Process analytical technology: a critical view of the chemometricians Alexey L. Pomerantsev a,b and Oxana Ye. Rodionova a * The role of chemometrics in process analytical technology (PAT) solutions development is presented in the review on the basis of publications from 1993 to 2011. Main areas of application, stages of implementation, instruments, and chemometric methods used for the PAT implementations are reviewed. Generally speaking, PAT is considered to be an approach applicable not only in pharmaceutical industry but also in any production area such as food industry and biotechnology. PAT is claimed to be a new flexible manufacturing concept that accounts for variability and adapts the process to fit it. Copyright © 2012 John Wiley & Sons, Ltd. Keywords: PAT; pharmaceuticals; biotechnology; food industry; feasibility; QbD; PLS; PCA; SIMCA; MIA; MSPC; filtering; MCR; TOS; N-way; DoE 1. INTRODUCTION The term process analytical technology (PAT) has become widely popular (in a rather small community) since 2004 when the Food and Drug Administration (FDA) published the Guidance for Industry [1]. We presume that the meaning of PAT is well known to the readers of this review; therefore, only a short quotation from the aforementioned guidance [1] is provided. “PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.” The history of this document could be found in a review [2] that gives a detailed account of the extensional and intentional aspects of the PAT phenomenon. The scope of the current paper is much more specific as it illuminates just a single issue being chemometrics in PAT. The word chemometrics is never mentioned in [1]. Instead, the term multivariate mathematical approaches is used. These approaches are declared to include “the design of experiments, response surface methodologies, process simulation, and pattern recognition tools”. However, it is clear now that chemometrics constitutes the essence of the matter. We can definitely state that such PAT was de facto used by many chemometricians, who, for more than 40 years, have been applying PAT without knowing it [3]. The PAT approach could be viewed in both narrow and wider scopes. In the first case, PAT may be applied to pharmaceutical industry only, and its methods are limited by a rather scanty list of the aforementioned PAT tools. In this case, PAT is an approach that has been exhaustively defined by the Food and Drug Administration functionaries, and therefore, it may not be interpreted in a broader sense. The wider view is not restricted to drug manufacturing alone, and so PAT can be used in any production area, that is, in biotechnology or food industry. PAT instruments, methods, and tools are being developed endlessly, and their list cannot be limited in principle. According to this interpretation, PAT is an approach that is continuously developed through collective input of researchers who are contributing by means of numerous publications. This can be seen in line with the old definition [4] that PAT is what PATtioners do. Needless to say, this review represents the wider scope of PAT. Therefore, we consider that the first paper [6] on PAT can be traced back to 1984. The numerous publications on multivariate statistical process control (MSPC) [6–10] followed shortly after. There is no doubt that MSPC is a PAT tool, and the Guidance for Industry [1] confirms this. It is even more striking that only 5% of papers that describe tools used in PAT apply MSPC. Process analytical chemistry (PAC) [11–22] is a direct forerunner of PAT. Sometimes, it is difficult to distinguish between the PAC and PAT approaches as they both aim at manufacturing control and quality improvement. One could say that PAT inclines to pharmaceutical manufacturing, whereas PAC is not restricted to any production area in particular. We suppose that the method of the process analysis can be seen as the discriminating rule: off-line and at-line monitoring is for PAC, and strictly on-line and in-line monitoring is for PAT [23]. This, however, could be disputed – as late as 1984, some in-line methods has been proposed [11] and applied [5]. Working on this review, we have analyzed about 690 relevant papers, which have been published between 1993 and 2011, with some exclusion. Fishing out the PAT papers was a difficult task, as many authors claim having conducted a PAT research but merely present roundabout reflections. On the other hand, there are plenty of studies, for example [24–26], which represent good PAT research but never mention this term. Among the 690 papers, directly or indirectly related to PAT, only 30% employ chemometrics. These 245 chemometrics-related PAT (CRPAT) papers constitute a representative set that is analyzed further in this review. Figure 1 demonstrates the distribution of the * Correspondence to: Oxana Ye. Rodionova, Semenov Institute of Chemical Physics RAS, Kosygin Str. 4, 119991 Moscow, Russia. E-mail: rcs@chph.ras.ru a A. L. Pomerantsev, O. Y. Rodionova Semenov Institute of Chemical Physics RAS, Kosygin Str. 4 119991 Moscow, Russia b A. L. Pomerantsev State South Research and Testing Site RAS, Teatral’naya 8a 354000 Sochi, Russia Review Received: 24 October 2011, Revised: 7 March 2012, Accepted: 17 March 2012, Published online in Wiley Online Library: 12 April 2012 (wileyonlinelibrary.com) DOI: 10.1002/cem.2445 J. Chemometrics 2012; 26: 299–310 Copyright © 2012 John Wiley & Sons, Ltd. 299 This article is protected by the copyright law. You may copy and distribute this article for your personal use only. Other uses are only allowed with written permission by the copyright holder.