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.

Impact of age and comorbidities on long-term survival of patients with high-risk prostate cancer treated with radical prostatectomy: a multi-institutional competing-risks analysis

Survival after surgical treatment using competing-risk analysis has been previously examined in patients with prostate cancer (PCa). However, the combined effect of age and comorbidities has not been assessed in patients with high-risk PCa who might have heterogeneous rates of competing mortality despite the presence of aggressive disease.

Analysis of state laws and regulations impacting animal waste management /

Mode of access: Internet.

Risk based post closure care analysis for Florida landfills

Subtitle D of the Resource Conservation and Recovery Act (RCRA) requires a post closure period of 30 years for non hazardous wastes in landfills. Post closure care (PCC) activities under Subtitle D include leachate collection and treatment, groundwater monitoring, inspection and maintenance of the final cover, and monitoring to ensure that landfill gas does not migrate off site or into on site buildings. The decision to reduce PCC duration requires exploration of a performance based methodology to Florida landfills. PCC should be based on whether the landfill is a threat to human health or the environment. Historically no risk based procedure has been available to establish an early end to PCC. Landfill stability depends on a number of factors that include variables that relate to operations both before and after the closure of a landfill cell. Therefore, PCC decisions should be based on location specific factors, operational factors, design factors, post closure performance, end use, and risk analysis. The question of appropriate PCC period for Florida’s landfills requires in depth case studies focusing on the analysis of the performance data from closed landfills in Florida. Based on data availability, Davie Landfill was identified as case study site for a case by case analysis of landfill stability. The performance based PCC decision system developed by Geosyntec Consultants was used for the assessment of site conditions to project PCC needs. The available data for leachate and gas quantity and quality, ground water quality, and cap conditions were evaluated. The quality and quantity data for leachate and gas were analyzed to project the levels of pollutants in leachate and groundwater in reference to maximum contaminant level (MCL). In addition, the projected amount of gas quantity was estimated. A set of contaminants (including metals and organics) were identified as contaminants detected in groundwater for health risk assessment. These contaminants were selected based on their detection frequency and levels in leachate and ground water; and their historical and projected trends. During the evaluations a range of discrepancies and problems that related to the collection and documentation were encountered and possible solutions made. Based on the results of PCC performance integrated with risk assessment, projection of future PCC monitoring needs and sustainable waste management options were identified. According to these results, landfill gas monitoring can be terminated, leachate and groundwater monitoring for parameters above MCL and surveying of the cap integrity should be continued. The parameters which cause longer monitoring periods can be eliminated for the future sustainable landfills. As a conclusion, 30 year PCC period can be reduced for some of the landfill components based on their potential impacts to human health and environment (HH&E).

Risk Based Post Closure Care Analysis for Florida Landfills

Subtitle D of the Resource Conservation and Recovery Act (RCRA) requires a post closure period of 30 years for non hazardous wastes in landfills. Post closure care (PCC) activities under Subtitle D include leachate collection and treatment, groundwater monitoring, inspection and maintenance of the final cover, and monitoring to ensure that landfill gas does not migrate off site or into on site buildings. The decision to reduce PCC duration requires exploration of a performance based methodology to Florida landfills. PCC should be based on whether the landfill is a threat to human health or the environment. Historically no risk based procedure has been available to establish an early end to PCC. Landfill stability depends on a number of factors that include variables that relate to operations both before and after the closure of a landfill cell. Therefore, PCC decisions should be based on location specific factors, operational factors, design factors, post closure performance, end use, and risk analysis. The question of appropriate PCC period for Florida’s landfills requires in depth case studies focusing on the analysis of the performance data from closed landfills in Florida. Based on data availability, Davie Landfill was identified as case study site for a case by case analysis of landfill stability. The performance based PCC decision system developed by Geosyntec Consultants was used for the assessment of site conditions to project PCC needs. The available data for leachate and gas quantity and quality, ground water quality, and cap conditions were evaluated. The quality and quantity data for leachate and gas were analyzed to project the levels of pollutants in leachate and groundwater in reference to maximum contaminant level (MCL). In addition, the projected amount of gas quantity was estimated. A set of contaminants (including metals and organics) were identified as contaminants detected in groundwater for health risk assessment. These contaminants were selected based on their detection frequency and levels in leachate and ground water; and their historical and projected trends. During the evaluations a range of discrepancies and problems that related to the collection and documentation were encountered and possible solutions made. Based on the results of PCC performance integrated with risk assessment, projection of future PCC monitoring needs and sustainable waste management options were identified. According to these results, landfill gas monitoring can be terminated, leachate and groundwater monitoring for parameters above MCL and surveying of the cap integrity should be continued. The parameters which cause longer monitoring periods can be eliminated for the future sustainable landfills. As a conclusion, 30 year PCC period can be reduced for some of the landfill components based on their potential impacts to human health and environment (HH&E).

Consumers' accounts of perceived risk online and the influence of communication sources

The purpose of this paper is to extend marketing knowledge into perceived risk in online transactions beyond the current positivistic, hypotheses-driven research by providing qualitative insights into how individuals construct their accounts of perceived risk online. Additionally, the study reported in this paper aims to explore how communication sources influence both these subjective constructions and individuals' behavioural experiences with transaction activity on the web. Design/methodology/approach - The study was developed within a grounded theory method.Ten in-depth interviews were conducted which were analysed using constant comparison of incidents procedures to provide rich descriptions of the interviewees' subjective perceptions and lived experiences with online transaction activity. Findings - The findings provide insights into how the human clement is present in individuals'perceptions and constructions of their accounts of the risk involved online.The findings also identify the influence of mass communication sources on the construction of these accounts. The study provides insights into whether change agent communication sources, such as marketers or web designers,influence consumers' behaviours towards online transaction activity through mediating their perceptions of the risks involved. The study also reveals how social communication networks influence the interviewees' decisions to use the web (or transaction activities, in particular online purchasing, and how the group in this study might act as a communication source to influence others. Research limitations/Implications - While the findings cannot be generalised to the internet population overall, the sample used was able to provide relevant information regarding the phenomenon of interest. Future research should continue to examine perceived risk and the influence of communications sources, such as e-mail, discussion groups and virtual communities. Originality/value - The value of the paper lies in permitting the participants to account for perceived risk for themselves. The findings ex.plore what this means at increasing levels of personal relevance and the influence of communication sources to create, sustain or mediate perceptions of this phenomenon.

Bayesian network for risk of diarrhea associated with the use of recycled water

Estimating potential health risks associated with recycled (reused) water is highly complex given the multiple factors affecting water quality. We take a conceptual model, which represents the factors and pathways by which recycled water may pose a risk of contracting gastroenteritis, convert the conceptual model to a Bayesian net, and quantify the model using one expert’s opinion. This allows us to make various predictions as to the risks posed under various scenarios. Bayesian nets provide an additional way of modeling the determinants of recycled water quality and elucidating their relative influence on a given disease outcome. The important contribution to Bayesian net methodology is that all model predictions, whether risk or relative risk estimates, are expressed as credible intervals.

Reliability analysis and economic equipment replacement appraisal for substation and sub-transmission systems with explicit inclusion of non-repairable failures

The modern society has come to expect the electrical energy on demand, while many of the facilities in power systems are aging beyond repair and maintenance. The risk of failure is increasing with the aging equipments and can pose serious consequences for continuity of electricity supply. As the equipments used in high voltage power networks are very expensive, economically it may not be feasible to purchase and store spares in a warehouse for extended periods of time. On the other hand, there is normally a significant time before receiving equipment once it is ordered. This situation has created a considerable interest in the evaluation and application of probability methods for aging plant and provisions of spares in bulk supply networks, and can be of particular importance for substations. Quantitative adequacy assessment of substation and sub-transmission power systems is generally done using a contingency enumeration approach which includes the evaluation of contingencies, classification of the contingencies based on selected failure criteria. The problem is very complex because of the need to include detailed modelling and operation of substation and sub-transmission equipment using network flow evaluation and to consider multiple levels of component failures. In this thesis a new model associated with aging equipment is developed to combine the standard tools of random failures, as well as specific model for aging failures. This technique is applied in this thesis to include and examine the impact of aging equipments on system reliability of bulk supply loads and consumers in distribution network for defined range of planning years. The power system risk indices depend on many factors such as the actual physical network configuration and operation, aging conditions of the equipment, and the relevant constraints. The impact and importance of equipment reliability on power system risk indices in a network with aging facilities contains valuable information for utilities to better understand network performance and the weak links in the system. In this thesis, algorithms are developed to measure the contribution of individual equipment to the power system risk indices, as part of the novel risk analysis tool. A new cost worth approach was developed in this thesis that can make an early decision in planning for replacement activities concerning non-repairable aging components, in order to maintain a system reliability performance which economically is acceptable. The concepts, techniques and procedures developed in this thesis are illustrated numerically using published test systems. It is believed that the methods and approaches presented, substantially improve the accuracy of risk predictions by explicit consideration of the effect of equipment entering a period of increased risk of a non-repairable failure.

Comparison of scoring systems for invasive pests using ROC analysis and Monte Carlo simulation

Different international plant protection organisations advocate different schemes for conducting pest risk assessments. Most of these schemes use structured questionnaire in which experts are asked to score several items using an ordinal scale. The scores are then combined using a range of procedures, such as simple arithmetic mean, weighted averages, multiplication of scores, and cumulative sums. The most useful schemes will correctly identify harmful pests and identify ones that are not. As the quality of a pest risk assessment can depend on the characteristics of the scoring system used by the risk assessors (i.e., on the number of points of the scale and on the method used for combining the component scores), it is important to assess and compare the performance of different scoring systems. In this article, we proposed a new method for assessing scoring systems. Its principle is to simulate virtual data using a stochastic model and, then, to estimate sensitivity and specificity values from these data for different scoring systems. The interest of our approach was illustrated in a case study where several scoring systems were compared. Data for this analysis were generated using a probabilistic model describing the pest introduction process. The generated data were then used to simulate the outcome of scoring systems and to assess the accuracy of the decisions about positive and negative introduction. The results showed that ordinal scales with at most 5 or 6 points were sufficient and that the multiplication-based scoring systems performed better than their sum-based counterparts. The proposed method could be used in the future to assess a great diversity of scoring systems.

Policy analysis of disaster health management in China

Humankind has been dealing with all kinds of disasters since the dawn of time. The risk and impact of disasters producing mass casualties worldwide is increasing, due partly to global warming as well as to increased population growth, increased density and the aging population. China, as a country with a large population, vast territory, and complex climatic and geographical conditions, has been plagued by all kinds of disasters. Disaster health management has traditionally been a relatively arcane discipline within public health. However, SARS, Avian Influenza, and earthquakes and floods, along with the need to be better prepared for the Olympic Games in China has brought disasters, their management and their potential for large scale health consequences on populations to the attention of the public, the government and the international community alike. As a result significant improvements were made to the disaster management policy framework, as well as changes to systems and structures to incorporate an improved disaster management focus. This involved the upgrade of the Centres for Disease Control and Prevention (CDC) throughout China to monitor and better control the health consequences particularly of infectious disease outbreaks. However, as can be seen in the Southern China Snow Storm and Wenchuan Earthquake in 2008, there remains a lack of integrated disaster management and efficient medical rescue, which has been costly in terms of economics and health for China. In the context of a very large and complex country, there is a need to better understand whether these changes have resulted in effective management of the health impacts of such incidents. To date, the health consequences of disasters, particularly in China, have not been a major focus of study. The main aim of this study is to analyse and evaluate disaster health management policy in China and in particular, its ability to effectively manage the health consequences of disasters. Flood has been selected for this study as it is a common and significant disaster type in China and throughout the world. This information will then be used to guide conceptual understanding of the health consequences of floods. A secondary aim of the study is to compare disaster health management in China and Australia as these countries differ in their length of experience in having a formalised policy response. The final aim of the study is to determine the extent to which Walt and Gilson’s (1994) model of policy explains how disaster management policy in China was developed and implemented after SARS in 2003 to the present day. This study has utilised a case study methodology. A document analysis and literature search of Chinese and English sources was undertaken to analyse and produce a chronology of disaster health management policy in China. Additionally, three detailed case studies of flood health management in China were undertaken along with three case studies in Australia in order to examine the policy response and any health consequences stemming from the floods. A total of 30 key international disaster health management experts were surveyed to identify fundamental elements and principles of a successful policy framework for disaster health management. Key policy ingredients were identified from the literature, the case-studies and the survey of experts. Walt and Gilson (1994)’s policy model that focuses on the actors, content, context and process of policy was found to be a useful model for analysing disaster health management policy development and implementation in China. This thesis is divided into four parts. Part 1 is a brief overview of the issues and context to set the scene. Part 2 examines the conceptual and operational context including the international literature, government documents and the operational environment for disaster health management in China. Part 3 examines primary sources of information to inform the analysis. This involves two key studies: • A comparative analysis of the management of floods in China and Australia • A survey of international experts in the field of disaster management so as to inform the evaluation of the policy framework in existence in China and the criteria upon which the expression of that policy could be evaluated Part 4 describes the key outcomes of this research which include: • A conceptual framework for describing the health consequences of floods • A conceptual framework for disaster health management • An evaluation of the disaster health management policy and its implementation in China. The research outcomes clearly identified that the most significant improvements are to be derived from improvements in the generic management of disasters, rather than the health aspects alone. Thus, the key findings and recommendations tend to focus on generic issues. The key findings of this research include the following: • The health consequences of floods may be described in terms of time as ‘immediate’, ‘medium term’ and ‘long term’ and also in relation to causation as ‘direct’ and ‘indirect’ consequences of the flood. These two aspects form a matrix which in turn guides management responses. • Disaster health management in China requires a more comprehensive response throughout the cycle of prevention, preparedness, response and recovery but it also requires a more concentrated effort on policy implementation to ensure the translation of the policy framework into effective incident management. • The policy framework in China is largely of international standard with a sound legislative base. In addition the development of the Centres for Disease Control and Prevention has provided the basis for a systematic approach to health consequence management. However, the key weaknesses in the current system include: o The lack of a key central structure to provide the infrastructure with vital support for policy development, implementation and evaluation. o The lack of well-prepared local response teams similar to local government based volunteer groups in Australia. • The system lacks structures to coordinate government action at the local level. The result of this is a poorly coordinated local response and lack of clarity regarding the point at which escalation of the response to higher levels of government is advisable. These result in higher levels of risk and negative health impacts. The key recommendations arising from this study are: 1. Disaster health management policy in China should be enhanced by incorporating disaster management considerations into policy development, and by requiring a disaster management risk analysis and disaster management impact statement for development proposals. 2. China should transform existing organizations to establish a central organisation similar to the Federal Emergency Management Agency (FEMA) in the USA or the Emergency Management Australia (EMA) in Australia. This organization would be responsible for leading nationwide preparedness through planning, standards development, education and incident evaluation and to provide operational support to the national and local government bodies in the event of a major incident. 3. China should review national and local plans to reflect consistency in planning, and to emphasize the advantages of the integrated planning process. 4. Enhance community resilience through community education and the development of a local volunteer organization. China should develop a national strategy which sets direction and standards in regard to education and training, and requires system testing through exercises. Other initiatives may include the development of a local volunteer capability with appropriate training to assist professional response agencies such as police and fire services in a major incident. An existing organisation such as the Communist Party may be an appropriate structure to provide this response in a cost effective manner. 5. Continue development of professional emergency services, particularly ambulance, to ensure an effective infrastructure is in place to support the emergency response in disasters. 6. Funding for disaster health management should be enhanced, not only from government, but also from other sources such as donations and insurance. It is necessary to provide a more transparent mechanism to ensure the funding is disseminated according to the needs of the people affected. 7. Emphasis should be placed on prevention and preparedness, especially on effective disaster warnings. 8. China should develop local disaster health management infrastructure utilising existing resources wherever possible. Strategies for enhancing local infrastructure could include the identification of local resources (including military resources) which could be made available to support disaster responses. It should develop operational procedures to access those resources. Implementation of these recommendations should better position China to reduce the significant health consequences experienced each year from major incidents such as floods and to provide an increased level of confidence to the community about the country’s capacity to manage such events.