Design Of Downstream Processes Research Articles

Solvent selection for chemical reactions toward optimal thermodynamic and kinetic performances: Group contribution and COSMO-based modeling

The chemical industry makes extensive use of solvents in both reaction and separation processes. The large number of existing and potentially new solvents calls for systematic methods for optimal solvent selection and design to reduce experimental efforts and accelerate process development in the early phase. There have been numerous contributions made towards the optimal selection and design of solvents as mass separating agents for various separation processes. In comparison, despite of the strong impact of solvents on chemical reactions by changing the reaction rate and/or shifting the chemical equilibrium, limited work on reaction solvent selection has been reported. Moreover, there is still a lack of insightful perspective article on model-based reaction solvent selection/design. In this work, we address this shortcoming by summarizing the state-of-the-art studies on reaction solvent selection/design using various computational methods, with a focus on group contribution and conductor-like screening model (COSMO)-based modeling approaches. Solvent selections for reactions integrated with up- and/or downstream process design, including the impact of catalyst and a group contribution extension to the COSMO models, are highlighted as potential future directions.

Decay of Trichomes of Arthrospira platensis After Permeabilization Through Pulsed Electric Fields (PEFs) Causes the Release of Phycocyanin

The cyanobacterium Arthrospira platensis is a promising source of edible proteins and other highly valuable substances such as the blue pigment-protein complex phycocyanin. Pulsed electric field (PEF) technology has recently been studied as a way of permeabilizing the cell membrane, thereby enhancing the mass transfer of water-soluble cell metabolites. Unfortunately, the question of the release mechanism is not sufficiently clarified in published literature. In this study, the degree of cell permeabilization (cell disintegration index) was directly measured by means of a new method using fluorescent dye propidium iodide (PI). The method allows for conclusions to be drawn about the effects of treatment time, electric field strength, and treatment temperature. Using a self-developed algorithm for image segmentation, disintegration of trichomes was observed over a period of 3 h. This revealed a direct correlation between cell disintegration index and decay of trichomes. This decay, in turn, could be brought into a direct temporal relationship with the release of phycocyanin. For the first time, this study reveals the relationship between permeabilization and the kinetics of particle decay and phycocyanin extraction, thus contributing to a deeper understanding of the release of cell metabolites in response to PEF. The results will facilitate the design of downstream processes to produce sustainable products from Arthrospira platensis.

A Gas Generating System for Complex Gas Mixtures – Multifunctional Application in PTR Method Optimization and Downstream Methanol Synthesis

AbstractThe multifunctional applicability of a gas mixing system is presented within the scope of Carbon2Chem® for the simulation of steel mill flue gases and their application in downstream processes. A special focus is set on the parallel operation of the gas mixing system to enable PTR‐MS method optimization and methanol synthesis with simulated real gas matrices. Information is gathered for the design of downstream processes and their application, where methanol synthesis is chosen as a model reaction. A proof‐of‐principle study is presented where operation of a catalytic reactor setup in combination with the gas mixing system and a compressor generate reproducible results. The addition of potential trace components in methanol synthesis is exemplarily demonstrated using ammonia. With respect to the PTR‐MS application, the dosing of two calibration gas standards, toluene and carbonyl sulfide, via the gas mixing system were analyzed in detail. The obtained results give insight into its applicability to simulate traces and enables the further development of analytical methods for the analysis of trace impurities in the ppb and ppt range in complex gas mixtures.

Mn-doped Ca2Fe2O5 oxygen carrier for chemical looping gasification of biogas residue: Effect of oxygen uncoupling

Anaerobic digestion is an important approach to treat and utilize kitchen waste, while kitchen waste derived biogas residue (BR) disposal remains a serious problem in this process. This study investigated the feasibility of chemical looping gasification (CLG) as an efficient way to treat and generate syngas from BR. Besides, Mn-doped Ca2Fe2O5 (MCF) as a novel oxygen carrier with mild oxygen uncoupling capability was developed, and its performance against traditional Ca2Fe2O5 (CF) oxygen carrier was compared. Results indicated that, significant oxygen release capability was observed on the prepared MCF oxygen carrier. In the gasification tests, CLG with MCF at 800 ℃ showed optimal total gas yield, carbon conversion, and cold gas efficiency, which increased 0.08 Nm3/kg, 17.22%, and 13.37% compared to CF, respectively. According to the XPS, H2-TPR and XRD characterization results, the optimal performance of MCF could be attributed to the oxygen uncoupling characteristic brought by Mn addition. The formation of the oxygen uncoupling capability of MCF could be explained by three reasons: (1) Mn in MCF mainly existed in form of Mn3+ and Mn4+, which resulted in the extremely strong oxidability at a temperature as low as 250 ℃. (2) The higher Fe3+/Fe2+ ratio of 1.55 in MCF than CF caused by Mn addition led to greater oxidability of Fe ions. (3) MCF had a higher lattice oxygen amount than CF at about 3.86%, and the lattice oxygen in its crystal structure had been transformed into active lattice oxygen species, which were between lattice oxygen (O2–) and atomic adsorbed oxygen (O−). As a result, this paper investigated the potential of CLG to treat and utilized BR, and the superiority of CLG with oxygen uncoupling (CLGOU) on MCF was highlighted. It’s hoped that this study could provide a fundamental knowledge on CLG and CLGOU of BR, and benefit to better downstream process design of anaerobic digestion industry.

Evaluation of ePC-SAFT for pH Calculation in Aqueous Itaconic Acid Solutions at High Ionic Strengths

In the context of the raw material change for sustainable production of chemicals, the selected bio-based amino acids and carboxylic acids are considered as promising platform chemicals. After fermentation, the acids are present in aqueous solutions with many side components and elevated ionic strength. The ionic strength is even further increased when pH-shift operations are applied for the separation of the target compounds. Since high ionic strengths strongly affect the solution properties, particularly the solid–liquid-equilibrium and the dissociation equilibrium in the solution, the high ionic strengths and the resulting effects on the solutions must also be taken into account in process modeling and the design of downstream processes. Various models have been reported in the literature but the majority cannot be applied for predicting the solution composition and pH at high ionic strengths. In this work, a procedure for the calculation of the composition, i.e. the distribution of the present species and pH, of aqueous itaconic acid solutions based on ePC-SAFT is developed and evaluated at different levels of ionic strengths. The ePC-SAFT parameters of itaconic acid are determined based on experimental solubility data from literature. The resulting model is validated with experimentally measured titration curves and compared with the ideal model and the Davies approximation to the Debye–Hückel model. It is demonstrated that the ePC-SAFT approach provides reliable results at high ionic strengths with lower deviations from experimental data than current literature models.

Medium optimization and downstream process design for the augmented yield of β-Carotene using fungi Blakeslea trispora

Purposeβ-Carotene is the most appropriate and significant precursor of vitamin A. Synthetic carotene supplements have been known to pose a threat to human health, making natural sources such as the indefensible choice for the production and extraction of carotene.Design/methodology/approachThis study considers Blakeslea trispora, a filamentous fungus, as a source of production of carotenoids by fermentation and wet and dry mycelium were used to analyse and obtain better extraction results.FindingsIn this study, natural oils such as soy oil and cottonseed oil were incorporated into fermentation media to increase the production of carotene. For the optimization process, Plackett–Burman and one-factor-at-a-time (OVAT) models were identified as being of great value.Originality/valueOVAT was carried out for corn starch because it plays a major role in the production of carotene and the corn starch at 30 g/L concentration has shown the maximum activity of 3.48 mg/gm. After optimizing process variables, submerged fermentation was eventually carried out under highly controlled media conditions. The resulting product was quantified using UV spectroscopy and extraction of carotene has been observed in the presence of various solvents. Among a range of solvents used, the methylene Di chloride produced-carotene at 86% recovery at a significantly lower temperature of 35°C.

Safety risk management for low molecular weight process-related impurities in monoclonal antibody therapeutics: Categorization, risk assessment, testing strategy, and process development with leveraging clearance potential.

Process‐related impurities (PRIs) derived from manufacturing process should be minimized in final drug product. ICH Q3A provides a regulatory road map for PRIs but excludes biologic drugs like monoclonal antibodies (mAbs) that contain biological PRIs (e.g. host cell proteins and DNA) and low molecular weight (LMW) PRIs (e.g., fermentation media components and downstream chemical reagents). Risks from the former PRIs are typically addressed by routine tests to meet regulatory expectations, while a similar routine‐testing strategy is unrealistic and unnecessary for LMW PRIs, and thus a risk‐assessment‐guided testing strategy is often utilized. In this report, we discuss a safety risk management strategy including categorization, risk assessment, testing strategy, and its integrations with other CMC development activities, as well as downstream clearance potentials. The clearance data from 28 mAbs successfully addressed safety concerns but did not fully reveal the process clearance potentials. Therefore, we carried out studies with 13 commonly seen LMW PRIs in a typical downstream process for mAbs. Generally, Protein A chromatography and cation exchange chromatography operating in bind‐and‐elute mode showed excellent clearances with greater than 1,000‐ and 100‐fold clearance, respectively. The diafiltration step had better clearance (greater than 100‐fold) for the positively and neutrally charged LMW PRIs than for the negatively charged or hydrophobic PRIs. We propose that a typical mAb downstream process provides an overall clearance of 5,000‐fold. Additionally, the determined sieving coefficients will facilitate diafiltration process development. This report helps establish effective safety risk management and downstream process design with robust clearance for LMW PRIs.

Understanding the mechanism of copurification of "difficult to remove" host cell proteins in rituximab biosimilar products.

Host cell proteins (HCPs) are considered a critical quality attribute and are linked to safety and efficacy of biotherapeutic products. Researchers have identified 10 HCPs in Chinese hamster ovary (CHO) that exhibit common characteristics of product association, coelution, and age-dependent expression and therefore are "difficult to remove" during downstream purification. These include cathepsin D, clusterin, galectin-3-binding protein, G-protein coupled receptor 56, lipoprotein lipase, metalloproteinase inhibitor, nidogen-1 secreted protein acidic and rich in cysteine (SPARC), sulfated glycoprotein, and insulin-like growth factor-2 RNA-binding protein. While the levels of HCPs in the investigated biosimilars were within the acceptable range of <100 ppm, certain "difficult to remove" HCPs were found in the biosimilar samples. This article aims to elucidate the underlying interactions between these "difficult to remove" HCPs and the mAb product. Surface study of rituximab exhibited unstable discontinuous patches of residues on the protein surface that have high propensity to get buried and lower the solvent exposed area. The higher order structure and the receptor binding were not affected, except for one of the biosimilars, owing to extremely low-HCP levels in its final drug product. Finally, based on the combined experimental and computational data from this study, a probable mechanism of retention for the 10 HCPs is proposed. The results presented here can guide downstream process design or avenues for protein engineering during product discovery to achieve more effective removal of the impurities.

Micromechanics of Anisotropic Cross-Linked Enzyme Crystals

Catalytic activity of protein crystals correlates with their particle size due to diffusion limitations. However, because the particles need to be restrained during, e.g., a filtration process, keeping a minimum particle size is required. Thus, knowledge of mechanical properties of enzyme crystals is needed for downstream process design in the biopharmaceutical industry to avoid particle breakage. In this study, hardness and Young’s modulus of cross-linked lysozyme crystals and cross-linked halohydrin dehalogenase from Ilumatobacter coccineus (HheG) crystals are evaluated using atomic force microscopy. The results show that hardness of lysozyme and HheG crystals is in the range of 2–22 MPa. For Young’s modulus of lysozyme crystals, values between 40 and 1820 MPa are measured, while HheG crystals ranging between 40 and 1200 MPa, respectively. The results for lysozyme crystals are comparable to those published in the current literature on native protein crystals. Hence, the cross-linking seems not to signif...

Investigation on CO2 bio-mitigation using Halomonas stevensii in laboratory scale bioreactor: Design of downstream process and its economic feasibility analysis

In the present study, H. stevensii was cultivated on a semi-continuous mode in a laboratory scale bio-reactor using CO2(g) [15% (v/v)] as carbon source and thiosulfate (S2O32−) as an energy source for the total duration of three days. Approximately, 100% CO2(g) removal from gaseous phase was achieved. Leachate obtained was subjected to different downstream bio-processing strategies. Biomass harvesting using filtration and recovery of metabolites without cell disruption using solvent extraction from wet biomass was observed as the best downstream processing strategy. Qualitative analysis of products was carried out using gas chromatography and mass spectroscopy (GC–MS) and their results have indicated fatty alcohols (C8–C27) as primary metabolites. Fourier transform infrared spectroscopy (FTIR) analysis, approximate material balance and thermodynamic analysis have confirmed the intracellular assimilation of CO2(g) as HCO3− and its metabolization into fatty alcohols. Economic feasibility of the process has suggested that the developed downstream process has the capability to replace coconut oil based process for the production of fatty alcohols (C12–C14) and it can be utilized for the production of dodecanol as compared to the tetradecanol.

Determination of protein phase diagrams by microbatch experiments: Exploring the influence of precipitants and pH

Knowledge of protein phase behavior is essential for downstream process design in the biopharmaceutical industry. Proteins can either be soluble, crystalline or precipitated. Additionally liquid–liquid phase separation, gelation and skin formation can occur. A method to generate phase diagrams in high throughput on an automated liquid handling station in microbatch scale was developed. For lysozyme from chicken egg white, human lysozyme, glucose oxidase and glucose isomerase phase diagrams were generated at four different pH values – pH 3, 5, 7 and 9. Sodium chloride, ammonium sulfate, polyethylene glycol 300 and polyethylene glycol 1000 were used as precipitants. Crystallizing conditions could be found for lysozyme from chicken egg white using sodium chloride, for human lysozyme using sodium chloride or ammonium sulfate and glucose isomerase using ammonium sulfate. PEG caused destabilization of human lysozyme and glucose oxidase solutions or a balance of stabilizing and destabilizing effects for glucose isomerase near the isoelectric point. This work presents a systematic generation and extensive study of phase diagrams of proteins. Thus, it adds to the general understanding of protein behavior in liquid formulation and presents a convenient methodology applicable to any protein solution.

Estimation of particle size distribution and aspect ratio of non-spherical particles from chord length distribution

Information about size and shape of particles produced in various manufacturing processes is very important for process and product development because design of downstream processes as well as final product properties strongly depend on these geometrical particle attributes. However, recovery of particle size and shape information in situ during crystallisation processes has been a major challenge. The focused beam reflectance measurement (FBRM) provides the chord length distribution (CLD) of a population of particles in a suspension flowing close to the sensor window. Recovery of size and shape information from the CLD requires a model relating particle size and shape to its CLD as well as solving the corresponding inverse problem.This paper presents a comprehensive algorithm which produces estimates of particle size distribution and particle aspect ratio from measured CLD data. While the algorithm searches for a global best solution to the inverse problem without requiring further a priori information on the range of particle sizes present in the population or aspect ratio of particles, suitable regularisation techniques based on relevant additional information can be implemented as required to obtain physically reasonable size distributions. We used the algorithm to analyse CLD data for samples of needle-like crystalline particles of various lengths using two previously published CLD models for ellipsoids and for thin cylinders to estimate particle size distribution and shape. We found that the thin cylinder model yielded significantly better agreement with experimental data, while estimated particle size distributions and aspect ratios were in good agreement with those obtained from imaging.

A New Downstream Process Design for a Fluid Catalytic Cracking Unit to Raise Propylene Yield and Decrease Gasoline Olefin Content

Based on the paraffins, olefins, naphthenes, aromatics (PONA) composition of crude light gasoline, crude heavy gasoline, stabilized gasoline, and wet gas of a pilot plant fluid catalytic cracking (FCC) unit, it was found that the root cause of high gasoline olefin content and low propylene yield was low C5 and C6 olefin content of crude light gasoline. A new design for the main fractionater and absorber–stripper–stabilizer was presented to obtain stabilized light gasoline that contains more C5 and C6 olefins recracked in the secondary riser. Industrial studies on the revamped unit showed that gasoline olefin content was decreased markedly, though research octane number (RON) was preserved. In addition, propylene yield was raised to a higher level and unit energy consumption (or operating cost) was not increased.

Process Development and Design of Downstream Processes

AbstractState‐of‐the‐art of process development, scale‐up and design for downstream processes is described for complex mixtures in biotechnology. The focus is on fermentation broth and plant‐based extracts to derive methodological arguments. Academic and industrial approaches are discussed with an assessment based on some process relevant criteria. Examples of monoclonal antibody, insulin and penicillin production processes are chosen to develop a sound argumentative basis. Demands of total process integration, accuracy and sensitivity of phenomena, resulting e.g. in miniaturization of laboratory experiments and linked with necessary in‐depth modeling are developed and implemented. Specific tasks of unit operation are displayed and their integration into an efficient process sequence is demonstrated. Based on that, further research needs are pointed out and corresponding activities are identified. For instance, the transfer of well established methods in chemical engineering like process modeling in combination with laboratory scale experiments and final miniplant validation should be followed consequently also in biotechnology applications. Some drawbacks in academic education and industrial training as well as organizational structures are discussed to help address this issue.

Profiling of host cell proteins by two‐dimensional difference gel electrophoresis (2D‐DIGE): Implications for downstream process development

Host cell proteins (HCPs) constitute a major group of impurities for biologic drugs produced using cell culture technology. HCPs are required to be closely monitored and adequately removed in the downstream process. However, HCPs are a complex mixture of proteins with significantly diverse molecular and immunological properties. An overall understanding of the composition of HCPs and changes in their molecular properties upon changes in upstream and harvest process conditions can greatly facilitate downstream process design. This article describes the use of a comparative proteomic profiling method viz. two-dimensional difference gel electrophoresis (2D-DIGE) to examine HCP composition in the harvest stream of CHO cell culture. The effect of upstream process parameters such as cell culture media, bioreactor control strategy, feeding strategy, and cell culture duration/cell viability on HCP profile was examined using this technique. Among all the parameters studied, cell viability generated the most significant changes on the HCP profile. 2D-DIGE was also used to compare the HCP differences between monoclonal antibody producing and null cell cultures. The HCP species in production cell culture was found to be well represented in null cell culture, which confirms the suitability of using the null cell culture for immunoassay reagent generation. 2D-DIGE is complimentary to the commonly used HCP immunoassay. It provides a direct comparison of the changes in HCP composition under different conditions and can reveal properties (pI, MW) of individual species, whereas the immunoassay sensitively quantifies total HCP amount in a given sample.

Optimizing the Concurrency for a Group of Design Activities

This research focuses upon the optimization of the concurrency between upstream product design activity and downstream process design activities in the concurrent engineering product development pattern. First, a new model of concurrent product development process, i.e., the design activity group model, is built. In this model, the product and process design activities are carried out concurrently with the whole design process divided into several stages, every two of which are separated by a design review activity. The design review activities may lead to design iterations at a certain rate of probability. Therefore, a probability theory-based method is proposed to compute the mean duration of the design activity group and the mean workloads of all the design and review activities, with design iterations taken into consideration. Then, the problem of concurrency optimization is defined mathematically, whose objective is to minimize the total costs for delay of design activity group completion time and unnecessary design revision workloads. Our research proves that the cost function is convex with respect to the concurrent (or overlap) degree between design activities and that it must have a minimum value at a unique optimum point. Based on this property, a one-dimensional search algorithm that is exponentially converged is finally proposed for solving the problem.

A design environment for downstream processes for Bioprocess-Engineering students

A bioprocess engineer should have at least a set of basic design skills. Bioprocess design is a complex cognitive skill, which should be trained in every year of an academic Bioprocess-Engineering curriculum. However, there is little existing learning material to support the initial training of design skills early in the curriculum. For this reason a web-based DownStream Process Design environment has been developed, called DSPD. This article describes the design criteria for the development of this design environment. It describes the design environment itself and it gives an impression of the use of the design environment in a course for first-year students.

A Quantitative Approach to the Process Modeling and Planning in Concurrent Engineering

This paper deals with the quantitative modeling and planning of the product development process in concurrent engineering (CE). CE requires that product design and its related process design be carried out concurrently. Many existing CE models highlight the impact of the upstream design on the downstream design. While in our research, a quantitative model of the product development process in CE based on the network of product-process design activity pairs is presented to describe both the impact of the upstream product design on the downstream process design and the process design's ability of discovering the faults in the product design. Based on this model, a method is presented to determine the appropriate concurrency degree between the product and process design activities and estimate the mean duration of product-process design activity pair. Then an approach is proposed to solve the integrated optimization problem of both the allocation of resources and the planning of the product development process in CE. Its objective is to allocate the resources for the product development project reasonably to complete it before the due date, minimize its lead-time and keep the average resource utilization rate above a given level. Unlike other project scheduling problems with pre-determined numbers of the resources allocated for the project, in our research, the numbers of the resources allocated for the project are determined along with the project planning. To solve the problem, a branch-and-bound algorithm is proposed and a heuristic rule is introduced to improve its efficiency. The computational result of an example from an automobile factory shows the effectiveness of the algorithm.

Optimal Design of Downstream Processes by Considering Interactions between Chromatography and Crystallisation in Biotechnology

Chemie Ingenieur TechnikVolume 73, Issue 6 p. 734-734 Article Optimal Design of Downstream Processes by Considering Interactions between Chromatography and Crystallisation in Biotechnology S. Jünemann, S. Jünemann D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorA. Jupke, A. Jupke D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorF. Giesselmann, F. Giesselmann D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorA. Epping, A. Epping D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorH. Schmidt-Traub, H. Schmidt-Traub D-Dortmund; D-Witten; D-DortmundSearch for more papers by this author S. Jünemann, S. Jünemann D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorA. Jupke, A. Jupke D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorF. Giesselmann, F. Giesselmann D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorA. Epping, A. Epping D-Dortmund; D-Witten; D-DortmundSearch for more papers by this authorH. Schmidt-Traub, H. Schmidt-Traub D-Dortmund; D-Witten; D-DortmundSearch for more papers by this author First published: 12 July 2001 https://doi.org/10.1002/1522-2640(200106)73:6<734::AID-CITE7341111>3.0.CO;2-SAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume73, Issue6Juni 2001Pages 734-734 RelatedInformation

Yeast cell permeabilizing β-1,3-Glucanases: A tool for the integration of downstream processes and metabolic engineering applications to yeast

In this article, we consider the impact on downstream process design resulting from the use of metabolically engineered yeast strains. We address the issue of how manipulation of cell wall permeability can improve the release and subsequent recovery of heterologous products produced in yeast.