Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. LAY ABSTRACT: Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments.

A Historical-Institutional Study of the Welfare Systems in the United States and Sweden: Net Social Wage Approach

In this study I first look at the historical developments of the welfare systems in Sweden and the United States to understand why these countries have produced two distinct systems over the years. After understanding their historical context I turn to the question of the relationship between the welfare system and economic growth. Policy makers and the mainstream media commonly cite the critique that through government deficit and public debt, welfare systems are a drag on the economy. By calculating the net social wage, the difference in taxes paid and benefits received by workers, I test this hypothesis to see if welfare systems are self-financed by the workers. My findings demonstrate that the net social wage has been negative in the U.S. from 1962 to the early 2000s and in Sweden from 1965 to 2012. This shows that the welfare systems are entirely self-financed by the workers for the full period in Sweden and until the recent financial crisis in the U.S.

Locational and Temporal Risk Associated With Campus Sexual Assault

The present study investigates the rates of victimization of sexual assault reported by undergraduates at Bucknell University. Specifically, the study aimed to determine where and when sexual assault took place, in order to pinpoint both temporal risks and locational risks associated with certain events on campus. Results of the survey were analyzed for victimization rates across class year, time of year, where victimization took place, as well as where victims and perpetrators met. Data for the study was gathered by means of anonymous survey, sent out to 1752 randomly selected undergraduates via email. Participants filled out the survey which asked if they had ever been sexually assaulted or committed a sexual assault during their past year studying at Bucknell. The results of the survey indicated that dormitories, fraternity houses, and off-campus student houses displayed significantly higher rates of victimization than other locations. In addition, increased risk of unwanted sexual contact in the fall semester was shown to be statistically significant. Moreover, results of the current study support that parties were statistically significant locations for meeting perpetrators of sexual assault. The results suggest that it may be beneficial to direct special attention towards campus sexual assault, specifically to certain locations, times of the year, and campus activities.

The Intersection of Economics and Politics in a Small OPEC Country: the Case of Ecuador, 1990 - March 2014

Today, crude oil remains a vital resource all around the world. This non-renewable resource powers countries worldwide. Besides serving as an energy source, crude oil is also the most important component for different world economies, especially in developing countries. Ecuador, a small member of the OPEC oil cartel, presents a case where its economy is oil dependent. A great percentage of the country¿s GDP and government¿s budget comes from oil revenues. Ecuador has always been a primary exporter of raw materials. In the last centuries, the country experienced three important economic booms: cacao, bananas, and, ultimately, crude oil. In this sense, the country has not been able to fully industrialize and begin to export manufactured goods, i.e., Ecuador suffers from the Dutch disease. The latter has deterred Ecuador from achieving broad-based economic development. Given crude oil¿s importance for the Ecuadorian economy, the government has always tried to influence the oil industry in search of profits and benefits. Therefore, this thesis, explores the question: how and to what extent have political interventions affected the oil industry in Ecuador from 1990 until March 2014? In general, this thesis establishes an economic history context during the last twenty-four years, attempting to research how political interventions have shaped Ecuador¿s oil industry and economy. In the analysis, it covers a period where political instability prevailed, until Rafael Correa became president. The thesis examines Ecuador¿s participation in OPEC, trying to find explanations as to why the country voluntarily left the organization in 1992, only to rejoin in 2007 when Correa rose to power. During the ¿Revolución Ciudadana¿ period, the thesis researches reforms to the Law of Hydrocarbons, variations in the relations with other nations, the controversy surrounding the Yasuní-ITT oil block, and the ¿Refinería del Pacífico¿ construction. The thesis is an Industrial Organization detailed case study that analyzes, updates, and evaluates the intersection of economics and politics in Ecuador¿s crude oil industry during the last 24 years. In this sense I have consulted past theses, newspaper articles, books, and other published data about the petroleum industry, both from a global and Ecuadorian perspective. In addition to published sources, I was able to interview sociologists, public figures, history and economics academics, and other experts, accessing unique unpublished data about Ecuador¿s oil industry. I made an effort to collect information that shows the private and public side of the industry, i.e., from government-related and independent sources. I attempted to remain as objective as possible to make conclusions about the appropriate Industrial Organization policy for Ecuador¿s oil industry, addressing the issue from an economic, social, political, and environmental point of view. I found how Ecuador¿s political instability caused public policy to fail, molding the conduct and market structure of the crude oil industry. Throughout history, developed nations have benefited from low oil prices, but things shifted since oil prices began to rise, which is more beneficial for the developing nations that actually possess and produce the raw material. Nevertheless, Ecuador, a victim of the Dutch disease due to its heavy reliance on crude oil as a primary product, has not achieved broad-based development.

Reciprocal cooperation between unrelated rats depends on cost to donor and benefit to recipient

Background Although evolutionary models of cooperation build on the intuition that costs of the donor and benefits to the receiver are the most general fundamental parameters, it is largely unknown how they affect the decision of animals to cooperate with an unrelated social partner. Here we test experimentally whether costs to the donor and need of the receiver decide about the amount of help provided by unrelated rats in an iterated prisoner's dilemma game. Results Fourteen unrelated Norway rats were alternately presented to a cooperative or defective partner for whom they could provide food via a mechanical apparatus. Direct costs for this task and the need of the receiver were manipulated in two separate experiments. Rats provided more food to cooperative partners than to defectors (direct reciprocity). The propensity to discriminate between helpful and non-helpful social partners was contingent on costs: An experimentally increased resistance in one Newton steps to pull food for the social partner reduced the help provided to defectors more strongly than the help returned to cooperators. Furthermore, test rats provided more help to hungry receivers that were light or in poor condition, which might suggest empathy, whereas this relationship was inverse when experimental partners were satiated. Conclusions In a prisoner's dilemma situation rats seem to take effect of own costs and potential benefits to a receiver when deciding about helping a social partner, which confirms the predictions of reciprocal cooperation. Thus, factors that had been believed to be largely confined to human social behaviour apparently influence the behaviour of other social animals as well, despite widespread scepticism. Therefore our results shed new light on the biological basis of reciprocity.

Immigrants in the Czech Republic (With Special Reference to Ukrainian Workers and "Western" Firms Operating in Prague)

International migration has increased rapidly in the Czech Republic, with more than 150,000 legally registered foreign residents at the end of 1996. A large proportion of these are in Prague - 35% of the total in December 1996. The aim of this project was to enrich the fund of information concerning the "environment", reasons and "mechanisms" behind immigration to the Czech Republic. Mr. Drbohlav looked first at the empirical situation and on this basis set out to test certain well-known migration theories. He focused on four main areas: 1) a detailed description and explanation of the stock of foreign citizens legally settled in Czech territory, concentrating particularly on "economic" migrants; 2) a questionnaire survey targeting a total of 192 Ukrainian workers (98 in the fall 1995 and 94 in the fall 1996) working in Prague or its vicinity; 3) a second questionnaire survey of 40 "western" firms (20 in 1996 and 20 in 1997) operating out of Prague; 4) an opinion poll on how the Czech population reacts to foreign workers in the CR. Over 80% of economic immigrants at the end of 1996 were from European countries, 16% from Asia and under 2% from North America. The largest single nationalities were Ukrainians, Slovaks, Vietnamese and Poles. There has been a huge increase in the Ukrainian immigrant community over both space (by region) and time (a ten-fold increase since 1993), and at 40,000 persons this represents one third of all legal immigrants. Indications are that many more live and work there illegally. Young males with low educational/skills levels predominate, in contrast with the more heterogeneous immigration from the "West". The primary reason for this migration is the higher wages in the Czech Republic. In 1994 the relative figures of GDP adjusted for parity of purchasing power were US$ 8,095 for the Czech Republic versus US$ 3,330 for the Ukraine as a whole and US$ 1,600 for the Zakarpatye region from which 49% of the respondents in the survey came. On an individual level, the average Czech wage is about US$ 330 per month, while 50% of the Ukrainian respondents put their last monthly wage before leaving for the Czech Republic at under US$ 27. The very low level of unemployment in the latter country (fluctuating around 4%) was also mentioned as an important factor. Migration was seen as a way of diversifying the family's source of income and 49% of the respondents had made their plans together with partners or close relatives, while 45% regularly send remittances to Ukraine (94% do so through friends or relatives). Looking at Ukrainian migration from the point of view of the dual market theory, these migrants' type and conditions of work, work load and earnings were all significantly worse than in the primary sector, which employs well educated people and offers them good earnings, job security and benefits. 53% of respondents were working and/or staying in the Czech Republic illegally at the time of the research, 73% worked as unqualified, unskilled workers or auxiliary workers, 62% worked more than 12 hours a day, and 40% evaluated their working conditions as hard. 51% had no days off, earnings were low in relation to the number of hours worked. and 85% said that their earnings did not increase over time. Nearly half the workers were recruited in Ukraine and only 4% expressed a desire to stay in the Czech Republic. Network theories were also borne out to some extent as 33% of immigrants came together with friends from the same village, town or region in Ukraine. The number who have relatives working in the Czech Republic is rising, and many wish to invite relatives or children to visit them. The presence of organisations which organised cross-border migration, including some which resort to organising illegal documents, also gives some support for the institutional theory. Mr. Drbohlav found that all the migration theories considered offered some insights on the situation, but that none was sufficient to explain it all. He also points out parallels with many other regions of the world, including Central America, South and North America, Melanesia, Indonesia, East Africa, India, the Middle East and Russia. For the survey of foreign and international firms, those chosen were largely from countries represented by more than one company and were mainly active in market services such as financial and trade services, marketing and consulting. While 48% of the firms had more than 10,000 employees spread through many countries, more than two thirds had fewer than 50 employees in the Czech Republic. Czechs formed 80% plus of general staff in these firms although not more than 50% of senior management, and very few other "easterners" were employed. All companies absolutely denied employing people illegally. The average monthly wage of Czech staff was US$ 850, with that of top managers from the firm's "mother country" being US$ 6,350 and that of other western managers US$ 3,410. The foreign staff were generally highly mobile and were rarely accompanied by their families. Most saw their time in the Czech Republic as positive for their careers but very few had any intention of remaining there. Factors in the local situation which were evaluated positively included market opportunities, the economic and political environment, the quality of technical and managerial staff, and cheap labour and low production costs. In contrast, the level of appropriate business ethics and conduct, the attitude of local and regional authorities, environmental production conditions, the legal environment and financial markets and fiscal policy were rated very low. In the final section of his work Mr. Drbohlav looked at the opinions expressed by the local Czech population in a poll carried out at the beginning of 1997. This confirmed that international labour migration has become visible in this country, with 43% of respondents knowing at least one foreigner employed by a Czech firm in this country. Perception differ according to the region from which the workers come and those from "the West" are preferred to those coming from further east. 49% saw their attitude towards the former as friendly but only 20% felt thus towards the latter. Overall, attitudes towards migrant workers is neutral, although 38% said that such workers should not have the same rights as Czech citizens. Sympathy towards foreign workers tends to increase with education and the standard of living, and the relatively positive attitudes towards foreigners in the South Bohemia region contradicted the frequent belief that a lack of experience of international migration lowers positive perceptions of it.

Development, feasibility and performance of a health risk appraisal questionnaire for older persons

BACKGROUND: Health risk appraisal is a promising method for health promotion and prevention in older persons. The Health Risk Appraisal for the Elderly (HRA-E) developed in the U.S. has unique features but has not been tested outside the United States. METHODS: Based on the original HRA-E, we developed a scientifically updated and regionally adapted multilingual Health Risk Appraisal for Older Persons (HRA-O) instrument consisting of a self-administered questionnaire and software-generated feed-back reports. We evaluated the practicability and performance of the questionnaire in non-disabled community-dwelling older persons in London (U.K.) (N = 1090), Hamburg (Germany) (N = 804), and Solothurn (Switzerland) (N = 748) in a sub-sample of an international randomised controlled study. RESULTS: Over eighty percent of invited older persons returned the self-administered HRA-O questionnaire. Fair or poor self-perceived health status and older age were correlated with higher rates of non-return of the questionnaire. Older participants and those with lower educational levels reported more difficulty in completing the HRA-O questionnaire as compared to younger and higher educated persons. However, even among older participants and those with low educational level, more than 80% rated the questionnaire as easy to complete. Prevalence rates of risks for functional decline or problems were between 2% and 91% for the 19 HRA-O domains. Participants' intention to change health behaviour suggested that for some risk factors participants were in a pre-contemplation phase, having no short- or medium-term plans for change. Many participants perceived their health behaviour or preventative care uptake as optimal, despite indications of deficits according to the HRA-O based evaluation. CONCLUSION: The HRA-O questionnaire was highly accepted by a broad range of community-dwelling non-disabled persons. It identified a high number of risks and problems, and provided information on participants' intention to change health behaviour.

Probabilistic-based hurricane risk assessment and mitigation considering the potential impacts of climate change

Studies are suggesting that hurricane hazard patterns (e.g. intensity and frequency) may change as a consequence of the changing global climate. As hurricane patterns change, it can be expected that hurricane damage risks and costs may change as a result. This indicates the necessity to develop hurricane risk assessment models that are capable of accounting for changing hurricane hazard patterns, and develop hurricane mitigation and climatic adaptation strategies. This thesis proposes a comprehensive hurricane risk assessment and mitigation strategies that account for a changing global climate and that has the ability of being adapted to various types of infrastructure including residential buildings and power distribution poles. The framework includes hurricane wind field models, hurricane surge height models and hurricane vulnerability models to estimate damage risks due to hurricane wind speed, hurricane frequency, and hurricane-induced storm surge and accounts for the timedependant properties of these parameters as a result of climate change. The research then implements median insured house values, discount rates, housing inventory, etc. to estimate hurricane damage costs to residential construction. The framework was also adapted to timber distribution poles to assess the impacts climate change may have on timber distribution pole failure. This research finds that climate change may have a significant impact on the hurricane damage risks and damage costs of residential construction and timber distribution poles. In an effort to reduce damage costs, this research develops mitigation/adaptation strategies for residential construction and timber distribution poles. The costeffectiveness of these adaptation/mitigation strategies are evaluated through the use of a Life-Cycle Cost (LCC) analysis. In addition, a scenario-based analysis of mitigation strategies for timber distribution poles is included. For both residential construction and timber distribution poles, adaptation/mitigation measures were found to reduce damage costs. Finally, the research develops the Coastal Community Social Vulnerability Index (CCSVI) to include the social vulnerability of a region to hurricane hazards within this hurricane risk assessment. This index quantifies the social vulnerability of a region, by combining various social characteristics of a region with time-dependant parameters of hurricanes (i.e. hurricane wind and hurricane-induced storm surge). Climate change was found to have an impact on the CCSVI (i.e. climate change may have an impact on the social vulnerability of hurricane-prone regions).

Pre- and postnatal therapy of lower urinary tract obstruction - an experience of 18 years

With prenatal detection of hydronephrosis and technological advances in surgical equipment, the management of lower urinary tract obstruction has evolved to include prenatal surgical intervention. Surgical intervention, was based upon the rationale that restoring amniotic fluid to normal levels by shunting fetal urine from the obstructed urinary system to the amniotic space would prevent lung hypoplasia and, thus, improve neonatal survival. Inaddition, relief of the obstruction would also reduce back pressure and reduce injury to the developing nephron, thus improving long-term renal function postnatally. However, this remains investigational, and the vast majority of affected infants are treated soon after birth. We have experience since 1991 with prenatal treatment of megacystis. In 23 cases of 50 detected megacystis with oligohydramnion in male and without other abnormalities a prenatal intervention by bladderpunction and in 12 cases additional vesicoamniotic shunt placement was performed. The prognosis of megacystis with oligohydramnion is stated with a survival rate of 10-30%. In our group 54% (13 children) survived. Also we want present 56 cases of urethral valves with a postnatal transurethral intervention. With a follow up time from 8.6 (3 to 15) years we attend 34 children (60%) with normal renal function, 21% (12) with mild or moderate renal insufficiency and there was a kidney transplantation in 6 cases necessary. With our multidisciplinary presentation we want to discuss the indication, interdisciplinary aspects,risks and the follow up of pre- and postnatal intervention in such cases.

Why Freeter and NEET are Misunderstood: Recognizing the New Precarious Conditions of Japanese Youth

In developed countries, the transition from school to work has radically changed over the past two decades. It has become prolonged, complicated and individualized (Bynner et al., 1997; Walther et al., 2004). Young people used to transition directly from school to stable employment, or with a very short unemployed period. In many European countries, this situation has been changing since the eighties: overall youth unemployment has increased, and many young people experience long periods of unemployment, government training schemes and part-time or temporary jobs. In Japan, this change has taken a decade later to appear, becoming prevalent by the late nineties (Inui, 2003). The transiting process has become not only precarious for young people, but also difficult for society to precisely understand the risks and problems. Traditionally, we have been able to recognize young people's situation by a simple category: in education, employed, in training or unemployed. However, these categories no longer accurately represent young people's state. In Japan, most young people used to move from school directly to full-time employment through the new graduate recruitment system (Inui, 1993). Therefore, in official statistics such as the School Basic Survey, 'employed' includes only those who are in regular employment, while those who are in part-time or temporary work are covered by the categories 'jobless' and 'others'. However, with the increase in non-full-time jobs in the nineties, these categories have become less useful for describing the actual employment conditions of young people. Indeed, this is why, in the late of nineties, the Japanese Ministry of Education changed the category name from 'jobless' to 'others'.

An economic assessment of drought effects on three grassland systems in Switzerland

This paper analyzes the economic impacts of summer drought on Swiss grassland production. We combine field trial data from drought experiments in three different grasslands in Switzerland with site-specific information on economic costs and benefits. The analysis focuses on the economic implications of drought effects on grassland yields as well as grassland composition. In agreement with earlier studies, we found rather heterogeneous yield effects of drought on Swiss grassland systems, with significantly reduced yields as a response to drought at the lowland and sub-alpine sites, but increased yields at the wetter pre-alpine site. Relative yield losses were highest at the sub-alpine site (with annual yield losses of up to 37 %). However, because income from grassland production at extensive sites relies to a large extent on ecological direct payments, even large yield losses had only limited implications in terms of relative profit reductions. In contrast, negative drought impacts at the most productive, intensively managed lowland site were dominant, with average annual drought-induced profit margin reductions of about 28 %. This is furthermore emphasized if analyzing the farm level perspective of drought impacts. Combining site-specific effects at the farm level, we found that in particular farms with high shares of lowland grassland sites suffer from summer droughts in terms of farm-level fodder production and profit margins. Moreover, our results showed that the higher competitiveness of weeds (broad-leaved dock) under drought conditions will require increasing attention on weed control measures in future grassland production systems. Taking into account that the risk of drought occurrence is expected to increase in the coming years, additional instruments to cope with drought risks in fodder production and finally farmers’ income have to be developed.

Supporting, Regulating, and Provisioning Hydrological Services

The natural regulation of the water cycle by tropical montane forests is an important ecosystem service. Within this chapter we focus on water balance and regulation of the water cycle. Differences of rainfall-runoff generation across scales change from a near-surface event water driven system in pristine rainforest-covered micro-catchments to a more groundwater pre-event water dominated one on the mesoscale. The highly dynamic discharges are often correlated with total suspended sediment loads. However, we also observed total suspended sediment peaks at times of low flow, indicating a decoupling of erosion and stream transport and a triggering of landslides not directly related to hydrological processes. We also summarize likely future trends of water-related ecosystem services and expect an increase in human use and benefits of fresh water use whereas changes in water regulation and water purification services remain unchanged on a high level.

Action crisis and cost–benefit thinking: A cognitive analysis of a goal-disengagement phase

The present research is based on the notion that disengagement from goals is not a discrete event but a process (Klinger, 1975). A critical phase in this process is when difficulties and setbacks in striving for a goal accumulate. This critical phase is termed here as an action crisis. Given the profound effects that people's thoughts have on their self-regulatory efficiency, it is essential to understand the cognitive correlates of an action crisis. In two experimental lab and two correlational field studies, the hypothesis that goal-related costs and benefits become cognitively highly accessible during an action crisis was tested and supported. Participants who were experiencing an action crisis in such diverse goal areas as intimate relationships, sports, and university studies, thought about goal-related costs and benefits more intensively and frequently in comparison to participants who were not in an action crisis. In an incidental learning task they recognized more of cost–benefit-items and less of implementation-items than the control group. Results are interpreted in terms of action phase specific mindsets (Gollwitzer, 1990, 2012).

Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis

OBJECTIVES To synthesise the available evidence on pharmacological and non-pharmacological interventions recommended for fibromyalgia syndrome (FMS). METHODS Electronic databases including MEDLINE, PsycINFO, Scopus, the Cochrane Controlled Trials Registry and the Cochrane Library were searched for randomised controlled trials comparing any therapeutic approach as recommended in FMS guidelines (except complementary and alternative medicine) with control interventions in patients with FMS. Primary outcomes were pain and quality of life. Data extraction was done using standardised forms. RESULTS 102 trials in 14 982 patients and eight active interventions (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors (SNRIs), the gamma-amino butyric acid analogue pregabalin, aerobic exercise, balneotherapy, cognitive behavioural therapy (CBT), multicomponent therapy) were included. Most of the trials were small and hampered by methodological quality, introducing heterogeneity and inconsistency in the network. When restricted to large trials with ≥100 patients per group, heterogeneity was low and benefits for SNRIs and pregabalin compared with placebo were statistically significant, but small and not clinically relevant. For non-pharmacological interventions, only one large trial of CBT was available. In medium-sized trials with ≥50 patients per group, multicomponent therapy showed small to moderate benefits over placebo, followed by aerobic exercise and CBT. CONCLUSIONS Benefits of pharmacological treatments in FMS are of questionable clinical relevance and evidence for benefits of non-pharmacological interventions is limited. A combination of pregabalin or SNRIs as pharmacological interventions and multicomponent therapy, aerobic exercise and CBT as non-pharmacological interventions seems most promising for the management of FMS.