PAT SUPPLEMENT


operation pertaining to these critical parameters and quality attributes as shown in Figure 1. For example, during high shear granulation, the end point could be monitored and controlled by the power consumption while during fluid bed drying, the end point could be controlled by the exhaust or product temperature measurements. Depending on the nature of CPP and CQA,


measurements can be taken either at-line (sample is removed, isolated and analysed close to the process stream), on-line (sample is removed from the process stream and returned


methodologies and computational modelling. This has aided the quality of gathered data and boosted the confidence of users. However, there are still numerous challenges to be overcome before the concepts of PAT can be widely implemented. The challenges involved in understanding and designing CPP and CQA have been the topic of many review. This review will focus on the challenges encountered during the development and implementation of spectroscopic techniques and feedback mechanisms for in-line or on-line


chemical characteristics. As a result, numerous research articles have been published on the various aspects and applications of spectroscopies in PAT3


. However, there exists no


standard method development protocol for developing calibration models and their installation in the manufacturing setting. NIR spectroscopy has been employed at various stages of product development and manufacturing and is currently used for end point determination in blending, granulation and drying processes4


. Apart from being


versatile, this technology is easy to deploy in various manufacturing environments and hence has currently become the most popular PAT tool. Raman spectroscopy is a particularly powerful alternative, providing both high selectivity and sensitivity5


. Raman also enables accurate


quantitative assessment of the concentration of compounds in liquids, solids and multiphase samples. Raman is less sensitive to variations in physical parameters than NIR and hence the use of Raman in pharmaceuticals is limited compared to NIR.


FIGURE 1Working principle of PAT


to the process stream following analysis), in-line (sample is not removed but analysed in place) or off-line (sample removed and analysed away from process stream). After performing any analysis, it is essential that the analytical results are available in the necessary timeframes to facilitate real time decision making. The significance and success of the control phase depends heavily on the level of process understanding. Based on this understanding, parameters influencing quality attributes are monitored and the data from this analysis is utilised as feedback to make real-time decisions in order to maintain consistent process performance and product quality. The ideal system will have a closed loop circuit where the feedback from the monitoring is used to tune and control the process. There have been significant advances in the design of instrumentation, sampling


10


European Pharmaceutical Review Volume 16 | Issue 6 | 2011


“ The success of developing an analytical technique as a PAT tool for an industrial process depends on the level of understanding ”


monitoring. These challenges include: selectivity, sensitivity and validation of the applied methods and data acquisition, analysis and feedback mechanisms. Various analytical techniques are


considered to be PAT analysers, with spectroscopic techniques being the most popular. NIR, Raman and UV-Visible spectroscopies are the most important PAT tools utilised in product development and manufacturing. Spectroscopy provides a range of efficient and non-destructive methods for the detection and quantification of physical and


Selectivity, sensitivity and validation of method The success of developing an analytical technique as a PAT tool for an industrial process depends on the level of understanding. The method needs to be selective enough to monitor the parameters defined as the CPP and should be able to maintain the sensitivity in the range required. Most of the reports highlight the utility of a particular analytical technique as a potential PAT tool. However, there is a need to conduct detailed studies demonstrating the selectivity and sensitivity of these methods in the range practically required in the commercial process. For example, Raman spectroscopy has been successfully used for monitoring drug loading during hot melt extrusion of a polymer drug system and found to be useful over the studied range6


. The study showed good


correlation between the predicted and actual drug concentration. The same study highlighted the utility of Raman spectroscopy in monitoring solid state changes in the system. The experiments were designed with batches containing 10 per cent increments of API in the polymeric matrix system. These studies indicate the need for understanding and developing more sensitive methods. These types of studies evaluate the suitability of the techniques for in-line monitoring of the changes in the


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