Changing Column Packing from an Art into a Science

Chromatography is often the most critical step in biopharmaceutical downstream processing because of its role as the engine for separating impurities from target biologics. The most demanding operation in production scale chromatography is typically packing the column in a way that ensures first time success and a validation result which meets the batch record standards. Traditionally column packing has been the responsibility of a few specialist operators and has been regarded almost as an art by most observers. When the artistry fails, the results can be unplanned plant downtime, loss of product or sorbent as well as inefficient use of resources.
To mitigate these risks the biopharmaceutical industry is moving toward a more sciencebased approach. The key is automating the key operations involved in preparing a column for production. Existing semi-automated packing technology typically only automates portions of the process, leaving considerable potential for operator error. Another limitation of some existing technologies is that the piston movement is controlled in only one centrally placed axis, creating the potential for skew that can cause packing failures and in extreme cases damage the column. This a risk which is heightened during fully or semi-automated operation where an operator may not be present.
The latest generation of automated packing technology addresses these challenges by fully automating the packing, unpacking and clean-in-place processes and controlling the piston with multi-axis control to prevent or detect skew conditions.

Case History
A multinational vaccine company that previously used manual methods throughout its global operations noted that creep in SOP execution and operator error was significantly affecting productivity. By moving to a fully automated packing platform, the company forecast an increase of packing success rate from 62% to 99%. The use of automation is on track to reduce labor costs by 35%, on average. The adoption of a single use slurry handling system also simplifies operation. The new columns also have a smaller clean room/storage footprint, which translates into additional space in tight cleanrooms.

Column Packing Challenges
The essence of column packing is to achieve an efficient and stable packed bed that duplicates the performance of previous packs. Process-scale bioseparations often involve a high turnover in packing activity which increases the potential for a packing failure to occur. In the case of global manufacturing, column packing performance is required to be consistent across multiple plants and geographies. Traditional manual and semi-automated packing methods are hard-pressed to achieve these goals because the outcome depends heavily on the capabilities and attention levels of a few skilled operators. At any time, these operators may leave the company or otherwise become unavailable, running the risk that their replacements will no longer be able to achieve the required level of performance. When the process is transferred to a new site, the standard operating procedure (SOP) is handed over but the new operator often has to learn how to make the packing procedure work. The operators in the new plant may develop their own ways of doing things, even after training, and it may take quite a while to consistently achieve the required performance levels.
Manual and semi-automated packing methods also tend to waste substantial amounts of media whose cost can run as high as $15,000 per liter; typically 5% to 10% of the total column volume of media is left in the slurry tank after packing. The validation issues with blending this excess into the next pack often mean that the excess media is thrown out. The use of manual or semi-automated packing relies heavily on the skill of the operator. For example, the valve adjustment, pump flowrates and piston movement must be manually or remotely directly controlled by the operators and recorded in a batch record.
A key challenge in packing with a moveable piston is keeping that piston level during movement. One simple approach is to move the piston up and down with a centrally mounted single actuator. At larger scales particularly the column is wide and the piston is thin so the potential exists for the piston to tilt at an angle to the horizontal. If the piston moves to out of level it can significantly damage the column.

New Generation of Automated Systems

The new generation provides a fully automated approach to packing, unpacking and cleaning that elevates packing from an art to a science. Ideally the packing system is fully integrated with the actuation system of the column, making a separate packing skid or pump unnecessary for all operations. To achieve full automation the column is supplied with system controlled mobile phase and bypass valve blocks. An additional valve block to control liquid flow from the buffer and slurry tanks is included. Valves dedicated to air entry are provided to both the slurry tank inlet and bottom mobile phase valve blocks, assisting buffer efficient re-suspension of settled slurry and packed media beds. The automated packing system has full control of this valving, as well as adjuster movement and nozzle operation during automated sequences. The system additionally has a liquid sensor that allows it to monitor the column fill status.

The software that controls the fully automated operation uses regionally appropriate industry-standard PLC control and touch screen interfaces. The software also permits full manual control of the column, while the on-screen schematic provides a real-time indication of the system status during all operations. For typical fullyautomated operation the operator is only required to push the start button (and in certain cases enter a slurry concentration) to begin the relevant process. From this point the automated packing system controls the entire sequence until packing is complete and no further operator attention is required. A selection of packing methods are provided, each fully configurable to match the target application.

Details of Automated Packing Sequence
During automated operation, the packing system has full control of piston movement, valves and safety systems, eliminating the risk of human error. For packing, a typical sequence starts by using the air sparge valve to resuspend the media in the slurry tank. Then, dependent on which of the inbuilt methods is chosen, the system can fully prime the column and pipework before moving to the slurry suction step. For priming, liquid is drawn in through the bottom nozzle from the liquid tank using piston movement. With the top nozzle in unpack position, the piston descends to meet the liquid level inside the column and the air inside the column is pushed through the nozzle port, triggering the liquid sensor. The rest of the system is then primed by sequential opening of the valves. Next, the system starts the slurry suction step. Tank agitation is stopped and slurry is drawn from the tank into the column. An exact amount of slurry can be drawn into the column through the packing nozzle. The nozzle ensures that the slurry is kept suspended as the piston draws in the required volume. The column is sized so that enough slurry (and therefore media) can be drawn into the column to meet the desired compression factor at the target bed height. The system can also empty the slurry tank during the suction phase, eliminating the waste that occurs with some conventional manual and semi-automated packing systems. The packing sequence then continues seamlessly into the consolidation and packing phase. The piston descends using the chosen packing profile to form an optimally packed bed. Dependent on the equipment, a bed detection algorithm can be used to detect an optimally compressed bed. At the end of the sequence the operator is informed that the packing is complete; the column is now ready for testing and production.

The column can also automatically unpack and clean itself at the push of a button. As with the automated packing sequences, these operations do not require any extra pumps or skids to complete. This reduces the cost burden of maintenance and cleaning of additional capital equipment.
Unpacking is made more efficient by the use of air to resuspend the media bed inside the column, often only consuming the same buffer as when the operation is controlled by an experienced operator. Latest versions of the equipment now allow a packed media bed to be resuspended and packed without removing the slurry from the column, providing further savings in buffer consumption and turnaround time. This methodology is useful in cases where the packing has failed before the media has reached end of life.
At all times during piston movement, the software monitors the position of the piston moving in the column over three axes and actively controls the levelness of the piston in response to a deviation from the set point. If the system cannot maintain the level (in the case for instance where a nut was in the path of the piston) the system will stop the skew of the piston before it can damage the column. With a single axis control system, it is generally not possible to actively keep the piston level or even monitor its levelness, resulting in an increased risk of damage from an undetected and uncontrolled skew event.
In common with non-automated systems the equipment also has a built-in maintenance function that provides easy operator access for safe change out of consumables from ground level without compromising the clean room footprint. Other solutions to providing hoist-free maintenance include functions that move assemblies out horizontally which means that extra floor space must be provided. The new generation provides a vertical form factor that eliminates the need for additional floor space.
Packing failure caused by human error or poor execution of an SOP is a major risk in the key unit operations of packing, unpacking and cleaning of process-scale chromatography columns. The new generation of automated packing systems provide automated sequences that assure reliable and consistent operation. The fully automated approach enables packing to be accomplished by any operator regardless of skill, thus eliminating error and reducing the dependence on key operators. By integrating all of the packing functionality into the movement system, the need for a separate packing skid or pump is eliminated. In addition, the ability to use all of the slurry in the tank means savings can be made in overall media consumption. All in all, the new generation of automated packing systems can enable biopharmaceutical manufacturers to produce product more efficiently at a lower cost.

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