ON-LINE PROCESS CONTROL: Automating the Control of Process-Scale Purification Columns Using On-Line Liquid Chromatography - Using on-line HPLC to monitor the eluent from process-scale columns allows t

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ON-LINE PROCESS CONTROL: Automating the Control of Process-Scale Purification Columns Using On-Line Liquid Chromatography
Using on-line HPLC to monitor the eluent from process-scale columns allows the process decision—when to start and stop collection—to be based on a critical quality attribute rather than on a surrogate measurement.


BioPharm International


Using on-line HPLC to Enable Unique Operational Approaches

Most biotech processes involve multiple column chromatography steps to achieve adequate purification of the biosynthetic origin product. By using on-line HPLC, Eli Lilly and Company was able to successfully combine two process-scale ion exchange chromatography steps into a single, automated process.1 This process is explained in Figures 2 through 7.


Figure 2. Two process-scale columns combined into a single operation. The positioning of the on-line HPLC downstream of the first four-way valve allows the one on-line HPLC analyzer to monitor the eluent stream from either process column.
Figure 2 shows the two process chromatography columns combined using one three-way and two four-way process valves to enable the columns to be operated either in parallel (i.e., as two independent columns) or in series (i.e., as one continuous column) and to allow the eluent stream to be diverted to the waste stream or product collection tank. In this operation, an on-line HPLC analyzer automatically samples and determines the purity of the product in the column eluent stream. The DCS uses these data to determine the appropriate position of the process valves (to operate the process columns either in parallel or series) and to divert the eluent stream to waste or to the product collection tank.


Figure 3. Columns operated in parallel mode. Frontside impurities from column 1 are automatically diverted to waste.
Figure 3 shows the two process scale columns operated in parallel mode. The on-line HPLC automatically analyzes the Column 1 eluent stream and sends the data to the DCS system where they are compared to the product purity setpoint. If only frontside impurities are detected in the eluent stream (i.e., no product is present), the stream is automatically diverted to waste and the two process columns continue to operate in the parallel operation mode.


Figure 4. Columns operated in series mode with the heart cut from column 1 are being automatically charged to column 2.
Figure 4 shows the two process scale columns operated in series mode. The on-line HPLC automatically analyzes the Column 1 eluent stream and sends the data to the DCS system where they are compared to the product purity setpoint. At this point in the process, the product of interest is detected in the Column 1 eluent stream, so the process valves are automatically positioned to operate the two process columns in series, thus allowing a "heart cut" from Column 1 to be automatically charged to Column 2 for further purification.


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