Novel developments in process optimisation using predictive control

In industrial practice, constrained steady state optimisation and predictive control are separate, albeit closely related functions within the control hierarchy. This paper presents a method which integrates predictive control with on-line optimisation with economic objectives. A receding horizon optimal control problem is formulated using linear state space models. This optimal control problem is very similar to the one presented in many predictive control formulations, but the main difference is that it includes in its formulation a general steady state objective depending on the magnitudes of manipulated and measured output variables. This steady state objective may include the standard quadratic regulatory objective, together with economic objectives which are often linear. Assuming that the system settles to a steady state operating point under receding horizon control, conditions are given for the satisfaction of the necessary optimality conditions of the steady-state optimisation problem. The method is based on adaptive linear state space models, which are obtained by using on-line identification techniques. The use of model adaptation is justified from a theoretical standpoint and its beneficial effects are shown in simulations. The method is tested with simulations of an industrial distillation column and a system of chemical reactors.

Pharmaceutical process optimisation of bulk lyophilisates:implications of powder handling

Lyophilisation or freeze drying is the preferred dehydrating method for pharmaceuticals liable to thermal degradation. Most biologics are unstable in aqueous solution and may use freeze drying to prolong their shelf life. Lyophilisation is however expensive and has seen lots of work aimed at reducing cost. This thesis is motivated by the potential cost savings foreseen with the adoption of a cost efficient bulk drying approach for large and small molecules. Initial studies identified ideal formulations that adapted well to bulk drying and further powder handling requirements downstream in production. Low cost techniques were used to disrupt large dried cakes into powder while the effects of carrier agent concentration were investigated for powder flowability using standard pharmacopoeia methods. This revealed superiority of crystalline mannitol over amorphous sucrose matrices and established that the cohesive and very poor flow nature of freeze dried powders were potential barriers to success. Studies from powder characterisation showed increased powder densification was mainly responsible for significant improvements in flow behaviour and an initial bulking agent concentration of 10-15 %w/v was recommended. Further optimisation studies evaluated the effects of freezing rates and thermal treatment on powder flow behaviour. Slow cooling (0.2 °C/min) with a -25°C annealing hold (2hrs) provided adequate mechanical strength and densification at 0.5-1 M mannitol concentrations. Stable bulk powders require powder transfer into either final vials or intermediate storage closures. The targeted dosing of powder formulations using volumetric and gravimetric powder dispensing systems where evaluated using Immunoglobulin G (IgG), Lactate Dehydrogenase (LDH) and Beta Galactosidase models. Final protein content uniformity in dosed vials was assessed using activity and protein recovery assays to draw conclusions from deviations and pharmacopeia acceptance values. A correlation between very poor flowability (p<0.05), solute concentration, dosing time and accuracy was revealed. LDH and IgG lyophilised in 0.5 M and 1 M mannitol passed Pharmacopeia acceptance values criteria with 0.1-4 while formulations with micro collapse showed the best dose accuracy (0.32-0.4% deviation). Bulk mannitol content above 0.5 M provided no additional benefits to dosing accuracy or content uniformity of dosed units. This study identified considerations which included the type of protein, annealing, cake disruption process, physical form of the phases present, humidity control and recommended gravimetric transfer as optimal for dispensing powder. Dosing lyophilised powders from bulk was demonstrated as practical, time efficient, economical and met regulatory requirements in cases. Finally the use of a new non-destructive technique, X-ray microcomputer tomography (MCT), was explored for cake and particle characterisation. Studies demonstrated good correlation with traditional gas porosimetry (R2 = 0.93) and morphology studies using microscopy. Flow characterisation from sample sizes of less than 1 mL was demonstrated using three dimensional X-ray quantitative image analyses. A platinum-mannitol dispersion model used revealed a relationship between freezing rate, ice nucleation sites and variations in homogeneity within the top to bottom segments of a formulation.

Freezing process optimisation of pharmaceutical formulations for freeze drying

The body of work presented in this thesis are in three main parts: [1] the effect of ultrasound on freezing events of ionic systems, [2] the importance of formulation osmolality in freeze drying, and [3] a novel system for increasing primary freeze drying rate. Chapter 4 briefly presents the work on method optimisation, which is still very much in its infancy. Aspects of freezing such as nucleation and ice crystal growth are strongly related with ice crystal morphology; however, the ice nucleation process typically occurs in a random, non-deterministic and spontaneous manner. In view of this, ultrasound, an emerging application in pharmaceutical sciences, has been applied to aid in the acceleration of nucleation and shorten the freezing process. The research presented in this thesis aimed to study the effect of sonication on nucleation events in ionic solutions, and more importantly how sonication impacts on the freezing process. This work confirmed that nucleation does occur in a random manner. It also showed that ultrasonication aids acceleration of the ice nucleation process and increases the freezing rate of a solution. Cryopreservation of animal sperm is an important aspect of breeding in animal science especially for endangered species. In order for sperm cryopreservation to be successful, cryoprotectants as well as semen extenders are used. One of the factors allowing semen preservation media to be optimum is the osmolality of the semen extenders used. Although preservation of animal sperm has no relation with freeze drying of pharmaceuticals, it was used in this thesis to make a case for considering the osmolality of a formulation (prepared for freeze drying) as a factor for conferring protein protection against the stresses of freeze drying. The osmolalities of some common solutes (mostly sugars) used in freeze drying were determined (molal concentration from 0.1m to 1.2m). Preliminary investigation on the osmolality and osmotic coefficients of common solutes were carried out. It was observed that the osmotic coefficient trend for the sugars analysed could be grouped based on the types of sugar they are. The trends observed show the need for further studies to be carried out with osmolality and to determine how it may be of importance to protein or API protection during freeze drying processes. Primary drying is usually the longest part of the freeze drying process, and primary drying times lasting days or even weeks are not uncommon; however, longer primary drying times lead to longer freeze drying cycles, and consequently increased production costs. Much work has been done previously by others using different processes (such as annealing) in order to improve primary drying times; however, these do not come without drawbacks. A novel system involving the formation of a frozen vial system which results in the creation of a void between the formulation and the inside wall of a vial has been devised to increase the primary freeze drying rate of formulations without product damage. Although the work is not nearly complete, it has been shown that it is possible to improve and increase the primary drying rate of formulations without making any modifications to existing formulations, changing storage vials, or increasing the surface area of freeze dryer shelves.

A III-V channel field effect transistor for non-classical CMOS: process optimisation for improved gate stack function

This thesis describes a collection of studies into the electrical response of a III-V MOS stack comprising metal/GaGdO/GaAs layers as a function of fabrication process variables and the findings of those studies. As a result of this work, areas of improvement in the gate process module of a III-V heterostructure MOSFET were identified. Compared to traditional bulk silicon MOSFET design, one featuring a III-V channel heterostructure with a high-dielectric-constant oxide as the gate insulator provides numerous benefits, for example: the insulator can be made thicker for the same capacitance, the operating voltage can be made lower for the same current output, and improved output characteristics can be achieved without reducing the channel length further. It is known that transistors composed of III-V materials are most susceptible to damage induced by radiation and plasma processing. These devices utilise sub-10 nm gate dielectric films, which are prone to contamination, degradation and damage. Therefore, throughout the course of this work, process damage and contamination issues, as well as various techniques to mitigate or prevent those have been investigated through comparative studies of III-V MOS capacitors and transistors comprising various forms of metal gates, various thicknesses of GaGdO dielectric, and a number of GaAs-based semiconductor layer structures. Transistors which were fabricated before this work commenced, showed problems with threshold voltage control. Specifically, MOSFETs designed for normally-off (VTH > 0) operation exhibited below-zero threshold voltages. With the results obtained during this work, it was possible to gain an understanding of why the transistor threshold voltage shifts as the gate length decreases and of what pulls the threshold voltage downwards preventing normally-off device operation. Two main culprits for the negative VTH shift were found. The first was radiation damage induced by the gate metal deposition process, which can be prevented by slowing down the deposition rate. The second was the layer of gold added on top of platinum in the gate metal stack which reduces the effective work function of the whole gate due to its electronegativity properties. Since the device was designed for a platinum-only gate, this could explain the below zero VTH. This could be prevented either by using a platinum-only gate, or by matching the layer structure design and the actual gate metal used for the future devices. Post-metallisation thermal anneal was shown to mitigate both these effects. However, if post-metallisation annealing is used, care should be taken to ensure it is performed before the ohmic contacts are formed as the thermal treatment was shown to degrade the source/drain contacts. In addition, the programme of studies this thesis describes, also found that if the gate contact is deposited before the source/drain contacts, it causes a shift in threshold voltage towards negative values as the gate length decreases, because the ohmic contact anneal process affects the properties of the underlying material differently depending on whether it is covered with the gate metal or not. In terms of surface contamination; this work found that it causes device-to-device parameter variation, and a plasma clean is therefore essential. This work also demonstrated that the parasitic capacitances in the system, namely the contact periphery dependent gate-ohmic capacitance, plays a significant role in the total gate capacitance. This is true to such an extent that reducing the distance between the gate and the source/drain ohmic contacts in the device would help with shifting the threshold voltages closely towards the designed values. The findings made available by the collection of experiments performed for this work have two major applications. Firstly, these findings provide useful data in the study of the possible phenomena taking place inside the metal/GaGdO/GaAs layers and interfaces as the result of chemical processes applied to it. In addition, these findings allow recommendations as to how to best approach fabrication of devices utilising these layers.

Free-stretch-blow Investigation of Poly(ethylene terephthalate) over a Large Process Window

This paper highlights for the first time a full comprehension of the deformation procedure during the injection stretch blow moulding (ISBM) process of poly(ethylene terephthalate) (PET) containers, namely thin-walled rigid bottles. The processes required to form PET bottles are complicated and extensive; any development in understanding the nature of material deformation can potentially improve the bottle optimisation process. Removing the bottle mould and performing free-stretch-blow (FSB) experiments revealed insight into the bottle forming characteristics at various preform temperatures and blowing rates. Process outputs cavity pressure and stretch-rod force were recorded using at instrumented stretch-rod and preform surface strain mapping was determined using a combination of a unique patterning procedure and high speed stereoscopic digital image correlation. The unprecedented experimental analysis reveals that the deformation behaviour varies considerably with contrasting process input parameters. Investigation into the effect on deformation mode, strain rate and final bottle shape provide a basis for full understanding of the process optimisation and therefore how the process inputs may aid development of the preferred optimised container.

Highly integrated and automated high-speed grinding system for printer heads constructed by combination materials

The fabrication of heavy-duty printer heads involves a great deal of grinding work. Previously in the printer manufacturing industry, four grinding procedures were manually conducted in four grinding machines, respectively. The productivity of the whole grinding process was low due to the long loading time. Also, the machine floor space occupation was large because of the four separate grinding machines. The manual operation also caused inconsistent quality. This paper reports the system and process development of a highly integrated and automated high-speed grinding system for printer heads. The developed system, which is believed to be the first of its kind, not only produces printer heads of consistently good quality, but also significantly reduces the cycle time and machine floor space occupation.

Variables affecting the fine grinding of minerals using stirred mills

Base metal resources are becoming more fine-grained and refractory and minerals separation processes require these ores to be milled to increasingly finer sizes. To cope with very fine grinding to below a P-80 of approximately 15 mum stirred milling technology has been adopted from other industries Neither this technology, nor the basic concepts of fine grinding, are well understood by the minerals processing industry. Laboratory studies were therefore carried out in order to investigate fine milling using different types of stirred mills. The variables analysed were stirrer speed, grinding media type and size, slurry solids content as well as the feed and product size. The results of the testwork have shown that all of these variables affect the grinding efficiency. The ratio of media size to material size was found to be of particular significance. The results were also analysed using the stress intensity approach and the optimum stress intensity ranges for the most efficient grinding were determined. Application of the results for process optimisation in the industrial size units is also discussed in this paper. (C) 2003 Elsevier Science Ltd. All rights reserved.

Tuotantoprosessin optimointi valmistusta ja kokoonpanoa harjoittavassa yrityksessä

Diplomityö on tehty Instrumentarium Oyj:hin kuuluvan Datex-Ohmedan Helsingin tehtaalla. Työn tavoitteena on ollut Helsingin tehtaan tuotantoprosessin ja sen mitoitussääntöjen kehittäminen. Työ on ollut osa sekä yrityksen toimituskyvyn kehittämisprojektia

On the development of object functions and restrictions for shapes made with a turret punch press

This study presents the information required to describe the machine and device resources in the turret punch press environment which are needed for the development of the analysing method for automated production. The description of product and device resources and their interconnectedness is the starting point for method comparison the development of expenses, production planning and the performance of optimisation. The manufacturing method cannot be optimized unless the variables and their interdependence are known. Sheet metal parts in particular may then become remarkably complex, and their automatic manufacture may be difficult or, with some automatic equipment, even impossible if not know manufacturing properties. This thesis consists of three main elements, which constitute the triangulation. In the first phase of triangulation, the manufacture occuring on a turret punch press is examined in order to find the factors that affect the efficiency of production. In the second phase of triangulation, the manufacturability of products on turret punch presses is examined through a set of laboratory tests. The third phase oftriangulation involves an examination of five industry parts. The main key findings of this study are: all possible efficiency in high automation level machining cannot be achieved unless the raw materials used in production and the dependencies of the machine and tools are well known. Machine-specific manufacturability factors for turret punch presses were not taken into account in the industrial case samples. On the grounds of the performed tests and industrial case samples, the designer of a sheet metal product can directly influence the machining time, material loss, energy consumption and the number of tools required on a turret punch press by making decisions in the way presented in the hypothesis of thisstudy. The sheet metal parts to be produced can be optimised to bemanufactured on a turret punch press when the material to be used and the kinds of machine and tool options available are known. This provides in-depth knowledge of the machine and tool properties machine and tool-specifically. None of the optimisation starting points described here is a separate entity; instead, they are all connected to each other.

Virtuaalisen lajittelujärjestelmän hyödyntäminen postipalveluyrityksen tuotannollisessa prosessissa

Työn tavoitteena oli kehittää toimintoperusteista kustannuslaskentaa soveltamalla laskentamalli, jonka avulla on mahdollista tutkia postipalveluyrityksen tuotannollisen prosessin kokonaistuottavuuden kannalta optimaalista tapaa hyödyntää virtuaalista lajittelujärjestelmää. Kimputuksen osalta syntyi teoreettinen laskentamalli, mutta kuljetusyksiköinnin osalta pyrittiin muodostamaan todellista prosessia mahdollisimman hyvin noudattava malli, jonka tuloksia on helppo tutkia erilaisilla kustannus- ja lähetysparametreillä. Virtuaalisen lajittelujärjestelmän tuotannollisen hyödyntämisen ohella työssä oli tarkoitus toteuttaa alustavaa analyysia siitä, millä tapaa järjestelmän avulla voidaan tuottaa myös muuta lisäarvoa postipalvelutuotannolle. Analyysissa havaittiin alustavia hyödyntämismahdollisuuksia palvelutuotannon kuormitussuunnittelun, osoitelaatusidonnaisten toimintojen sekä postiin jätön ja prosessiin ohjauksen osalta. Ottamatta kantaa hyödyntämismahdollisuuksien toteutettavuuteen analyysin keskeinen tulos oli kuitenkin se, että järjestelmän hyödyntämisen osalta tutkimattomia teitä on vielä lukuisia.

Aplicació d'algoritmes genètics en l'optimització dels processos de fabricació del paper

La creciente preocupación y concienciación de la sociedad respecto el medio ambiente, y en consecuencia la legislación y regulaciones generadas inducen a la modificación de los procesos productivos existentes en la industria química. Las configuraciones iniciales deben modificarse para conseguir una mayor integración de procesos. Para este fin se han creado y desarrollado diferentes metodologías que deben facilitar la tarea a los responsables del rediseño. El desarrollo de una metodología y herramientas complementarias es el principal objetivo de la investigación aquí presentada, especialmente centrada en el desarrollo y la aplicación de una metodología de optimización de procesos. Esta metodología de optimización se aplica sobre configuraciones de proceso existentes y pretende encontrar nuevas configuraciones viables según los objetivos de optimización fijados. La metodología tiene dos partes diferenciadas: la primera se basa en un simulador de procesos comercial y la segunda es la técnica de optimización propiamente dicha. La metodología se inicia con la elaboración de una simulación convenientemente validada que reproduzca el proceso existente, en este caso una papelera no integrada que produce papel estucado de calidad, para impresión. A continuación la técnica de optimización realiza una búsqueda dentro del dominio de los posibles resultados, en busca de los mejores resultados que satisfazcan plenamente los objetivos planteados. Dicha técnica de optimización está basada en los algoritmos genéticos como herramienta de búsqueda, junto a un subprograma basado en técnicas de programación matemática para el cálculo de resultados. Un número reducido de resultados son finalmente escogidos y utilizados para modificar la simulación existente fijando la redistribución de los flujos del proceso. Los resultados de la simulación del proceso determinan en último caso la viabilidad técnica de cada reconfiguración planteada. En el proceso de optimización, los objetivos están definidos en una función objetivo dentro de la técnica de optimización. Dicha función rige la búsqueda de resultados. La función objetivo puede ser individual o una combinación de objetivos. En el presente caso, la función persigue una minimización del consumo de agua y una minimización de la pérdida de materia prima. La optimización se realiza bajo restricciones para alcanzar este objetivo combinado en forma de una solución de compromiso. Producto de la aplicación de esta metodología se han obtenido resultados interesantes que significan una mejora del cierre de circuitos y un ahorro de materia prima, sin comprometer al mismo tiempo la operabilidad del proceso producto ni la calidad del papel.

Production of pH-responsive microparticles by spray drying: investigation of experimental parameter effects on morphological and release properties

During spray drying, emphasis is placed on process optimisation to generate favourable particle morphological and flow properties. The effect of the initial feed solution composition on the drug release from the prepared microparticles is rarely considered. We investigated the effects of solvent composition, feed solution concentration and drug-loading on sodium salicylate, hydrocortisone and triamcinolone release from spray dried Eudragit L100 microparticles. Eudragit L100 is a pH-responsive polymer whose dissolution threshold is pH 6 so dissolution testing of the prepared microparticles at pH 5 and 1.2 illustrated non-polymer controlled burst release. Increasing the water content of the initial ethanolic feed solution significantly reduced hydrocortisone burst release at pH 5, as did reducing the feed solution concentration. These findings caution that changes in feed solution concentration or solvent composition not only affect particles’ morphological characteristics but can also negatively alter their drug release properties. This work also illustrate that drug-free microparticles can have different morphological properties to drug-loaded microparticles. Therefore, process optimisation needs to be carried out using drug-loaded systems. Depending on the physicochemical properties of the encapsulated API, drug-loading can affect the polymer solubility in the initial feed solution with consequent impact on microparticles morphological and release properties.

The impact of climate change on the treatability of dissolved organic matter (DOM) in upland water supplies: A UK perspective

Climate change in the UK is expected to cause increases in temperatures, altered precipitation patterns and more frequent and extreme weather events. In this review we discuss climate effects on dissolved organic matter (DOM), how altered DOM and water physico-chemical properties will affect treatment processes and assess the utility of techniques used to remove DOM and monitor water quality. A critical analysis of the literature has been undertaken with a focus on catchment drivers of DOM character, removal of DOM via coagulation and the formation of disinfectant by-products (DBPs). We suggest that: (1) upland catchments recovering from acidification will continue to produce more DOM with a greater hydrophobic fraction as solubility controls decrease; (2) greater seasonality in DOM export is likely in future due to altered precipitation patterns; (3) changes in species diversity and water properties could encourage algal blooms; and (4) that land management and vegetative changes may have significant effects on DOM export and treatability but require further research. Increases in DBPs may occur where catchments have high influence from peatlands or where algal blooms become an issue. To increase resilience to variable DOM quantity and character we suggest that one or more of the following steps are undertaken at the treatment works: a) ‘enhanced coagulation’ optimised for DOM removal; b) switching from aluminium to ferric coagulants and/or incorporating coagulant aids; c) use of magnetic ion-exchange (MIEX) pre-coagulation; and d) activated carbon filtration post-coagulation. Fluorescence and UV absorbance techniques are highlighted as potential methods for low-cost, rapid on-line process optimisation to improve DOM removal and minimise DBPs.

Microbial hyaluronic acid production

Hyaluronic acid (HA) is a commercially valuable medical biopolymer increasingly produced through microbial fermentation. Viscosity limits product yield and the focus of research and development has been on improving the key quality parameters, purity and molecular weight. Traditional strain and process optimisation has yielded significant improvements, but appears to have reached a limit. Metabolic engineering is providing new opportunities and HA produced in a heterologous host is about to enter the market. In order to realise the full potential of metabolic engineering, however, greater understanding of the mechanisms underlying chain termination is required.