George S. Weeden, Jr., is a scientist in global manufacturing science and technology (MSAT) process science at Sanofi. We recently chatted about the topic of continuous chromatography.
What are the general reasons for companies to consider continuous chromatography? And what are the caveats? The main driver for considering continuous chromatography is reducing the cost of goods (CoG). Continuous chromatography improves productivity (mass of product per volume of stationary phase over time) and thus increases throughput or decreases volumes of stationary phase needed. If cost savings are insignificant, then the many additional benefits to continuous processing won’t matter. A secondary driver would be that continuous processes generally provide more consistent product quality and increased process robustness compared with their batch counterparts.
Generally, continuous processes have smaller equipment footprints for more efficient use of plant floor space. Compared with an equivalent batch process, solvent and buffer volumes are reduced for a continuous process, which can free up resources (e.g., water for injection, WFI) for other uses. Reduced buffer volumes also lessen waste disposal with potential environmental benefits. Continuous processes require increased automation, which simplifies operation with fewer operators than manual processes need. An extreme case would combine these benefits and enable a dedicated plant to produce an additional product, saving a company from outsourcing or building another facility.
Technology transfer generally is simplified with a continuous process because the scale-up factor from pilot to manufacturing scale is smaller than that of a batch process. For orphan drugs or similar low-volume products, pilot and manufacturing scales even could be the same size.
What point in development is the optimum time to implement a continuous process? As early as possible. Batch experiments have to come first for screening resins, buffer conditions, and so on. But the sooner a purification process can be changed to continuous, the better. Continuous processes can speed a product into clinical testing by generating required materials in small footprints with low volumes of stationary phases. Generally, such processes also make the necessary quantity of material faster than can a traditional batch approach.
The later a company waits in development to change to continuous processing, the less likely it is that such a change actually will occur. There seems to be a lot of momentum in development and a large focus on getting to market as quickly as possible.
If a batch process already has been proven to work sufficiently well, then why change to something new and delay a product launch? Do yield and productivity improvements outweigh the lost revenue? Those are valid questions. For a risk-averse industry, the answer tends to be “stick to what we know.”
In a best-case scenario, a development team would begin with the goal of making a continuous process. That way, there would be no (or at least minimal) backtracking or repetition of experiments when moving from the batch version to the continuous version. And doing so gives outside stakeholders better peace of mind because most of the development history would be on the continuous process, so it would show a short history of success already.
Simulated moving-bed (SMB) technology isn’t a new idea, but there are new variations on that theme. Are they finally making continuous chromatography viable for commercial bioprocesses? And are single-use technologies key to making them work? Periodic countercurrent (PCC) is used in the biopharmaceutical industry for continuous capture, usually with protein A affinity resins (generally the most expensive stationary phase in downstream processing). It can increase their capacity use. PCC can accept a continuous feed stream (e.g., from a perfusion bioreactor) and elutes product elutions at discrete times.
SMB has been around for decades (invented by Broughton and Gerhold in 1961) and has slowly made its way around industries from petrochemicals to foods (e.g., high-fructose corn syrup) to small chemicals (e.g., organic acids). Some small-molecule chiral drugs are produced using SMB. But to my knowledge, there have been no manufacturing-scale SMB processes for biopharmaceutical production. SMB generally has a continuous feed and product flow.
There are always variants, including intermittent SMB (I-SMB). And almost all of them operate under the concept of countercurrent chromatography, in which the resin-bed movement is “simulated” by changing valve positions to alternate which columns receive which liquid streams. The benefits of this style of separation include increased capacity use, increased productivity, and reduced consumption of solvents and buffers. SMB also can perform separations for which there is a relatively low selectivity between target and impurities (weak partitioning) and obtain high purity without sacrificing yield.
On the topic of single-use technologies, I would say that although they are not the key to making continuous chromatography work, they are the key for speed to clinic or market. Disposables eliminate the need for cleaning validation and save on cleaning solution and liquid waste disposal. Nothing about the operation of the step(s) would change, but reusable equipment would require additional work before a process could be filed.
What benefits and challenges come with increasing the number of columns from one to two, four, six, and beyond? Benefits: As the number of columns increases, a system approaches the “ideal” case of a true moving bed, especially in SMB applications. Many design and modeling equations for countercurrent chromatography are based on solutions obtained in such a limiting case. Some assumptions used to generate those theoretical solutions may not hold for just three or four columns. Additionally, increasing the number generally corresponds to decreasing the size of each column.
Challenges: With more columns, the equipment becomes more complex (and costly). Discrete jumps (e.g., 1–2, 2–4, 4–8, >8) depend on commercially available systems, but generally those that can handle more columns will cost more than systems that are limited to only a few. Using many columns in a purification step also tends to have the problem of “perceived complexity,” in which people can judge it to be too complex to be feasible because it is not a standard operation for the industry.
Can you comment on the importance of process control, sensors, and process analytical technology (PAT) in continuous chromatography? Going forward, they will be essential for continuous chromatography to reach the prevalence and scales in bioprocessing that it has reached in other industries. A deep process understanding and robust process control strategy, along with PAT for feedback (or feed-forward) control, would go very far in assuaging potential concerns from risk-averse stakeholders. In the most advanced cases, model predictive control (common in the petrochemical industries) would be used to handle foreseeable changes in feed materials, column-packing issues, lifetime assessments, and so on. In addition to process control, PAT also can serve real-time release rather than analysis by quality control (QC) groups in laboratories separate from manufacturing suites.
In my opinion, one large hurdle for continuous processing in the biopharmaceutical industry is going to be the validation of systems and processing steps. It seems to be an unexplored space. PCC and continuous capture are the first options to make it into this space, and those remain bind-and-elute steps that are essentially overloaded. The first validation of an SMB or similar operation would have a large regulatory burden to demonstrate process understanding and control with something that has (to my knowledge) not yet been done in the industry.
Cheryl Scott is cofounder and senior technical editor of BioProcess International, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cscott@ bioprocessintl.com.