A chemo-enzymatic process for the production of beta-thymidine, a key intermediate in antiretrovirol manufacture
- Authors: Gordon, Gregory Ernest Robert
- Date: 2010
- Subjects: HIV infections -- Treatment -- South Africa , HIV infections -- South Africa -- Prevention , Antiretroviral agents
- Language: English
- Type: Thesis , Doctoral , DTech
- Identifier: vital:10423 , http://hdl.handle.net/10948/d1016217
- Description: The socio-economic impact of HIV/AIDS on South Africa has resulted in lower gross domestic product, loss of skills in key sectors such as education, and increased health-care costs in providing access to treatment. Currently active pharmaceutical ingredients (API’s) such as stavudine (d4T) and azidothymidine (AZT) are imported from India and China, while formulation is conducted locally. A strategy was initiated between CSIR Biosciences and LIFElab under the auspices of Arvir Technologies to investigate the feasibility of local antiretroviral manufacture (d4T and AZT) or the manufacture of a key intermediate such as β- thymidine (dT). Several advantages associated with successful implementation of this strategy include ensuring a local supply of API’s, thus reducing reliance on procurement from foreign sources and reducing the effect of foreign exchange rate fluctuations on providing cost effective access to treatment. A local supply source would also reduce the imports and thus aid the balance of payments deficit, and in addition to this, provide stimulus in the local pharmaceutical manufacturing industry (which has been in decline for several decades), resulting in increased skills and employment opportunities. This thesis describes the development of a superior chemo-enzymatic process for the production of β-thymidine (72 percent yield, prior to isolation), a key intermediate in the preparation of anti-retrovirals. Alternative processes based purely on chemical or bioprocess transformations to prepare either 5-methyluridine (5-MU) or dT suffer from several disadvantages: lengthy transformations due to protection/deprotection strategies, low selectivties and product yields (30 percent in the chemical process) and isolation of the product from dilute process streams requiring the use of large uneconomical reactors (bioprocesss). This contributes significantly to the cost of d4T and AZT manufacture. Our novel chemoenzymatic process comprises of a biocatalytic reaction for the production of 5-MU, with subsequent chemical transformation into dT (3 steps) negating and circumventing the limitations of the chemical or bioprocess routes. During the course of this project development, the β-thymidine selling price declined from 175 $/kg (2005) to 100 $/kg (2008). However, the process described in this work is still competitive based on the current β- thymidine selling price of 100 $/kg. The process economics show that with further optimization and increasing the isolated dT yield from 70 percent to 90 percent, the variable cost decreases from 136 $/kg to 110 $/kg. The increase in isolated yield is highly probable, based on solubility data of β-thymidine. The decrease in β-thymidine selling price and technological improvement in dT manufacture should translate into lower API manufacture costs and more cost effective access to treatment. Our novel biocatalytic process producing 5-MU uses a coupled enzyme system employing PNP, Purine Nucleoside Phosphorylase and PyNP, Pyrimidine Nucleoside Phosphorylase. The overall transglycosylation reaction may be decoupled into the phosphorolysis reaction (PNP) and synthesis reaction (PyNP). During the phosphorolysis reaction, guanosine is converted into guanine and ribose-1-phosphate (R-1-P) in the presence of PNP enzyme. The reaction intermediate R-1-P is then coupled to thymine in the presence of PyNP enzyme during the synthesis reaction, producing 5-MU. The process was scaled up from lab-scale to bench-scale (10 - 20 L) and demonstrated to be robust and reproducible. This is evident from the average guanosine conversion (94.7 percent ± 2.03) and 5-MU yield (88.2 percent ± 6.21) and mole balance (104 percent ± 7.61) which were obtained at bench-scale (3 replicates, 10 L). The reaction was carried out at reactor productivities of between 7 – 11 g.L-1.h-1. The integration of the biocatalytic process and chemical processes was successfully carried out, showing that 5-MU produced using our novel biocatalytic process behaved similarly to commercially available 5- MU (ex. Dayang Chemicals, China). A PCT patent application (Ref. No. P44422PC01) on this chemo-enzymatic process has been filed and currently public private partnerships are being explored through Arvir Technologies to evaluate and validate this technology at one ton scale.
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- Date Issued: 2010
An evaluation of leadership characteristics required to meet the demands of a strategic change process in the automative cluster in the Eastern Cape region
- Authors: Angloher, Sanette
- Date: 2010
- Subjects: Leadership , Organizational change
- Language: English
- Type: Thesis , Doctoral , DTech
- Identifier: vital:9341 , http://hdl.handle.net/10948/1261 , Leadership , Organizational change
- Description: Against a backdrop of increasing globalisation, deregulation, the rapid pace of technological innovation, a growing knowledge workforce, and shifting social and demographic trends, the primary task of management today is the leadership of organisational change (Graetz, 2000:550). In the words of Lussier and Achua Abstract v (2001:9): “The companies that will survive in the new global competitiveness environment are those that can attract and maintain leaders”. The above emphasises the important role of managers during times when change take place in the organisation. Yet employees are often managed inappropriately in a period of change. There are two reasons for this: (1) managers managing change are under pressure which undermines their own performance, (2) organisations often do not possess managers who are skilful at handling change. It is this second reason that will form the focus of this study. Carnall (1999:105) states that managing change effectively requires an understanding of both what is and seems likely to happen and of how people react to change, and a skilful management performance. Leaders must take on more facilitative roles, as competencies in change management become critical to creating and sustaining effective organisations. The major technological advances of today rely heavily on leaders to facilitate change. Leaders need to encourage people to “collaborate, take risks, take responsibility and be accountable for the change process the organisation must continually undergo to maintain a leadership position in its industry”, according to Moran and Brightman (2000:3). They furthermore argue that “change leaders recognise that they are always trying to balance stability and change. It is a delicate balance to accomplish since employees desire order and stability, while organisations must be ready to adapt to changing conditions quickly”. In this rapidly changing world, organisations must become more flexible, more responsive, and more willing to change and adapt. They must create and assimilate new knowledge at an increasing pace, encourage innovation, and learn to compete in new ways. Dess and Picken (2000:30) argue that the leaders of these organisations must be proactive in facilitating organisational learning and encouraging positive adaptation to external changes. The above shows what an important role leaders/managers have to play in the strategic change process. They need to possess the requisite skills in leadership, problem solving, continuous improvement, team effectiveness, and customer service in order to ensure the long-term growth and stability in the organisation which change can bring about. This research project will identify the various skills needed to successfully manage a change initiative.
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- Date Issued: 2010
Analysis processes as antecedents for decision-making related to growth strategies of South African Game Ranchers
- Authors: Van Eyk, Marlé
- Date: 2010
- Subjects: Tourism -- Marketing , Game farms -- South Africa
- Language: English
- Type: Thesis , Doctoral , DTech
- Identifier: vital:9356 , http://hdl.handle.net/10948/1546 , Tourism -- Marketing , Game farms -- South Africa
- Description: Game ranching offers an economic alternative to conventional stock farming and is a means of supplementing income derived from agricultural activities. Competition is intensifying as ranchers continuously look for ways to improve and expand their businesses and gain a competitive advantage. Ranchers consequently have to find strategies that can ensure growth. Since a reciprocal relationship and dependency exists between a game ranch and the environment in which it operates, it is essential that ranchers take cognizance of aspects in the marketing environment that can either limit, and hence encumber the choice of growth strategy, or stimulate the growth potential of game ranches. As the objective of marketing is to offer customers superior value, it is pertinent for ranchers to know and understand the needs, requirements and motivations of visitors. Failure to do so will cause visitors to patronise other game ranches, or alternative tourism offerings that meet their expectations. A literature review was conducted to define strategy and assist in identifying growth strategies available to a game ranch. The literature review assisted in categorising elements in the external, internal and customer analysis phases of strategic marketing management. Surveys were conducted by means of self-completion questionnaires which were distributed throughout South Africa. Two sets of questionnaires were distributed - one to respondents with prior experience of a game ranch, and one to respondents with no-prior experience. A qualifying question directed the fieldworker to decide which questionnaire should be completed by the respondent. The surveys were constructed in such a way as to determine to what extent various factors would persuade respondents to visit a ranch or extend their stay. Based on a factor analysis, an eight factor structure emerged which represented the personal values of respondents and their levels of expectation for each of the factors. The eight factors were stimulation, universalism, tradition, security, hedonism, power, socialisation, and self-direction. The study revealed the following. - The majority of respondents with no-prior experience of a game ranch is either unaware of the offerings of game ranches, or perceives them as too expensive. - The sustainable use of natural resources is not only essential for the existence of a game ranch, but is also an important motivator for respondents to either visit a game ranch or extend their stay at a ranch. - Staff play a critical role in the overall experience of visitors and act as an important motivator to either visit/revisit a game ranch or extend their stay at the ranch. - Clean and comfortable overnight facilities are deemed important by all respondents. - Respondents have a strong desire to relax and spend time with family and friends. A decision-making framework from which game ranches can select applicable growth strategies resulted from the study. The decision-making framework comprises a three-phase process; phase 1 is the identification of a game ranch's target market; phase 2 is the use of a simplistic framework to determine a possible growth strategy for a game ranch; phase 3 is the identification of ways to implement the selected strategy. As the game ranch industry makes significant contributions to the economic, social and ecological welfare of South Africa, this study added to the body of knowledge of game ranching in South Africa, particularly with regard to the growth options available to game ranches. Recommendations for consideration of future research included the following. - As the current study investigated hunting and tourism, future research on growth strategies for game ranches could also include other aspects of game ranching such as the sale of live game and game products. - More focused empirical research into external and internal strategic analysis should be considered to supplement the empirical research into customer analysis resulting from the current study. - Finally, additional information obtained on the external and internal strategic analysis process could lead to expanding the decision-making framework developed in this study into a more holistic tool to be used in selecting a growth strategy, or combination of strategies for a game ranch3.
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- Date Issued: 2010
Characterisation of dissimilar friction stir welds between 5754 Aluminium alloy and C11000 copper
- Authors: Akinlabi, Esther Titilayo
- Date: 2010
- Subjects: Friction stir welding , Aluminum alloys , Copper alloys
- Language: English
- Type: Thesis , Doctoral , DTech
- Identifier: vital:9629 , http://hdl.handle.net/10948/1536 , Friction stir welding , Aluminum alloys , Copper alloys
- Description: Friction Stir Welding (FSW) is a solid state welding process invented and patented by The Welding Institute (TWI) in 1991, for joining ferrous and non-ferrous materials1. The FSW of Aluminium and its alloys has been commercialised; and recent interest is focused on joining dissimilar materials. However, in order to commercialise the process, research studies are required to characterise and establish process windows. This research work through material characterisation of the welded joints establishes a process window for the Friction Stir welding of 5754 Aluminium Alloy and C11000 Copper. Furthermore, preliminary studies83,85 on the FSW of aluminium and copper have revealed the presence of intermetallic compounds which are detrimental to the weld qualities. This research work is also aimed at establishing process parameters that will result in limited or no intermetallic formation in the weld. The joint integrity of the resulting welds will also be correlated with the input process parameters. Based on the preliminary investigations conducted, a final weld matrix consisting of twenty seven welds was produced by varying the rotational speed between 600 and 1200 rpm, and the feed rate between 50 and 300 mm/min using three different shoulder diameter tools – 15, 18 and 25 mm to compare the heat input into the welds and to achieve the best results. The welds were characterised through microstructural evaluation, tensile testing, microhardness profiling, X-Ray Diffraction analysis, electrical resistivity and statistical analysis – in order to establish the interrelationship between the process parameters and the weld qualities. viii Microstructural evaluation of the weld samples revealed that the interfacial regions are characterised by mixture layers of aluminium and copper; while 33 percent of the tensile samples are within the acceptable range (> 75 percent joint efficiency). High Vickers microhardness values were measured at the joint interfaces, which corresponded with the intermetallic compounds. The Energy Dispersive Spectroscopy analysis revealed the presence of thin layers of intermetallics in nanoscale at the interfacial regions. The diffractograms of the X-Ray Diffraction analysis showed small peaks for intermetallics in some of the welds. Low electrical resistivities were measured at the joint interfaces. The statistical analysis showed that the downward vertical force, (Fz) can significantly influence the resulting weld qualities. An overall summary of the analysis of the weld qualities - with respect to the shoulder diameter tools employed showed that the 18 mm shoulder diameter tool is most appropriate among the three shoulder diameters considered, and a process window of medium spindle speed of 950 rpm and low-to-medium feed rate between 50 and 150 mm/min is established for FSW of Aluminium and Copper. Welds produced at 1200 rpm and 300 mm/min with low heat input did not have intermetallics formed at the joint interface.
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- Date Issued: 2010