Process Analytical Technology

Concepts and Principles

Mark L. Balboni

T
Process analytical technologies are a multifaceted group of concepts that comprise one of many initiatives that form FDAs Pharmaceutical GMPs for the 21st Century.Yet what constitutes a process analytical technology or whether it is in fact a new technology remains unclear. This article outlines the key concepts that define process analytical technology and emphasizes the relevant theory and applications of chemometrics.
PHOTODISC, INC.

he current process analytical technology (PAT) initiative underway within FDA exemplifies the latest consortium between FDA and the industry that aims to encourage the concepts of quality by design, use of computerized data gathering and evaluation techniques, and process- and product-monitoring methods through advanced instrumentation and data evaluation. Although this partnership between FDA and the industry is relatively new (2001), methods related to PAT such as chemometrics have been studied and have been in use for quite some time. Yet, the PAT initiative has raised several questions: What does PAT really encompass? Is it a new technology or is it a series of proven scientific principles? How can PAT be used in a pharmaceutical operation to gain better process understanding and possibly reduce cycle times and associated costs? This article discusses the concepts that embody PAT. Emphasis is placed on chemometrics, which is the use of mathematical and statistical models to extract and interpret chemical data.

What is PAT?
FDA defines PAT as a system for the analysis and control of manufacturing processes based on timely measurements of critical quality parameters and performance attributes of raw materials and in-process materials a process to ensure acceptable end-product quality at the completion of the processing (1). FDA also states that PAT involves the optimal application of process analytical chemistry (PAC) tools feedback process-control strategies information management tools and/or productprocess optimization strategies for the manufacture of pharmaceuticals (1). In summary, PAT can be defined as the optimal application of PAC tools, feedback process-control strategies, information management tools, and/or productprocess optimization strategies to the manufacture of pharmaceuticals. PAT focuses on the principles of building quality into the product and process as well as continuous process improvement. A few examples of PAT tools and strategies are as follows:
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Mark L. Balboni is a senior compliance consultant at KMI, a division of PAREXEL International, LLC, 28241 Crown Valley Parkway, F601, Laguna Niguel, CA 92677, tel/fax 949.830.2355, mbalboni@belmont. kminc.com.

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at-line, in-line, or on-line measurement of process quality and performance attributes using a variety of instrumentation and measurement strategies such as near-infrared (NIR), vibrational, acoustical, and X-ray spectroscopy chemometric approaches such as multivariate statistical and pattern recognition methods. real-time data and information management systems for process control (2). FDAs PAT initiative is supported by many large pharmaceutical corporations and distinguished members of academia. Another potential advantage of PAT is the opportunity to place more reliance on in-process testing as the basis for final product release. This type of product-release methodology requires both a significant amount of data to be compiled and heavy correlations to be determined by analysis and evaluation (3). The theory is that product release could be based on relationships (i.e., correlations between observed in-process test results and predictive qualitative results of the final product) established during productprocess development and confirmed by both validation and routine review of productprocess data for commercial lots. These relationships coupled with confirmation testing of the finished product would serve as the basis for release, or the product could possibly be released on the basis of the observed in-process results and how a currently produced lot favorably compares with other previously released product lots. FDAs PAT initiative is being spearheaded by the Center for Drug Evaluation and Research (CDER), Office of Pharmaceutical Science. Since 2001, FDA has held and participated in a series of PAT meetings as part of the Process Analytical Technologies Subcommittee for the Office of Pharmaceutical Sciences and with the FDA Science Board. These meetings have included not only FDA personnel but also pharmaceutical industry representatives, members of academia, and engineering and consulting professionals. The PAT initiative is part of a larger FDA initiative called Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach(4). The agency seeks to improve the regulation of pharmaceutical manufacturing using a science- and risk-based approach to product-quality regulation while incorporating an integrated quality-systems approach. Complete descriptions of FDAs PAT initiative and the Pharmaceutical CGMPs for the 21st Century approach, including electronic links to associated documents and reference materials, are provided in References 1 and 4.

ing the synthesis of active pharmaceutical ingredients). One particular industryuniversity partnership, The Center for Process Analytical Chemistry (CPAC) at the University of Washington, has been in existence since at least 1986 (6). Although PAC is not a new approach, many of the related techniques have been tested and used only on a limited basis by a very small percentage of the pharmaceutical industry. The following is a partial list of the various sensors and instrumentation recently discussed at the 2003 Arden House Conference either in-use or currently being evaluated for feasible use for production monitoring: NIR spectroscopy for moisture determination X-ray spectroscopy radio frequency for moisture determination microwaves for moisture determination RAMAN spectroscopy, with vibrational spectroscopy being the most common. RAMAN complements IR spectroscopy and is used for raw-material identification, polymorph differentiation, and reaction monitoring. fluorescence for water quality on-line measurement of color X-ray fluorescence for the detection of inorganic materials photoacoustic spectroscopy. Because most of these technologies are extremely sophisticated, one must realize that the key emphasis of PAT is not so much how to collect the data or what kind of instrumentation should be used, but rather what data should be collected, what is done with these data, and what associated conclusions are reached. Therefore, a complete and thorough understanding of the manufacturing process is paramount.

Chemometrics
To fully understand PAT, one must first understand the science behind manufacturing processes, including how these processes operate, their limitations, and their expected outcomes. In 1974 Sante Wold, from the Institute of Chemistry at Umea University (Umea, Sweden) described the art of extracting chemically relevant information from data provided in chemical experiments as chemometrics (7). He stated that this art is heavily dependent on the use of different kinds of mathematical models and that it was important to have knowledge in statistics, numerical analysis, and applied mathematics, including the challenge to structure the chemical problem to a form that can be expressed in a mathematical relation. Twenty years later, during a 1994 presentation, Professor Wold said his definition of chemometrics had not changed much. He said chemometrics requires us to ask ourselves How do we get chemically relevant information out of measured chemical data; how do we represent and display this information; and, how do we get such information into data? In 1996, Wise and Gallagher stated chemometrics is the science of relating measurements made on a chemical system to the state of the system via application of mathematical or statistical methods (8). Similarly, Hardy noted that data are raw information, both qualitative and quantitative (9). He observed that in and of themselves, raw data are meaningless and that a method of analysis and a model are needed to gain knowlwww.phar mtech.com

PAC and in/at/on-line monitoring

According to Hailey et al., PAC is the technique of gathering analytical information in real time at the point of manufacture (5). As they noted, PAC places an emphasis on the process rather than the final product, including an understanding of the relationship between final product specification [sic] and the critical variables during the manufacturing process. Although the approaches and instrumentation currently being discussed are in some cases categorized as being novel or new, real-time measurement (PAC) has existed for some time (e.g., real-time temperature monitoring of reaction vessels dur56

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edge from the data. He also identified the clear need for a process to convert data to knowledge. Dosage forms recently have been described as complex multifactorial physiochemical systems (10), sometimes referred to as multivariate. Multivariate analysis consists of methods of statistical analysis of multivariate data, characterized as consisting of several observations on each set of objects or mathematically represented by a collection of points in a finite-dimensional Euclidean space RP (11). So, multivariate analysis is an important statistical method widely used by chemometricians. Described below are a few of the tools commonly used by chemometricians, all of which are helpful for evaluating processing data generated during pharmaceutical unit operations or when synthesizing active pharmaceutical ingredients. Principle component analysis (PCA). PCA is a technique used to express variations of many variables by a small number of indicies (11). Wise and Gallagher describe PCA as a favorite tool of chemometricians for data compression and information extraction and note that PCA finds combinations of variables or factors that describe major trends in a data set (8). Sans et al. (12) observed that PCA can be used to determine the number of components that influence the data of the process as well as to identify the chemical meaning of the components. They proposed that PCA enables one to approach multivariate chemical problems in order to obtain underlying information about the correlation of the raw data and the real meaning interpretation. Finally, Wise and Gallagher (8) acknowledged that generally there is a great deal of correlated or redundant information in process measurements, and often essential information lies not in any individual process variable but how the variables change with respect to one another or how they co-vary. They also noted that some sort of signal averaging would be useful in cases in which a large amount of noise is created from the volume of data and a lack of clear understanding of the data exists. However, Wu et al. point out two limitations of PCA: When an object is added or removed as displayed in a plane, principal components (PCs) must be recalculated all over again by following the process of selection and interpretation of the PCs. No more than two PCs at a time can be viewed (inspected) in a plane, and this prevents one from using the information contained in other PCs (13). The authors also note that their star-plot method could be used as an alternative way to display and analyze multivariate data. Application of PCA to chemical processes. Wise and Gallagher (8) studied data obtained from a slurry-fed ceramic reactor using thermocouples placed at 20 locations (8). They found a great deal of correlation as the data generated followed a sawtooth pattern. In addition, the study revealed the following: PCA performed on this data found three factors that captured approximately 97% of the variance in the data set. This previously noted finding allowed 16 variables to be replaced with three new ones, which were linear combinations of the original variables.
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The sawtooth pattern was attributed to changes in the level of molten glass, which was a controlled variable. The three factors (PCs) were identified as the level of molten glass in the reactor, the variation between two groups of measured locations, and the variation of overall process temperature (also a controlled variable). Sans et al. also used PCA to determine stoichiometric models from on-line spectroscopy for selecting the number of reactions and the number of chemical absorbing species to better describe a chemical reaction (12). They chose to use spectroscopy methods because they can reveal information about the dynamic evolution of the reaction mass during a chemical reaction. Although the outcome of this study is not discussed in this article, Sans et al. did note that semibatch processes are examples of complex reaction networks that generally are difficult to interpret because of the large number of reactions occurring simultaneously and because of the effects related to the addition of materials that may cause complex volume changes during the processing time. Multiway principle component analysis (MPCA). An analog of PCA is what is known as multiway PCA, which is equivalent to performing PCA on a very large two-dimensional matrix formed by unfolding the three-way array X into one of six possible ways, only three of which are mathematically unique (8). General PCA methods do not take into account the ordered nature of the data sets, meaning that the data were not collected in a sequential manner. Multiway methods take into account the ordered (sequential) nature regarding when data were generated because the data usually are organized into time-ordered blocks that are each representative of a single sample or process run (8). Nomikos and MacGregor (14) describe another aspect of MPCA; namely, the use of on-line measurements to identify significant deviations from the normal operating behavior by using SPC charts. An empirical model is based on data generated when the process is operating within a state of control. They noted, future unusual events are detected by referencing the measured process behavior against the in-control model and its statistical properties. Partial least squares (PLS). Wise and Gallagher described PLS as a regression related to both principle component regression (regression of properties on the principle component scores of the measured variable) and multiple linear regression (also known as inverse least squares) (8). They observed that this analysis can be used to predict properties of a system based on variables that are only indirectly related to the property. Accordingly, by using PLS, one attempts to find factors that both capture variation and achieve correlation. Multiway partial least squares (MPLS). Nomikos and MacGregor observed that MPCA using statistical process-control charts only makes use of the process variable trajectory measurements (X) taken throughout the duration of the batch (14). In contrast, multiway partial least squares (MPLS) can be performed using both the process data (X) and the product quality data (Y), and focuses more on the variance of X that is more predictive for the product quality Y (14). Other statistical tools. Two other statistical tools that may be useful in PAT efforts are

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capability studies, which measure the ability of the process to consistently meet specifications by evaluating select process outputs and calculating the average and ranges over a specified time on control charts. From these studies, capability indicies Cp (used to evaluate the variation) and Cpk (used to evaluate the centering of the process) are calculated. design of experiments, which are experiments that involve changing one or more of the process inputs and measuring the results to one or more of the process outputs (15).

Rapid microbiology test methods

Another part of FDAs PAT initiative involves discussion about the feasibility of developing so-called rapid microbiology methods (emphasis added, as most microbiological testing can take anywhere from several days to a couple of weeks to complete). This topic is of heightened interest within the industry as manufacturers seek additional ways to reduce cycle times. Rapid microbiology testing was discussed during the FDA Advisory Committee for Pharmaceutical Science meeting on 2324 October 2002 (16). During that meeting, the committee identified at least two problems or risks associated with the development of rapid microbiology methods; namely, validation of test methods may not yield results equal to those for traditional test methods acceptance by regulators (e.g., FDA).

The group also categorized microbial determinations as follows: qualitative methods (presence or absence of microbes; e.g., sterility testing) quantitative methods (enumeration of microorganisms present; e.g., microbial limits tests) microbial identification. FDA did concede that rapid microbiology test methods are an important part of the PAT initiative but that at this time it has not yet been discussed extensively (16). FDA also commented that the general guidance document on PAT would not specify details about rapid microbiology methods but would rather cover them in a general sense to encourage their use. Finally, the group felt that microbial identification probably has the most rapid method systems presently available, and quantitative testing probably has the least detection systems.

Real-time data information and management systems

Another PAT tool being discussed is the use of real-time data information and management systems. Although a detailed overview of this topic is not provided in this article, some of the possible concerns include possible 21 CFR Part 11 implications, adding complexity to already complex computer system architecture, and the amount of data retention necessary, given that continuous monitoring will generate very large volumes of data.

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With FDAs recent withdrawal of Part 11 guidance documents, it would be advisable to first review the anticipated PAT guidance document for information concerning data information and management issues and secondly review the 21 CFR Part 11 implementation portion of the Pharmaceutical CGMPs for the 21st Century Initiative, which includes both a Notice of Availability and a draft guidance on Part 11. The draft guidance on Part 11 attempts to clarify the scope and applicability of the regulation, which ultimately may undergo revision to clarify the scope and requirements.

Benefits and challenges: an industry perspective

Most industry representatives that either were involved in discussions regarding the feasibility of PAT or who have conducted successful PAT efforts thus far have had many more positive than negative comments regarding the advantages of adopting PAT principles. Positive perceived benefits of PAT include decrease in cycle times lower costs increased efficiency and batch-to-batch consistency process fingerprinting (signature) that would be useful for validation, scale-up, and confirming acceptable handling of changes increased process understanding and a decrease in variability, rejects, and lot failures possible continuous processing and the ability to adjust process on the basis of real-time monitoring data.

Conversely, the most-common perceived or actual challenges include product-approval delays by inclusion of PAT methodologies into relatively traditional drug development and validation activities lack of a written PAT guidance document from FDA an increase in the amount of data being generated, including not only what one should do with the extra data but also possible Part 11 implications increased pressures to meet aggressive filing timelines, added costs to make changes, lack of senior management support, and resource constraints (Source: Reference 1 and 2003 AAPS Arden House Conference.

Where we go from here

Although no one can clearly predict how widely accepted PAT will become, it is clear that FDA does support innovation. The agency is appealing to the industry to take a more active role in understanding its manufacturing processes and is seeking quick and effective resolution of problems associated with good manufacturing practices that result in rejected batches, stability failures, field alerts, and product recalls. Currently there are many actions a company can take to prepare for what FDA is calling the GMPs for the 21st Century. By reading the contents provided on FDAs Web site regarding PAT (http://www.fda.gov/cder/OPS/PAT.htm), which

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includes committee meeting minutes and dozens of presentations, one will see that many large pharmaceutical firms already have made significant accomplishments through the successful implementation of PAT principles. In spite of the industrys dwindling profit margins, fewer new products in the pipeline, and a more competitive marketplace, these companies already have recognized the positive aspects of implementing PAT. The following are some active steps that a company can take right now.

Develop a plan for the future.

Wait for FDAs much anticipated guidance document about PAT before making significant decisions regarding how your company will handle certain PAT principles (e.g., validation of new analytical methods for a unique in-process test). Analyze existing product lines and determine which may benefit most from PAT. For example, the compounding and filling of a well-established product that is a true solution composed of 99.5% water is probably not the best candidate for PAT. The manufacture of complex dosage forms such as tableted products, which also includes in-process monitoring using process control charts, would probably be a better choice. Products with recurring quality problems are also good candidates because process deviations or exceptions are sometimes results of a less-than-complete understanding of the process rather than more-obvious causative factors. Obtain/retain employees with education, training, and expe

rience in disciplines necessary to be successful in PAT efforts. For example, FDA is seeking to hire persons experienced in in-process/chemical engineering, PAC, chemometrics, and industrial pharmacy. For your companys efforts to be successful, similar expertise will be needed. Gain executive managements support for PAT. Although it may be easier to make the scientific case, management must understand how PAT could reduce cycle times and costs and add value. Make a business case for adopting PAT. Benchmark with industry and academic partners. Speak with company representatives from firms that already are using PAT principles. Many major universities also are heavily involved in the PAT initiative and could provide guidance, including, but not limited to, the following schools that have had representatives at several FDA committee meetings about PAT: MIT Pharmaceutical Manufacturing Initiative Purdue University, School of Pharmacy Center for Process Analytical Chemistry at the University of Washington. Texas A&M Department of Chemistry and Chemical Engineering. Gather information about the topic. A significant amount of information concerning PAT can be found on FDAs Web site (1). Additional new information continues to be added, and plenty of information already is available on many university and industry association Web sites regarding topics such as PAT, PAC,

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PCA, and chemometrics. Internet keyword searches can yield significant additional information. Attend future PAT workshops, seminars, or symposia. Find out what FDA and others are saying first-hand. If the workshops are sponsored by an industry association, you may need to attend in person to get the handouts and presentations because all of that information may not be published on FDAs or the associations Web site. Provide comments directly to FDA using the Internet. If you have substantial comments regarding FDAs PAT initiative and you feel it is information that others could benefit from, consider providing electronic comments to FDA. The agency already has established a Web-based feedback tool for this purpose (www. fda.gov/ohrms/dockets/). You will need to search for docket number 03N-0059. Alternatively, you could send questions or comments regarding the PAT initiative by email to pat@cder.fda.gov.

Ensure quality is designed into your products and processes.

Confirm compliance with good manufacturing practices. Remember, CGMP is the minimum standard according to 21 CFR 211.1(a). Most of the successful companies strive for and achieve substantial compliance with these regulations as well as carry out best practices. Poorly developed manufacturing processes, untrained employees, or equipment that has not been properly qualified will hinder any PAT efforts. Complete thorough product and process development work

to ensure processes are adequately defined. Include robust specifications and critical process-control points. Confirm that active drug substances are well characterized. Use validation efforts to demonstrate consistency and reproducibility, not as a means to conduct range finding, process adjustments, or enhancements. These are development tasks, not validation. Optimize processes and improve yields after successful validation, not during validation. Consider process or equipment changes carefully, especially postapproval, because this usually will result in much unanticipated work and undoubtedly more development activities and data. Complete risk or impact assessments on the basis of data and not on opinions or theories. Many years ago, Alexander Hamilton said, Experience teaches that men are often so much governed by what they are accustomed to see and practice, that the simplest and most obvious improvements, in the most ordinary occupations, are adopted with hesitation, reluctance, and by slow gradations. Men would resist changes, so long as even bare support could be ensured by an adherence to ancient courses, and perhaps even longer. Sometimes changes do take time, so we should look to the future potential of PAT to enhance our pharmaceutical processes
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Continued from page 66

and applaud FDA for encouraging the application of new technologies and for their willingness to work with industry on this important initiative.

Acknowledgment
The author would like to acknowledge the following individuals for their assistance in the writing of this article: KMI senior compliance consultant Eric S. Weilage and PAREXEL senior biostatistician Chunzhang Wu, PhD.

References
1. CDER, Office of Pharmaceutical Sciences, Process and Analytical Technologies Initiative, http://www.fda.gov/cder/OPS/ PAT.htm. 2. A. Hussain and J. Famulare, FDAs PAT Initiative and its Role in the Proposed Drug Quality System for the 21st Century, presented at the AAPS Arden House Conference, 27 January 2003. 3. T. Layloff, Process Analytical Technology (PAT) Subcommittee Report, presented at the ACPS meeting 21 October 2002. 4. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach, http://www.fda.gov/cder/gmp/index.htm. 5. P. Hailey et al., Automated System for the On-line Monitoring of Powder Blending Processes Using Near-Infrared Spectroscopy Part I. System Development and Control, J. Pharma. Biomed. Analysis 14, 551559 (1996). 6. D. Illman, CPAC: An IndustryUniversity Cooperative Research Center for Process Analytical Chemistry, TrAC: Trends in Analytical Chemistry 5 (7), 164172 (1986). 7. S. Wold, Chemometrics: What Do We Mean with It and What Do We Want from It? presented at InCINC 94, Institute of Chemistry, Umea University (Umea, Sweden, 1994). 8. B. Wise and N. Gallager, The Process Chemometrics Approach to Process Monitoring and Fault Inspection, J. Proc. Ctrl. 6 (6), 329348 (1996). 9. J. Hardy, Special Topics: Chemometrics, lecture presentation associated with 3150: 710 (University of Akron, 2000), available at http://ull.chemistry.uakron.edu/chemometrics/introduction. 10. FDA, Emerging Issues in Pharmaceutical Manufacturing: Process Analytical Technology, science board meeting presentation (16 November 2001). 11. N. Sugakkai, Iwanami Sugaku Ziten, original publication by Iwanami Shoten Publishers (Tokyo, Japan, 1954), copyright by Nihon Sugakkai (Mathematics Society of Japan); English translation provided by the Massachusetts Institute of Technology (1977). 12. D. Sans, R. Nomen, and J. Sempere, Interactive Self-Modelling of Chemical Reaction System Using Multivariate Data Analysis, supplement to Comput. Chem. Eng. 21, S631S636 (1997). 13. W. Wu et al., The Star-Plot: an Alternative Display Method for Multivariate Data in the Analysis of Food and Drugs, J. Pharma. Biomed. Analysis 17 (6-7), 10011013 (September 1998). 14. P. Nomikos and J. MacGregor, Multiway Partial Least Squares in Monitoring Batch Processes, Chemometrics and Intelligent Laboratory Systems 30, 97108 (1995). 15. FDA Global Harmonization Task Force Study Group #3, draft Process Validation Guidance (1 June 1998). 16. FDA Advisory Committee for Pharmaceutical Science transcripts, 23 T October 2002. P

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