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This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

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A continuously operated single stage mixedsuspension, mixed-product-removal (MSMPR) crystallizer using intermittent withdrawal via a dip pipe with combined pressure/vacuum was successfully developed for the manufacture of active pharmaceutical ingredients. Approximately 5.8% of the total operating volume was intermittently removed at a high velocity using vacuum. The transfer line was also periodically purged with nitrogen to ensure complete removal of residual solids. In situ process analytical technologies (focused beam reflective measurement (FBRM) and process video microscopy (PVM)) were successfully applied to monitor and characterize the MSMPR crystallization process. In this study, a cooling crystallization of paracetamol from an aqueous isopropyl alcohol solution was investigated. Experimental results indicate that the crystallization system was able to operate without any clogging issues for over 10 residence times, before which the system had approached steady state. Three different start-up strategies for continuous crystallization were investigated, and the results indicate that the chord length distributions at steady state were the same for all cases. Also, starting the continuous operation from a saturated solution that was seeded with product from a previous MSMPR run offered the quickest route to steady state. To better control and scale up the crystallization process, the nucleation and crystal growth kinetics of the model compound were also determined through use of the newly developed process. The growth rates were found to be size dependent, and an exponential three-parameter model was employed to characterize the size-dependent growth. It was seen that the crystal growth rate was extremely low and increased linearly with particle size when the particle size was below 10 μm. However, the growth rate increased dramatically with particle size when the particle size was between 10 and 1000 μm. The nucleation kinetics was correlated by the semiempirical equation B TOT = 1.11 × 10 15 M T 0.98 G avg 1.12 . The orders of the total nucleation rate with respect to the magma density and average growth rate were 0.98 and 1.12, respectively. Therefore, the effect of supersaturation (or residence time) and magma density on the steady state crystal size was investigated.

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In this study, the application of Raman spectroscopy to the simultaneous quantitative determination of glucose, glutamine, lactate, ammonia, glutamate, total cell density (TCD), and viable cell density (VCD) in a CHO fed-batch process was demonstrated in situ in 3 L and 15 L bioreactors. Spectral preprocessing and partial least squares (PLS) regression were used to correlate spectral data with off-line reference data. Separate PLS calibration models were developed for each analyte at the 3 L laboratory bioreactor scale before assessing its transferability to the same bioprocess conducted at the 15 L pilot scale. PLS calibration models were successfully developed for all analytes bar VCD and transferred to the 15 L scale.