This book deals with batch process modeling, monitoring, fault diagnosis, and control, focusing on batch fermentation processes. Fermentation is one of the main bioprocesses used in pharmaceutical, food, and chemical industries. Most fermentation processes are carried out as batch or fed-batch operations. Batch processes have been around for many millennia, and received increasing attention in the second half of the twentieth century. Although batch processes are simple to set up and operate, modeling, monitoring, and control of these processes is quite challenging. Even in simple fermentation processes, diverse organisms and the large numbers of cells that are produced in various phases of the batch by complex metabolic reactions provide significant challenges to successful process operation. Slight changes in operating conditions during critical phases may have a significant influence on the growth and differentiation of organisms, and impact the quality and yield of the final product. Accurate process models are necessary to monitor and control the progress of the batch, determine transition times to new phases of activity, and diagnose the causes of unacceptable process behavior and product quality. Significant advances have been made in recent years in the development of powerful modeling, monitoring, diagnosis, and control techniques. Various new modeling paradigms have been proposed to develop models of desired accuracy for a specific task. Real-time multivariate process monitoring techniques have been developed to complement quality control based on laboratory analysis of the final product and to permit timely corrective actions to save a batch run destined to produce low quality products during the progress of the run. Control methods that consider desired future trajectories of critical variables, process constraints, and sensor faults have been developed for tighter control of multivariate processes. This book offers a unified presentation of these new methods and illustrates their implementation with a case study of penicillin fermentation.

The book integrates fundamental concepts from biochemical engineering, multivariate statistical theory, model identification, systems theory, and process control, and presents powerful methods for multivariable non linear processes with nonstationary and correlated data. Methods are introduced for finding optimal reference trajectories and operating conditions, and for manufacturing the product profitably in spite of variations in the characteristics of raw materials and ambient conditions, malfunctions in equipment, and variations in operator judgment and experience. The book presents both fundamental and data-based empirical modeling methods, several monitoring techniques ranging from simple univariate statistical process control to advanced multivariate process monitoring techniques, many fault diagnosis paradigms and a variety of simple to advanced process control approaches. The integration of techniques in model development, signal processing, data reconciliation, process monitoring, fault detection and diagnosis, quality control, and process control for a comprehensive approach in managing batch process operations by a supervisory knowledge-based system is illustrated. Most of these methods have been presented in various conferences and have been discussed in research journals, but they have not appeared in books for the general technical audience. The focus of the book is on batch fermentation in pharmaceutical processes. However, the methods presented can be used for batch processes in other areas by paying attention to the special characteristics of a specific process.

The book will be a useful resource for engineers and scientists working with fermentation processes, as well as students in biotechnology, modeling, reaction engineering, quality control, and process control courses. One objective of the book is to provide detailed information for understanding, comparing, and implementing new techniques reported in the research literature. Various paradigms are introduced in each subject to provide a balanced view. Some of them are based on the research of the authors, while others have been proposed by other researchers. A well-documented industrial process, penicillin fermentation, is used throughout the book to illustrate the methods, their strengths and limitations. Another objective is to provide a detailed case study to the reader to practice these methods and become comfortable in using them. Data sets, models, and software are provided to encourage the reader to gain hands-on experience. A dynamic simulator for batch penicillin fermentation is available as a web-based application and downloadable material. The fermentation simulator, batch process monitoring software, and software tools for supervision of batch process operations are provided at the website www. chee. iit. edu/~cinar/batchbook.html.

Convincing the reader about the strengths and limitations of the techniques discussed in this book would be impossible without reference to proper theory. Theoretical derivations are kept at an appropriate level to enhance the readability of the text, and references are provided for readers seeking more rigorous theoretical treatment. The level of the treatment of methodology in the book requires little background information in various areas such as biotechnology, statistics, system theory, and process control. An outline of the book and various roadmaps to read it are presented in Section 1.4. Introductory books to review the fundamentals are also suggested in Section 1.4, and advanced books are referenced in appropriate chapters in the book. Details of the algorithms are summarized in the text to permit the reader to develop software in his/her favorite environment. Executable software modules are also provided in the aforementioned website for readers who may prefer using our programs.

The book also discusses recent advances that may have an impact on the next generation of modeling, monitoring, and control methods. Metabolic pathway engineering, real-time knowledge-based systems, and nonlinear dynamics are introduced as some of the powerful paradigms that would be of interest.

This book could not have been written without the strong cooperation of the authors and the sacrifices of many family members and friends. The labor and agony of writing a multidisciplinary book tested the strength of several relationships. All four authors are grateful for the encouragement and support they have received from their loved ones. One of the authors, Cenk Undey, has done a magnificent job in coordinating the work of all authors, integrating the manuscript and providing technical support in the use of LaTeX to the others. All four authors are also grateful to Dr. Inane Birol for contributing an important chapter on System Science Methods for Nonlinear Model Development (Chapter 5). It is certain that the impact of the methods and tools discussed in that chapter will increase in future years in analyzing the dynamics of many nonlinear batch fermentation processes and developing new monitoring and control methods. His insight and knowledge have enhanced the value of the book. It seems that no book can be published free of errors. As time progresses, errors, omissions, and better ways to express the material discussed in the book will be discovered. Each author apologizes for the remaining errors and agrees that they are the fault of the other three.

Batch fermentation operations are abundant in industries that touch many human lives. Pharmaceutical, food, and chemical industries have made significant contributions in improving health and the quality of life. They have also been cited at times for causing challenges to nature and humans. Health, food, comfort, and safety also remind us of disease, limited resources, hunger, and pollution. Advances in technology may play an important role in resolving many conflicts. The authors hope that the methods presented in this book will contribute to the safety and productivity of batch process operations, and ultimately to improving the quality of life and harmony with nature.

Ali Cinar

Satish J. Parulekar Cenk Ăśndey Giilnur Birol

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