Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

"Kirjailijoiden tapaus" Venäjällä vuonna 1997

In the autumn of 1997, Russian government was faced with media pressure when owners of the TV channels ORT and NTV joined forces against it. This study is based on media sources from October 1997 to December 1997. It shows clearly how the enormous power of the media was able to dictate what happened in Russia. In the mid-1990s Russians started to talk about political technology, which became a commonly used term by professionals, journalists, politicians and intelligence services. As a result of this action, two leading reformers in the government, Anatoliy Chubais and Boris Nemtsov, were dismissed from their highly influential posts as finance and energy ministers respectively, but retained their power as first deputy prime ministers. According to the correspondents, the real reason was to resolve a conflict within the parliament, which had demanded the dismissal of Mr. Chubais. This demand was presented after Chubais had accepted $90,000 as a reward for co-writing a book on privatization. Chubais was considered to be Russia’s “business card” towards the west – the"Authors’ case" (Delo avtorov) was only solved after President Boris Yeltsin took part in the public debate. According to the research, the media owned by powerful businessmen Boris Berezovsky and Vladimir Gusinski, was able to use its own security services to expose sensitive material (Russian term ‘kompromat’), if necessary, concerning any given person. The so-called Authors’ case can be considered as a part of the battle and the tip of the iceberg in arrangements designed to organize the funding of the Russian presidential election campaign in 2000. The reason why this particular incident was so widely covered on television was because several programs aimed to reveal to the public "hidden bribes" that, as they claimed, government officials had received. The political aspect, however, was quite mild, when the concrete issues of possible dismissals of Ministers were debated in the Parliament. Everything was dealt with as a “family matter” inside Kremlin. Yeltsin's "family" consisted of practically anybody from oligarch Berezovsky to Chubais, the father of Russia's privatization policy. Methods of critical history implementation analysis has been used in this research in determining the use of the source material. Literature and interviews have also provided a good base for the study. The study proves that any literature dealing with the subject has not paid enough attention to how the dismissal of Alexander Kazakov, deputy of President’s administration, was linked directly with Gazprom, the state gas monopoly. Kazakov had to leave Gazprom and lose his position as Chubais' ally when the influential ORT television company was deteriorated.

A Critical Assesment of Occluded Fronts

The aim of this work was the assessment about the structure and use of the conceptual model of occlusion in operational weather forecasting. In the beginning a survey has been made about the conceptual model of occlusion as introduced to operational forecasters in the Finnish Meteorological Institute (FMI). In the same context an overview has been performed about the use of the conceptual model in modern operational weather forecasting, especially in connection with the widespread use of numerical forecasts. In order to evaluate the features of the occlusions in operational weather forecasting, all the occlusion processes occurring during year 2003 over Europe and Northern Atlantic area have been investigated using the conceptual model of occlusion and the methods suggested in the FMI. The investigation has yielded a classification of the occluded cyclones on the basis of the extent the conceptual model has fitted the description of the observed thermal structure. The seasonal and geographical distribution of the classes has been inspected. Some relevant cases belonging to different classes have been collected and analyzed in detail: in this deeper investigation tools and techniques, which are not routinely used in operational weather forecasting, have been adopted. Both the statistical investigation of the occluded cyclones during year 2003 and the case studies have revealed that the traditional classification of the types of the occlusion on the basis of the thermal structure doesn t take into account the bigger variety of occlusion structures which can be observed. Moreover the conceptual model of occlusion has turned out to be often inadequate in describing well developed cyclones. A deep and constructive revision of the conceptual model of occlusion is therefore suggested in light of the result obtained in this work. The revision should take into account both the progresses which are being made in building a theoretical footing for the occlusion process and the recent tools and meteorological quantities which are nowadays available.

Kirkko, Kekkonen ja kommunismi poliittisina kriisivuosina 1958-1962

This study explores the relationship of the Evangelical Lutheran Church of Finland to communism and political power during the period of crises in Finnish foreign relations with the Soviet Union from 1958 to 1962. During this period the USSR repeatedly interfered in Finland´s domestic affairs and limited her foreign political freedom of action. The research subjects for this dissertation are the bishops of the Church of Finland and the newspaper Kotimaa, which can be regarded as the unofficial organ of the church at the time. A typical characteristic of the Church of Finland from the beginning of the twentieth century was patriotism. During the interwar years the church was strongly anti-communist and against the Soviet Union. This tendency was also evident during the Second World War. After the war the Finnish Church feared that the rise of the extreme left would jeopardize its position. The church, however, succeeded in maintaining its status as a state church throughout the critical years immediately following the war. This study indicates that, although the manner of expression altered, the political attitude of the church did not substantially change during the postwar period. In the late 1950s and early 1960s the church was still patriotic and fear of the extreme left was also evident among the leaders of the church. The victory of the Finnish People's Democratic League in the general election of 1958 was an unwelcome surprise to the church. This generated fear in the church that, with Soviet support, the Finnish communists might return to governmental power and the nation could become a people's democracy. Accordingly, the church tried to encourage other parties to set aside their disagreements and act together against the extreme left throughout the period under study. The main characteristics of the church´s political agenda during this period of crisis were to support the Finnish foreign policy led by the president of the republic, Urho Kekkonen, and to resist Finnish communism. The attitude of Finnish bishops and the newspaper Kotimaa to the Cold War in general was generally in agreement with the majority of western Christians. They feared communism, were afraid of the USSR, but supported peaceful co-existence because they did not want an open conflict with the Soviets. Because of uncertainties in Finland's international position the Finnish Church regarded it as necessary to support the Finnish policy of friendship towards the USSR. The Finnish Church considerer it unwise to openly criticize the Soviet Union, tried resist the spread of communism in Finnish domestic policy. This period of foreign policy crises was principally seen by the church as a time when there was a need to strengthen Finland's unstable national position.

From the river to the open sea - a critical life phase of young Atlantic salmon migrating from the Simojoki river

Long-term monitoring data collected from wild smolts of Atlantic salmon (Salmo salar) in the Simojoki river, northern Finland, were used in studying the relationships between the smolt size and age, smolt and postsmolt migration, environmental conditions and postsmolt survival. The onset of the smolt run was significantly dependent on the rising water temperature and decreasing discharge of the river in the spring. The mean length of smolts migrating early in the season was commonly higher and the mean age always older than among smolts migrating later. Many of the smolts migrating early in the season and almost all smolts migrating later had started their new growth in spring in the river before their sea entry. Among postsmolts, the time required for emigration from the estuary was dependent on the sea surface temperature (SST) off the river, being significantly shorter in years with warm than cold sea temperatures. After leaving the estuary, the postsmolts migrated southwards along the eastern coast of the northern Gulf of Bothnia, the geographical distribution of the tag recoveries coinciding with the warm thermal zone in spring in the coastal area. After arriving in the southern Gulf of Bothnia in late summer the postsmolts mostly migrated near the western coast, reaching the Baltic Main Basin in late autumn. Until the early 1990s there was only a weak positive association between smolt length and postsmolt survival. However, following a subsequent decrease in the mean smolt size, a significant positive dependence was observed between smolt size and the reported recapture rate of tagged salmon. The differences in recapture rates between smolts tagged during the first and second half of the annual migration season were insignificant, indicating that the seasonal variation in smolt size and age seem to be too small to affect survival. Among the climatic factors examined, the summer SST in the Gulf of Bothnia was most clearly related to the survival of the wild postsmolts. Postsmolt survival appeared to be highest in years when the SST in June in the Bothnian Bay varied between 9 and 12 ºC. In addition, the survival of wild postsmolts showed a significant positive dependence on the SST in July in the Bothnian Sea, but not on the abundance of the prey fish (0+ herring, Clupea harengus and sprat, Sprattus sprattus) in the Bothnian Sea and in the Baltic Main Basin. The results suggest, that if the incidence of extreme weather conditions were to increase due to climatic changes, it would probably reduce the postsmolt survival of wild salmon populations. For improving the performance of hatchery-reared smolts, it could be useful to examine opportunities to produce smolts that are in their smolt traits and abilities more similar to the wild smolts described in this thesis.

A Critical Evaluation of the MARS Treatment in Finland

The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal albumin dialysis device which is used in the treatment of liver failure patients. This treatment was first utilized in Finland in 2001, and since then, over 200 patients have been treated. The aim of this thesis was to evaluate the impact of the MARS treatment on patient outcome, the clinical and biochemical variables, as well as on the psychological and economic aspects of the treatment in Finland. This thesis encompasses 195 MARS-treated patients (including patients with acute liver failure (ALF), acute-on-chronic liver failure (AOCLF) and graft failure), and a historical control group of 46 ALF patients who did not undergo MARS. All patients received a similar standard medical therapy at the same intensive care unit. The baseline data (demographics, laboratory and clinical variables) and MARS treatment-related and health-related quality-of-life data were recorded before and after treatment. The direct medical costs were determined for a period of 3.5 years.Additionally, the outcome of patients (survival, native liver recovery and need for liver transplantation) and survival predicting factors were investigated. In the outcome analysis, for the MARS-treated ALF patients, their 6-month survival (75% vs. 61%, P=0.07) and their native liver recovery rate (49% vs. 17%, P<0.001) were higher, and their need for transplantations was lower (29% vs. 57%, P= 0.001) than for the historical controls. However, the etiological distribution of the ALF patients referred to our unit has changed considerably over the past decade and the percentage of patients with a more favorable prognosis has increased. The etiology of liver failure was the most important predictor of the outcome. Other survival predicting factors in ALF included hepatic encephalopathy, the coagulation factors and the liver enzyme levels prior to MARS treatment. In terms of prognosis, the MARS treatment of the cirrhotic AOCLF patient seems meaningful only when the patient is eligible for transplantation. The MARS treatment appears to halt the progression of encephalopathy and reduce the blood concentration of neuroactive amino acids, albumin-bound and water-soluble toxins. In general, the effects of the MARS treatment seem to stabilize the patients, thus allowing additional time either for the native liver to recover, or for the patients to endure the prolonged waiting for transplantation. Furthermore, for the ALF patients, the MARS treatment appeared to be less costly and more cost-efficient than the standard medical therapy alone. In conclusion, the MARS treatment appears to have a beneficial effect on the patient outcome in ALF and in those AOCLF patients who can be bridged to transplantation.

On the Problem of Participation in Strategy: A Critical Discursive Perspective

We still know little of why strategy processes often involve participation problems. In this paper, we argue that this crucial issue is linked to fundamental assumptions about the nature of strategy work. Hence, we need to examine how strategy processes are typically made sense of and what roles are assigned to specific organizational members. For this purpose, we adopt a critical discursive perspective that allows us to discover how specific conceptions of strategy work are reproduced and legitimized in organizational strategizing. Our empirical analysis is based on an extensive research project on strategy work in 12 organizations. As a result of our analysis, we identify three central discourses that seem to be systematically associated with nonparticipatory approaches to strategy work: “mystification,” “disciplining,” and “technologization.” However, we also distinguish three strategy discourses that promote participation: “self-actualization,” “dialogization,” and “concretization.” Our analysis shows that strategy as practice involves alternative and even competing discourses that have fundamentally different kinds of implications for participation in strategy work. We argue from a critical perspective that it is important to be aware of the inherent problems associated with dominant discourses as well as to actively advance the use of alternative ones.

Critical Incidents in Internal Relationships

Critical incidents have had an important role in service quality and service management research. The focus of critical-incident studies has gradually shifted from separate acts and episodes towards relationships, and even switching from one relationship to another. The Critical Incident Technique has mainly been used when studying the service sector, concentrating on the customer's perception of critical incidents. Although some studies have considered the perceptions of employees important, critical incidents have not been considered a tool for studying internal relationships to any larger extent. This paper takes a process approach and shifts the focus from an external to an internal setting. It puts forward a new technique for analysing internal relationships from a critical-incident perspective. The technique captures the dynamism in relationships through considering internal critical incidents as micro-processes affecting not only internal but also external relationships.

Acidification of lakes in Finland : regional estimates of lake chemistry and critical loads

Yhteenveto: Järvien happamoituminen Suomessa: Alueellinen vedenlaatu ja kriittinen kuormitus

On the force potential of strategy texts: a critical discourse analysis of a strategic plan and its power effects in a city organization

Despite increasing interest in the discursive aspects of strategy, few studies have examined strategy texts and their power effects. We draw from Critical Discourse Analysis to better understand the power of strategic plans as a directive genre. In our empirical analysis, we examined the creation of the official strategic plan of the City of Lahti in Finland. As a result of our inductive analysis, we identified five central discursive features of this plan: self-authorization, special terminology, discursive innovation, forced consensus and deonticity. We argue that these features can, with due caution, be generalized and conceived as distinctive features of the strategy genre. We maintain that these discursive features are not trivial characteristics; they have important implications for the textual agency of strategic plans, their performative effects, impact on power relations and ideological implications.