Market Trends Driving the Need for Continuous Processing
May 30, 2019
Across all sectors of commerce there is a desire to complete tasks in the most expedient manner. Almost irrespective of what tasks are asked of us, we are striving for improvements in efficiency and effectiveness. Within the pharmaceuticals sector, the overwhelming desire is to improve patient access to medicines.
Many approaches have been proposed to realise this ambition but in the context of this blog my focus will be assessing the trends to improve overall manufacturing efficiency which in turn leads to improved productivity. In this context productivity can be measured in terms of numbers of therapeutic doses produced per year per m2 of facility footprint. If one can improve productivity without compromising product quality then facility output will increase and arguably manufacturing costs should reduce.
As has been described in the origins of continuous processing, one proven approach to improve productivity is to move from the traditional batch manufacturing practices into a continuous mode of operation. This has been proven in several industry sectors and has been implemented within the pharmaceutical industry especially for small molecule API’s where for example tabletting lines operate in a continuous manner. Now it’s the time for the biotech industry to embrace continuous processing and reap the potential benefits that are on offer.
The move from a batch bioprocess to a continuous bioprocess is an evolutionary change and should be considered as such. The process flow from the cell culture to drug substance is essentially identical in batch and continuous. The cell culture media used will be similar, the chromatographic resins and membranes used for purification will be similar, the membranes used for concentration and diafiltration will be similar as will all the process buffer solutions and reagents.
The major difference is in the design of the hardware used for continuous operations and even then, the wetted components will use similar materials of construction to the batch hardware. Why? Because we are trying to purify the same molecule to at least the same degree of purity and efficacy as that produced in batch, we just want to do it more efficiently, so the simplest way is to keep everything as identical as possible.
Over the past 2-3 years there have been major technology advances by the biotech suppliers to introduce scalable continuous bioprocessing equipment. There are now multiple suppliers that offer commercial process solutions for continuous cell culture, continuous clarification, continuous chromatography and continuous filtration. In fact, they can address each unit operation starting with cell culture and resulting in drug substance. These technology platforms are designed to operate over a range of bioreactor sizes and cell culture volumes typically up to 2000 L and are available in stainless steel and single-use formats. This scale of operation aligns well to the next generation of higher potency biological medicines where higher titers and reduced total mass requirements indicate use of smaller bioreactors with process scale-out rather than scale-up. One concern that gets raised in conference presentations and webinars on continuous processing is that it is all or nothing. It is either an end-to-end continuous process or it remains as batch. This is far from the truth. In fact, hybrid approaches using the best of batch with the best of continuous is a good starting place to gradually ease yourself into continuous processing and mitigate risk.
When considering process improvements or expedient process developments it is important to scrutinise the entire process flow in the context of your target product requirements. Consider using techniques such as value stream mapping to identify the process bottlenecks and areas of non-productive waiting time. These are the low-hanging fruit that could be the first stages to consider switching from batch to continuous. Once this has demonstrated productivity gains, review your value stream map as undoubtedly you will discover new areas of waste. An iterative cycle of continuous improvement will become established and your process will become optimised incrementally. Certain unit operations are more-costly and less efficient than others. With each process being different there is no definitive rule of thumb here and good process economic modelling using your real costs is warranted. One area that has received the greatest attention in continuous bioprocessing is continuous chromatography. This is especially so where the therapeutic product itself is labile so process time becomes a key driver or in the monoclonal antibody area where the affinity capture step using Protein A resins can be significantly more efficient when carried out under continuous conditions compared with the traditional batch approach. If you are contemplating use of perfusion techniques for continuous cell culture then continuous downstream processing makes sense to accommodate the continuous flow of product-laden cell culture media being removed from the bioreactor. With the development of high titer and high cell density culture becoming established alongside more effective feeding strategies, perfusion culture is emerging as a highly cost-effective production vehicle for biotherapeutics and we see this being a core driver for continuous bioprocesses going forward.
So, I hope that my blog has provided you with some insights as to where we are today and where we may need to go in the future. Is continuous processing the answer to everything? Clearly no. If you have a batch process that meets all your productivity requirements and doesn’t need fixing then leave it alone and scale-out or up as necessary. If, however, your process is sub-optimal or continuous improvements are your way of life then I recommend you investigate options for process improvements. You may well find that introduction of selected continuous operations improves your productivity to a level that surpasses your expectations!
More to follow next time.
Peter Levison – Executive Director Business Development
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