Anal. Chem. 2005, 77, 3789-3806
Process Analytical Chemistry Jerome Workman, Jr.,*,† Mel Koch,‡ and Dave Veltkamp‡
Thermo Electron Corporation, 5225 Verona Road, Madison, Wisconsin 53711-4495, and Center for Process Analytical Chemistry (CPAC), University of Washington, Seattle, Washington 98195-1700 Flow Injection Analysis (FIA) Ultrasound Miscellaneous Sensors Handheld High throughput Homeland Security Waveguides Literature Cited
Review Contents Resources Consortiums Conferences Websites Books Dissertations Workshops National Laboratories Microanalytical Systems Microelectromechanical Systems Micro Total Analytical Systems (µTAS) Microanalytical Microfluidics Microreactors Nanotechnology Biosensors Sensor Development Biological Agent Detection Chemical Agent Detection Sampling and New Sampling Systems NeSSI Remote Sensing Sampling Systems Electrochemistry or Electrophoresis Chromatography 2D Chromatography GC/MS Liquid Chromatography LC-MS Spectroscopy UV-Visible Spectroscopy Fluorescence Imaging Infrared Spectroscopy Laser-Induced Breakdown Spectroscopy (LIBS) Near-Infrared NMR Raman Spectroscopy Surface Plasmon Resonance Terahertz Spectroscopy X-ray Mass Spectrometry Process Chemometrics Artificial Intelligence (AI) Calibration Transfer and Data Preprocessing Informatics Cheminformatics Process Control Automation of Processes and Analytical Systems Control Systems Process Control 10.1021/ac050620o CCC: $30.25 Published on Web 04/29/2005
© 2005 American Chemical Society
3790 3790 3791 3791 3791 3791 3791 3792 3792 3792 3792 3793 3793 3793 3793 3793 3793 3794 3794 3794 3794 3794 3794 3794 3795 3795 3795 3795 3795 3795 3795 3796 3796 3797 3797 3797 3798 3798 3798 3798 3798 3799 3799 3800 3800 3800 3800 3800 3800 3801 3802
3802 3803 3803 3803 3803 3803 3804 3804
This review of process analytical chemistry is the sixth in a series of review articles on this subject published in 2003 (A1), 2001 (A2), 1999 (A3), 1995 (A4), and 1993 (A5). This review covers the period from March 2003 through March 2005. Technology is rapidly advancing in analytical chemistry, and the field is being redefined by miniaturization, sampling systems, highthroughput requirements, and increased sophistication in data modeling and processing. Research is focused on improvements in real-time measurement for both chemical and biological phenomena. Requirements for real-time, portable, electrooptical/ photonics sensors capable of detecting and quantifying biological or chemical hazards are creating new opportunities for technological advances in the field. This review article is in the condensed format requirements of the journal, yet still attempts to provide comprehensive coverage of the key developments within the field over the past two years. Coverage extends to analytical technologies applicable toward process, remote, real-time, and high-throughput measurements. The review covers the key developments for an extensive array of measurement techniques as well as those traditionally associated with process analytical chemistry. Other advances in nanotechnology, microelectromechanical systems (MEMS), and microanalytical systems as relevant are also addressed. Detail is given for research papers that encompass the most recent developments in process analytical chemistry over the past two years. Other reviews of process analysis occur within the literature periodically. One very basic review of trends related to process analytical chemistry was published in 2003 covering multiple analytical techniques as well as process control issues (A6). The term process analytical technology (PAT) has continued to evolve as a more appropriate term than process analytical chemistry (PAC) to describe the field of process analysis, as measurement technologies are expanding to include many physical characterization tools. This term has existed since the turn of the century (ca. 1911) but is only now found in common usage. It is increasingly important to develop measurements that correlate with, or predict, final product properties. This approach, called ‘inferential analysis’, has become a key process monitoring † ‡
Thermo Electron Corp. Center for Process Analytical Chemistry (CPAC), University of Washington.
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005 3789
parameter and has led to an emphasis on measurement science to characterize product properties beyond those technologies that are traditionally based on laboratory-based analytical chemistry. Properties such as material science (rheology) characterization, physical properties, and interfacial characteristics are being used increasingly for this purpose. The field of process analysis, and ‘inferential analysis’ in particular, has received a huge boost in popularity by the emphasis that the Center for Drug Evaluation and Research within the U.S. Food and Drug Administration (FDA) has given to the use of PAT in the pharmaceutical industry (A7). The FDA realizes that using PAT tools under the recently reissued current Good Manufacturing Practice (cGMP) guidelines (A8) will help to achieve process understanding and result in improved process control strategies for high quality, cost-effective pharmaceutical products. Measurement science continues to build on advances in technology found within the computing and communication industries as well as from sensor-related research conducted in university and government laboratories and agencies. These developments, in areas of miniaturization, electrooptics, new materials, and information/data handling, are exposing great potential for measurement improvements using the attributes of the emerging areas of nanomaterials, photonics, improved bioassays, and the like. The field of nanoscience is already having an influence, as nanomaterials are showing significant improvements in separation science (A9) and sensing, as well as providing a potential building material for new sensors. Over the past 10 years, the Center for Process Analytical Chemistry (CPAC) has conducted a Summer Institute that has focused on the value of miniaturization of analytical systems. It was predicted that this was the way of the future, as it would provide flexibility needed to improve laboratory and process control operations. The CPAC Summer Institute has matured into a venue for gathering engineers, measurement scientists, microinstrumentation vendors, and data handling specialists for brainstorming on how to merge microinstrumentation developments with measurement and engineering needs. Recent themes of the Summer Institute have been on how microinstrumentation can affect high-throughput experimentation and process intensification. Process intensification has gained importance as a means to reduce capital and operating expenditure. It is preferably based on a sound understanding of the underlying fundamentals of the process and often comprises the combination of unit operations within one reaction or mixing vessel. The advent of microtechnology has significantly impacted this field. This technology has been found to achieve drastic reductions in resource use and waste generation while maintaining productivity as well as the quality of the desired product. High-throughput experimentation and process intensification are fields where large numbers of small-volume samples are being created for product development and process optimization studies. Combinatorial approaches have shown value in new product leads, and now miniaturization of production unit operations is a costeffective way to gather data for process engineering. The demand for miniaturized measurement devices, scanning sensor devices, and rapid data handling is growing. These analytical tools need to mesh with high-throughput experimentation platforms as well as microreactors and other MEMS-based developments. 3790
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
CPAC has served as a focal point for the development of the New Sampling and Sensor Initiative (NeSSI) that is now an ANSI/ ISA standard 76.00.02 (A10), defining the footprint and the flow geometry of components. Importantly, this standard also defines the interconnect specifications that make up the platform. The use of NeSSI has already begun to show benefits in production operations as a sampling system for traditional process analyzers and in process development activities. The standard NeSSI platform has not had significant installation or maintenance concerns and is becoming cost-effective, as more of the components for sampling systems (e.g., valves, filters, and regulators) are available as “NeSSI compatible”. In addition to serving as an improvement to traditional sampling systems, NeSSI has proven to be an ideal template for demonstrating new microanalytical devices. As NeSSI units are being used in production, it is being recognized that the process analyzer does not need to be a large or laboratory-level modified instrument. A NeSSI platform containing analytical instrumentation will be of value not only to monitoring process streams but also for a number of laboratory-based applications. As analytical technologies are developed or adapted to be NeSSI compatible, the number of potential applications for a portable analytical laboratory on a NeSSI platform will increase markedly. The availability of a standardized platform and flow channels opens up a fertile area for discussion of future developments. These discussion areas include the use of “cluster analysis”, where a variety of measurement tools can be placed on the NeSSI platform. Uniform sample conditioning and data logging will improve the ability to use multivariant data analysis technology. The fact that NeSSI meshes with many MEMS developments allows it to link with high-throughput experimentation (combinatorial chemistry approaches) and microreactor systems for process optimization studies. A communication system has been selected for the NeSSI platform which will facilitate data transmission and diagnostics. The first system adopted was the FOUNDATION fieldbus, as it fit the conditions necessary to be operated in an “intrinsically safe” mode. NeSSI with communication to control system and sensoractuator managers will help the automation industry adapt to the smaller size and multivariable capability necessary for the emerging microsensors to a miniature/modular ‘“smart” manifold. This could fundamentally change the way industry does process development and optimization, as well as process analysis. With continued progress in the technology to develop low-power wireless communication, it is expected that applications of NeSSI within processes and at remote on-site locations will grow. RESOURCES Consortiums. The three main consortiums involving university, government laboratories, and industrial partners for the purpose of advancing research in process analysis and control technologies include the following: The Center for Process Analytical Chemistry (CPAC) located at the University of Washington, Seattle, WA 98195-1700; The Measurement & Control Engineering Center (MCEC) resident at the University of Tennessee, Knoxville, TN 37996-0750; and The Control Theory and Applications Centre (CTAC), which is based within the School of Mathematical and Information Sciences, Coventry University,
Priory Street, Coventry, United Kingdom CV1 5FB. The URLs for these consortiums are found in the Web site section of this paper. A fourth consortium, the Centre for Process Analytics and Control Technology (CPACT), has been active since 1997 and has been gaining momentum as an important contributor to PAT. CPAC was established in 1984 to provide a forum for research where costs are shared among sponsors (B1). CPAC accomplishes this mission through the sharing of research funding between the University of Washington, corporate research groups, national laboratories, and other government agencies. Involvement in CPAC is intended to help each sponsoring organization develop process control and manufacturing technology. Process monitoring and control is useful for producing better performing products, more efficiently, and with greater safety. Consortiums such as CPAC enable process research with reduced cost to sponsors. The reduced cost comes through the sharing of research funding between the member organizations. Core CPAC research areas include the following: chemometrics and process control algorithms, sensors, spectroscopy/imaging, chromatography, flow injection analysis and automated wet chemical methods, and process control devices. The MCEC is a cooperative venture among The University of Tennessee (UT) College of Engineering, Oak Ridge National Laboratory (ORNL), the National Science Foundation (NSF), Oklahoma State University College of Engineering, Architecture, and Technology (OSU), and numerous industrial partners (B2). The MCEC directs research from faculty and students across the departments of Chemistry, Chemical Engineering, Electrical Engineering, Materials Science Engineering, and Computer Engineering. Visiting Principal Investigators from other university, industrial, and government laboratories also contribute research. MCEC is able to consolidate a variety of innovative research for solving industrial applications. MCEC’s research emphasis includes analytical instrumentation and process control, optimization, and process modeling. Research currently covers on-line sensor development, molecular spectroscopy, mass spectrometry, openpath Fourier transform IR (FT-IR), and a variety of polymer applications. Control and optimization research emphasizes the applied process automation laboratory (APAL), control and analysis of nonlinear dynamics for industrial engineering systems (CANDIES), batch monitoring and control, control to economic optimum, automatic initiation of model adjustment, experimental batch optimization, and visual and auditory data assisted process control and Monitoring. CTAC is part of the School of Mathematical and Information Sciences at Coventry University (B3). CTAC has been designated as a center for process-related research since 1992. CTAC’s interdisciplinary research group includes diverse university staff expertise. CTAC has solved real problems across diverse industrial sectors. Industrial funding supports the majority of CTAC work. CTAC is composed of a number of research groups performing research in control theory and applications. The research programs and consultancy activities include the following: adaptive control and fault detection, biomedical engineering systems, industrial computing, industrial control applications, computational intelligence and optimization, and robust control system theory and design.
The three senior consortiums described provide state-of-theart research covering process control and analytical sensor technologies. CPAC, MCEC, and CTAC provide sponsor organizations the best available research in process control and analysis. Conferences. The main scientific conference covering this topic is the International Forum on Process Analytical Chemistry (IFPAC). This annual conference covers multiple aspects of process analytical technology (B4). The conference is generally located in attractive venues and gathers many of the key researchers from process research organizations throughout the world. Further information on IFPAC can be found in the Web site section of this review. Web Sites. Websites provide updated information related to technologies commonly applied for process analytical chemistry; however, the Web sites listed here have very specific process analytical relevance. The URLs listed in this section are not intended to be comprehensive but precisely targeted: Journal of Process Analytical Chemistry (JPAC) (B5) http://www. infoscience.com/JPAC/. International Forum on Process Analytical Chemistry (IFPAC) (B6) http://www.ifpac.com/IFPAC03/ IFPAC03InfoForm.html. Center for Process Analytical Chemistry (CPAC) (B7) http://www.cpac.washington.edu/. The Measurement & Control Engineering Center (MCEC) (B8) http:// mcec.engr.utk.edu/. The Control Theory and Applications Center (CTAC) (B9) http://www.ctac.mis.coventry.ac.uk/links.php. Chemometrics Web site link site (B10) http://www.chemometrics.se/. U.S. Food and Drug Administration Process Analytical Technology initiative (FDA PAT) (B11) http://www.fda.gov/cder/ OPS/journalClub.htm. Books. In general, there are very few books dealing specifically with the topic of process analytical chemistry. Three texts published during this review period were identified: Analysis and Purification Methods in Combinatorial Chemistry (B12); Comprehensive Coordination Chemistry II, Volume 2: Fundamentals: Physical Methods, Theoretical Analysis, and Case Studies (B13); and Special Issue: On Professor John F. MacGregor: a Pioneer of Multivariate Statistical Process Control and Recipient of the Fourth Herman Wold Medal (B14). Dissertations. In this review, relevant dissertations were found using the CAS database. The titles of these are given. In some cases, the work covers broader aspects of analytical chemistry but is included if found to be pertinent to the basic process analysis subject matter. The titles and schools are as follows: “Analysis of natural and synthetic polymers by analytical chemical chromatographic and spectroscopic methods.” University of South Carolina, Columbia, SC (B15); “Study of trimethylgallium-ammonia-nitrogen system using in situ Raman spectroscopy.” University of Florida, Gainesville, FL (B16); “New modeling and solution approaches for combinatorial optimization, with application to exam time-tabling and batch scheduling in chemical manufacturing.” University of Pennsylvania, Philadelphia, PA (B17); “Qualitative reasoning framework for process systems with spatial patterns,” Georgia Institute of Technology, Atlanta, GA (B18); and “A systematic approach for multiobjective process design in multipurpose batch plants,” Eidgenoessische Technische Hochschule Zuerich, Zurich, Switzerland (B19). Workshops. Process analytical chemistry is a vital discipline in modern chemical process industries, but it is virtually unknown Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
3791
in academia, and students rarely learn about this relevant and growing area of analytical chemistry. The Dow Chemical Co., the University of Texas at Dallas, and the University of Washington have collaborated to develop a week-long intensive short course on the Practical Aspects of Process Analytical Chemistry, in cooperation with other organizations, including Eastman Chemical Co., Air Products and Chemicals, Procter and Gamble, the University of Tennessee, CWCS, and the Greater Baton Rouge Metropolitan Area chapter of the National Organization for the Professional Advancement of Black Chemists and Chemical Engineers. Three workshops, with attendance totaling more than 50 faculty from community colleges, four-year colleges, and universities, have been held. Workshops are held near company sites, and field trips to actual analyzer house installations are an important part of the learning process. Faculty participants receive a CD-ROM with the course materials for use on the home campus (B20). The Center for Workshops in the Chemical Sciences (CWCS) offers week-long workshops to provide an up-to-date perspective on selected topics and to illustrate how these might be incorporated into the undergraduate curriculum. The workshops are free to faculty from four- and two-year colleges, instructional staff, and postdoctoral scientists and graduate students who plan a career in college teaching. Topics of recent workshops include the following: forensic science, molecular genetics, computational and theoretical chemistry, environmental chemistry, chemistry of art, practical process analytical chemistry, and molecular modeling (B21). A workshop for faculty giving instruction on how to teach chemical graduates process analytical chemistry is described in a paper (B22). National Laboratories. The Savannah River Site (SRS) has processed hydrogen isotopes for storage applications for over 50 years. The Savannah River National Laboratory (SRNL) was created to support the research and development tasks of the various processing efforts at the SRS, including hydrogen processing. Optimization of hydrogen processing conditions must be accomplished by monitoring process conditions such as ammonia and moisture levels. Most commercially available ammonia and moisture sensors rely on electrolytic permeable polymers for detection. These permeable polymers suffer from the lack of resolving power to differentiate between ammonia and moisture and rely on electrolytic measurements in a potentially explosive (>4% H2) environment. To overcome these limitations, researchers at SRNL have been collaborating with researchers at the University of Minnesota and the Center for Process Analytical Chemistry to employ fluorescence emission from inorganic complexes (vapochromes) to detect both vapor-phase moisture and ammonia. These vapochromic crystals show both intensity changes and signature shifts in the fluorescence maximums after sorption of various gas-phase analytes. A partial least-squares (PLS) algorithm was utilized to evaluate the sensor response to ammonia. The data were found to track linearly with a correlation coefficient. of 0.9998 (B23). MICROANALYTICAL SYSTEMS Micro Electro Mechanical Systems. MEMS-based sensors are demonstrating that microbased technologies have a great 3792
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
potential to be a disruptive technology. Miniaturization packaging, MEMS, and nanotechnologies are disruptive for several reasons. They allow miniaturization providing for complex platforms in tiny places; they allow lower cost assembly and lower cost of goods and can be manufactured more reproducibly than current macrotechnologies. Additionally they are more adaptable to highthroughput screening (HTS) applications, automation, in situ placement, medical applications, and multitechnologies in the same package (e.g., UV, NIR, IR, and Raman). In addition, they are green friendly (e.g., utilize fewer natural resources and are easier to dispose of due to small size). They are adaptable to the future of microreactors and small sensors in everyday life. They have the potential for higher performance overall for separation sciences and optical sciences. This is due to the decreased sample requirements and the unique and special flow dynamics of microchannels. For optical devices, these systems can accommodate increased complexity in optical design with greater precision (angstrom-level alignment). They require smaller optical paths; less mass means less temperature sensitivity for optical systems; and they can utilize simpler and higher performing electronics mainly due to the requirement for lower power consumption. A review with 26 references describes the increasing amount of pocket-size chemical equipment based on the so-called “labon-a-chip” approach that has become available. Besides the popular application in the analysis of biological macromolecules, such chips in combination with portable electronic equipment are applicable in, for example, “point-of-care” analysis of body fluids, forensics, identification of explosives, tracking of pollution in the environment or wastewater, monitoring nutrients in agricultural or horticultural water, controlling quality in food production, or for process control in the chemical industry (C1). MEMS sensors combine mechanical parts, sensors, actuators, and electronics on a common substrate through the use of microfabrication technology. A new application of MEMS technology is described, namely, a new generation of, and new approach to, miniaturized optical spectrometers that are ideal for process applications. Compact, rugged, and reliable microoptic spectrometer technology, developed, qualified, and first deployed for the telecommunications industry, has immediate application in industrial vibrational spectroscopy, especially in the emerging field of distributed process analytical spectroscopy in the chemical and pharmaceutical industries. A very small size is achieved, without loss of either signal-to-noise ratio or resolution. The small size and ruggedness of these devices allow their deployment in harsh temperature and vibration environments, where traditional design instruments, derived from laboratory systems, are not suitable. This technology represents a paradigm shift for industrial spectroscopy and enables a variety of new industrial applications for these spectroscopic sensors (C2). Micro Total Analytical Systems (µTAS). A review introducing microanalytical systems for bioanalytical and pharmaceutical applications is given. This review presents a brief overview of recent developments in miniaturization of analytical instruments utilizing microfabrication technology. The concept micro total analytical systems, also termed lab-on-a-chip, and the latest progress in the development of microfabricated separation devices and on-chip detection techniques are discussed. Applications of
microanalytical methods to bioanalytical and pharmaceutical studies are also described, including chemical reactions, assays, and analytical separations of biomolecules in microscale (C3). The effective design and control of a capillary electrophoresis microchip requires a thorough understanding of the electrokinetic transport phenomena associated with its microfluidic injection system. A study utilized a numerical simulation approach to investigate these electrokinetic transport processes and to study the control parameters of the injection process. Injection systems with a variety of different configurations are designed and tested, including the cross-form, T-form, double-T-form, variable-volume focused flow cross-form, and variable-volume triple-T-form configurations. Each injection system cycles through a predetermined set of steps in which the magnitudes and distributions of the applied electric field are precisely manipulated in order to effectuate a virtual valve. The injection methods presented in this paper have an exciting potential for use in high-quality, highthroughput chemical analytical applications and throughout the micro total analytical systems field (C4). A review of lab-on-a-chip systems for biomedical and environmental monitoring is given. During the past decade, pocket-sized analytical equipment based on the lab-on-a-chip approach has become available. These chips, in combination with portable electronic equipment, are applicable in, for example, point-of-care ion analysis of body fluids, forensics, identification of explosives, tracking of pollution in environmental waters or wastewaters, monitoring nutrients in agricultural or horticultural water, controlling quality in food production, or process control in the chemical industry. This paper discusses several demonstrator systems with applications in these fields (C5). Microanalytical. A review of the impact of microinstrumentation on PAT: An overview is given on the work of the CPAC with the aim to develop and evaluate new measurement capabilities for the optimization of process analytical technology. First, the services of the CPAC organization are outlined including university research projects, sponsor meetings, and technological workshops with the key aspect of communication by bringing together individuals from across a wide spectrum of industries with an interest in process analytical chemistry and related issues. Further, some examples of the current work of CPAC are given focusing on the development of new sensors and nontraditional instruments based on fundamentally different sensing mechanisms (e.g., acoustic, thermal, and imaging technologies) (C6). Microfluidics. This research explores the potential of hydrogels for biological assays of high specificity in areas such as biosensing, biological interaction, and diagnosis of disease. The conventional approach to developing such methods, particularly in areas of protein analysis, involves surface immobilization of probes to microchannel walls using surface chemical or streptavidin/biotin linkages through multistep or coupled chemical reactions. Hydrogel plugs provide another approach for immobilizing probes in microchannels. Sensors can be easily formed in microchannels within minutes by incorporating antibody probes in the monomer solution. Upon polymerization using a photoinitiator, these probes are immobilized by physical entrapment. In this presentation, hydrogel sensors capable of specific capture of target antigens are presented as a demonstration of the potential of this technology for protein-based assays. Effects such as
microchannel surface treatment, hydrogel composition, and incubation time are illustrated using antibody/antigen model systems and quantitative methods are discussed (C7). Microreactors. A review discusses the developments in microreactor technology and how these reactors are being implemented in pharmaceutical and chemical syntheses, particularly in plant concepts, fluidic and electronic interfaces and platforms, sensory and analytical devices, and process automation (C8). A review of many chemical reactions carried out on credit cardsized microdevices or in larger microflow processing tools for screening and analysis of organic synthesis is presented. At present, the aims of the investigations with microchemical processing devices are changing from simply proving feasibility for one chemical reaction toward more in-depth scientific studies and industrial piloting. Microreactor quantities which characterize each process, comparing the product on a molecular and supramolecular level, as well as the downstream processing are compared for both microreactor and conventional processing, benchmarking the performance of microflow devices at micro- and macrothroughput scales (C9). Nanotechnology. A review of current trends in modern pharmaceutical analysis for drug discovery is given. Traditionally, pharmaceutical analysis referred to the chemical analysis of drug molecules However, over the years, modern pharmaceutical analysis has evolved beyond this to encompass combination techniques, high-throughput technologies, chemometrics, microdosing studies, miniaturization, and nanotechnology. These analytical advances are now being employed in all stages of drug discovery, and the focus of this review is on how these technologies are being employed within the drug discovery process. With new, improved, and evolving technologies, as well as new applications for existing technology, the search for new drugs for the prevention and treatment of human diseases continues. The changing nature of technologies and methods used for chemical analysis is directly relevant to the pharmaceutical industry today. Successful application of such technologies opens new opportunities for drug discovery (C10). NIST is developing methods for elemental, molecular, and isotopic nanoscale analysis to address a wide array of needs for chemical characterization at high spatial resolution. The rapid advance of nanotechnology, the increasing use of materials engineered at the nanoscale, and the desire to characterize inherently nanostructured samples demand a better understanding of existing characterization tools and the development of methods beyond the current state of the art. Driven by the needs of industry (semiconductors, optoelectronics, catalysts, coatings) and the government (homeland security, defense, biomedical and health care), NIST is tackling the difficult challenge of developing chemical analytical methods that are broadly applicable for biological, inorganic, and polymeric-based samples that have near scale resolution (C11). BIOSENSORS Sensor Development. A report presents a succession of theoretical and experimental work on sensors using the LbL technique to produce spectroscopic devices on optical fibers and micro/nanocarriers using fluorescence and surface plasmon Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
3793
resonance interactions as specific biosensors. Examples of engineering optochemical transducers for in vitro, in vivo, and intracellular biochemical analysis demonstrate the versatility of the process (D1). A review of fiber-optic chemical sensors and biosensors is available. This biannual review covers the time period from January 2002 to January 2004 and is written in continuation of previous reviews. An electronic search in SciFinder and MedLine resulted in 532 hits. Since the number of citations in this review is limited, a stringent selection to reduce the review to essential papers was performed. Priority was given to fiber-optic sensors for defined chemical, environmental, and biochemical significance and to new approaches and materials (D2). Increasing efforts have been put into the developments of cantilever-based microsensors. These devices show fast responses and high sensitivity and are suitable for mass production. Currently, they are mainly applied for quality and process control, diagnostic biosensing for medical analysis, fragrance sensors design (“artificial noses”), and gas analysis (D3). A review of instrumental analysis and chemical sensors, especially biosensors, indicates remarkable progress during the past decade. With respect to the analytical performance characteristics the sensitivities could still be increased drastically. Types of sensors, design, and performance features are discussed in a review paper covering this specialized subject (D4). An electronic tongue based on a sensor array composed of 23 potentiometric cross-sensitive chemical sensors combined with pattern recognition and multivariate calibration data processing tools was applied to the analysis of Italian red wines. The electronic tongue was demonstrated to be sensitive to multiple substances that determine wine taste and flavor. The system was able to predict human sensory scores with an average precision of 13% for Barbera d’Asti wines and 8% for Gutturnio wines (D5). The rapid determination of wastewater quality for wastewater treatment plants in terms of pollution strength, i.e., biological oxygen demand (BOD), is difficult or even impossible using the chemical determination method. A study reports the determination of BOD within minutes using microbial BOD sensors, as compared to the 5-day determination using the conventional method (D6). Biological Agent Detection. As part of the Emergency Preparedness Program, the Food Research Division at Health Canada has initiated a collaborative program with European research institutions for the development of analysis methods to detect and identify chemical and biological agents that might be added deliberately to the food supply, to harm or to provoke panic among the population. Targeted methodologies include rapid screening systems for high-throughput sample handling, fieldadapted techniques, or both. An ELISA-based technique specific to domoic acid was presented. Assay optimization procedures to minimize the analysis time, as well as the application of the method to food matrixes, were discussed. The possible use of the developed immunoreagents in immunosensor applications were discussed (D7). CHEMICAL AGENT DETECTION Laser interrogation of surface agents (LISA) is a UV-Raman technique which provides short-range standoff detection and 3794
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
identification of surface-deposited chemical agents. Several applications, putting in perspective the overall evolution undergone by the technique within the last years, are described in a paper. These applications include LISA-Recon (joint contaminated surface detector, JCSD) for incorporation on future Army reconnaissance vehicles and designed to demonstrate single-shot, on-the-move measurements of chemical pollutants at concentrations below Army requirements (E1). SAMPLING AND NEW SAMPLING SYSTEMS NeSSI. The emergence of miniature, modular sample system technology in the chemical processing industry established a platform to drive the development of new analytical technology. Used for many years in the semiconductor industry, miniature, modular sample conditioning substrates and components proved to be an effective and reliable technology for regulating and controlling the corrosive vapor sample streams common to this industry. The potential benefits of modular sample system technologysimproved reliability, reduced maintenance, decreased space requirements, and reduced engineering and fabrication laborsprovide the impetus and justification to pursue its implementation and further development in the chemical industry. The Dow Chemical Co., as a technology leader in the chemical industry, has chosen to pursue both the development and the implementation of miniature, modular analytical technology. A paper details Dow’s involvement with the development of miniature, modular analytical technology by discussing its involvement with The Instrumentation, Systems and Automation Society (ISA), CPAC, and the NeSSI open initiative (F1). Remote Sensing. A method for the passive remote monitoring of chemical vapors by differential Fourier transform IR radiometry is presented in a paper for the determination of the characteristics of a chemical vapor plume from a stack located at a distance of more than 1 km from the sensor. This measurement technique is based on the use of a double-beam Fourier transform IR spectrometer that is optimized for optical subtraction. The accuracy of a simplified plume radiance model implemented in the detection algorithm is specifically addressed. The measurement technique has been successfully used to detect and identify low, medium, and high concentrations of vapor mixtures (F2). Sampling Systems. An initial study of online remote systems for the monitoring of trace metals using an inductively coupled plasma mass spectrometer (ICPMS) equipped with a dynamic reaction cell system has been described. A remote sampling system for online monitoring with the combination of the ICPMS is demonstrated (F3). The content of a published review covers atomic absorption spectroscopy, atomic fluorescence spectroscopy, atomic emission spectroscopy, inductively coupled plasma mass spectroscopy, sampling systems, and preconcentration sampling systems for spectrochemical analysis. The review covers speciation of inorganic elements, process analytical chemistry, and analysis of inorganic elements (F4). ELECTROCHEMISTRY OR ELECTROPHORESIS A novel, rapid method to determine chemical oxygen demand (COD) based on the photoelectrochemical oxidative degradation (PECOD) principle was proposed and experimentally validated. With this new method, the extent of dissolved organic matter
degradation in water was measured simply by directly quantifying the extent of electron transfer at a TiO2 nanoporous film electrode during an exhaustive photoelectrocatalytic degradation of organic matter in a thin-layer photoelectrochemical cell. The PECOD method demonstrated is a direct method, not requiring the use of standards for calibration (G1). A review with references concerning recent advances in electroanalytical flow measurements is presented. General trends in the development of electroanalytical devices for chemical analysis are moving toward a search for faster, multianalyte, miniaturized measuring devices, including mechanization and automation of analytical processes. Within these trends, a significant role is played by measurements in flow conditions. The major advantage of flow electroanalytical measurements is the possibility of utilizing a kinetic discrimination in potentiometric measurements and enhancement of mass transport determination using voltammetric techniques. Flow injection techniques provide shortening of time of a single analytical determination due to reproducible use of transient signal from the detector without need of obtaining a steady-state equilibrium signal. Electrochemical detection in HPLC gives often improved selectivity and detection limit for electroactive solutes, whereas in capillary electrophoresis it allows a convenient design of portable, integrated chips for field application. This review presents a state-of-the-art survey of flow electroanalytical devices (G2). CHROMATOGRAPHY 2D Chromatography. Trends continue in the research and development of rapid, information-rich analytical methods. One such initiative involves the development of multidimensional chromatography. These second- and higher-order methods provide more information from chromatograms offering methods to discriminate mixtures of compounds more readily than traditional first-order chromatography. Computational power is providing access in real-time to such methodologies for rapid analysis of complex chemical mixtures. A rapid retention time alignment algorithm was developed as a preprocessing utility program applied to chemometric analysis of large data sets of diesel fuel profiles obtained using gas chromatography (GC). For second-order chromatography to be useful, retention time variation from chromatogram-to-chromatogram must be eliminated. An alignment algorithm recently developed is shown to increase the efficacy of pattern recognition methods applied to diesel fuel chromatograms by retaining chemical selectivity while reducing chromatogram-to-chromatogram retention time variations and to do so on a time scale that makes analysis of large sets of chromatographic data practical (H1). GC/MS. A comparative study of the performance of liquid chromatography (LC)-chemical ionization (APCI)-mass spectrometry (MS) and GC/MS techniques for the determination of resin and fatty acids from paper mill process waters was carried out. These compounds are responsible for the high toxicity of paper mill effluents, and little research has been carried out regarding their analysis using mass spectrometric techniques. Although LC-APCI-MS presented coelution of the nonaromatic resin acids, it also shows good sensitivity (limits of detection 0.935) in the calibration and prediction. Raman spectroscopy coupled with multivariate data analysis was demonstrated to be capable of monitoring rich chemical and physical information simultaneously and significantly in a process. The analytical information allowed the control of the final properties of automotive coatings such as strength and weather durability (I22). 3798
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
Surface Plasmon Resonance. A method for the determination of bisphenol A (BPA), a representative endocrine-disrupting chemical, was developed using a SPR sensor. The method is based on an indirect competitive immunoassay, where a BPA sample containing an anti-BPA antibody is introduced into the SPR sensor system. A sensor chip immobilized with a specialized layer membrane was prepared by depositing specialized reagents on a gold film on the sensor chip. The BPA detection limit of the method was determined to be ∼10 ppb (I23). Terahertz (THz) Spectroscopy. A paper demonstrates the potential of inspection of chemical mixtures by THz spectroscopic imaging using known spectral data of pure chemical components. This method, which is based on principal component data analysis, is capable of determining the existence of chemical components. It is demonstrated to be able to identify them, to map the spatial distribution of each component, and to measure their concentration in a target sample. The paper demonstrates the qualitative and quantitative analysis of components in pure samples as well as mixtures (I24). A paper demonstrated the separation of the component spatial patterns of chemical samples in transillumination THz images using known spectral curves. The images and spectral data were measured at 1.3-1.8 THz, using a widely tunable coherent THzwave parametric oscillator source. This method could be effective for analyzing spatial patterns and the concentrations of components with a variety of chemical compositions (I25). X-ray. The development of new materials from which to construct controlled chemical-release systems has been an active area of research for the past four decades. Using XPS analysis, researchers have demonstrated that graphite powder and multiwalled carbon nanotubes covalently derivatized are important new micro- and nanoscale materials for use as voltammetrically controlled chemical-release reagents in applications where the small size of the material is advantageous. It is envisaged that derivatives of these materials could be used in vivo in a wide range of areas including medical diagnosis and targeted drug delivery systems as well as in vitro applications such as analytical chemistry, sensor technology, and industrial process monitoring and control (I26). By means of examination of rock and ore and heavy sand, X-ray analysis, spectral analysis, and chemical analysis, process mineralogy of run-of-mine ore is researched systematically. X-ray analysis demonstrates a viable method for monitoring silver ore containing As and Sb (I27). Chemical and mineralogical characterizations of a copper converter slag, and its products obtained by curing with strong sulfuric acid and leaching with hot water, were carried out using ore microscopy, scanning electronic microscopy with energy dispersive spectrometry, wavelength dispersive X-ray fluorescence spectrometry, X-ray diffractometry, and chemical phase analysis, which provided necessary information to develop a new process for treating such slag and further understanding of the chemical and mineralogical changes in the process (I28). A review of process monitoring in a cement plant is presented, detailing the development of sophisticated software packages, fast X-ray detectors, and modern computer and specialized preparation procedures for sample preparation in the cement plant. State-ofthe-art X-ray hard- and software and automated sample preparation
systems have been installed to monitor the clinkering and cement grinding process. These systems provide a valuable tool for optimizing cement production in terms of mineralogical composition rather than just simple chemical composition, providing better assessment and prediction of cement quality (I29). MASS SPECTROMETRY A new experimental method is described for online isotope dilution mass spectrometry, speciated isotope dilution mass spectrometry, and speciated isotope dilution mass spectrometric calibration. These online methods have been developed to enable automated, timely, chemical species analyses during chemical processing and manufacturing. The system implements a unique calibration methodology permitting automated, unattended operation of a mass spectrometer. The information transformed from automated data, in near real time, makes possible chemical constituent control and demonstrates potential to improve process control in many industries (J1). A new method and apparatus are described for online mass spectrometry that enables real-time, automated, trace contamination and chemical species analyses focused on the semiconductor manufacturing application. The scaleable ion source produces not only elemental ions for quantitative analysis but also enables quantitative and qualitative elemental, species, ligand, and organic molecular analyses. The system uses a unique calibration methodology permitting automated, continuous, unattended operation for up to a week without intervention. These new capabilities are expected to enable rapid yield learning, contamination and chemical constituent quantification, and significantly improved process control (J2). PROCESS CHEMOMETRICS Chemometrics has been a valuable toolbox for obtaining information from multivariate data. Chemometrics might refer to the capability of computationally analyzing multivariate data in real time to obtain useful information for analytical applications. Recently the term informatics, or the application of computer and mathematical/statistical techniques to the management of information, might be a more appropriate term covering the broader aspects of information management. The utilization of this information management is required for efficient control of pharmaceutical processes. Whatever terminology is used, it is clear that such computational power is key to providing essential information in real time from ever increasing quantities, and variable quality, of data measured from process streams. Information management is required during raw material identification, API production, product production, and final product packaging. A series of articles describing chemometrics and the role of PAT in spectroscopy has been described in a special supplement to Spectroscopy magazine in January 2005 (K1). There were several excellent reviews of chemometrics methods published during this review period. In a review entitled “The evolution of chemometrics” (K2), the author describes some of the early struggles to establish chemometrics as a viable research discipline within the chemical sciences and goes on to review the major areas of chemometrics related to analytical chemistry. A particularly readable paper describes multivariate calibration and the advantages realized by applying chemometrics techniques (K3). A concise framework for sequential multiblock component
methods that form the basis for many of the methods used to analyze multiple data sets simultaneously to find the underlying relationships between and within the data sets was published (K4). A review of the latest trends in multivariate resolution applied to multicomponent processes and mixtures has been presented (K5). A good overview of a strategy for implementing NIR spectroscopy and chemometrics in the petrochemical industry was described (K6). Similarly, a somewhat more in-depth overview of implementing PAC to monitor polymerization and spray drying processes in the polymer industry has been presented (K7). A very interesting paper describing the effects of moving solids (pellets and powders) on NIR spectroscopic measurements and the artifacts it can introduce in the resulting spectra was published (K8). As in the other technical areas within this process analytical review, the PAT initiative by the FDA has had an impact on the publications related to process chemometrics. Publication numbers have drastically increased as demonstrated by a literature search containing both the terms chemometrics and pharmaceutical over the past 10 years (2005 estimate based on four times the current publications). Two papers (K9, K10) provide good examples of how chemometrics and measurement instrumentation fit into the PAT framework. The use of NIR spectroscopy and chemometrics is discussed (K11) for classification of clinical trial tablets and to verify raw materials with attention to regulatory requirements and guidance’s (K12). A paper describes NIR spectroscopy and chemometrics applied to the wet granulation process to obtain increased process understanding of the three different subphases of this important operation in the pharmaceutical industry (K13). Finally, ATR-FT-IR monitoring of crystallization processes showing a useful methodology for implementing sensitivity analysis, orthogonal signal correction, and multivariate statistical process control (MSPC) to verify and refine PLS models of the crystallization process was demonstrated (K14). MSPC and related process monitoring and control methods continued to gain acceptance and application in many different industries. This fact was reflected in John MacGregor receiving the fourth Herman Wold medal, awarded by the Chemometrics Division of the Swedish Chemical Society, for his pioneering efforts and continued contributions to this field. A review was published of within-batch and batch-to-batch control options for PLS-based inferential-adaptive control of semibatch emulsion polymerization reactors, and an extension of this approach to multiway methods was demonstrated (K15, K16). A paper discussed process optimization using support vector machines and decision trees (K17). The interesting aspect of this work was that, by shifting the modeling criteria learned from the training set away from “decision optimization” toward “generalization capacity”, one can use the data collected under statistical control to identify important operational regions likely to lead to eventual process upsets and then optimize the process to avoid those regions. A publication (K18) provided a descriptive example of MSPC applied to monitor high-pressure polymerization processes and detect faults. Other researchers (K19) discuss implementation details of performance monitoring and quality prediction from batch and fed-batch bioprocess operations. Of particular interest is the integration of alerts and display systems for presenting the results to operators. Similar implementation details, including information Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
3799
on data and control transmission networks and expert systems server topology, can be found in reference (K20). Artificial Intelligence (AI). Implementation of automation and process analysis for real-time measurements requires a certain integrated intelligence to apply calibration, operation, and control to systems. AI has provided such technological adaptation for intelligent systems developments. Rapid, objective techniques for monitoring the ripening process of fermentation products are of interest in the food industry. An electronic nose (e-nose) technology offers an easy-to-use, more economical, and automated system incorporating AI and easily used for quality screening. A paper describing the use of an e-nose for analysis of headspace samples from two types of Danish blue cheese (traditional cheese and from pasteurized milk) is described. Results indicate that the e-nose technology can be directly applied in quality assessment of Danish blue cheese products including the monitoring of ripening of cheese (K21). A review paper describes a project referred to as CHEM to develop and implement an advanced decision support system for the purposes of process monitoring, data and event analysis, and operation support for industrial processes. The CHEM system is a synergistic integration of innovative software tools based on statistical, system theoretic, and artificial intelligence (K22). Calibration Transfer and Data Preprocessing. A novel algorithm based on coupling of the fast wavelet transform (FWT) with MLR and PLS regression techniques for the selection of optimal regression models between matrixes of signals and response variables was demonstrated. The technique has been termed wavelet interface to linear modeling analysis (WILMA). The algorithm decomposes each signal into the FWT domain and then, by proper criteria, selects the wavelet coefficients that give the best regression models, as evaluated by the leave-one-out cross-validation criterion. Good results were obtained for all the studied data sets; in particular, the data sets from Kalivas the WILMA models showed improved predictive capability (K23). In analytical chemistry, the peaks of narrow-band signals are so sharp that those signals cannot be denoised by the usual methods. A denoising technique named Mexican Hat wavelet least-squares, effective for narrow band signals is presented. The method is powerful and reliable for narrow-band signals. Satisfactory results can be obtained even when the signals have very high noise with a signal-to-noise ratio approximating 1.5:1 (K24).
INFORMATICS Cheminformatics. Web-based molecular processing tools installed on corporate intranets bring easy-to-use chemoinformatics and molecular modeling capabilities directly to the desks of synthetic chemists, giving them comfortable access to data and their visualization and analysis, considerably improving efficiency of the drug design and development process. User-friendly tools that use a standard Web browser as an interface allow users access to a broad range of expert molecular processing tools and techniques, without the need for specialized expertise in their use (L1). While cheminformatics and bioinformatics use completely different data formats and analysis tools, the data pipeline approach makes is possible to apply them together. Chemical compound structures and activities can be processed in the same computing 3800
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
environment that analyzes gene expression profiles or protein sequences. Some interesting research questions can only be addressed sufficiently by the coordinated analysis in bioinformatics and cheminformatics (e.g., clustering gene targets using the correlation of their expression levels in a series of cells with the biological activity on those cells of a set of test compounds) (L2). Web-based tools offer many advantages for processing chemical information, most notably ease of use and high interactivity. Therefore, more and more pharmaceutical companies are using Web technology to deliver sophisticated molecular processing tools directly to the desks of their chemists, to assist them in the process of designing and developing new drugs. In this paper, the Web-based cheminformatics system developed at Novartis and currently used by more than a thousand users is described (L3). There is tremendous pressure in pharmaceutical companies to eliminate compounds early in the drug discovery process before they get to clinical trial. As a result, the demand for in silico methods to facilitate this elimination and optimize leads is ever increasing, as is the demand to integrate different types and sources of information, including chemical, biological, and analytical information, and ultimately to generate knowledge from that information. A paper examines the convergence of new pharmaceutical informatics tools with analytical informatics and cheminformatics tools (L4). The continuing surge in computer power, combined with new algorithms allowing molecular dynamics (MD) simulations to span enormous time and length scales, has led to an explosion of MD data. Although the need for new algorithms to analyze the wealth of MD data is critical, most algorithms for establishing molecular properties are rooted in the classical statistical mechanics of the mid-20th century. A paper describes the adaptation of data-mining techniques used extensively in multivariate statistical analytical, signal processing, pattern recognition, chemometrics, and bioinformatics to mine MD data sets for vibrational frequencies and modes. (L5). PROCESS CONTROL Automation of Processes and Analytical Systems. The use of automated sample processing, analytics, and screening technology for profiling absorption, distribution, metabolism, excretion, and physicochemical properties, early in the drug discovery process, is becoming more widespread. The use and application of these technologies is both diverse and innovative. HTS technologies have been utilized enabling the profiling of an increased number of compounds emerging from the drug discovery process. Although the drivers for using these technologies are common, different approaches can be taken (M1). The dynamic simulation of the wastewater treatment plant of a large chemical factory on the basis of online process analysis data using the SIMBA code is reported. It is demonstrated, with the example of nitrification in a biological tower reactor, how simulation results are used to evaluate the stability of processes under various conditions. The realization of automated online simulation is in progress and will enable the prediction of plant behavior under assumed future load (M2). An online, real-time semiconductor process liquid monitoring tool, LMS-300 TCA, was developed. This tool uses an electrospray (ES)-TOF-MS for sample analyses. Since the ES-TOF-MS is able
to provide harsh (elemental) and soft (molecular) ionizations in both positive and negative modes, metallic, anionic, cationic, elemental, and organic species can be analyzed. For automatic sample handling, an in-process mass spectrometry approach and automated peak fitting algorithms enable an unattended quantitative measurement of contamination present in wet station process baths as well as other process analytical chemistry monitoring problems (M3). Process modeling and simulation have emerged as important tools for detailed study and analysis of chemical processes. Although considerable literature is available on process modeling from a subjective or theoretical viewpoint, little has been published on the application of these ideas to complex industrial-scale processes. A paper focuses on a case study of an object-oriented model for automatic generation of a fluid catalytic cracking unit (FCCU) reactor/regenerator. In this paper, the utility of the framework is illustrated by demonstrating how the model for FCCU could be fine-tuned both structurally and parametrically to represent the behavior of the process under changing process operating conditions (M4). A two-step clustering method based on PCA is proposed for control in an agile chemical plant. Process states are first classified into modes corresponding to quasi-steady states and transitions. A novel multivariate algorithm is used to segment historical data into modes and transitions. Dynamic PCA-based similarity measures are then used in the second phase to compare the different modes and the different transitions and cluster them. This twostep methodology can be applied directly to multivariate process data and has low computational requirements. Extensive testing on a fluidized catalytic cracking unit and the Tennessee Eastman process simulations illustrates the effectiveness of the proposed method (M5). Process optimization is a difficult task due to the nonlinear, nonconvex, and often discontinuous nature of the mathematical models used. Although significant advances in deterministic methods have been made, stochastic procedures, specifically genetic algorithms, provide an attractive technology for solving such optimization problems. However, genetic algorithms are not naturally suited to highly constrained problems. A targeted genetic algorithm for process optimization suitable for highly constrained problems is described. The genetic operators, crossover and mutation, are defined based on information gained about the feasible region and the behavior of the objective function through the use of a data analysis procedure. Results from the application of the new targeted genetic algorithm to an oil stabilization problem are presented, demonstrating the effective, efficient, and robust nature of the implementation. The use of visualization as the core of the data analysis step also provides a useful tool for explaining the results obtained by the optimization procedure (M6). Automated techniques and philosophies, which have become increasingly important in modern laboratories, are not traditionally covered in undergraduate chemistry curricula. Automated sample preparation methods have now been incorporated in an undergraduate chemical analysis laboratory using robotic workstations. The pedagogical aspects of incorporating automation into the undergraduate curriculum as well as results obtained for manual
and automated experiments conducted by students are described (M7). Process fault analyzers are computer programs that can monitor process operations to identify the underlying cause(s) of operating problems. A general method for creating process fault analyzers for chemical and nuclear processing plants has been sought ever since the incorporation of computers into process control. The motivation has been the enormous potential for improving process plant operations in terms of safety and productivity. Automated process fault analysis should help process operators prevent catastrophic operating disasters such as explosions, fires, meltdowns, and toxic chemical releases, while reducing downtime after emergency process shutdowns. Such an approach could also enable better quality control of the desired process products. The Method of minimal evidence (MOME) is a model-based diagnostic strategy. MOME has now been used to hand compile the Data Validation and Fault Analysis (DV&FA) diagnostic rules necessary to competently perform such analysis in two facilities: one an adipic acid plant owned and operated by DuPont in Victoria, TX, and the other a electrolytic sodium persulfate plant owned and operated by FMC in Tonawanda, NY. The MOME strategy provides a means to directly perform continuous, online, real-time fault analyses at these facilities (M8). Control Systems. Safe, efficient, and economical operation of chemical processes relies more and more on online analyzers. The use of component properties for control is becoming more common. The combination of online analyzers and advanced control technologies holds an enormous economic potential. As a result, the number of existing applications is growing slowly, but steadily. A publication describes the potential of the combination of advanced control technologies and online analyzers using some illustrative examples such as a batch distillation column, a continuous isomer distillation unit, and the automation of a complete fine chemicals production unit. Based on the experiences and problems encountered with past projects, some guidelines and requests are formulated to optimize the definition and implementation of these projects by an interdisciplinary team and the integration of online analyzers in a distributed control system (M9). PAT requires the integrated use of industrial process analytical chemistry techniques combined with classical process systems engineering tools, for the analysis and control of manufacturing processes. A published report outlines and describes the development and integration of an at-line monitoring technique with a kinetic model of the process, to establish a basic understanding of an industrial catalytic hydrogenation of an API. A suitable process spectroscopy technique (NIR) is described to monitor the most relevant reaction constituents, in terms of process performance (product distribution, reagent conversion, and catalyst selectivity and stability). A kinetic model is also proposed for the process, which is capable of describing the industrial process under diverse operating conditions. The success of the industrial PAT application described is indicative of this methodology for industrial process analytical, control, and optimization without production disruption (M10). Process industries rely on process control and safety instrumented systems (SIS) to minimize the potential for hazardous incidents. As computer-based systems become more complex, Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
3801
there is a potential for inaccuracies and errors in program logic to introduce new causes of process deviations (abnormal situations) in process facilities. Finding these errors requires extensive review of software using traditional documentation and review tools. Novel chain-of-events analysis provides an effective aid in this process by examining linkage information from the system and creating an interaction table from which displays and reports may be generated to illustrate influencing relationships between process control and SIS entities (points and their parameters). This method is also useful for routine facility maintenance and operation and provides assistance in analyzing alarms for abnormal situation management (M11). Fuzzy logic is a modeling method well suited for the control of complex and nonlinear systems. A paper illustrates some of the power of fuzzy logic through a simple control example. For the analytical chemist, fuzzy logic incorporates imprecision from measurement noise as well as from linguistic process descriptions to produce operational control systems (M12). Process analyzers perform many different functions in the chemical processing environment. Three examples of these functions are as follows: safety systems, optimization systems, and quality systems. In safety systems, process analyzers are used as area monitors and as “critical” analyzers that provide engineering interlocks for process control. Optimization systems incorporate analyzers to enable plants to run tighter control limits and reduce laboratory sampling thereby reducing overall cost for product production. In remote areas, such as pipeline stations, process analyzers can be used as quality systems to characterize the products being transported prior to their use in production (M13). Process Control. The Defense Waste Processing Facility (DWPF) at the Savannah River Site immobilizes high-level radioactive defense waste by mixing it with glass-forming chemistries and heating the mixture. at 1100 °C in a slurry-fed melter to form borosilicate glass logs contained in stainless steel canisters. The key process control parameters in the DWPF is the elemental analysis of the melter feed. Elemental analytical determinations that the waste- and glass-forming chemistries are in the correct proportions to produce glass with the desired durability and waste processing properties. The new method is more efficient in all aspects of the analysis, including the sampling, shielded cell utilization, sample digestions, and elemental analysis by inductively coupled plasma-atomic emission spectroscopy. Development of the improved analytical scheme and results of the testing program are discussed (M14). PAT is considered to be a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. The pharmaceutical industry has used process analytical chemistry for years in API/drug substance manufacturing for process control and process understanding. Additional implementation of process analytical tools and techniques such as statistical data analysis and real-time quality control will require significant investment and the development of new skills. PAT could be a vehicle to improve process reliability, speed, and quality of pharmaceutical manufacturing (M15). 3802
Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
In this paper, fault detection and diagnosis modeling using a support vector machine (SVM) is proposed. This model is applied to develop an inferential model that detects faults of a chemical process and diagnoses them. The existing multivariate method including PLS and neural network was a powerful technique for process modeling and multivariate statistical process control. However, for systems that exhibit nonlinear behavior and have sparse data, they can be inappropriate. In this paper, by using SVM regression, a more accurate and fast fault detection model is proposed. And then SVM classification is used for the fault diagnosis model using known fault data. To verify the superior performance of the proposed model, the data sets of the Tennessee Eastman Process are applied (M16). VAI, in cooperation with the Institute of Experimental Physics of the Johannes Kepler University in Linz, Austria, has developed a new system that enables the continuous analysis of the chemical composition of steel baths in metallurgical process vessels. Termed the VAI-CON Chem, this system was successfully tested on an industrial scale in a vacuum degassing plant. For selected elements, VAI-CON Chem furnishes precise analytical data over the entire steel treatment period, offering considerable potential for improved process control in the steel production process (M17). A review discusses the fast measurement of product quality in dairy processing for the determination of physical parameters, chemical concentration, and microorganism density. Examples are given for in-line measurements for process control in fermentation of yogurt, renneting of milk, preparation of milk powder, and pasteurization. Applications for monitoring biofouling and cleaning are also included (M18). In industrial processes, measured data are often contaminated by noise, which causes poor performance of many analytical techniques. The wavelet transform is a useful tool to denoise the process data, but conventional methods directly employ the wavelet transform to the measured variables, which makes the method less effective when the process variables have collinear relationships. A paper demonstrates a novel multivariate statistical projection analysis (MSPA) method based on a data denoised process using a wavelet transform and blind signal analysis. This method can detect faults more quickly and improve the monitoring performance of the process. The simulation results applied to the data from a double-effect evaporator verify the higher effectiveness and better performance of the new MSPA method as compared to classical MSPC (M19). A paper describes the advantages of having access to realtime analytical data in chemical problem solving. Real-time data can provide a consistent data stream allowing process control parameters to be linked with the chemistry. Traditional “grab samples” do not provide a continuous stream of in situ data, and they provide only periodic glimpses of the process. A technical presentation described examples in manufacturing and R&D where real-time data, not grab samples, provided optimized data to solve problems (M20). Flow Injection Analysis (FIA). An online FIA COD monitoring method is described with a detection range of 0-6000 mg/L, as compared to 0-130 mg/L for conventional FIA. The method uses cerium sulfate as an oxidizing agent. The linearity range described was found to be 1000-6000 mg/L. The relative standard
deviation was 2.8%, in 11 measurements of samples at the 1000 mg/L COD level (N1). An interdisciplinary project in chemical instrumentation, graphical programming, computer interfacing, and analytical chemistry is presented. The project involves the design, construction, automatic control, and optimization of a FIA instrument with chemiluminescence (CL) detection. The project was composed of three independent phases: the construction of the detector, the construction and control of the flow system, and the chemical measurement issues. The apparatus developed was used to optimize the chemical and instrumental variables of a FIA-CL method for the quantitative determination of Co(II) (N2). A review of the design methodology for a lab-on-a-chip for chemical analysis: the MAFIAS chip is described. This book chapter gives insight into the design path that has to be followed to complete a chemical analytical system based on micromachined components. This method led to the design of a lab-on-a-chip device for the measurement of ammonia in surface water, referred to as a micro ammonia flow injection analytical system (MAFIAS). The MAFIAS chip is a miniaturized FIA system incorporating pumps, mixers, a reaction chamber. and the detector all on one chip. The Berthelot reaction for the conversion of ammonia into indophenol blue is employed in this system to convert ammonia into a blue dye, which can be quantified by a visible absorption measurement (N3).
ULTRASOUND A review on the analytical uses of ultrasound for sample preparation is given. Ultrasound use as an analytical tool is a growing trend in analytical chemistry. From the most basic use for cleaning surfaces to the facilitation of methods for analyses of process parameterssparticularly those involved in sample preparation. Ultrasonic devices are gaining the confidence of analytical chemists who use them for helping in steps ranging from sampling through to detection. The authors present an overview of the principles and the uses of ultrasound devices for improving, accelerating, or automating sample preparation. The authors compare them with well-established alternatives and critically comment upon them (O1). A review of hazard analysis and critical control point (HACCP) analysis for an ultrasound food processing operation is presented. Emerging technologies, such as ultrasound, used for food and drink production often causes hazards for product safety. Classical quality control methods are inadequate to control these hazards. HACCP is the most secure and cost-effective method for controlling possible product contamination or cross-contamination, due to physical or chemical hazards during production. A published case study on the application of HACCP to a U.S. food-processing operation demonstrates how the hazards at the critical control points of the process are effectively controlled through the implementation of HACCP (O2).
MISCELLANEOUS SENSORS Handheld Sensors. Microfabrication techniques are providing the technological means for producing accurate and precise battery powered and rugged analytical systems. These systems are becoming more commonplace due to the necessity of
improved field monitoring of hazards and threats to security and safety. They are also applicable for field-portable quality and process assessment devices. Gas chromatography is the preferred analytical method for analysis of odors, fragrances, and other chemical vapors. A handheld electronic nose, called the zNose, incorporating an ultrahigh-speed GC column, a solid-state sensor, a programmable gate array processor, and an integrated preconcentrator, can now provide near-real-time analysis of odors from explosives. The zNose is able to create an almost unlimited number of virtual chemical sensors for monitoring the concentrations of target compounds within odors or fragrances. Virtual chemical sensors provide compound-specific data for principal component analysis and neural network learning algorithms (P1). The development of a battery-powered portable chemical identification device for field use is reported. These devices are becoming much more common in the commercial realm, although publications related to these developments are still scarce. The device discussed in this reference consists of an acoustooptic tunable filter-based Raman spectrometer with integrated data processing and analytical software. The various components and custom circuitry are integrated into a self-contained instrument by control software that runs on an embedded single-board computer (SBC), which communicates with the various instrument modules through a 48-line bidirectional TTL bus. The user interacts with the instrument via a touch-sensitive liquid crystal display unit (LCD) that provides soft buttons for user control as well as visual feedback (e.g., spectral plots, stored data, instrument settings) from the instrument. The control software manages all operational aspects of the instrument with the exception of the power management module that is run by embedded firmware. The instrument can acquire 198-point spectra over a spectral range of 238-1620 cm-1, perform a library search, and display the results in less than 14 s. The operating modes of the instrument are demonstrated illustrating the utility and flexibility afforded the system by the SBC-LCD control module (P2). High Throughput. With the advances in analytical techniques, higher-throughput screening for drug metabolism and pharmacokinetics (DMPK) attributes has become an integral part of drug discovery. However, as the number of compounds and work loads increase, the volume of data requiring analysis is increasing exponentially. As a result, a major challenge for the analytical chemist is how to quickly process the vast amount of data to keep up with the throughput of the screening assays. The authors have reported a customized computer program for automated evaluation of the LC/MS/MS data generated from the in vitro DMPK screening assays. This program performs automatic data processing and quality control. It identifies analytical anomalies, such as low internal standard intensity and poor reproducibility of replicates. All analytical anomalies for individual compounds are summarized into an “E-Log” in a color-coded format for reviewing. With the use of this program and other supporting software, data processing and evaluation for up to 100 compounds are accomplished in several minutes (P3). Homeland Security. Chemical imaging combines molecular spectroscopy and digital imaging and has been demonstrated to be a powerful tool for the rapid, molecular analysis of trace materials in complex backgrounds. Chemical imaging microscopy Analytical Chemistry, Vol. 77, No. 12, June 15, 2005
3803
provides molecular compositional and structural information, without the use of dyes or stains, at submicrometer spatial resolution (
