USD3056Article

Changing Column Packing from an Art into a Science

Chromatography is often the most critical step in biopharmaceutical downstream process-ing because of its role as the engine for separating impurities from target biologics. Themost demanding operation in production scale chromatography is typically packing thecolumn in a way that ensures first time success and a validation result which meets thebatch 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 theartistry fails, the results can be unplanned plant downtime, loss of product or sorbent aswell as inefficient use of resources.

To mitigate these risks the biopharmaceutical industry is moving toward a more science-based approach. The key is automating the key operations involved in preparing a columnfor production. Existing semi-automated packing technology typically only automates portions of the process, leaving considerable potential for operator error. Another limitationof some existing technologies is that the piston movement is controlled in only one centrallyplaced axis, creating the potential for skew that can cause packing failures and in extremecases damage the column. This a risk which is heightened during fully or semi-automatedoperation 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 itsglobal operations noted that creep in SOP execution and operator error was significantlyaffecting 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 slurryhandling system also simplifies operation. The new columns also have a smaller cleanroom/storage footprint, which translates into additional space in tight cleanrooms.

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Column Packing Challenges

The essence of column packing is to achieve an efficient and stable packed bed that duplicates the performanceof previous packs. Process-scale bioseparations often involve a high turnover in packing activity which increasesthe potential for a packing failure to occur. In the case of global manufacturing, column packing performance isrequired to be consistent across multiple plants and geographies. Traditional manual and semi-automated packingmethods are hard-pressed to achieve these goals because the outcome depends heavily on the capabilities andattention 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) ishanded 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 whileto consistently achieve the required performance levels.

Manual and semi-automated packing methods also tend to waste substantial amounts of media whose cost canrun as high as $15,000 per liter; typically 5% to 10% of the total column volume of media is left in the slurry tankafter packing. The validation issues with blending this excess into the next pack often mean that the excessmedia 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 directlycontrolled 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 particularlythe column is wide and the piston is thin so the potential exists for the piston to tilt at an angle to the horizontal. Ifthe piston moves to out of level it can significantly damage the column.

New Generation of Automated Systems

Figure 1Columns equipped with the latest automated packing 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 thecolumn, making a separate packing skid or pump unnecessary for all operations. To achieve full automation thecolumn is supplied with system controlled mobile phase and bypass valve blocks. An additional valve block tocontrol liquid flow from the buffer and slurry tanks is included. Valves dedicated to air entry are provided to boththe slurry tank inlet and bottom mobile phase valve blocks, assisting buffer efficient re-suspension of settled slurryand packed media beds. The automated packing system has full control of this valving, as well as adjuster move-ment and nozzle operation during automated sequences. The system additionally has a liquid sensor that allowsit to monitor the column fill status.

Figure 2Typical Hardware to enable fully automated packing

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 fully-automated operation the operator is only required to push the start button (and in certain cases enter a slurryconcentration) to begin the relevant process. From this point the automated packing system controls the entiresequence until packing is complete and no further operator attention is required. A selection of packing methodsare provided, each fully configurable to match the target application.

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Figure 3Fully automated packing sequence

* Dependent upon packing method.** Alternatively, AutoPak can accurately control the slurry volume introduced into the column.

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 systemcan fully prime the column and pipework before moving to the slurry suction step. For priming, liquid is drawn inthrough 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 throughthe nozzle port, triggering the liquid sensor. The rest of the system is then primed by sequential opening of thevalves. Next, the system starts the slurry suction step. Tank agitation is stopped and slurry is drawn from the tankinto the column. An exact amount of slurry can be drawn into the column through the packing nozzle. The nozzleensures that the slurry is kept suspended as the piston draws in the required volume. The column is sized so thatenough slurry (and therefore media) can be drawn into the column to meet the desired compression factor at thetarget bed height. The system can also empty the slurry tank during the suction phase, eliminating the waste thatoccurs 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 packingprofile 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.

SEQUENCE COMPLETE

OPTIONAL EXTRA RINSE OPTIONAL EXTRA RINSE

AUTOMATED SEQUENCES

OPERATOR START

TANK CHANGE

RINSE

UNPACKING

RESUSPEND SORBENT

RINSE

EMPTY COLUMN CIP

CLEAN COLUMN & PIPEWORK

PACK TO OPTIMAL BED

SUCK ENTIRE SLURRY VOLUME**

PACKING

PRIME COLUMN*

TARTOR ST TAROPERAATOR ST

CLEAN COLUMN & PIPEWORK

EMPTY COLUMN CIP

AUTOMA

ANK CHANGE

CLEAN COLUMN & PIPEWORK

EMPTY COLUMN CIP

TTANK CHANGE

TED SEQUENCES

RINSE

RESUSPEND SORBENT

ACKING

SUCK ENTIRE SLURR

UNPPACKING

AUTOMAATED SEQUENCES

Y VOLUME**

PRIME COLUMN*

ACKINGPPACKING

SUCK ENTIRE SLURR

OPTIONAL EXTRA RINSE OPTIONAL EXTRA RINSEOPTIONAL EXTRA RINSE

RINSE

SEQUENCE COMPLETE

OPTIONAL EXTRA RINSE

RINSEACK TO OPTIMAL BEDPPACK TO OPTIMAL BED

Figure 4Built-in maintenance function has vertical form factor

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 thecost 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 onlyconsuming the same buffer as when the operation is controlled by an experienced operator. Latest versions ofthe equipment now allow a packed media bed to be resuspended and packed without removing the slurry fromthe column, providing further savings in buffer consumption and turnaround time. This methodology is useful incases 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 overthree axes and actively controls the levelness of the piston in response to a deviation from the set point. If thesystem cannot maintain the level (in the case for instance where a nut was in the path of the piston) the systemwill stop the skew of the piston before it can damage the column. With a single axis control system, it is generallynot 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 provideseasy operator access for safe change out of consumables from ground level without compromising the cleanroom footprint. Other solutions to providing hoist-free maintenance include functions that move assemblies outhorizontally which means that extra floor space must be provided. The new generation provides a vertical formfactor that eliminates the need for additional floor space.

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Packing failure caused by human error or poor execution of an SOP is a major risk in the key unit operations ofpacking, unpacking and cleaning of process-scale chromatography columns. The new generation of automatedpacking systems provide automated sequences that assure reliable and consistent operation. The fully automatedapproach 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 slurryin the tank means savings can be made in overall media consumption. All in all, the new generation of automatedpacking systems can enable biopharmaceutical manufacturers to produce product more efficiently at a lower cost.

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The information provided in this literature was reviewed for accuracy at the time of publication. Product datamay be subject to change without notice. For current information consult your local Pall distributor or contactPall directly.

© 2015, Pall Corporation. Pall, and Resolute are trademarks of Pall Corporation. ® indicates atrademark registered in the USA and TM indicates a common law trademark. Filtration.Separation.Solution.is a service mark of Pall Corporation.

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