Early Stages Of Development Process Research Articles

Enzymatic synthesis of N-alkanoyl-N-methylglucamide surfactants: solvent-free production and environmental assessment

A biocatalysis based method for the solvent-free production of N-alkanoyl-N-methylglucamide (MEGA) surfactants was developed and used as a case study for the evaluation of different environmental assessment tools, such as the freeware package EATOS (Environmental Assessment Tool for Organic Synthesis). In order to also consider energy usage and process facilities, e.g. heating, stirring and vacuum, a complementary tool was needed; hence the EcoScale method and the use of an energy monitoring socket were also exploited. The solvent-free method followed by a simple hydrolysis step gave a final amide yield of 99% and a product essentially free of remaining substrate, N-methylglucamine (MEG). The latter is important since MEG can potentially be converted to carcinogenic nitrosamines. The absence of solvent in the reaction medium was also found to result in a significantly reduced potential environmental impact. The environmental tools used in this study were further scrutinized, and even if they represent some of the best freely available tools for evaluation of early stage process development, some points for further improvements are suggested.

Effects of Defects on the Thermal and Optical Performance of High-Brightness Light-Emitting Diodes

Defects in terms of voids, cracks, and delaminations are often generated in light-emitting diodes (LEDs) devices and modules. During various manufacturing processes, accelerated testing, inappropriate handling, and field applications, defects are most frequently induced in the early stage of process development. One loading is due to the nonuniform loads caused by temperature, moisture, and their gradients. In this research, defects in various cases are modeled by a nonlinear finite-element method (FEM) to investigate the existence of interfaces, interfacial open and contacts in terms of thermal contact resistance, stress force nonlinearity, and optical discontinuity, in order to analyze their effects on the LED's thermal and optical performance. The simulation results show that voids and delaminations in the die attachment would enhance the thermal resistance greatly and decrease the LED's light extraction efficiency, depending on the defects' sizes and locations generated in packaging.

High‐throughput screening of chromatographic separations: IV. Ion‐exchange

Ion-exchange (IEX) chromatography steps are widely applied in protein purification processes because of their high capacity, selectivity, robust operation, and well-understood principles. Optimization of IEX steps typically involves resin screening and selection of the pH and counterion concentrations of the load, wash, and elution steps. Time and material constraints associated with operating laboratory columns often preclude evaluating more than 20-50 conditions during early stages of process development. To overcome this limitation, a high-throughput screening (HTS) system employing a robotic liquid handling system and 96-well filterplates was used to evaluate various operating conditions for IEX steps for monoclonal antibody (mAb) purification. A screening study for an adsorptive cation-exchange step evaluated eight different resins. Sodium chloride concentrations defining the operating boundaries of product binding and elution were established at four different pH levels for each resin. Adsorption isotherms were measured for 24 different pH and salt combinations for a single resin. An anion-exchange flowthrough step was then examined, generating data on mAb adsorption for 48 different combinations of pH and counterion concentration for three different resins. The mAb partition coefficients were calculated and used to estimate the characteristic charge of the resin-protein interaction. Host cell protein and residual Protein A impurity levels were also measured, providing information on selectivity within this operating window. The HTS system shows promise for accelerating process development of IEX steps, enabling rapid acquisition of large datasets addressing the performance of the chromatography step under many different operating conditions.

Determination of Operating Regimes for Chemical Reactors Using Incomplete Mechanistic Knowledge and a Mutual Information-Based Dependency Test

A chemical process that involves the interplay between chemical reaction(s) and transport phenomena may be operated in one of several possible operating regimes. In the development of such a process, the operating regime which yields desirable performance at a smaller scale should be identified to help realize successful scale-up of the process. In the past, experimental procedures for identifying operating regimes have been proposed, which utilize the qualitative trends of the response of a process to changes in operating conditions. In this study, an alternative approach which utilizes both experimental data and mathematical modeling is explored. The rationale behind this approach is that an incorrect assumption with regard to an operating regime may result in a false dependency between particular process variables. On the basis of this hypothesis, operating regime determination can be formulated around a dependency test. In this paper, the computation of a dependency measure is based on the mutual information approach as defined in information theory. The methodology proposed is able to handle the situation where mechanistic knowledge such as chemical reaction kinetics is missing. In practice, this information is often not available during the early stages of process development. The proposed methodology is tested and compared with alternative approaches on a simulated toluene nitration process. Its potential in terms of achieving a reliable discrimination between different assumptions with regard to the operating regime with fewer constraints on the experimental requirements is demonstrated.

Toward People-Centered Development: A Reflection on the Korean Experience

By reflecting upon Korea's state-led development, its socio-economic consequences, and its current reform efforts and trends, this article calls for reconstructing the state and redefining the identity of its political economy towards people-centered development. Crafting a democratic and empowering dirigisme and institutionalizing democratic values such as public trust and rule of law constitute the nation's pressing task in its quest for a good society. However, dirigiste choice of growth over equity at an early stage of development process may not be easily reversible at a later stage. Dirigiste development and undemocratic governance create entrenched, self-sustaining interests and structures that no amount of reform politics as usual can touch.

Assessment of chemical process hazards in early design stages

A new method called SREST-layer-assessment method with automated software tool is presented that in a hierarchical approach reveals the degree of non-ideality of chemical processes with regard to SHE (safety, health and environment) aspects at different layers: the properties of the chemical substances involved (substance assessment layer (SAL)), possible interactions between the substances (reactivity assessment layer (RAL)), possible hazard scenarios resulting from the combination of substances and operating conditions in the various equipments involved (equipment assessment layer (EAL)), and the safety technologies that are required to run a process safely and in accordance with legal regulations (safety-technology assessment layer (STAL)). In RAL, EAL and STAL the main focus is put on process safety. A case study is used to show the principles of the method. It is demonstrated how the method can be used as a systematic tool to support chemical engineers and chemists in evaluating chemical process safety in early process development stages.

Enhancing Fine Chemicals Process Chemistry: A Practical Approach

In the fine chemicals industry, development is driven by a constant strive for higher yields and selectivity of existing processes and faster development of new processes and products. Key constraints in process development in today's low-tonnage chemicals sectors (fine and effect chemicals) remain the time and cost spent obtaining data to identify and verify new processes. This often limits the amount of knowledge of the process chemistry acquired from any process development activity. In the present work, the capability of a simple high throughput experimental device is exploited to develop, apply and evaluate some laboratory-based tools to provide valuable insights into the process chemistry, especially in the critical early stages of process development. This paper discusses the experimental and modelling approaches (based on a model heterogeneous solid-catalysed acylation reaction) adopted to investigate a set of conditions that should deliver good process performance. The use of the experimental design and data reconciliation concepts in an integrated way to deliver a better process design is also demonstrated.

574. Early Stage Product Development to Scale-Up: Use of Mini-Fermentation System for Screening and Process Development of Plasmid DNA Products

Top of pageAbstract Introduction: As the number of gene therapy studies and trials has increased in the past few years, an ever-increasing demand for plasmid DNA-based products exists. In this expanding field of plasmid production, emphasis has always been placed on the quality and safety of the plasmid product. Much of the focus has been placed on increasing the expression of these products, while few focus on the early-stage screening and development of efficient plasmid production. The typical transition of a plasmid from research to the manufacturing group begins with shaker flask culture productions, which often yield little information on the cell growth and yield characteristics. Scale-up of these shaker flask-derived products has been difficult to achieve, and there is a need to translate the results from these cultures to lab scale and pilot or production scale. Adequate information of growth and yield characteristics for various plasmid products is important in the early developmental stage of any product. Method: We have successfully demonstrated the use of the Sixfors|[trade]| mini-fermentation system for the efficient screening of early-stage development products along with process development of plasmid DNA production and the ability to scale up the process to more than 100L. The Sixfors|[trade]| mini-fermenters, with a maximum working volume of 500mL, have been configured to mimic a large-scale fermenter with efficient control of dissolved oxygen. These fermenters were used for process development of plasmid DNA production. Their use has been established in the screening of bacterial strains and the optimization of fermentation media and process parameters using statistical experimental design techniques. Results: Using the mini-fermenter system, we were able to achieve early-stage predictability of the use of bacterial strains and growth conditions for growing a particular plasmid along with the scalability of fermentation conditions. The use of statistical design techniques for optimizing media formulations and process conditions resulted in the optimum process conditions in a limited amount of time with excellent reproducibility. The studies conducted to demonstrate the successful scale-up of the fermentation process indicated that the data obtained from the mini-fermenters are reproducible even at larger scales of operation. The use of this mini-fermenter system resulted in overall reduction of the time required for the completion of plasmid DNA production. Conclusions: The use of Sixfors|[trade]| has been shown as an excellent tool for early stage process development, including plasmid DNA screening studies. This method is far superior to performing early experiments with shaker flasks and is an ideal replacement for using these cultures for screening studies. The process using this Sixfors|[trade]| system has been tested in the lab scale (10L) and the pilot scale (100L) fermenters and has been shown to scale-up with excellent reproducibility.

Epitaxial thickening of AIC poly-Si seed layers on glass by solid phase epitaxy

A novel method for producing high-quality polycrystalline silicon (poly-Si) films on glass by means of solid phase epitaxy (SPE) of evaporated amorphous silicon on aluminium-induced crystallisation (AIC) poly-Si seed layers is introduced. Optical transmission microscope, Raman, UV reflectance spectroscopy and cross-sectional transmission electron microscope measurements show consistently that a transfer of the crystal properties of the AIC poly-Si seed layer into the crystallised amorphous silicon layer has been achieved. A 1-sun open-circuit voltage of 337 mV is realised with a hydrogenated SPE/AIC p–n junction device, which is a promising result considering the early stage of process development. The SPE/AIC method appears well suited for the fabrication of poly-Si thin-film solar cells on glass and, due to the high crystal quality and the much larger average grain size, could lead to improved energy conversion efficiencies compared to Si solar cells made by solid phase crystallisation.

Yield learning and the sources of profitability in semiconductor manufacturing and process development

A numerical model that identifies the high-leverage variables associated with profitability in semiconductor manufacturing is presented. Varying the parameters of the model demonstrates that a rapid yield-learning rate determines profitability more than any other factor does. Factors such as ramping-up early, adding fab capacity, depressing the terminal fault density, and shrinking die size all yield diminishing returns. The model also suggests that developing a rapid problem-solving capability in the early stages of process development enables successful yield learning.

Selection of inherently safer process routes: a case study

Increased public concern about safety issues and stringent environmental standards has led plant designers to consider inherently safer design. The term ‘inherently safer’ implies that the process is safe by its very nature and not externally constrained to be safe by the use of add-on systems and devices. Such opportunities for developing inherently safer process are highest in the early stages of design. Constraints such as time, lack of knowledge and inadequate inherent safety analysis tools are often cited as obstacles to development and implementation of inherently safer design. In this paper, we describe an inherent safety analysis methodology that can be applied in the early stages of process development. The methodology is based on an inherent safety index for comparing process routes and heuristics for identifying hazards and generating alternative designs. This methodology has been implemented as one module in iSafe, an intelligent system that automates inherent safety analysis. One key benefit of iSafe is substantial reduction in the time and effort required to perform safety analysis. Automation of the inherent safety analysis also makes it more thorough and detailed, minimizes or eliminates human errors, facilitates documentation and makes the study results available online for detailed safety analysis and review in the later stages of process design. The details of inherent safety analysis at the route selection stage are discussed in this paper and illustrated by comparing competing processes for acetic acid manufacture.

313 開発設計上流におけるシンキングCAEについて

313 開発設計上流におけるシンキングCAEについて

Process synthesis for reactive separations

The integration of reaction and separation in one single process unit proved to lead to enormous savings in capital as well as in operating costs. This paper provides a systematic framework to consider reactive separations in the early stages of process development. It highlights a process synthesis procedure guaranteeing that processes like reactive distillation, reactive crystallization, reactive extraction or reactive stripping will not be overlooked during conceptual flowsheet development. First step of this procedure is the analysis of the chemical reaction system. In case a separation of one or more products, by-products or solvents seems to be beneficial for the performance of the reactor the physical separation behavior of the components has to be checked. The chemical reaction, the physical separation and the design on the apparatus need a defined operation window. Only when an overlap of these windows can be identified a reactive separation process is feasible and might lead to advantages in the overall process performance. The paper finally demonstrates that the integration of reaction and separation in one unit does not necessarily lead to economic benefits as the overall performance of the total chemical process has to be considered.

Thermoplastic filament winding with online-impregnation. Part A: process technology and operating efficiency

Process combinations of filament winding with online-impregnation of fibre bundles have previously been widely neglected, due to the technical difficulties of impregnating a large number of slender filaments with a highly viscous thermoplastic melt. An innovative impregnation technology, called impregnation wheel, has been developed which allows to produce high quality impregnated tapes or tows at considerable speeds. Due to the specific characteristics of the technology it offers itself to be adopted for a process combination with filament winding. The realised process technology is described in detail. To assess the operating profitability of the novel processing routine a simple cost comparison calculation with filament winding utilising preimpregnated tapes was conducted. Even though in the early stage of process development a number of values could only be roughly estimated, the required minimum impregnation speed for economic production of a glass fibre reinforced model component was deducted.

Developing GSK's green technology guidance: methodology for case-scenario comparison of technologies

There is growing interest in introducing environmental, health, and safety considerations during early stages of process development to achieve sustainable processes and products. GlaxoSmithKline (GSK) has previously described the concept of a Green Technology Guide (GTG) within the broader context of its programs to move the company towards more sustainable business practices. The concept for the Green Technology Guide is a series of case-scenario comparisons that provide scientists and engineers with comparative environmental and safety information on technologies for operations commonly found in the pharmaceutical industry.

Integrated decision support system for waste minimization analysis in chemical processes.

The need to build and operate environmentally friendly plants has challenged the chemical industry to consider waste minimization or even elimination starting from the early stages of process development. A thorough waste minimization analysis requires specialized expertise and is laborious, time-consuming, expensive, and knowledge-intensive. This has caused a major technical barrier for implementing waste minimization programswithin the industry. Previously, we had reported a systematic methodology and a knowledge-based system, called ENVOPExpert, for identifying waste minimization opportunities in chemical processes. In this paper, we propose an integrated qualitative-quantitative methodology to identify waste minimization alternatives and assess their efficacy in terms of environmental impact and process economics. A qualitative analysis is first conducted to identify the sources of wastes and to propose alternatives for eliminating or minimizing them. Environmental impact of each alternative is then calculated by doing a quantitative pollutant balance. The capital expenditure required for implementing the alternative and the resulting plant operating costs are also calculated and used in the evaluation of the waste minimization alternatives. Through this, practical and cost-effective options can be identified. This methodology has been implemented as an integrated decision support system and tested using the hydrodealkylation process case study with satisfactory results.

Characterization of flow intensity in continuous centrifuges for the development of laboratory mimics

Predicting the recovery of “delicate” biological materials by centrifugation using laboratory centrifuges has been a major challenge to biochemical engineers partly because of the difficulty in accurately quantifying the shear stresses in continuous-flow industrial centrifuges and partly because the clarification and dewatering conditions in the laboratory units do not represent those occurring in industrial centrifuges. In this paper, the flow field in the feed zone of an industrial multichamber-bowl centrifuge is mapped and its profile of energy dissipation rate established using computational fluid dynamics (CFD). A small high-speed rotating-disc device is designed with the capacity to reproduce the CFD-predicted energy dissipation rates in the feed zone. Milliliter quantities of the process material are shear-treated in the device operating at a speed that mimics the local critical flow conditions in the industrial centrifuge. The results are used to assess the impact of flow conditions in the feed zone of the centrifuge on the physical properties of protein precipitates and on their predicted recovery using a laboratory centrifuge. This approach was used to explain the reduction in the performance of the centrifuge from the predicted 88% clarification to the observed 39% clarification of the precipitate particles. The combination of the small high-speed disc device and the laboratory centrifuge is particularly advantageous when dealing with biological products at the early stages of process development for which only small quantities of test material are often available.

A Subjective Design Framework for Conceptual Design of Polymeric Processes with Multiple Parameters

Polymer processes are in general difficult to model, especially because of coupling between process conditions, polymeric behaviors and geometries. Arising from high thermal gradients, non-Newtonian viscous behaviors and non-linear pressure effects, polymer processing is not well described mathematically. A conceptual design methodology is proposed formally as a useful tool for treating polymeric processes with multiple performance parameters on a structured design platform. Without resorting to engineering models, this approach deals with the initial selection of process conditions within a three-stage framework: (1) qualitative design; (2) process modeling; and (3) quantitative design. Based on subjective reasoning, this procedure makes it possible to account for one’s prior experience, and incorporate it into the process development. The notion of conceptual robutstness is introduced to ensure deesign quality in the early-stage process development. A case study of compression molding is illustrated in a step-by-step manner.

Cell array structure test in EEPROM reliability assessment at an early process development stage

We present a simple structure and a simple test to obtain important information on EEPROM cells’ reliability, such as the threshold voltage distribution of the cell array and its evolution during a bake retention experiment. Both intrinsic and extrinsic characteristics can be determined, thanks to the clamping effect of the select transistor in series to each memory transistor. The method is useful not only during the early process development stage, but also as a process monitor.

Screening multiphase reactors for nonisothermal multiple reactions

A screening procedure developed synthesizes a multiphase reactor and the accompanying heat-transfer devices desired for a given reaction scheme. It is an extension of a procedure, previously described for isothermal systems with a single reaction to multiple reactions involving heat effects. The three key elements to this approach include a generic reactor model, an accompanying sensitivity model, and a knowledge base consisting of heuristics, as well as correlations on hydrodynamics, heat, and mass transport. The generic reactor model is extended to include various topologies and reactor constituent parts for heat and mass transfer. The sensitivity model quantifies the potential impact of various reactor parameters on reactor performance. The knowledge base is expanded to tackle multiple, nonisothermal reactions. In this procedure, reactor attributes and constituent parts are aggregated to form a reactor for the specific reaction under consideration. It is especially useful at the early stage of process development, when there is a great deal of uncertainty regarding reaction kinetics, and potential limitations of heat and mass transfer.