Nanotechnology and microfluidics:formulation design and on-chip manufacture of nanoparticles

Nanoparticles offer an ideal platform for the delivery of small molecule drugs, subunit vaccines and genetic constructs. Besides the necessity of a homogenous size distribution, defined loading efficiencies and reasonable production and development costs, one of the major bottlenecks in translating nanoparticles into clinical application is the need for rapid, robust and reproducible development techniques. Within this thesis, microfluidic methods were investigated for the manufacturing, drug or protein loading and purification of pharmaceutically relevant nanoparticles. Initially, methods to prepare small liposomes were evaluated and compared to a microfluidics-directed nanoprecipitation method. To support the implementation of statistical process control, design of experiment models aided the process robustness and validation for the methods investigated and gave an initial overview of the size ranges obtainable in each method whilst evaluating advantages and disadvantages of each method. The lab-on-a-chip system resulted in a high-throughput vesicle manufacturing, enabling a rapid process and a high degree of process control. To further investigate this method, cationic low transition temperature lipids, cationic bola-amphiphiles with delocalized charge centers, neutral lipids and polymers were used in the microfluidics-directed nanoprecipitation method to formulate vesicles. Whereas the total flow rate (TFR) and the ratio of solvent to aqueous stream (flow rate ratio, FRR) was shown to be influential for controlling the vesicle size in high transition temperature lipids, the factor FRR was found the most influential factor controlling the size of vesicles consisting of low transition temperature lipids and polymer-based nanoparticles. The biological activity of the resulting constructs was confirmed by an invitro transfection of pDNA constructs using cationic nanoprecipitated vesicles. Design of experiments and multivariate data analysis revealed the mathematical relationship and significance of the factors TFR and FRR in the microfluidics process to the liposome size, polydispersity and transfection efficiency. Multivariate tools were used to cluster and predict specific in-vivo immune responses dependent on key liposome adjuvant characteristics upon delivery a tuberculosis antigen in a vaccine candidate. The addition of a low solubility model drug (propofol) in the nanoprecipitation method resulted in a significantly higher solubilisation of the drug within the liposomal bilayer, compared to the control method. The microfluidics method underwent scale-up work by increasing the channel diameter and parallelisation of the mixers in a planar way, resulting in an overall 40-fold increase in throughput. Furthermore, microfluidic tools were developed based on a microfluidics-directed tangential flow filtration, which allowed for a continuous manufacturing, purification and concentration of liposomal drug products.

The automation of protein crystal presentation for X ray diffraction experiments using standing acoustic waves in a microfluidic chip environment

As the pressure continues to grow on Diamond and the world's synchrotrons for higher throughput of diffraction experiments, new and novel techniques are required for presenting micron dimension crystals to the X ray beam. Currently this task is both labour intensive and primarily a serial process. Diffraction measurements typically take milliseconds but sample preparation and presentation can reduce throughput down to 4 measurements an hour. With beamline waiting times as long as two years it is of key importance for researchers to capitalize on available beam time, generating as much data as possible. Other approaches detailed in the literature [1] [2] [3] are very much skewed towards automating, with robotics, the actions of a human protocols. The work detailed here is the development and discussion of a bottom up approach relying on SSAW self assembly, including material selection, microfluidic integration and tuning of the acoustic cavity to order the protein crystals.

Large volume metrology process model:measurability analysis with integration of metrology classification model and feature-based selection model

Aircraft manufacturing industries are looking for solutions in order to increase their productivity. One of the solutions is to apply the metrology systems during the production and assembly processes. Metrology Process Model (MPM) (Maropoulos et al, 2007) has been introduced which emphasises metrology applications with assembly planning, manufacturing processes and product designing. Measurability analysis is part of the MPM and the aim of this analysis is to check the feasibility for measuring the designed large scale components. Measurability Analysis has been integrated in order to provide an efficient matching system. Metrology database is structured by developing the Metrology Classification Model. Furthermore, the feature-based selection model is also explained. By combining two classification models, a novel approach and selection processes for integrated measurability analysis system (MAS) are introduced and such integrated MAS could provide much more meaningful matching results for the operators. © Springer-Verlag Berlin Heidelberg 2010.

Novel formulation strategies for the fabrication of lyophilised orally disintegrating tablets

Orally disintegrating Tablets (ODTs), also known as fast-disintegrating, fast-melt or fast-dissolving tablets, are a relatively novel dosage technology that involves the rapid disintegration or dissolution of the dosage form into a solution or suspension in the mouth without the need for water. The solution containing the active ingredients is swallowed, and the active ingredients are then absorbed through the gastrointestinal epithelium to reach the target and produce the desired effect. Formulation of ODTs was originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patient population, especially children and elderly. The current work investigates the formulation and development of ODTs prepared by freeze drying. Initial studies focused on formulation parameters that influence the manufacturing process and performance of lyophilised tablets based on excipients used in commercial products (gelatin and saccharides). The second phase of the work was followed up by comprehensive studies to address the essential need to create saccharide free ODTs using naturally accruing amino acids individually or in combinations. Furthermore, a factorial design study was carried out to investigate the feasibility of delivering multiparticulate systems of challenging drugs using a novel formulation that exploited the electrostatic associative interaction between gelatin and carrageenan. Finally, studies aimed to replace gelatin with ethically and morally accepted components to the end users were performed and the selected binder was used in factorial design studies to investigate and optimise ODT formulations that incorporated drugs with varies physicochemical properties. Our results show that formulation of elegant lyophilised ODTs with instant disintegration and adequate mechanical strength requires carful optimisation of gelatin concentration and bloom strength in addition to saccharide type and concentration. Successful formulation of saccharides free lyophilised ODTs requires amino acids that crystallise in the frozen state or display relatively high Tg', interact and integrate completely with the binder and, also, display short wetting time with the disintegrating medium. The use of an optimised mixture of gelatin, carrageenan and alanine was able to create viscous solutions to suspend multiparticulate systems and at the same time provide tablets with short disintegration times and adequate mechanical properties. On the other hand, gum arabic showed an outstanding potential for use as a binder in the formulation of lyophilised ODTs. Compared to gelatin formulations, the use of gum arabic simplified the formulation stages, shortened the freeze drying cycles and produced tablets with superior performance in terms of the disintegration time and mechanical strength. Furthermore, formulation of lyophilised ODTs based on gum arabic showed capability to deliver diverse range of drugs with advantages over commercial products.

Purification of phosphoric acid by solvent extraction

This work follows a feasibility study (187) which suggested that a process for purifying wet-process phosphoric acid by solvent extraction should be economically viable. The work was divided into two main areas, (i) chemical and physical measurements on the three-phase system, with or without impurities; (ii) process simulation and optimization. The object was to test the process technically and economically and to optimise the type of solvent. The chemical equilibria and distribution curves for the system water - phosphoric acid - solvent for the solvents n-amyl alcohol, tri-n-butyl phosphate, di-isopropyl ether and methyl isobutyl ketone have been determined. Both pure phosphoric acid and acid containing known amounts of naturally occurring impurities (Fe P0 4 , A1P0 4 , Ca3(P04)Z and Mg 3(P0 4 )Z) were examined. The hydrodynamic characteristics of the systems were also studied. The experimental results obtained for drop size distribution were compared with those obtainable from Hinze's equation (32) and it was found that they deviated by an amount related to the turbulence. A comprehensive literature survey on the purification of wet-process phosphoric acid by organic solvents has been made. The literature regarding solvent extraction fundamentals and equipment and optimization methods for the envisaged process was also reviewed. A modified form of the Kremser-Brown and Souders equation to calculate the number of contact stages was derived. The modification takes into account the special nature of phosphoric acid distribution curves in the studied systems. The process flow-sheet was developed and simulated. Powell's direct search optimization method was selected in conjunction with the linear search algorithm of Davies, Swann and Campey. The objective function was defined as the total annual manufacturing cost and the program was employed to find the optimum operating conditions for anyone of the chosen solvents. The final results demonstrated the following order of feasibility to purify wet-process acid: di-isopropyl ether, methylisobutyl ketone, n-amyl alcohol and tri-n-butyl phosphate.

Facility closure management:the case of Vauxhall Motors Luton

Purpose – The purpose of the paper is to present the findings of a study of factory closure management. It details the sequence and the results of the key strategic manufacturing management decisions made from the time of the announcement of the plant closure to the cessation of operations. The paper also includes an analysis of the human resource management (HRM) actions taken during this same time period and their consequences upon all those involved in the closure management process. Design/methodology/approach – The case study methodology consisted of two initial site visits to monitor closure management effectiveness (adherence to plan and the types and frequency of closure management communications). During these visits, documentary evidence of the impact of the closure decision upon production performance was also collected (manufacturing output and quality performance data). Following plant closure, interviews were held with senior business, production and HRM managers and production personnel. A total of 12 interviews were carried out. Findings – The case study findings have informed the development of a conceptual model of facility closure management. Information obtained from the interviews suggests that the facility closure management process consists of five key management activities. The unexpected announcement of a factory closure can cause behavioural changes similar to those of bereavement, particularly by those employees who are its survivors. In addition, similar reactions to the closure announcement may be displayed by those who choose to remain employed by the factory owner throughout the phased closure of the plant. Originality/value – Facility closure management is an insufficiently researched strategic operations management activity. This paper details a recommended procedure for its management. A conceptual model has also been developed to illustrate the links between the key facility closure management tasks and the range of employee changes of behaviour that can be induced by their execution.

The case for the organisational use of simulation

This paper describes the use of simulation in a large manufacturing organisation and analyses how it could have been used more fully. Although the benefits from using simulation were clear, it was seen that the technique could have been deployed more effectively by considering the organisational context of the use. From the analysis of the case study, certain recommendations are made on how to maximise the benefits from simulation within the organisation, thereby extending the benefits from what is often a considerable investment in developing a simulation model. Recent developments in simulation software in terms of improvements in usability and integration with organisational data are seen to increase the feasibility of a wider role for simulation if the organisational barriers discussed can be overcome.

Stimulating design reuse through automated coding

In designing new product the ability to retrieve drawings of existing components is important if costs are to be controlled by preventing unnecessary duplication if parts. Component coding and classification systems have been used successfully for these purposes but suffer from high operational costs and poor usability arising directly from the manual nature of the coding process itself. A new version of an existing coding system (CAMAC) has been developed to reduce costs by automatically coding engineering drawings. Usability is improved be supporting searches based on a drawing or sketch of the desired component. Test results from a database of several thousand drawings are presented.

Economists' perceptions versus managers' decisions:an experiment in transaction cost analysis

Are the perceptions of professional economists on transaction costs consistent with make-or-buy decisions made within firms? The answer may have important implications for transaction cost research. Data on firms' outsourcing during the new product development process are taken from a largescale survey of UK, German and Irish manufacturing plants, and we test the consistency of these outsourcing decisions with the predictions derived from the transaction cost perceptions of a panel of economists. Little consistency is evident between actual outsourcing patterns and the predictions of the (Williamsonian) transactions cost model derived from the panel of economists. There is, however, evidence of a systematic pattern to the differences, suggesting that a competence or resource-based approach may be relevant to understanding firm outsourcing, and that firms are adopting a strategic approach to managing their external relationships. © Cambridge Political Economy Society 2005; all rights reserved.

HRM as a predictor of innovation

There is growing evidence available to suggest that HR practice is an important predictor of organisational performance. In this article, we argue that HR practices also have the potential to promote organisational innovation. We describe a longitudinal study of 22 UK manufacturing companies and examine the relationship between such practices and product and technological innovation. Results reveal that training, induction, team working, appraisal and exploratory learning focus are all predictors of innovation. Contingent reward, applied in conjunction with an exploratory learning focus, is positively associated with innovation in technical systems. Furthermore, training, appraisal and induction, combined with exploratory learning focus, explain variation between companies in product and technological innovation above and beyond the main effects observed. © 2006 Blackwell Publishing Ltd.

Computer integrated system for form-roll manufacture

Computer integrated manufacture has brought about great advances in manufacturing technology and its recognition is world wide. Cold roll forming of thin-walled sections, and in particular the design and manufacture of form-rolls, the special tooling used in the cold roll forming process, is but one such area where computer integrated manufacture can make a positive contribution. The work reported in this thesis, concerned with the development of an integrated manufacturing system for assisting the design and manufacture of form-rolls, was undertaken in collaboration with a leading manufacturer of thin-walled sections. A suit of computer programs, written in FORTRAN 77, have been developed to provide computer aids for every aspect of work in form-roll design and manufacture including cost estimation and stock control aids. The first phase of the development programme dealt with the establishment of CAD facilities for form-roll design, comprising the design of the finished section, the flower pattern, the roll design and the interactive roll editor program. Concerning the CAM facilities, dealt with in the second phase, an expert system roll machining processor and a general post-processor have been developed for considering the roll geometry and automatically generating NC tape programs for any required CNC lathe system. These programs have been successfully implemented, as an integrated manufacturing software system, on the VAX 11/750 super-minicomputer with graphics facilities for displaying drawings interactively on the terminal screen. The development of the integrated system has been found beneficial in all aspects of form-roll design and manufacture. Design and manufacturing lead times have been reduced by several weeks, quality has improved considerably and productivity has increased. The work has also demonstrated the promising nature of the expert systems approach to computer integrated manufacture.

Some aspects of system design for production management in the rolling-mill industry

Case studies in copper-alloy rolling mill companies showed that existing planning systems suffer from numerous shortcomings. Where computerised systems are in use, these tend to simply emulate older manual systems and still rely heavily on modification by experienced planners on the shopfloor. As the size and number of orders increase, the task of process planners, while seeking to optimise the manufacturing objectives and keep within the production constraints, becomes extremely complicated because of the number of options for mixing or splitting the orders into batches. This thesis develops a modular approach to computerisation of the production management and planning functions. The full functional specification of each module is discussed, together with practical problems associated with their phased implementation. By adapting the Distributed Bill of Material concept from Material Requirements Planning (MRP) philosophy, the production routes generated by the planning system are broken down to identify the rolling stages required. Then to optimise the use of material at each rolling stage, the system generates an optimal cutting pattern using a new algorithm that produces practical solutions to the cutting stock problem. It is shown that the proposed system can be accommodated on a micro-computer, which brings it into the reach of typical companies in the copper-alloy rolling industry, where profit margins are traditionally low and the cost of widespread use of mainframe computers would be prohibitive.

Smart microsystems for cell manipulations

This thesis documents the design, manufacture and testing of a passive and non-invasive micro-scale planar particle-from-fluid filter for segregating cell types from a homogeneous suspension. The microfluidics system can be used to separate spermatogenic cells from testis biopsy samples, providing a mechanism for filtrate retrieval for assisted reproduction therapy. The system can also be used for point-of-service diagnostics applications for hospitals, lab-on-a-chip pre-processing and field applications such as clinical testing in the third world. Various design concepts are developed and manufactured, and are assessed based on etched structure morphology, robustness to variations in the manufacturing process, and design impacts on fluid flow and particle separation characteristics. Segregation was measured using image processing algorithms that demonstrate efficiency is more than 55% for 1 µl volumes at populations exceeding 1 x 107. the technique supports a significant reduction in time over conventional processing, in the separation and identification of particle groups, offering a potential reduction in the associated cost of the targeted procedure. The thesis has developed a model of quasi-steady wetting flow within the micro channel and identifies the forces across the system during post-wetting equalisation. The model and its underlying assumptions are validated empirically in microfabricated test structures through a novel Micro-Particle Image Velocimetry technique. The prototype devices do not require ancillary equipment nor additional filtration media, and therefore offer fewer opportunities for sample contamination over conventional processing methods. The devices are disposable with minimal reagent volumes and process waste. Optimal processing parameters and production methods are identified with any improvements that could be made to enhance their performance in a number of identified potential applications.

Hierarchical case-based reasoning to support knitwear design

Knitwear design is a creative activity that is hard to automate using the computer. The production of the associated knitting pattern, however, is repetitive, time-consuming and error-prone, calling for automation. Our objectives are two-fold: to facilitate the design and to ease the burden of calculations and checks in pattern production. We conduct a feasibility study for applying case-based reasoning in knitwear design: we describe appropriate methods and show their application.

A production planning system for plastic footwear in a seasonal market

Modern injection-moulding machinery which produces several, pairs of plastic footwear at a time brought increased production planning problems to a factory. The demand for its footwear is seasonal but the company's manning policy keeps a fairly constant production level thus determining the aggregate stock. Production planning must therefore be done within the limitations of a specified total stock. The thesis proposes a new production planning system with four subsystems. These are sales forecasting, resource planning, and two levels of production scheduling: (a) aggregate decisions concerning the 'manufacturing group' (group of products) to be produced in each machine each week, and (b) detailed decisions concerning the products within a manufacturing group to be scheduled into each mould-place. The detailed scheduling is least dependent on improvements elsewhere so the sub-systems were tackled in reverse order. The thesis concentrates on the production scheduling sub-systems which will provide most. of the benefits. The aggregate scheduling solution depends principally on the aggregate stocks of each manufacturing group and their division into 'safety stocks' (to prevent shortages) and 'freestocks' (to permit batch production). The problem is too complex for exact solution but a good heuristic solution, which has yet to be implemented, is provided by minimising graphically immediate plus expected future costs. The detailed problem splits into determining the optimal safety stocks and batch quantities given the appropriate aggregate stocks. It.is found that the optimal safety stocks are proportional to the demand. The ideal batch quantities are based on a modified, formula for the Economic Batch Quantity and the product schedule is created week by week using a priority system which schedules to minimise expected future costs. This algorithm performs almost optimally. The detailed scheduling solution was implemented and achieved the target savings for the whole project in favourable circumstances. Future plans include full implementation.