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.

Majestic Gamification:a case study in the adoption of a service innovation

Purpose: A case study is presented concerning a gamified awards system designed to encourage software users to explore a suite of tools, and to share their expertise level in profile pages. Majestic is a high-tech business based in the West Midlands (UK) w hich offers a Link Intelligence database using a Software as a Service (SaaS) business model. Customers leverage the database for tasks including Search Engine Optimisation (SEO) by using a suite of web-based tools. Getting to know all the tools and how they can be deployed to good effect represents a considerable learning challenge, and Majestic were aware that. Design/methodology/approach: We present the development of Majestic Awards as a case study highlighting the most important design decisions. Then we reflect on the development process as an example of innovation adoption, thereby identifying resources and cu ltura l factors which were critical in ensuring the success of the project. Findings: The gamified awards system makes learning the tools an enjoyable, explorative experience. Success factors included identifying a clear business goal, the process/ project f it, senior management buy in, and identifying the knowledge and resources to resolve t echnical issues. Originality/value: Prior to gamification of the system, only the most expert users regu larly utilized all the tools. The user base is now more knowl edgable about the system and some users choose to use the system to publicize their expertise.

A Delphi study to explore the adoption of servitization in UK companies

This paper explores and rationalises the process of servitization adoption across manufacturing firms. A Delphi research methodology has been applied to capture evidence and opinion from 33 senior executives, in 28 different sized organisations, from a cross section of British industry. The findings focus on five areas: (1) servitization and advanced services, (2) transformation: stimulus, drivers and organisational change, (3) impact on the customer and manufacturer, (4) enablers and inhibitors and (5) potential for business and the economy. Six findings are presented and collectively these contribute to our understanding of the broader change management processes that transform manufacturers to compete through advanced services.

A Conceptual Foresight Model to Investigate the Adoption of Radio Frequency Identification Technology in the English National Health Service

Radio Frequency Identification Technology (RFID) adoption in healthcare settings has the potential to reduce errors, improve patient safety, streamline operational processes and enable the sharing of information throughout supply chains. RFID adoption in the English NHS is limited to isolated pilot studies. Firstly, this study investigates the drivers and inhibitors to RFID adoption in the English NHS from the perspective of the GS1 Healthcare User Group (HUG) tasked with coordinating adoption across private and public sectors. Secondly a conceptual model has been developed and deployed, combining two of foresight’s most popular methods; scenario planning and technology roadmapping. The model addresses the weaknesses of each foresight technique as well as capitalizing on their individual, inherent strengths. Semi structured interviews, scenario planning workshops and a technology roadmapping exercise were conducted with the members of the HUG over an 18-month period. An action research mode of enquiry was utilized with a thematic analysis approach for the identification and discussion of the drivers and inhibitors of RFID adoption. The results of the conceptual model are analysed in comparison to other similar models. There are implications for managers responsible for RFID adoption in both the NHS and its commercial partners, and for foresight practitioners. Managers can leverage the insights gained from identifying the drivers and inhibitors to RFID adoption by making efforts to influence the removal of inhibitors and supporting the continuation of the drivers. The academic contribution of this aspect of the thesis is in the field of RFID adoption in healthcare settings. Drivers and inhibitors to RFID adoption in the English NHS are compared to those found in other settings. The implication for technology foresight practitioners is a proof of concept of a model combining scenario planning and technology roadmapping using a novel process. The academic contribution to the field of technology foresight is the conceptual development of foresight model that combines two popular techniques and then a deployment of the conceptual foresight model in a healthcare setting exploring the future of RFID technology.

Understanding and improving the manufacturing and changeover process in Saudi Arabian business - a multiple case study approach

The importance of the changeover process in the manufacturing industry is becoming widely recognised. Changeover is a complete process of changing between the manufacture of one product to manufacture of an alternative product until specified production and quality rates are reached. The initiatives to improve changeover exist in industry, as better changeover process typically contribute to improved quality performance. A high-quality and reliable changeover process can be achieved through implementation of continuous or radical improvements. This research examines the changeover process of Saudi Arabian manufacturing firms because Saudi Arabia’s government is focused on the expansion of GDP and increasing the number of export manufacturing firms. Furthermore, it is encouraging foreign manufacturing firms to invest within Saudi Arabia. These initiatives, therefore, require that Saudi manufacturing businesses develop the changeover practice in order to compete in the market and achieve the government’s objectives. Therefore, the aim of this research is to discover the current status of changeover process implementation in Saudi Arabian manufacturing businesses. To achieve this aim, the main objective of this research is to develop a conceptual model to understand and examine the effectiveness of the changeover process within Saudi Arabian manufacturing firms, facilitating identification of those activities that affect the reliability and high-quality of the process. In order to provide a comprehensive understanding of this area, this research first explores the concept of quality management and its relationship to firm performance and the performance of manufacturing changeover. An extensive body of literature was reviewed on the subject of lean manufacturing and changeover practice. A research conceptual model was identified based on this review, and focus was on providing high-quality and reliable manufacturing changeover processes during set-up in a dynamic environment. Exploratory research was conducted in sample Saudi manufacturing firms to understand the features of the changeover process within the manufacturing sector, and as a basis for modifying the proposed conceptual model. Qualitative research was employed in the study with semi-structured interviews, direct observations and documentation in order to understand the real situation such as actual daily practice and current status of changeover process in the field. The research instrument, the Changeover Effectiveness Assessment Tool (CEAT) was developed to evaluate changeover practices. A pilot study was conducted by examining the CEAT, proposed for the main research. Consequently, the conceptual model was modified and CEAT was improved in response to the pilot study findings. Case studies have been conducted within eight Saudi manufacturing businesses. These case studies assessed the implementation of manufacturing changeover practice in the lighting and medical products sectors. These two sectors were selected based on their operation strategy which was batch production as well as the fact that they fulfilled the research sampling strategy. The outcomes of the research improved the conceptual model, ultimately to facilitate the firms’ adoption and rapid implementation of a high-quality and reliability changeover during the set-up process. The main finding of this research is that Quality’s factors were considering the lowest levels comparing to the other factors which are People, Process and Infrastructure. This research contributes to enable Saudi businesses to implement the changeover process by adopting the conceptual model. In addition, the guidelines for facilitating implementation were provided in this thesis. Therefore, this research provides insight to enable the Saudi manufacturing industry to be more responsive to rapidly changing customer demands.

Az euróövezet bővítése és euróbevezetési stratégiák (Euro-area enlargement and euro adoption strategies)

Tanulmányunk azokat a kockázatokat és kihívásokat vizsgálja, amelyekkel az új EU tagállamok szembesülnek az euróhoz vezető úton, valamint elemzi az euró bevezetésével és a bevezetés időzítésével kapcsolatos stratégiákat is. Megvizsgáljuk a reál- és nominálkonvergencia kapcsolatát az euróövezetbe csatlakozás szemszögéből. Véleményünk szerint a gazdaság egy főre jutó jövedelemben mért kezdeti fejlettségi szintje, valamint a reálkonvergencia sebessége kihatnak a követendő stratégiákra és a belépés időzítésére. Minél alacsonyabb ugyanis egy ország egy főre jutó jövedelme, annál nagyobb az árszínvonalbeli lemaradása (amit be kell hoznia), és az új tagok jelenlegi helyzetét figyelembe véve annál nagyobb a veszélye annak, hogy a hitelek növekedése túlzottá, a gazdaság túlfűtötté válik. Úgy gondoljuk, hogy az inflációkövetés lebegő árfolyam mellett megfelelőbb az árszínvonal felzárkózási folyamatának kezelésére, mint valamilyen merev árfolyamrögzítés. Elemezzük a maastrichti kritériumokat az új EU-tagállamok gazdasági jellemzőinek szempontjából, és az inflációs kritérium módosítását javasoljuk, amely jelenlegi formájában elvesztette közgazdasági értelmét. JEL kód: E31, E52, E60, F30. /===/ This paper commissioned by DG ECFIN from the EU Commission as part of the EMU@10 project and published in Hungarian by the permission of the EU Commission. The origi-nal English version is available at http://ec.europa.eu/economy_finance/publications/ publication_summary12103_en.htm. The paper discusses the risks and challenges faced by new members on the road to the euro and the strategies and timing of euro adoption. It investigates the real/nominal convergence nexus from the perspective of euro-area entry, arguing that the initial level of economic development, as measured by per capita income, and the speed of real convergence have a bearing on the strategies to follow and the timing of entry into the euro area, for the lower per capita income is, the larger is the price-level gap to close and the greater the danger of credit booms and overheating. It is argued argue that inflation targeting with floating rates is better suited than hard pegs to managing the price-level catch-up process. A suggestion is made for modifying the Maastricht inflation criterion, which as currently defined has lost its economic logic.

AIDS workplace *policy adoption and implementation in local government: An analysis of departmental variation

This is an empirical study whose purpose was to examine the process of innovation adoption as an adaptive response by a public organization and its subunits existing under varying degrees of environmental uncertainty. Meshing organization innovation research and contingency theory to form a theoretical framework, an exploratory case study design was undertaken in a large, metropolitan government located in an area with the fourth highest prevalence rate of HIV/AIDS in the country. A number of environmental and organizational factors were examined for their influence upon decision making in the adoption/non-adoption as well as implementation of any number of AIDS-related policies, practices, and programs.^ The major findings of the study are as follows. For the county government itself (macro level), no AIDS-specific workplace policies have been adopted. AIDS activities (AIDS education, AIDS Task Force, AIDS Coordinator, etc.), adopted county-wide early in the epidemic, have all been abandoned. Worker infection rates, in the aggregate and throughout the epidemic have been small. As a result, absent co-worker conflict (isolated and negligible), no increase in employee health care costs, no litigation regarding discrimination, and no major impact on workforce productivity, AIDS has basically become a non-issue at the strategic core of the organization. At the departmental level, policy adoption decisions varied widely. Here the predominant issue is occupational risk, i.e., both objective as well as perceived. As expected, more AIDS-related activities (policies, practices, and programs) were found in departments with workers known to have significant risk for exposure to the AIDS virus (fire rescue, medical examiner, police, etc.). AIDS specific policies, in the form of OSHA's Bloodborn Pathogen Standard, took place primarily because they were legislatively mandated. Union participation varied widely, although not necessarily based upon worker risk. In several departments, the union was a primary factor bringing about adoption decisions. Additional factors were identified and included organizational presence of AIDS expertise, availability of slack resources, and the existence of a policy champion. Other variables, such as subunit size, centralization of decision making, and formalization were not consistent factors explaining adoption decisions. ^

Behavioral Perspectives on Organizational Change: Practice Adoption, Product Culling, and Technological Search

This dissertation explores the complex process of organizational change, applying a behavioral lens to understand change in processes, products, and search behaviors. Chapter 1 examines new practice adoption, exploring factors that predict the extent to which routines are adopted “as designed” within the organization. Using medical record data obtained from the hospital’s Electronic Health Record (EHR) system I develop a novel measure of the “gap” between routine “as designed” and routine “as realized.” I link this to a survey administered to the hospital’s professional staff following the adoption of a new EHR system and find that beliefs about the expected impact of the change shape fidelity of the adopted practice to its design. This relationship is more pronounced in care units with experienced professionals and less pronounced when the care unit includes departmental leadership. This research offers new insights into the determinants of routine change in organizations, in particular suggesting the beliefs held by rank-and-file members of an organization are critical in new routine adoption. Chapter 2 explores changes to products, specifically examining culling behaviors in the mobile device industry. Using a panel of quarterly mobile device sales in Germany from 2004-2009, this chapter suggests that the organization’s response to performance feedback is conditional upon the degree to which decisions are centralized. While much of the research on product exit has pointed to economic drivers or prior experience, these central finding of this chapter—that performance below aspirations decreases the rate of phase-out—suggests that firms seek local solutions when doing poorly, which is consistent with behavioral explanations of organizational action. Chapter 3 uses a novel text analysis approach to examine how the allocation of attention within organizational subunits shapes adaptation in the form of search behaviors in Motorola from 1974-1997. It develops a theory that links organizational attention to search, and the results suggest a trade-off between both attentional specialization and coupling on search scope and depth. Specifically, specialized unit attention to a more narrow set of problems increases search scope but reduces search depth; increased attentional coupling also increases search scope at the cost of depth. This novel approach and these findings help clarify extant research on the behavioral outcomes of attention allocation, which have offered mixed results.

Process Monitoring and Defect Detection of Additive Manufacturing Using Inline Coherent Imaging

With applications ranging from aerospace to biomedicine, additive manufacturing (AM) has been revolutionizing the manufacturing industry. The ability of additive techniques, such as selective laser melting (SLM), to create fully functional, geometrically complex, and unique parts out of high strength materials is of great interest. Unfortunately, despite numerous advantages afforded by this technology, its widespread adoption is hindered by a lack of on-line, real time feedback control and quality assurance techniques. In this thesis, inline coherent imaging (ICI), a broadband, spatially coherent imaging technique, is used to observe the SLM process in 15 - 45 $\mu m$ 316L stainless steel. Imaging of both single and multilayer builds is performed at a rate of 200 $kHz$, with a resolution of tens of microns, and a high dynamic range rendering it impervious to blinding from the process beam. This allows imaging before, during, and after laser processing to observe changes in the morphology and stability of the melt. Galvanometer-based scanning of the imaging beam relative to the process beam during the creation of single tracks is used to gain a unique perspective of the SLM process that has been so far unobservable by other monitoring techniques. Single track processing is also used to investigate the possibility of a preliminary feedback control parameter based on the process beam power, through imaging with both coaxial and 100 $\mu m$ offset alignment with respect to the process beam. The 100 $\mu m$ offset improved imaging by increasing the number of bright A-lines (i.e. with signal greater than the 10 $dB$ noise floor) by 300\%. The overlap between adjacent tracks in a single layer is imaged to detect characteristic fault signatures. Full multilayer builds are carried out and the resultant ICI images are used to detect defects in the finished part and improve upon the initial design of the build system. Damage to the recoater blade is assessed using powder layer scans acquired during a 3D build. The ability of ICI to monitor SLM processes at such high rates with high resolution offers extraordinary potential for future advances in on-line feedback control of additive manufacturing.

Product and Process Innovation: Antecedents and Performance outcomes in small IT firms in India

Innovation is a strategic necessity for the survival of today’s organizations. The wide recognition of innovation as a competitive necessity, particularly in dynamic market environments, makes it an evergreen domain for research. This dissertation deals with innovation in small Information Technology (IT) firms in India. The IT industry in India has been a phenomenal success story of the last three decades, and is today facing a crucial phase in its history characterized by the need for fundamental changes in strategies, driven by innovation. This study, while motivated by the dynamics of changing times, importantly addresses the research gap on small firm innovation in Indian IT.This study addresses three main objectives: (a) drivers of innovation in small IT firms in India (b) impact of innovation on firm performance (c) variation in the extent of innovation adoption in small firms. Product and process innovation were identified as the two most contextually relevant types of innovation for small IT firms. The antecedents of innovation were identified as Intellectual Capital, Creative Capability, Top Management Support, Organization Learning Capability, Customer Involvement, External Networking and Employee Involvement.Survey method was adopted for data collection and the study unit was the firm. Surveys were conducted in 2014 across five South Indian cities. Small firm was defined as one with 10-499 employees. Responses from 205 firms were chosen for analysis. Rigorous statistical analysis was done to generate meaningful insights. The set of drivers of product innovation (Intellectual Capital, Creative Capability, Top Management Support, Customer Involvement, External Networking, and Employee Involvement)were different from that of process innovation (Creative Capability, Organization Learning Capability, External Networking, and Employee Involvement). Both product and process innovation had strong impact on firm performance. It was found that firms that adopted a combination of product innovation and process innovation had the highest levels of firm performance. Product innovation and process innovation fully mediated the relationship between all the seven antecedents and firm performance The results of this study have several important theoretical and practical implications. To the best of the researcher’s knowledge, this is the first time that an empirical study of firm level innovation of this kind has been undertaken in India. A measurement model for product and process innovation was developed, and the drivers of innovation were established statistically. Customer Involvement, External Networking and Employee Involvement are elements of Open Innovation, and all three had strong association with product innovation, and the latter twohad strong association with process innovation. The results showed that proclivity for Open Innovation is healthy in the Indian context. Practical implications have been outlined along how firms can organize themselves for innovation, the human talent for innovation, the right culture for innovation and for open innovation. While some specific examples of possible future studies have been recommended, the researcher believes that the study provides numerous opportunities to further this line of enquiry.