Using NIR to Move Bioprocessing into a PAT Framework - Pharmaceutical Technology

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Using NIR to Move Bioprocessing into a PAT Framework
The author provides a review of PAT and tools such as near infrared analysis that may facilitate the use of PAT in the biopharmaceutical sector.

Pharmaceutical Technology
Volume 33, Issue 7

NIR in a PAT-compliant bioprocess

There are several places within this process stream that are conducive to query and analysis by PAT instrumentation and, specifically, NIR equipment. The monitored variables are described as quality variables or manipulated variables. Quality variables describe the state of the process at a given point (e.g., concentration of the target protein), whereas manipulated variables are used to control the process (e.g., glutamine concentration) (7). NIR is easily used in conjunction with both types, and is also commonly used in raw material identification and analysis (7, 8). In addition, quality control of the process-ready medium before use is important while quality checks of the inoculums eliminate suspect samples or select the best candidates that lead to improved batch performance and reduced variability (7).

During the cell growth stage and production of the target molecule, several variables related to nutrients, waste, and overall health (e.g., glucose, glutamine, lactate, ammonia, pH, dissolved oxygen, and cell density) are monitored. In non-PAT processes, many of these components are monitored off-line using sophisticated and expensive bioanalytical systems such as a Nova Biomedical BioProfile 100 Plus analyzer (Waltham, MA) or a YSI 7100 MBS (YSI Life Sciences, Yellow Springs, OH). These analyzers are electrochemical and typically use immobilized enzyme membranes in the analysis. Considerable work and cost is required, however, to maintain consistent calibration because the enzymes degrade with time, which is a critical issue for monitoring processes that can last several weeks. In addition to destroying valuable samples in the analysis, these electrochemical analyzers require purchase and replacement of reagents, electrodes, and membranes. As a result, high annual cost for consumables can easily climb into the tens of thousands of dollars.

Figure 2: Plots of multiple component concentrations within a growing cell culture. All data were collected with an FT-NIR spectrophotometer (Antaris model, Thermo Fisher Scientific, Madison, WI) in-line in real time. Blue diamonds represent data collected from the spectrophotometer; red squares represent primary analytical data taken from thieved samples for comparison.
In a PAT process, however, many of these same components are monitored and controlled in real time with NIR analyzers coupled to process-control systems (9, 10). Figure 2 shows the results of monitoring some of these cell-culture components during a multiple day batch run. NIR is also used during the filtration, purification, and finishing steps to ensure the product has been properly concentrated and handled. Finally, the end products are often lyophilized with concurrent monitoring of the moisture content. NIR is supremely suited for controlling the lyophilization process and determining when the optimal moisture content has been achieved (7, 11, 12).


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