Continuous Bioprocessing: An Interview with Fritjof Linz
VP Purification Technologies, Sartorius-Stedim Biotech
What is driving the biopharmaceutical industry to explore continuous processing?
F. Linz: The idea behind continuous bioprocessing is to intensify the production of biopharmaceuticals, increase the output from facilities and thereby reduce manufacturing costs. Of course, continuous processing makes sense for labile products but it also makes sense for non-labile biopharmaceuticals where the annual production quantities needed by the market are large. In either case, continuous bioprocessing should improve the quality of biopharmaceuticals because it has the potential to deliver more consistent product.
What are the current trends in continuous downstream processing?
F. Linz: Companies are trying to reduce the time it takes to purify biologics. If they can do this, they can purify a greater number of batches each year and therefore increase their facility throughput. You could argue that many of the techniques companies are employing are not true continuous processing as is understood in other industries. In other sectors, the term is synonymous with a continuous flow of process fluid through a unit operation that improves the quality of the product. In the downstream processing of biopharmaceuticals, we are seeing a move towards companies operating batch operations in parallel and then switching between streams to allow the replenishment of consumables. Whether this is truly continuous processing or not is perhaps not so important if it allows the processing of the necessary product stream volume in the shortest possible time.
Can you provide some examples of how companies can intensify their downstream processes?
F. Linz: Sanofi have described downstream process intensification well in their article on Accelerated Seamless Antibody Purification. They rapidly processed a large number of small aliquots of cell culture harvest, minimized buffer exchanges and removed product hold steps.
I know of a number of companies that are using the idea of continuous process flow by running the final and penultimate chromatographic steps in their process using a flowthrough mode. They focus on capturing impurities from the process stream using enabling technologies such as membrane adsorbers.
Multi-column chromatography is an option and a number of companies are investigating this approach at smaller scales. Production managers are commonly concerned with questions about equipment complexity, maintenance and robustness. Development engineers will need to address these concerns if the technology is to be applied within the commercial manufacturing environment.
How does process intensification affect facility design?
F. Linz: Intensification can decrease the footprint of the downstream process. Companies can reduce the chromatography column sizes they are using and their resin requirements. This may lead to an incremental improvement in processing performance but not the step-change the biopharmaceutical industry really needs. A relatively small reduction in buffer usage will not have a large effect on the infrastructure required to support the process. The buffer consumption can actually have a significant impact on the process economics and the overall footprint of the facility. To realise the full benefit of purification processes with shorter residence times for the production of biopharmaceuticals we must optimize the whole facility concept.
What technologies are required to accelerate the adoption of continuous downstream processing?
F. Linz: We need to improve the analytical technologies to realise fully the promise of continuous processing. Companies need to have product quality influencing parameters under control to make sure that the continuous bioprocess will stay within pre-defined limits. If the process starts to move outside of limits, companies must know what to do to get it back on track and to do this they must be taking the right measurements. You cannot control something that you cannot measure.
How can Sartorius Stedim Biotech contribute to continuous downstream processing?
F. Linz: We can contribute to improve processing technologies for continuous downstream processing. For example, our experience working with Sanofi on the single-use ASAP process provided us with insights into how we can optimize and intensify the capture of monoclonal antibodies. This is something we are working on.
We are also working on understanding the quality attributes that the industry must measure in order to process biopharmaceutical products in this way. These could be either on-line or at-line measurements. An at-line measurement requires a sample to be taken from the process but a readout is generated very quickly to allow real-time decision making. An example is the ViroCyt® technology that Sartorius recently acquired. This provides vaccine manufacturers with the opportunity to measure the number of active virus particles they have during each step. With this information, they can better control and optimize their manufacturing processes.
We can take a similar approach with mAbs and consider parameters such as glycosylation patterns, activity or product variants but we are not there yet. Again it is important the technology be can be used in a manufacturing setting. Merck, for example, uses at-line mass spectroscopy measurements but this equipment can be difficult to run in an operational environment.
What I like about our offering is that we are able to influence product quality by the cell lines we provide, by the media we provide and by our understanding of how our technology works. Controlling the product quality from upstream processing in this way allows us to make life easier in downstream processing. We can optimize the overall process with respect to product quality and thereby allow new approaches for the purification of biologics.
What will the purification of biologics look like in 10 years’ time?
F. Linz: We will see a mix of processes depending on the size of the annual demand for the product. There will be batch processes and those that are operated in a more continuous manner. Whether we use the term continuous processing or process intensification, the trend is to shorten the residence time for downstream processing. Companies will use new combinations of unit operations and make use of new technologies. Downstream operations will need to process the necessary volume of the product stream in the shortest possible time.