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Process Analytical Technology (PAT) is a method for designing, analyzing, and controlling the pharmaceutical manufacturing process through the measurement of Critical Process Parameters (CPP) with Critical Quality Attributes (CQA) of the product. According to the Food and Drug Administration guidance, "PAT is a framework for innovative pharmaceutical development, manufacturing and quality assurance". This promotes incorporating quality into the product's design and the creation of PAT solutions to digitize and offer real-time control over a number of crucial elements that affect the output and quality of the product. PAT solutions have been widely used in the process design of different sorts of sectors, including the gas, petroleum, and food industries, to streamline product output. PAT technologies, such as near-infrared spectroscopy (NIR), are well known for their ability to accurately monitor the processing of complex matrices. NIR has a proven track record of process monitoring in a number of processing industries, including the determination of fuel octane ratings and benzene levels in fuel. The nature of the products in the biopharmaceutical sector is typically quite dynamic and complicated, making it more difficult to adapt the PAT solutions already employed in other industries. However, there is a great need and opportunity for PAT solutions to be developed to expedite bioproducts in the pharmaceutical sector. During the past several years there has been a lot of PAT development into bioproduct design. When a process is initiated in an ideal regulated manufacturing industry, its progress should be easily tracked and managed until that process is finished. This indicates that the state and quality of the product in terms of yield are transparent and known at any given stage in the process. Due to a dearth of information feedback throughout the manufacturing process, this knowledge is inadequate in the production of pharmaceuticals today. This knowledge gap can be filled by PAT solutions that enable the introduction of a feedback loop to control a process based on the reported parameters and report the condition of a product in real time. This Quality by design (QbD) strategy enables product quality testing at multiple phases of production, from raw materials through intermediate products to the finished pharmaceutical product.[1-3]

Near-infrared (NIR) spectroscopy, Raman, and radio-frequency (RF) impedance are the three most important developments in analytical techniques for monitoring upstream processes in biopharmaceutical manufacturing. NIR and Raman are useful for real-time monitoring of cell culture parameters, such as pH, dissolved oxygen, and different metabolites, in upstream processing. These two technologies, once calibrated for a certain method and culture medium, deliver continuous information about the culture without the need for human intervention for sampling. The RF impedance is used to monitor the cell population density inside a cell culture in a similar way. These technologies are crucial for closely monitoring the entire cell culture process. Utilizing these three in-process analytical tools also has the benefit of lowering contamination risks associated with manual sampling and offline analysis. The full integration of ready-to-use, single-use inline sensors, such as in-line capacitance for biomass monitoring in bioreactor bags, the use of optical spectroscopic equipment and methods for inline integration into bioprocess solutions and the use of data analytics, such as multivariate statistical and other chemometric methods, are some of the most significant developments of analytical tools for use in biopharmaceutical processes.[2,4]

In contrast to chemical or pharmaceutical manufacture, PAT tool is not as commonly used in the biopharmaceutical industry. Biopharmaceutical companies have previously developed and investigated instruments for complicated biologics analysis, such as MS, but the MS instruments' inability to be deployed inline and the limited software analysis that was then available did not lend themselves well to being PAT tools. The introduction of miniature mass spectrometers has marked a significant advancement in the acceptance of point-of-need MS by the biopharmaceutical industry. PAT is not a brand-new idea in the pharmaceutical production industry. However, it is still largely outside of the state-of-the-art to be able to consistently and robustly measure, monitor, and manage such complex processes as the manufacturing of biologics. It is largely because of the challenges involved in accurately measuring macromolecular properties when they are being produced. There have been many developmental PAT tools proposed that use indirect measurement techniques that rely on intricate statistical correlations between conventional physical online measurements and the parameter being inferred. A number of PAT tools, including the design of experiments (DoE), inline sensors, spectroscopic probes, and the application of multivariate statistical approaches, have recently been put into practice. These tools have expanded fundamental process understanding and provided insight into the effects of CPPs on CQAs. As a result, process automation has become more dependable, and QbD application in bioprocesses is making significant progress.[3,4]

Three types of obstacles to PAT implementation for bioprocessing could be identified. We have to monitor and operate complex biological systems, whose responses to changes in macroscopic environmental elements such as pH, temperature and dissolved oxygen in a bioreactor cannot be totally foreseen. There are, of course, both technical and application issues. Furthermore, the number and complexity of significant characteristics are considerable, necessitating the use of analytical techniques that are selective and sensitive enough to measure the required parameters in real-time. Additionally, the industry's current tendency toward using single-use equipment necessitates the technical application of PAT tools in single-use systems, which extends beyond process development to the manufacturing scale. Second, the acting individuals must alter their mindsets in order to execute PAT in bioprocess. The operators might still get the impression that they are dealing with a black box batch process that they should not touch, even though they can operate it somewhat optimally. There is an obvious need for PAT technologies to be implemented effectively if the biopharma industry has to evolve toward continuous or intensified operations so that the processes may be performed in a reliable environment. The absence of a powerful economic driving force is the third crucial factor preventing PAT deployment in bioprocessing. In the industry, there are still certain old production methods in use that are not at all efficient or high-quality. The demand for more cost-competitive production will grow as a result of the recent growth in the number of biosimilars entering the market, more industry consolidation, and changes in local markets. These factors will soon result in a greater level of PAT adoption. The ultimate goal of the PAT developments should be to make biologics more affordable, effective and safe for everyone who needs them. [1,4] There will be a scientific workshop on PAT tools chaired by experts from academia and industry at the BiosimilarWorkshop2023 in Goa and if you wish to join, please visit www.biosimilarworkshop.com.

References:

1. Gerzon, G., Sheng, Y., & Kirkitadze, M. (2022). Process analytical technologies–advances in bioprocess integration and future perspectives. Journal of Pharmaceutical and Biomedical Analysis, 207, 114379.

2. Kim, E. J., Kim, J. H., Kim, M. S., Jeong, S. H., & Choi, D. H. (2021). Process analytical technology tools for monitoring pharmaceutical unit operations: a control strategy for continuous process verification. Pharmaceutics, 13(6), 919.

3. PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance: Guidance for Industry (2004) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pat-framework-innovative-pharmaceutical-development-manufacturing-and-quality-assurance

4. Bioprocessing Sees Advances in Analytical Tools by Dr. Adeline Siew in Pharmaceutical Technology's In the Lab eNewsletter-08-01-2018, Volume 13, Issue 8 https://www.pharmtech.com/view/bioprocessing-sees-advances-analytical-tools

5. Implementing Process Analytical Technology (PAT) in Continuous Bioprocessing by Brandy Sargent, May 2018 https://downstreamcolumn.com/implementing-process-analytical-technology-pat-in-continuous-bioprocessing/