Technical Forum: Disposable Chromatography - Industry experts from GE Healthcare, Tarpon Biosystems, Polybatics, Merck Millipore, and Repligen discuss the challenges of adapting disposable technology

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Technical Forum: Disposable Chromatography
Industry experts from GE Healthcare, Tarpon Biosystems, Polybatics, Merck Millipore, and Repligen discuss the challenges of adapting disposable technology to the chromatography process.


BioPharm International Supplements
Volume 25, Issue 11, pp. s10-s15

CHOOSING A DISPOSABLE PLATFORM

BioPharm: A few disposable chromatography platforms are currently available, including packed-bed, simulated moving bed (SMB), and membrane chromatography. What are the factors that would influence the choice of platform for a process?

Grund (GE Healthcare): Packed beds are used in steps following feed clarification, when binding capacity and resolving power are prioritized. Conventionally, the first step in downstream purification is product capture, in bind/elute mode, and a packed bed is needed to achieve the objectives of the unit operation.

The question of whether or not to use SMB is different. Frequently, a small number of cycles is used to handle large volumes of feed. SMB takes this further by providing a continuous processing approach with several small columns cycled in sequence. Generally, SMB offers higher loading capacity, greater exploitation of resin life, and more efficient use of buffers. So, SMB can be a door-opener to using disposable chromatography columns because small columns are used for multiple cycles to handle material from the bioreactor. This helps address the cost equation because the resin is used for many cycles before disposal. Accurate control and synchronization of the different phases in the chromatography cycle is critical. Single-use components are attractive in SMB since they assure reproducible performance and avoid multiple column-packing in the production work-flow. The downside in SMB is system complexity. Multiple columns require many valves and sophisticated control to assure accurate column switching without cross contamination.

Chromatography is also used in product flow-through mode to remove impurities. The further downstream you are in your process, the fewer the impurities. When there are only small amounts remaining, membrane chromatography is attractive for impurity scavenging. The low binding capacity and low resolving power is not an issue and the high flow rates that can be used can be fully exploited. Single-use components are often preferred for scavenging, especially because cleaning may be challenging for several reasons.

For producing tons of product, the column volumes are large, several hundred or even thousands of liters, and at this size, single-use designs are not viable. In general, the smaller the scale, the more attractive single-use chromatography is.

Bisschops (Tarpon): First of all, disposable technologies will generally result in more flexibility in manufacturing and in a shorter change-over time. These features are particularly important for multiproduct facilities such as clinical manufacturing facilities and contract manufacturing organizations. For these types of operations, the advantage of disposable bioprocessing technologies is more obvious than for single-product facilities.

Prepacked chromatography columns fit very well in streamlining the workflow in a facility by taking away the packing operations. The costs for prepacked columns were, until recently, cost prohibitive to consider them as a single-use or disposable product for other applications than clinical manufacturing. The scale limitations of prepacked columns also restricts the application of this technology to clinical-scale manufacturing.

SMB enables manufacturing of large amounts of product with reasonably small columns, which are cycled many times during a batch. As a result, this technology can make prepacked disposable chromatography a viable alternative, especially when you pair disposable columns with a fully disposable, simplified valving system. Disposable valving is the missing link in providing economically viable, fully disposable downstream processing for bind/elute applications. Another feature of continuous chromatography is that it allows the entire cascade of downstream processing unit operations to be operated as a fully continuous train. This continuity eliminates or significantly reduces interstage product hold steps and allows multiple unit operations to be operated simultaneously. Thus, the time in facility can be shortened by a factor of two, which in many cases translates into a significant increase in facility throughput.

Mann (Merck Millipore): Probably, the specific application is the first criterion, in so much as to how much freedom there is to pick and chose a chromatography platform. For instance, if the product is a monoclonal antibody, then likely there is a template already in place for purification, typically protein A affinity chromatography, followed by cation exchange bind-elute and then anion exchange flow through. Both the protein A affinity and cation exchange are almost certainly going to be conventional packed-bed columns. Although traditionally the anion exchange was also a packed-bed column, anion exchange flow through membrane adsorbers are being deployed because of convenience (i.e., no column packing) and buffer savings (i.e., no cleaning/reuse).

Membrane adsorbers are also finding application elsewhere when used in flow through mode for capture of impurities. Generally, they are less competitive with conventional packed columns for bind-elute applications because of lower capacity compared with resins.

SMB is relatively new to biotech. While frequently used for small molecule purification, it has not found adoption in protein separations primarily due to the greater complexity of the flowpath and the difficulty with engineering it in a sanitary manner. The new single-use systems coming onto the market may address that aspect, but the added complexity of operation compared to conventional batch chromatography will likely continue to be a hurdle to adoption. One attraction of SMB or similar multicolumn approaches is that, compared with batch, it uses smaller columns that make it more amenable to prepacked columns and coupled to the fact that the resin is cycled more times per batch. This has benefits especially for clinical-scale batches where, conventionally, the resin may be thrown away after only a few batches and so is nowhere near its end of life point. Multicolumn approaches enable better resin utilization, getting closer to the lifetime of the resin and thus saving cost.

The second criterion is probably scale, which is linked to cost. Although single-use implementation shows clear cost benefits at the smaller pilot/clinical scale manufacturing, at large commercial scale, stainless-steel installation can be more cost-effective. In addition, larger scale will require larger columns than currently available in a prepacked, disposable format.

Tingley (Repligen): In stepping back a little bit, you can ask—why do people want to adopt single-use technologies? I don't think the answer has changed as we've changed the technologies—it's speed—getting through the process quicker, being able to develop multiproduct facilities, being able to put more molecules through a facility in a short period of time. This is the reason why the disposable trend has developed and has been so successful over the past 15 or 20 years.

When you look at chromatography and ask what do people want to do with a disposable system, there are two answers. At one end of the continuum are users who really want to use chromatography columns the way they've always used chromatography columns, they just don't want to pack them any more. At the other end of the continuum are companies that have built truly single-use platforms, and don't have any capability to manage hardware. These companies are buying disposable columns and they're throwing away the columns and the media, because although on a per-process basis it may seem expensive, in terms of the overall operation, they get the economy of scale. Users operate on a continuum, and you see systems ranging from pure disposables to hybrid facilities. So, when you ask what factors influence the choice of platform, the answer for me is that the traditional process and the traditional technologies are the number one drivers. How do people get the convenience of disposables doing what they do today?

In addition to packed columns, there are also alternate technologies such as membranes that are good for some of the flow through applications. I think it's still early days, but some of these technologies are working well and tend to be in smaller processes.


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