Risk Assessment of a Supplier in the Pharmaceutical Industry

The topic of this Master’s Thesis is risk assessment in the supply chain, and the work was done for a company operating in the pharmaceutical industry. The unique features of the industry bring additional challenges to risk management, due to high regulatory, docu-mentation and traceability requirements. The objective of the thesis was to generate a template for assessing the risks in the supply chain of current and potential suppliers of the case company. Risks pertaining to the case setting were sought mainly from in-house expertise of this specific product and supply chain as well as academic research papers and theory on risk management. A questionnaire was set up to assess the found risks on impact, occurrence and possibility of detection. Through this classification of the severity of the risks, the supplier assessment template was formed. A questionnaire template, comprised of the top 10 risks affecting the flow of information and materials in this setting, was formulated to serve as a generic tool for assessing risks in the supply chain of a pharmaceutical company. The template was tested on another supplier for usability and accuracy of found risks, and it demonstrated functioning in a differing supply chain and product setting.

The early activities of front end of innovation in oem companies using a new fei platform as a framework for renewal

The main goal of this study is to create a seamless chain of actions and more detailed structure to the front end of innovation to be able to increase the front end performance and finally to influence the renewal of companies. The main goal is achieved through by the new concept of an integrated model of early activities of FEI leading to a discovery of new elements of opportunities and the identification of new business and growth areas. The procedure offers one possible solution to a dynamic strategy formation process in innovation development cycle. In this study the front end of innovation is positioned between a strategy reviews and a concept creation with needed procedures, tools, and frameworks. The starting point of the study is that the origins of innovation are not well enough understood. The study focuses attention on the early activities of FEI. These first activities are conceptualized in order to find out successful innovation initiatives and strategic renewal agendas. A seamless chain of activities resulting in faster and more precise identification of opportunities and growth areas available on markets and inside companies is needed. Three case studies were conducted in order to study company views on available theory doctrine and to identify the first practical experiences and procedures in the beginning of the front end of innovation. Successful innovation requires focus on renewal in both internal and external directions and they should be carefully balanced for best results. Instead of inside-out mode of actions the studied companies have a strong outside-in thinking mode and they mainly co-develop their innovation initiatives in close proximity with customers i.e. successful companies are an integral part of customers business and success. Companies have tailor-made innovation processes combined their way of working linked to their business goals, and priorities of actual needs of transformation. The result of this study is a new modular FEI platform which can be configured by companies against their actual business needs and drivers. This platform includes new elements of FEI documenting an architecture presenting how the system components work together. The system is a conceptual approach from theories of emergent strategy formation, opportunity identification and creation, interpretation-analysis-experimentation triad and the present FEI theories. The platform includes new features compared to actual models of FEI. It allows managers to better understand the importance of FEI in the whole innovation development stage and FEI as a phase and procedure to discover and implement emergent strategy. An adaptable company rethinks and redirects strategy proactively from time to time. Different parts of the business model are changed to remove identified obstacles for growth and renewal which gives them avenues to find right reforms for renewal.

Oxidative stress may explain how hypertension is maintained by normal levels of angiotensin II

It is well known that essential hypertension evolves in most patients with "near normal" levels of plasma renin activity. However, these levels appear to be responsible for the high levels of arterial pressure because they are normalized by the administration of angiotensin II converting inhibitors or angiotensin receptor antagonist. In experimental animals, hypertension can be induced by the continuous intravenous infusion of small doses of angiotensin II that are not sufficient to evoke an immediate pressor response. However, this condition resembles the characteristics of essential hypertension because the high levels of blood pressure exist with normal plasma levels of angiotensin II. It is suggested that small amounts of angiotensin whose plasma levels are inappropriate for the existing size of extracellular volume stimulate oxidative stress which binds nitric oxide forming peroxynitrite. The latter compound oxidizes arachidonic acid producing isoprostaglandin F2a (an isoprostane) which is characterized by a strong antinatriuretic vasoconstrictor renal effect. In this chain of reactions the vasoconstrictor effects derived from oxygen quenching of nitric oxide and increased isoprostane synthesis could explain how hypertension is maintained with normal plasma levels of renin.

Further biochemical characterization of Mycobacterium leprae laminin-binding proteins

It has been demonstrated that the alpha2 chain of laminin-2 present on the surface of Schwann cells is involved in the process of attachment of Mycobacterium leprae to these cells. Searching for M. leprae laminin-binding molecules, in a previous study we isolated and characterized the cationic proteins histone-like protein (Hlp) and ribosomal proteins S4 and S5 as potential adhesins involved in M. leprae-Schwann cell interaction. Hlp was shown to bind alpha2-laminins and to greatly enhance the attachment of mycobacteria to ST88-14 Schwann cells. In the present study, we investigated the laminin-binding capacity of the ribosomal proteins S4 and S5. The genes coding for these proteins were PCR amplified and their recombinant products were shown to bind alpha2-laminins in overlay assays. However, when tested in ELISA-based assays and in adhesion assays with ST88-14 cells, in contrast to Hlp, S4 and S5 failed to bind laminin and act as adhesins. The laminin-binding property and adhesin capacity of two basic host-derived proteins were also tested, and only histones, but not cytochrome c, were able to increase bacterial attachment to ST88-14 cells. Our data suggest that the alanine/lysine-rich sequences shared by Hlp and eukaryotic H1 histones might be involved in the binding of these cationic proteins to laminin.

Decorin is one of the proteoglycans expressed in Walker 256 rat mammary carcinoma

Proteoglycan and glycosaminoglycan content was analyzed in a model of rat mammary carcinoma to study the roles of these compounds in tumorigenesis. Hyaluronic acid and proteoglycans bearing chondroitin and/or dermatan sulfate chains were detected in solid tumors obtained after subcutaneous inoculation of Walker 256 rat carcinoma cells. About 10% of sulfated glycosaminoglycan chains corresponded to heparan sulfate. The small leucine-rich proteoglycan, decorin, was identified as one of the proteoglycans, in addition to others of higher molecular weight, by cross-reaction with an antiserum raised against pig laryngeal decorin and by N-terminal amino acid sequencing. Decorin was separated from other proteoglycans by hydrophobic chromatography and its complete structure was determined. It has a molecular weight of about 85 kDa and a dermatan chain of 45 kDa with 4-sulfated disaccharides. After degradation of the glycosaminoglycan chain, three core proteins of different molecular weight (36, 46 and 56 kDa) were identified. The presence of hyaluronic acid and decorin has been reported in a variety of tumors and tumor cells. In the Walker 256 mammary carcinoma model, hyaluronic acid may play an important role in tumor progression, since it provides a more hydrated extracellular matrix. On the other hand, decorin, which is expressed by stromal cells, represents a host defense response to tumor growth.

The demand-supply balancing process in supply chain management - case mining & metals industry equipment

The aim of this thesis is to search how to match the demand and supply effectively in industrial and project-oriented business environment. The demand-supply balancing process is searched through three different phases: the demand planning and forecasting, synchronization of demand and supply and measurement of the results. The thesis contains a single case study that has been implemented in a company called Outotec. In the case study the demand is planned and forecasted with qualitative (judgmental) forecasting method. The quantitative forecasting methods are searched further to support the demand forecast and long term planning. The sales and operations planning process is used in the synchronization of the demand and supply. The demand forecast is applied in the management of a supply chain of critical unit of elemental analyzer. Different meters on operational and strategic level are proposed for the measurement of performance.

Characterization of ß-trypsin at acid pH by differential scanning calorimetry

Trypsin is a serino-protease with a polypeptide chain of 223 amino acid residues and contains six disulfide bridges. It is a globular protein with a predominance of antiparallel ß-sheet and helix in its secondary structure and has two domains with similar structures. We assessed the stability of ß-trypsin in the acid pH range using microcalorimetric (differential scanning calorimetry) techniques. Protein concentrations varied in the range of 0.05 to 2.30 mg/ml. Buffer solutions of 50.0 mM ß-alanine and 20.0 mM CaCl2 at different pH values (from 2.0 to 4.2) and concentrations of sorbitol (1.0 and 2.0 M), urea (0.5 M) or guanidinium hydrochloride (0.5 and 1.0 M) were used. The data suggest that we are studying the same conformational transition of the protein in all experimental situations using pH, sorbitol, urea and guanidinium hydrochloride as perturbing agents. The observed van't Hoff ratios (deltaHcal/deltaHvH) of 1.0 to 0.5 in the pH range of 3.2 to 4.2 suggest protein aggregation. In contrast, deltaHcal/deltaHvH ratios equal to one in the pH range of 2.0 to 3.2 suggest that the protein unfolds as a monomer. At pH 3.00, ß-trypsin unfolded with Tm = 54ºC and deltaH = 101.8 kcal/mol, and the change in heat capacity between the native and unfolded forms of the protein (deltaCp) was estimated to be 2.50 ± 0.07 kcal mol-1 K-1. The stability of ß-trypsin calculated at 298 K was deltaG D = 5.7 kcal/mol at pH 3.00 and deltaG D = 15.2 kcal/mol at pH 7.00, values in the range expected for a small globular protein.

Role of a GenoType MTBDRplus line probe assay in early detection of multidrug-resistant tuberculosis at a Brazilian reference center

Resistance to Mycobacterium tuberculosis is a reality worldwide, and its diagnosis continues to be difficult and time consuming. To face this challenge, the World Health Organization has recommended the use of rapid molecular tests. We evaluated the routine use (once a week) of a line probe assay (Genotype MTBDRplus) for early diagnosis of resistance and for assessment of the main related risk factors over 2 years. A total of 170 samples were tested: 15 (8.8%) were resistant, and multidrug resistance was detected in 10 (5.9%). The sensitivity profile took 3 weeks (2 weeks for culture and 1 week for rapid testing). Previous treatment for tuberculosis and the persistence of positive acid-fast smears after 4 months of supervised treatment were the major risk factors observed. The use of molecular tests enabled early diagnosis of drug-resistant bacilli and led to appropriate treatment of the disease. This information has the potential to interrupt the transmission chain of resistant M. tuberculosis.

Carbon footprint of recycled paper

Industrial production of pulp and paper is an intensive consumer of energy, natural resources, and chemicals that result in a big carbon footprint of the final product. At present companies and industries aspire to calculate their gas emissions into the atmosphere in order to afterwards reduce atmospheric contamination. One of the approaches allowing to increase carbon burden from the pulp and paper manufacture is paper recycling. The general purpose of the current paper is to establish methods of quantifying and minimizing the carbon footprint of paper. The first target of this research is to derive a mathematical relationship between virgin fibre requirements with respect to the amount of recycled paper used in the pulp. One more purpose is to establish a model to be used to clarify the contribution of recycling and transportation to decreasing carbon dioxide emissions. For this study sensitivity analysis is used to investigate the robustness of obtained results. The results of the present study show that an increasing of recycling rate does not always lead to minimizing the carbon footprint. Additionally, we derived that transportation of waste paper throughout distances longer than 5800 km has no sense because the use of that paper will only increase carbon dioxide emissions and it is better to reject recycling at all. Finally, we designed the model for organization of a new supply chain of paper product to a customer. The models were implemented as reusable MATLAB frameworks.

Continuity of patient care in day surgery

Continuity is a part of high-quality patient care. The purpose of this study was to analyse what factors are important in the continuity of patients’ care, and how well continuity is achieved in different stages of the care of day surgical patients. Day surgery has become significantly more prevalent in the past few decades, and in order for it to be carried out successfully, continuity in care is particularly essential. The study was carried out in two stages. In the first stage (2001–2005) of the study, continuity was examined through a review of literature from the perspective of critical pathways, naming the continuity categories of time flow, coordination flow, caring relationship flow, and information flow. The first stage also entailed an analysis of matters important to the patient and problems concerning the achievement of care continuity, carried out by interviewing 25 day surgical patients. In the second stage (2006–2015), the degree to which the continuity of day surgical patient care was achieved was analysed from the perspective of patients (n=203, 58%) and nurses working in day surgery units (n=83, 69%), and suggestions for developing the continuity of day surgery patient care were made. In this study continuity of care was examined through a review of literature from the perspective of critical pathways, naming the continuity categories of time flow, coordination flow, caring relationship flow, and information flow. Within these categories, several important factors for the patient were found. According to both patients and nurses, continuity of care is generally achieved to a high degree. Continuity of care is improved by patients being acquainted with and meeting the staff attending to them (nurse and surgeon) before and after the operation. From patients’ perspective, there is room for improvement especially in terms of being admitted to care and in the carer-patient relationship. From nurses’ perspective, there is room for improvement in terms of the smoothness of care. Nurses evaluated the continuity of care to be the least successful before and after the operation. An extensive social and health care reform is planned in Finland in the coming years, aiming to enhance social and health care services and to create smoothly functioning service and care. As a topic of further study supporting the development of the service system, it is important to follow the patient’s progress throughout the entire chain of care, e.g. as a case study. On the other hand, there is also a need to study the views of nurses and other health care professionals in health care, e.g. in primary health care.

Using stimulus equivalence to teach monetary skills to school-age children with autism

The present study evaluated the use of stimulus equivalence in teaching monetary skills to school aged children with autism. An AB within-subject design with periodic probes was used. At pretest, three participants demonstrated relation DA, an auditory-visual relation (matching dictated coin values to printed coin prices). Using a three-choice match-to-sample procedure, with a multi-component intervention package, these participants were taught two trained relations, BA (matching coins to printed prices) and CA (matching coin combinations to printed prices). Two participants achieved positive tests of equivalence, and the third participant demonstrated emergent performances with a symmetric and transitive relation. In addition, two participants were able to show generalization of learned skills with a parent, in a second naturalistic setting. The present research replicates and extends the results of previous studies by demonstrating that stimulus equivalence can be used to teach an adaptive skill to children with autism.

Factors influencing the seasonal changes in primary productivity of the photosynthetic bacteria of Crawford Lake, Ontario

A naturally occurring population of photosynthetic bacteria, located in the meromictic Crawford Lake, was examined during two field seasons (1979-1981). Primary production, biomass, light intensity, lake transparency, pH and bicarbonate concentration were all monitored during this period at selected time intervals. Analysis of the data indicated that (l4C) bacterial photosynthesis was potentially limited by the ambient bicarbonate concentration. Once a threshold value (of 270 mg/l) was reached a dramatic (2 to 10 fold) increase in the primary productivity of the bacteria was observed. Light intensity appeared to have very little effect on the primary productivity of the bacteria, even at times when analyses by Parkin and Brock (1980a) suggested that light intensity could be limiting (i.e., 3.0-5.0 ft. candles). Shifts in the absorption maxima at 430 nrn of the .bacteriochlorophyll spectrum suggested that changes in the species or strain composition of the photosynthetic bacteria had occurred during the summer months. It was speculated that these changes might reflect seasonal variation in the wavelength of light reaching the bacteria. Chemocline erosion did not have the same effect on the population size (biomass) of the photosynthetic bacteria in Crawford Lake (this thesis) as it did in Pink Lake (Dickman, 1979). In Crawford Lake the depth of the chemocline was lowered with no apparent loss in biomass (according to bacteriochlorophyll data). A reverse current was. proposed to explain the observation. The photosynthetic bacteria contributed a significant proportion (10-60%) of the lake1s primary productivitya Direct evidence was obtained with (14C) labelling of the photosynthetic bacteria, indica.ting that the zooplankton were grazing the photosynthetic bacteria. This indicated that some of the photosynthetic bacterial productivity was assimilated into the food chain of the lake. Therefore, it was concluded that the photosynthetic bacteria made a significant contribution to the total productivity of Crawford Lake.

Synthetic studies on prostaglandins: "synthesis of a new thia-PGEI analog"

A PGE1 analog, namely (±)-trans-2-(6'-carbomethoxyhexyl)-3- (E-3"-thia-1 "-octene)-4-hydroxycyclopentanone 71, has been prepared for the first time. Towards the synthesis of this compound, several synthetic approaches aimed at the preparation of the required acetylenic and E-halovinylic sulfides as building blocks were investigated. Among all the methods examined, it appeared evident that the best route to ethynyl n.pentyl sulfide 81 is via a double dehydrohalogenation of the corresponding 1,2-dibromoethyl sulfide with sodium amide in liquid ammonia. In addition, the isomerically pure E-2-iodoethenyl n.pentyl sulfide 85 is conveniently prepared in high yield and stereoselectivity by hydrozirconation-iodination of the terminal ethynyl sulfide 81. The classical hydroalumination and hydroboration reactions for the preparation of vinyl halides from alkynes gave only small yields when applied as methods towards the synthesis of 85 . The building block 2-(6'-carbomethoxyhexyl)-4-hydroxy-2- cyclopentenone (±)-1 carrying the upper side-chain of prostaglandin E 1 was prepared by a step-wise synthesis involving transformations of compounds possessing the required carbocyclic framework (see scheme 27). The synthesis proved to be convenient and gave a good overall yield of (±)-1 which was protected as the TH P-derivative 37 or the siloxy derivative 38. With the required building blocks 81 and 37 in hand, the target 1S-thia-PGE1 analog (±)-71 was prepared via the in situ higher cuprate formation-conjugate addition reaction. This method proved to be convenient and stereospecific. The standard cuprate method, involving an organocuprate reagent generated from an isolated vinyl iodide, did not work well in our case and gave a complicated mixture of products. The target compound will be submitted for assessment of bio log ical activity.

The nature of avidyÄ in Buddhism and VedÄ nta

This thesis deals with the nature of ignorance as it was interpreted in the Upani~adic tradition, specifically in Advaita Vedanta, and in early and Mahayana Buddhism , e specially in the Madhyamika school of Buddhism. The approach i s a historical and comparative one. It examines the early thoughts of both the upanis.a ds and Buddhism abou t avidya (ignorance), shows how the notion was treated by the more speculative and philosphically oriented schools which base d themselves on the e arly works, and sees how their views differ. The thesis will show that the Vedinta tended to treat avidya as a topic for metaphysical s peculation as t he s chool developed, drifting from its initial e xistential concerns, while the Madhyamika remained in contact with the e xistential concerns evident in the first discourses of the Buddha. The word "notion" has been chosen for use in referring t o avidya, even though it may have non-intellectual and emotional connotations, to avoid more popular a lternatives such as "concept" or "idea". In neither the Upani,ads, Advaita Vedanta, or Buddhism is ignorance merely a concept or an idea. Only in a secondary sense, in texts and speech , does it become one. Avidya has more to do with the lived situation in which man finds himself, with the subjectobject separation in which he f eels he exists, than with i i i intel lect ual constr ucts . Western thought has begun to r ealize the same with concerns such as being in modern ontology, and has chosen to speak about i t i n terms of the question of being . Avidya, however, i s not a 'question' . If q ue stions we r e to be put regarding the nature of a vidya , they would be more of t he sort "What is not avidya?", though e ven here l anguage bestows a status t o i t which avidya does not have. In considering a work of the Eastern tradition, we f ace t he danger of imposing Western concepts on it. Granted t hat avidya is customari ly r endered i n English as ignorance, the ways i n which the East and West view i gno rance di f f er. Pedagogically , the European cultures, grounded in the ancient Greek culture, view ignorance as a l ack or an emptiness. A child is i gnorant o f certain t hings and the purpose o f f ormal education , in f act if not in theory, is to fill him with enough knowledge so that he can cope wit h t he complexities and the e xpectations of s ociety. On another level, we feel t hat study and research will l ead t o the discovery o f solutions, which we now lack , for problems now defying solut i on . The East, on the o t her hand, sees avidya in a d i fferent light.Ignorance isn't a lack, but a presence. Religious and philosophical l iterature directs its efforts not towards acquiring something new, but at removing t.he ideas and opinions that individuals have formed about themselves and the world. When that is fully accomplished, say the sages , t hen Wisdom, which has been obscured by those opinions, will present itself. Nothing new has to be learned, t hough we do have t o 'learn' that much. The growing interest in t he West with Eastern religions and philosophies may, in time, influence our theoretical and practical approaches to education and learning, not only in the established educati onal institutions, but in religious , p sychological, and spiritual activities as well. However, the requirements o f this thesis do no t permit a formulation of revolutionary method or a call to action. It focuses instead on the textual arguments which attempt to convince readers that t he world in which they take themselves to exist is not, in essence, real, on the ways i n which the l imitations of language are disclosed, and on the provisional and limited schemes that are built up to help students see through their ignorance. The metaphysic s are provisional because they act only as spurs and guides. Both the Upanisadic and Buddhist traditions that will be dealt with here stress that language constantly fails to encompass the Real. So even terms s uch as 'the Real', 'Absolute', etc., serve only to lead to a transcendent experience . The sections dealing with the Upanisads and Advaita Vedanta show some of the historical evolution of the notion of avidya, how it was dealt with as maya , and the q uestions that arose as t o its locus. With Gau?apada we see the beginnings of a more abstract treatment of the topic, and , the influence of Buddhism. Though Sankhara' S interest was primarily directed towards constructing a philosophy to help others attain mok~a ( l iberation), he too introduced t echnica l t e rminology not found in the works of his predecessors. His work is impressive , but areas of it are incomplete. Numbers of his followers tried to complete the systematic presentation of his insi ghts . Their work focuses on expl anat i ons of adhyasa (superimposition ) , t he locus and object of ignorance , and the means by which Brahman takes itself to be the jiva and the world. The section on early Buddhism examines avidya in the context o f the four truths, together with dubkha (suffering), the r ole it p l ays in t he chain of dependent c ausation , a nd t he p r oblems that arise with t he doctrine of anatman. With t he doct rines of e arly Buddhism as a base, the Madhyamika elaborated questions that the Buddha had said t e nded not t o edi f ication. One of these had to do with own - being or svabhava. Thi s serves a s a centr e around which a discussion o f i gnorance unfolds, both i ndividual and coll ective ignorance. There follows a treatment of the cessation of ignorance as it is discussed within this school . The final secti on tries to present t he similarities and differences i n the natures o f ignorance i n t he two traditions and discusses the factors responsible for t hem . ACKNOWLEDGEMENTS I would like to thank Dr. Sinha for the time spent II and suggestions made on the section dealing with Sankara and the Advait.a Vedanta oommentators, and Dr. Sprung, who supervised, direoted, corrected and encouraged the thesis as a whole, but especially the section on Madhyamika, and the final comparison.

ORGANOSILICON BIOTECHNOLOGY: A BIO-INSPIRED APPROACH TO THE HYDROLYSIS OF ALKOXYSILANES and THE LIPASE-CATALYZED SYNTHESIS OF SILOXANE-CONTAINING POLYESTERS AND POLYAMIDES

The first part of this thesis studied the capacity of amino acids and enzymes to catalyze the hydrolysis and condensation of tetraethoxysilane and phenyltrimethoxysilane. Selected amino acids were shown to accelerate the hydrolysis and condensation of tetraethoxysilane under ambient temperature, pressure and at neutral pH (pH 7±0.02). The nature of the side chain of the amino acid was important in promoting hydrolysis and condensation. Several proteases were shown to have a capacity to hydrolyze tri- and tet-ra- alkoxysilanes under the same mild reaction conditions. The second part of this thesis employed an immobilized Candida antarctica lipase B (Novozym-435, N435) to produce siloxane-containing polyesters, polyamides, and polyester amides under solvent-free conditions. Enzymatic activity was shown to be temperature dependent, increasing until enzyme denaturation became the dominant pro-cess, which typically occurred between 120-130ᵒC. The residual activity of N435 was, on average, greater than 90%, when used in the synthesis of disiloxane-containing polyesters, regardless of the polymerization temperature except at the very highest temperatures, 140-150ᵒC. A study of the thermal tolerance of N435 determined that, over ten reaction cycles, there was a decrease in the initial rate of polymerization with each consecutive use of the catalyst. No change in the degree of monomer conversion after a 24 hour reaction cycle was found.