vessel (responsible for the continuous recovery of butanol from the broth). The efficiency of this process was experimentally validated for the ethanol fermentation, whose main results are also shown. With the proposed design the concentration of butanol in the fermentor was lowered from 11.3 to 7.8 g/l, which represented a significant reduction in the inhibitory effect. As a result, the final concentration of butanol was 28.2 g/l for a broth with 140 g/l of glucose. Solvents productivity and yield were, respectively, 11.7 g/l.h and 33.5 % for a sugar conversion of 95.6 %. Positive aspects about the flash fermentation process are the solvents productivity, the use of concentrated sugar solution and the final butanol concentration. The last two features can be responsible for a meaningful reduction in the distillation costs and result in environmental benefits due to lower quantities of wastewater generated by the process.

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Virtual Thermocouple: A Non-Invasive Multipoint Product Temperature Measurement for Lyophilization

10.21203/rs.3.rs-1093493/v1 ◽

2021 ◽

Author(s):

Xiaofan Jiang ◽

Petr Kazarin ◽

Michael Sinanis ◽

Nithin Raghunathan ◽

Alina Alexeenko ◽

...

Keyword(s):

Temperature Measurement ◽

Process Development ◽

Threshold Value ◽

Development Stage ◽

Temperature Sensing ◽

Critical Importance ◽

Point Temperature ◽

Product Temperature ◽

Non Invasive ◽

Drying Behavior

Abstract Monitoring product temperature during lyophilization is of critical importance, especially during the process development stage, as the final product may be jeopardized if its process temperature exceeds a threshold value. While conventional thermocouples can track product temperature, they are invasive and can significantly alter the freezing and drying behavior. In this work, a new methodology for non-invasive product temperature monitoring and drying behavior during the entire lyophilization process is proposed and experimentally validated. The method is based on a new flexible wireless multi-point temperature sensing probe that is attached to the outside of the vial. Combining the wirelessly-collected data with advanced multi-physics simulations allows the accurate extraction of the product temperature non-invasively.

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