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



Figure 5. Columns operated in parallel mode. Backside impurities are eluted from Column 1 while frontside impurities are eluted from Column 2 and automatically diverted to waste.
In the next step, shown in Figure 5, backside impurities are detected eluting from Column 1. As a result, the DCS automatically adjusts the process valves so that the two process columns operate in parallel, allowing the backside impurities from Column 1 to be eluted to waste. Repositioning the process valves also allows the same on-line HPLC that was monitoring the eluent from Column 1 to begin monitoring the eluent stream from Column 2. The frontside impurities are detected eluting from Column 2 and are automatically diverted to waste under the control of the DCS.


Figure 6. Columns operated in parallel mode. Column 1 is undergoing regeneration while the high purity product is automatically collected from Column 2.
When the on-line HPLC detects high purity product eluting from Column 2 (Figure 6), the DCS repositions the valves to allow the product to be automatically collected in the product collection tank. With the process valves in this position, the columns operate independently (i.e., in parallel mode). This allows Column 1 to undergo regeneration while Column 2 is being eluted. Performing these two operations simultaneously further reduces the overall process cycle time.


Figure 7. Columns operated in parallel mode. The regeneration of Column 1 is completed and ready to receive the next production lot. The backside impurities are automatically eluted to waste from Column 2 to make it ready it for regeneration.
In the final step of the process, the columns continue to be operated in parallel mode (Figure 7). The backside impurities are eluted from Column 2 and are automatically diverted to waste. At this point, the regeneration of Column 1 is complete and the column is ready to receive the next production lot. Column 2 can be regenerated while Column 1 is charged with the next lot to be purified.

Thus, by using on-line HPLC to provide a near–real time measurement of product purity, two batch purification steps have been combined into a single operation. This combination reduces the overall cycle time because the elution of Column 1 occurs simultaneously with the charging of Column 2. All fraction handling is eliminated along with its associated opportunities for errors, thus removing a significant potential for process failure.

The on-line measurement of product purity provides the information necessary to automatically sequence the column operation as well. In addition, since the product never leaves the process piping and all valves are equipped with position switches, the control system has continuous confirmation of where the product is flowing.

Eliminating the off-line HPLC analysis of fractions in the central laboratory reduced the overall cycle time of the process by two days. The combination of automated process sequencing and eliminating off-line analysis allowed the throughput of this particular process step to be increased tenfold.1 These process changes also reduced process variability and increased process yield.


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