Effect Of Critical Process Parameters Research Articles

Non-planar 5-axis directional additive manufacturing of plastics: Machine, process, and tool path

Additive manufacturing (AM) of plastics is a rising research and application area for light weighting. The conventional way of AM is conducted layer-by-layer, whereas recently non-planar AM is proposed with several advantages such as better use of the material through decreased weight-to-strength ratio, reuse of support material and increased conformity for AM of complex shapes. As for all the tool path-based manufacturing processes, generation of the tool path, selection of process parameters and the machine tool configuration significantly affects the product quality. In this study, non-planar AM of plastics is handled in a holistic manner covering tool path, process, and machine perspectives. Tool path generation for non-planar and directional AM is discussed in accordance with the CAD-CAM software, where the tool path is generated using a novel approach which works with the bead directions obtained from FEM based mechanical analysis. The effects of critical process parameters on the geometrical conformity for non-planar AM are discussed through visual inspection. The proposed cluster-based tool path planning is successfully shown demonstrated from the geometrical perspective.

Optimization of laser-based glass frit bonding for optoelectronic packaging using response surface methodology

Laser-based glass frit bonding presents considerable advantages, including fast bonding speed and minimal thermal impact, showing significant application prospects in the packaging of temperature-sensitive optoelectronic devices. In this study, the individual effects of critical process parameters on bonding performance have been investigated through single-factor experiments. Response surface methodology is employed to design experiments systematically for the laser-based glass frit bonding process, focusing on exploring the interactive effects among these process parameters. The Box-Behnken design method is implemented for experimental setup, and a regression model has been developed to analyze the resulting data. Analysis of variance, 3D response surface plots, and contour plots are conducted to comprehensively evaluate the interaction effects of parameters on the bonding seam width and strength. The mathematical model is validated and an optimal combination of process parameters is identified, which significantly enhances the bonding quality. The optimized process parameters are also applied for the laser bonding of square-shaped seam to validate the feasibility of the optimized results and to promote the engineering application of glass laser-based glass frit bonding technology in microelectronic component packaging. Inspection of the bonded specimens shows excellent formation quality of the square-shaped bonding seams, confirming the methodology’s effectiveness in advancing optoelectronic packaging technology.

Scalable microfluidic method for tunable liposomal production by a design of experiment approach

Liposomes constitute a widespread drug delivery platform, gaining more and more attention from the pharmaceutical industry and process development scientists. Their large-scale production as medicinal products for human use is all but trivial, especially when parenteral administration is required. In this study an off-the-shelf microfluidic system and a methodological approach are presented for the optimization, validation and scale-up of highly monodisperse liposomes manufacturing. Starting from a Doxil®-like formulation (HSPC, MPEG-DSPE and cholesterol), a rational approach (Design of Experiments, DoE) was applied for the screening of the process parameters affecting the quality attributes of the product (mainly size and polydispersity). Additional DoEs were conducted to determine the effect of critical process parameters “CPPs” (cholesterol concentration, total flow rate “TFR” and flow rate ratio “FRR”), thus assessing the formulation and process robustness. A scale-up was then successfully accomplished. The procedure was applied to a Marqibo®-like formulation as well (sphingomyelin and cholesterol) to show the generality of the proposed formulation, process development and scale-up approach. The application of the system and method herein presented enables the large-scale manufacturing of liposomes, in compliance with the internationally recognized regulatory standards for pharmaceutical development (Quality by Design).

Failure analysis and formability improvement of GLARE laminates in warm active hydroforming technology: Experimental and numerical approach

Warm hydroforming shows considerable promise as a forming technology for Fiber Metal Laminates (FMLs) parts due to its capacity to enhance the formability of materials. However, a detailed investigation into the failure behavior during hydroforming is still lacking. In this paper, a systematic experiment was performed to analyze the possible failure modes for GLARE in warm active hydroforming. Five main defect modes have been identified, including fiber crack, combined Al & fiber crack, wrinkle, low resin, and voids defects. The related formation mechanisms have been analyzed based on both experiments and numerical methods. Additionally, the effects of critical process parameters, including the blank holder force (BHF), liquid pressure rate (PR), and temperature (T) on failure behavior are thoroughly investigated and quantified. The use of step-loading BHF was recommended to enhance formability, which caused a nearly 36% decrease in the prepreg tensile damage criteria coefficient. Conversely, decreasing PR or increasing T significantly improved the formability of GLARE but resulted in low resin content and significant void defects. Consequently, a feasibility map that quantified the BHF and liquid pressure effects on various defects was developed, leading to optimized parameters for manufacturing a box-shaped part. This study not only explores the failure model of FMLs but also offers valuable insights for process parameter improvement and how to optimize key parameters in engineering processes.

A Review on Quality by Design

The recent advancement in pharmaceutical quality, known as "quality by design" or "QbD," is crucial. Every regulatory authority for pharmaceutical products has placed a high priority on quality. In terms of services, goods, and procedures, quality means client satisfaction. All pharmaceutical items can be made with higher quality by using QbD. This essay discusses the use of Quality by Design (QbD) in the pharmaceutical industry and how it may be used to guarantee the accuracy of pharmaceutical analyses. It's critical to recognise your desired product performance report within this notion of being throughout product design and growth. the quality target product profile (QTPP), the target product profile (TPP), and the identification of essential quality attributes (CQA). Understanding the effects of critical process parameters (CPP), critical material attributes (CAM), and raw material.

Multivariate data analysis of process parameters affecting the growth and productivity of stable Chinese hamster ovary cell pools expressing SARS-CoV-2 spike protein as vaccine antigen in early process development.

The recent COVID-19 pandemic revealed an urgent need to develop robust cell culture platforms which can react rapidly to respond to this kind of global health issue. Chinese hamster ovary (CHO) stable pools can be a vital alternative to quickly provide gram amounts of recombinant proteins required for early-phase clinical assays. In this study, we analyze early process development data of recombinant trimeric spike protein Cumate-inducible manufacturing platform utilizing CHO stable pool as a preferred production host across three different stirred-tank bioreactor scales (0.75, 1, and 10 L). The impact of cell passage number as an indicator of cell age, methionine sulfoximine (MSX) concentration as a selection pressure, and cell seeding density was investigated using stable pools expressing three variants of concern. Multivariate data analysis with principal component analysis and batch-wise unfolding technique was applied to evaluate the effect of critical process parameters on production variability and a random forest (RF) model was developed to forecast protein production. In order to further improve process understanding, the RF model was analyzed with Shapley value dependency plots so as to determine what ranges of variables were most associated with increased protein production. Increasing longevity, controlling lactate build-up, and altering pH deadband are considered promising approaches to improve overall culture outcomes. The results also demonstrated that these pools are in general stable expressing similar level of spike proteins up to cell passage 11 (~31 cell generations). This enables to expand enough cells required to seed large volume of 200-2000 L bioreactor.

In-situ synthesis of nitrides and oxides through controlling reactive gas atmosphere during laser-powder bed fusion of Fe-12Cr-6Al

This study endeavors to investigate the feasibility of in situ synthesis of nitrides and oxides within Fe-12Cr-6Al alloys through precise modulation of reactive gas atmosphere during the Laser-Powder Bed Fusion process. A focused study on elucidating the effects of critical process parameters, such as laser power, scanning speed, and hatch distance, was undertaken to discern their impact on the material's microstructure, oxygen/nitrogen content, and hardness. Synthesis of nano-sized AlN and Al2O3 precipitates within the Fe-12Cr-6Al matrix was achieved when nitrogen was used for a process gas. A rise in laser power from 120 W to 200 W, coupled with a reduction in scanning speed from 1200 mm/s to 400 mm/s, resulted in decreased porosity and an increase in grain size. Additionally, all printed samples showed lower oxygen content compared to the initial powder, while nitrogen ratios were notably higher. A marginal increase of the Vickers hardness value, from 240 ± 4.5 to 266 ± 3 HV, was observed as the laser power increased and the scanning speed decreased. The hardness values were higher than those obtained from different production methods with identical compositions. These compelling results suggest a positive impact of nitride precipitates and oxide precipitates to improve hardness values.

Quality-by-Design Approach to Process Intensification of Bioinspired Silica Synthesis.

Characterizing nanomaterials is challenging due to their macromolecular nature, requiring suites of physicochemical analysis to fully resolve their structure. As such, their synthesis and scale-up are notoriously complex, especially when compared to small molecules or bulk crystalline materials, which can be provided a unique fingerprint from nuclear magnetic resonance (NMR) or X-ray diffraction (XRD) alone. In this study, we address this challenge by adopting a three-step quality-by-design (QbD) approach to the scale-up of bioinspired silica nanomaterials, demonstrating its utility toward synthesis scale-up and intensification for this class of materials in general. First, we identified material-specific surface area, pore-size distribution, and reaction yield as critical quality attributes (CQAs) that could be precisely measured and controlled by changing reaction conditions. We then identified the critical process parameters (CPPs) controlling bioinspired synthesis properties, exploring different process routes, incorporating commercial reagents, and optimizing reagent ratios, comparing silica properties against original CQA values to identify acceptable limits to each CPP. Finally, we intensified the synthesis by increasing reagent concentration while simultaneously incorporating the optimized CPPs, thereby modifying the bioinspired silica synthesis to make it compatible with existing manufacturing methods. We increased the specific yield from ca. 1.1 to 38 g/L and reduced the additive intensity from ca. 1 to 0.04 g/g product, greatly reducing both synthesis cost and waste production. These results identify a need for mapping the effects of critical process parameters on material formation pathways and CQAs to enable accelerated scale-up and transition from the lab to the market.

Characterization of Anisotropic Shape Memory Behavior of Thermoresponsive Components in 4D Printing.

Four-dimensional (4D) printing has emerged as a promising manufacturing technology in recent years and revolutionized products by adding shape-morphing capabilities when exposed to certain stimuli. Increasing research attention has been dedicated to studying the shape memory behaviors of the 4D fabricated structures. However, in-depth discussions on quantifying the influence of process parameters on shape fixity and recovery properties are limited, and the anisotropy induced by the layer-wise fabrication nature is significantly underreported. To further exploit the shape memory property of 4D printed structures, it is essential to investigate the process-induced anisotropic shape memory behaviors. In this study, the effects of critical process parameters on anisotropy in shape memory properties are mathematically quantified; meanwhile, the feasibility of tailoring the anisotropy of 4D printed parts is examined with joint consideration of total build time. Different scanning patterns are experimentally analyzed for their influence on anisotropic behaviors. It is found that the Triangle scanning pattern often leads to the best shape memory behaviors in different directions. The outcome of this study confirms the existence of anisotropy in both shape fixity and shape recovery ratios. In addition, the results also reveal that a smaller scanning angle tends to minimize the anisotropy and total fabrication time while ensuring satisfactory shape memory performance. Furthermore, layer thickness shows negligible effects on anisotropy, while the scanning angle and shape memory temperature suggest the opposite.

Enhancing the borosilicate glass micromachining by using mixed alkaline electrolytes in the ECDM process

ABSTRACT This article investigates the effects of mixing different alkaline electrolytes on the geometrical features created by the ECDM. Sodium hydroxide (NaOH) and potassium hydroxide (KOH) were mixed in varying volumetric proportions. Effect of critical process parameters on the depth and width of the microchannels and the associated tool wear was investigated. Pure NaOH electrolyte has resulted in the highest depth compared to the pure KOH electrolyte. Process mechanism behind the role of mixed electrolytes on the opening sizes and depths of microchannels is explained. Higher material removal by the NaOH electrolyte was due to the larger number of sodium (Na+) ions in the electrolyte, resulting in more aggressive electrochemical discharge; however, it also resulted in severe tool wear. Mixed electrolytes with a KOH yielded lower width and low tool wear. Increasing the volumetric proportion of KOH in the mixed electrolyte gradually decreased the machining depth, width, and tool wear.

High-Titer Recombinant Adenovirus 26 Vector GMP Manufacturing in HEK 293 Cells with a Stirred Single-Use Bioreactor for COVID-19 Vaccination Purposes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus) pandemic has shown the importance of pursuing various vaccine manufacturing strategies. In the present study, the HEK 293 cells were infected with recombinant adenovirus serotype 26 (rAd26), and the effects of critical process parameters (CPPs) including viable cell density (VCD) at infection time (0.5 × 106, 0.8 × 106, 1.4 × 106, 1.8 × 106, and 2.5 × 106 cells/mL), the multiplicity of infection (MOI) = 3, 6, 9, 12, and 15, and two aeration strategies (high-speed agitation with a sparging system and low-speed agitation with an overlay system) were investigated experimentally. The results of small-scale experiments in 2 L shake flasks (SF 2L) demonstrated that the initial VCD and MOI could affect the cell proliferation and viability. The results at these experiments showed that VCD = 1.4 × 106 cells/mL and MOI = 9 yielded TCID50 /mL = 108.9, at 72 h post-infection (hpi), while the virus titer at VCD = 0.5 × 106 and 0.8 × 106 cells/mL was lower compared to that of VCD = 1.4 × 106 cells/mL. Moreover, our findings showed that VCDs > 1.8 × 106 cells/m with MOI = 9 did not have a positive effect on TCID50 /mL and MOI = 3 and 6 were less efficient, whereas MOI > 12 decreased the viability drastically. In the next step, the optimized CPPs in a small scale were exploited in a 200 L single-use bioreactor (SUB), with good manufacturing practice (GMP) conditions, at RPM = 25 with an overlay system, yielding high-titer rAd26 manufacturing, i.e., TCID50/mL = 108.9, at 72 hpi.

An ab initio simulation on electron beam physical vapor deposition of Gd2Zr2O7 coating by density functional theory and kinetic Monte Carlo

AbstractWithout any experimental inputs, the electron beam physical vapor deposition (EB‐PVD) of Gd2Zr2O7 with much potential for thermal barrier coatings was investigated by use of the kinetic Monte Carlo, after fitting the potential function using lattice inversion method and “coarse‐grained” mapping on the cohesive energy calculated by density functional theory, to reveal the effect of critical processing parameters of EB‐PVD on the microstructures and porosity of the deposited coating, for example, substrate temperature, deposition rate and incident angle. Based on the lower energy barrier calculated by a nudged elastic band, intra‐layer diffusion is easier than interlayer diffusion, attributed to the fewer bonds in the former. Furthermore, the porosity of the coating decreases with the increase of temperature or decrease of deposition rate, with the gradual disappearing large gaps among columnar crystals and filled pores, because of the increase of transition probability and transition times. With the decreasing incident angle, the area of the shadow zone decreases and less particles can be blocked by previously deposited ones, making the columnar crystals disappear gradually, with more like laminated structures.

Air gasification of high-ash solid waste in a pilot-scale downdraft gasifier: Experimental and numerical analysis

The present work investigates the effect of process parameters on the gasification potential of high-ash solid wastes in a downdraft gasifier using experimental and simulation studies. The air gasification of lignocellulosic garden waste was conducted in a lab-scale fixed bed reactor for the equivalence ratio range of 0.25–0.39. An exhaustive model was devised in Aspen Plus process simulator incorporating the parametric geometry of the gasifier and comprehensive gasification kinetics. Furthermore, the developed model was validated using the experimental results and a fair agreement was obtained. Both the experimental and simulation studies affirmed that the maximum gasification efficiency was obtained at an equivalence ratio of around 0.32. Sensitivity analysis was conducted to scrutinize the effect of critical process parameters on output parameters such as producer gas composition, lower heating value, carbon conversion efficiency, and system's cold gas efficiency. This modeling approach provides valuable insight for generating producer gas from low-grade biomass by optimizing the operating parameters of the downdraft gasifiers. This research can also assist as a guide for stakeholders in renewable energy, waste to energy, and environmentally friendly technologies.

The effect of critical process parameters in manufacturing (filling process) of dry powders for oral suspensions

The effect of critical process parameters in manufacturing (filling process) of dry powders for oral suspensions

Optimization of a mAb production process with regard to robustness and product quality using quality by design principles.

Quality by Design principles are well described and widely used in biopharmaceutical industry. The characterization of a monoclonal antibody (mAb) production process is crucial for novel process development and control. Yet, the application throughout the entire upstream process was rarely demonstrated. Following previously published research, this study marks the second step toward a complete process characterization and is focused on the effect of critical process parameters on the antibody production efficiency and quality of the process. In order to conduct the complex Design of Experiments approach with optimal control and comparability, the ambr®15 micro bioreactor platform was used. Investigated parameters included the pH and dissolved oxygen set points, the initial viable cell density (iVCD) as well as the N‐1 duration. Various quality attributes (e.g., growth rate, viability, mAb titer, and peak proportion) were monitored and analyzed using multivariate data analysis to evaluate the parameter effects. The pH set point and the initial VCD were identified as key process parameters with strong influence on the cell growth as well as the mAb production and its proportion to the total protein concentration. For optimization and improvement in robustness of these quality attributes the pH must be increased to 7.2, while the iVCD must be lowered to 0.2 × 106 cells/mL. Based on the defined design space, additional experiments verified the results and confirmed the intact bioactivity of the antibody. Thereby, process control strategies could be tuned toward high cell maintenance and mAb production, which enable optimal downstream processing.

A new nanosuspension prepared with wet milling method for oral delivery of highly variable drug Cyclosporine A: development, optimization and in vivo evaluation

Cyclosporine A (CsA) is a cyclic polypeptide, that has been widely used for immunosuppression. This study aims to develop nanosuspension for oral administration of CsA using the wet milling (WM) method one of the top-down technologies. The WM method was optimized by studying the effects of critical process parameters for WM on the particle size (PS), particle size distribution (PDI), and zeta potential (ZP) of nanosuspensions using the Design of Experiment (DoE) approach. Nanosuspension was developed using hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) and in vitro characterization studies were performed. In vitro dissolution and in vivo pharmacokinetic studies were conducted with biorelevant media (fasted and fed state simulated fluids) and fasted and fed states in rats, respectively. In vivo immunological studies were also performed. PS, PDI, and ZP values for nanosuspension were approximately 600 nm, 0.4, -25 mV, respectively. The solubility of CsA was increased by 4.5-folds by nanosuspensions. Dissolution studies showed that nanosuspension had higher dissolution than the commercial product in the FeSSIF medium. The pharmacokinetic study indicated that AUC0–24 values of CsA nanosuspension were to be 2.09 and 5.51-fold higher than coarse powder in fasted and fed conditions, respectively. Immunological studies were carried out after oral administration of nanosuspension for 21 days, the ratio of CD4+/CD8+ was found to be more acceptable than the commercial product. These results demonstrated that nanosuspension is a promising approach for increasing the bioavailability and avoiding the food effect on absorption of CsA which one of the highly variable drugs.

Mechanistic modeling of continuous capture step purification of biosimilar monoclonal antibody therapeutic

AbstractBACKGROUNDContinuous multicolumn Protein A chromatography offers various advantages for capture stage purification of monoclonal antibody therapeutics, like higher productivity and resin capacity utilization, lower buffer consumption, small footprint, etc. Due to the complexity of the continuous process, experimental optimization is time‐consuming and cost‐intensive. This investigation proposes a hybrid process development approach integrating experimental and mechanistic modeling for time‐ and cost‐effective development and optimization of continuous Protein A affinity chromatography.RESULTSProductivity and capacity utilization of the continuous CaptureSMB process under varying operating conditions were predicted using the Chromatography Analysis and Design Toolkit (CADET) framework and validated with experimental results. Effects of critical process parameters like feed concentration (c0), loading breakthrough (s) and residence time (RT) on productivity and capacity utilization were evaluated. Model predictions were validated using the experimental results proving the reliability and feasibility of the modeling approach. At 15.00 ± 0.20 mg mL–1 feed model mAb concentration, the model‐based approach predicted the best performance giving 27.56 g L–1 h–1 productivity (RT = 2 min, s = 80%) using MabSelect™ PrismA resin. This productivity prediction was validated by performing the continuous CaptureSMB experiment at the same operating conditions and was found to be 25.59 g L–1 h–1 with a root mean square error of 1.96.CONCLUSIONSThe hybrid process development and optimization approach for CaptureSMB purification of biosimilar mAb purification is demonstrated and validated using the experimental and model‐based framework. The observed results showcase the effectiveness of the proposed hybrid process development approach, enabling a better understanding of the chromatography process and parameters affecting the CaptureSMB process. © 2021 Society of Chemical Industry (SCI).

Kinetic Monte Carlo simulation of ZrO2 coating deposited by EB‐PVD

AbstractKinetic Monte Carlo (KMC) simulations have been used for electron beam physical vapor deposition (EB‐PVD) of ZrO2 coatings, with the critical potential function fitted by full first‐principles calculations in the framework of density functional theory, emphasizing the effect of critical processing parameters, for example, the substrate temperature (600–1150 K), deposition rate (0.03–7.5 μm/min), and initial kinetic energy (0–0.5 eV). Here, the interaction between ZrO2 particles is described by coarse grain (CG) model with a numerical non‐bonded potential developed by multi‐iterative boltzmann inversion (multi‐IBI). Overall, the calculated energy barrier by the nudged elastic band (NEB) shows the internal diffusion (3.29–4.80 eV) requires more energy than the surface diffusion (2.90–3.42 eV), because of fewer surrounding particles in the latter. Moreover, the energy barrier of Line Jump is smaller than that of Schwoebel Jump, contributing to the columnar grains rather than a dense coating. Of importance, the simulated morphologies of ZrO2 coatings are well consistent to experiments, with a weaker effect from the substrate temperature, initial kinetic energy to deposition rate. Furthermore, the porosity can be effectively reduced by increasing the temperature and initial kinetic energy, however, with a slight increase when increasing the deposition rate.

Effect of processing conditions and material attributes on the design space of lysozyme pellets prepared by extrusion/spheronization

The present work aimed to investigate the impact of the critical material attributes on the design space of the production of lysozyme pellets with suitable biological and physical properties for the subsequent coating process. The effect of two brands of both lysozyme and conformation stabilizing mannitol on the behavior of the composition in an extrusion/spheronization process was studied, while the experiments were designed according to 23 factorial design. The kneading of the mass was carried out in a high shear granulator equipped with a specially designed granulation chamber (Opulus Ltd, Hungary) constructed with seven built-in sensors for the measurement of temperature and relative humidity (RH). The special chamber is a novel tool for the identification of the critical points during processing a thermolabile drug by providing the online monitoring of critical environmental parameters and could be used to accurately determine the effect of critical process parameters and material attributes. The prepared samples were investigated for their biological and physical properties. It was found that the critical material attributes have a potential effect on the production process and product quality, and highly influence the size of the process design space. Therefore, the screening of the formulation materials is a key factor in macromolecular drug development.

Study on Controllable Thickness and Flatness of Wafer-Scale Nickel Shim in Precision Electroforming Process: Simulation and Validation

Abstract A new approach to precision electroforming of a wafer scale nickel shim using a rotating cathode with an auxiliary cathode mask is developed to improve thickness uniformity and flatness. The effects of critical process parameters, including cathode rotating speed, cathode mask size, and current density, on the thickness uniformity and flatness of electroformed nickel shim are systematically studied based on experiments and simulations. The results show that the thickness uniformity of the deposits is highly dependent on the current density distribution, where a cathode mask can effectively tune electrical field lines and induce a more uniform current density distribution. The simulations and experimental results consistently agree that a minimum thickness nonuniformity of 8% and below 1% on the wafer with a diameter of 80 mm and 40 mm, respectively, can be achieved using a mask with a 70 mm opening size. However, for flatness, the cathode rotating speed influences the surface warpage due to the intrinsic stress. It is also found that the gradient current density can significantly reduce the intrinsic stress with better flatness. The best flatness is controlled below 47 µm and 32 µm on the wafer with diameters of 80 mm and 40 mm, respectively, under the synergistic effect of optimal cathode rotating speed (30 rpm) and gradient current density.