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.

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.

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.

Joseph A. Schumpeter's Theory of Social and Economic Evolution : a Reconstruction and Critique

The book presents a reconstruction, interpretation and critical evaluation of the Schumpeterian theoretical approach to socio-economic change. The analysis focuses on the problem of social evolution, on the interpretation of the innovation process and business cycles and, finally, on Schumpeter s optimistic neglect of ecological-environmental conditions as possible factors influencing social-economic change. The author investigates how the Schumpeterian approach describes the process of social and economic evolution, and how the logic of transformations is described, explained and understood in the Schumpeterian theory. The material of the study includes Schumpeter s works written after 1925, a related part of the commentary literature on these works, and a selected part of the related literature on the innovation process, technological transformations and the problem of long waves. Concerning the period after 1925, the Schumpeterian oeuvre is conceived and analysed as a more or less homogenous corpus of texts. The book is divided into 9 chapters. Chapters 1-2 describe the research problems and methods. Chapter 3 is an effort to provide a systematic reconstruction of Schumpeter's ideas concerning social and economic evolution. Chapters 4 and 5 focus their analysis on the innovation process. In Chapters 6 and 7 Schumpeter's theory of business cycles is examined. Chapter 8 evaluates Schumpeter's views concerning his relative neglect of ecological-environmental conditions as possible factors influencing social-economic change. Finally, chapter 9 draws the main conclusions.

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.

A Curious Harpour in Helle : An Edition of the Commentary on the Orpheus Metre of De consolatione philosophiae in MS Thott 304,2

Tutkielmani on tekstieditio keskiaikaisesta kommentaarista, joka löytyy Kööpenhaminan Kuninkaallisen kirjaston käsikirjoituksesta Thott 304,2. Käsikirjoitus voidaan ajoittaa 1400-luvun ensimmäiselle neljännekselle ja se on kirjoitettu keskienglanniksi. Se sisältää John Waltonin runomuotoisen käännöksen Boethiuksen 500-luvun alussa latinaksi kirjoittamasta teoksesta De consolatione philosophiae (Filosofian lohdutus) sekä teosta kommentoivan proosamuotoisen kommentaarin. Käsikirjoitus on vaillinainen, mutta sen säilyneet foliot ovat enimmäkseen erittäin hyväkuntoisia. Itse käsikirjoitusta on tutkittu vain muutamissa artikkeleissa ja yhdessä tutkielmassa; kommentaarista ei ole toistaiseksi tehty kattavaa tutkimusta. Tavoitteeni onkin tuoda kommentaari keskiaikaisen filosofian, keskienglannin ja käsikirjoitusten tutkijoiden käytettäviin. Käsikirjoitus Thott 304,2 on esimerkki epätyypillisestä myöhäiskeskiaikaisesta maallikkomesenaattiudesta Englannissa. Tavanmukaisesti maallikkomesenaatit tukivat uskonnollisten tekstien tuottamista ja kääntämistä, kun taas Thott 304,2 sisältää käännöksen filosofisesta tekstistä. Sen lisäksi mesenaatti oli nainen, aatelistoon kuuluva Elizabeth Berkeley. Varsin harvinaiseksi käsikirjoituksen tekee sen painaminen kirjaksi 1500-luvun alussa. Kirjanpainajan käsikirjoituksen sivuille tekemistä merkinnöistä saadaan korvaamatonta tietoa varhaisesta painotekniikasta, sillä kirjanpainajien käyttämiä käsikirjoituskopioita ei ole säilynyt kovin runsaasti. Waltonin käännös on säilynyt yli kahdessakymmenessä käsikirjoituskopiossa, joista vain Thott 304,2 sisältää laajan kommentaarin. 1500-luvun painoksesta on jäljellä kolme kopiota, ja ne sisältävät saman kommentaarin kuin Thott 304,2. Valitsin editoitavaksi niin kutsuttua Orfeus-runoa kommentoivan osan kommentaarista, sillä se muodostaa ehjän kokonaisuuden ja sopii pituutensa puolesta Pro gradu -tutkielmaan. Orfeus-runo on myös yksi käsikirjoituksen kattavimmin kommentoiduista runoista. Editio on niin sanottu diplomaattinen transkriptio, jossa käsikirjoituksen piirteet on pyritty säilyttämään mahdollisimman tarkasti edition luettavuuden siitä kuitenkaan kärsimättä. Perinteisistä editioista poiketen tutkielmani sisältää myös kommentaarin ja Orfeus-runon transkriptiot, joissa rivijako, lyhenteet ja erikoismerkit on säilytetty. Näiden transkriptioiden toivon auttavan erityisesti käsikirjoituksessa esiintyvien lyhenteiden, erikoismerkkien ja kirjanpainajan merkintöjen tulkinnassa ja tutkimisessa. Editiota ja transkriptioita täydentävät nykyenglanniksi kirjoitettu lyhennelmä kommentaarista ja kuvat käsikirjoituksen sivuista, joilla editoimani kommentaari on. Tutkielmaan sisältyy alkuperäisen tekstin, käännöksen, kommentaarin ja käsikirjoituksen taustaa valottava osuus. Esittelen myös kaikki löytämäni lähteet, joissa käsikirjoitus on mainittu tai joissa sitä on tutkittu. Liitteeksi olen laatinut sanaston helpottamaan kommentaarin tulkitsemista.

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.