Economical Truths

When it comes to hard cash and cost-savings, data do not lie – new economic models developed by Pall Biotech expose the real value of continuous processes.

By Mark Schofield and Jonathan Hummel

Historically, the biopharma industry has not prioritized reduction of manufacturing costs – instead, the main concerns have been quality, safety, and time to market. However, the industry is facing cost pressures from increased competition from both biosimilars and multiple treatments for the same disease. Additionally, as patient populations grow and new drugs are introduced, drug pricing increasingly becomes a societal issue. Hence, the issue of manufacturing costs has started to become a serious challenge for the industry. At Pall Biotech, we recognize that continuous bioprocessing offers the greatest potential for cost savings in biomanufacturing. Accordingly, we have developed a portfolio of continuous processing technologies and supporting consumables. We continue to expand this portfolio through inhouse development programs. Our aim is to develop a complete suite of products applicable not just to commercial-scale drug manufacture, but also to early stage drug development. In all cases, the focus is firmly on maintaining or improving biopharmaceutical quality and lowering costs.

Not just another supplier
The philosophy at Pall is that for customers to get the most out of continuous bioprocessing, the supplier must do more than simply supply products. We believe that the future involves working closely with biopharmaceutical companies to optimize their processes and deploy the best systems for their particular needs.
One of the great advantages of continuous bioprocessing is that it permits a reduction in the size of single-use components – this is because of the implementation of more purification cycles to produce more product as an alternative to scaling up. The most striking example is protein A chromatography sorbent, which is commonly discarded after a few batches in clinical stage processes. Continuous bioprocessing spreads process operations over more time, which allows manufacturers to reduce the component size and cost per batch. For example, we see reductions as high as 80 to 90 percent by moving to continuous purification. Therefore, there is a huge advantage to be gained from switching to continuous bioprocessing, which uses these consumables more efficiently. Singleuse batch processes use disposables at a relatively large scale and hence suffer from inefficiencies related to large tanks, large bufferstorage bags, or large volumes of protein A sorbent. To get the best out of disposable technologies, they must be coupled with continuous operation; single-use per se is relatively expensive to scale up, but continuous systems permit reduced size of disposable components at a given scale. Overall, this means that continuous manufacturing is less sensitive to consumable prices, and therefore more likely to be viable in a cost-competitive environment.
But are these assertions verifiable? Historically, data to support the economic advantages of continuous bioprocessing have been hard to gather, mainly because there are few examples of continuous processing in real-world biopharmaceutical manufacturing. However, Pall employed Biosolve Process to model and compare the relative costs of continuous, single-use batch and stainless steel downstream processes in monoclonal antibody production1.

New systems, new model
The modeling was initiated to enable the analysis of a wide range of downstream purification scenarios. In particular, the model was used to represent clinical and commercial design spaces, respectively. These two design spaces allows us to distinguish between (i) cases with very high disposable turnover and few batches per year (clinical scenario), and (ii), cases where all parameters have been validated, levels of consumables re-use will be higher, bioreactor titers will be higher, and more batches per year will be produced (commercial scale operations).
Modeling various scenarios in these two full-factorial design spaces (Figure 1) has generated uniquely detailed data regarding the comparative cost advantages of different strategies for downstream manufacturing.

The modeling indicates that for all scenarios, single-use batch and continuous single-use processes are more cost-effective than stainless steel systems (Figure 2).

Continuous processes are generally the most cost-effective; 78 percent of all of the scenarios investigated are most cost effective when performed continuously; single-use is more cost effective for the other 22 percent of scenarios. These scenarios are at low volumes and low titers, where the modest amount of product produced (< 2 kg/year) do not support the increased capex of continuous manufacturing equipment.
The specific sources of these cost-savings per process scenario, in the clinical design space, are shown in Figure 3; the effect on capital requirements resulting from avoiding the need to buy a centrifuge, as well as reduced operating expenses due to lower volumes of protein A sorbent and fewer single-use filter holders, is clear.

At the commercial scale (Figure 4), the continuous platform provides the lowest costs for all scenarios. For the very lowest volumes and titers, continuous and single-use batch processes are of similar costs, but at larger volumes and higher titers continuous is clearly the most cost-effective option. We attribute this to the lack of sensitivity to scale noted above; continuous manufacturing benefits from upfront capital savings by using disposables, but also makes savings from employing smaller disposable items, and from operating more efficiently. The longer operation times of continuous systems permit smaller consumable items, which means less sensitivity to the scale of monoclonal antibody throughput. This is possible with a shorter total downstream processing time than batch, due to the ability of continuous systems to operate at the same time after startup operations conclude.

In the commercial design space, breaking down the cost savings by category (Figure 5) shows that continuous processing, again, generates large capital and operating cost savings. Operating cost reductions still largely derive from the need for fewer consumables, including protein A sorbent. Labor cost savings also play a role, due to the reduction of cleaning and buffer preparation activities, particularly in the purification and polishing steps.

Our model also allows us to predict the percentage cost savings achieved across the entire project lifetime by adopting continuous bioprocessing (Figure 6). At 5 g/L and 20 batches/year, switching from a single-use batch process to continuous would save 15 to 20 percent in costs, and switching from stainless steel to continuous would save 34 to 39 percent.

Do these predictions reflect the real world? Like any model, ours is based on assumptions, but it’s important to note that our assumptions were developed using feedback from an independent third party (BioProcess Technology Consultants, Inc.) and from current users of Pall systems. This approach does not perfectly fit every manufacturing scenario, but does supply a broad indication of the available cost savings and the scenarios where continuous purification can be employed most effectively. One strength of this approach is that the modeling can be adjusted to reflect a particular manufacturing scenario so that the outputs can be relevant and tailored to a particular biopharmaceutical company’s needs. Hence, we are confident that we have developed a tool that is sufficiently robust and flexible to apply to the vast majority of realworld situations.
Interestingly, the data from our model can provoke two opposite responses: people from a batch processing background think the projected savings are too high, and people from continuous processing backgrounds think the anticipated cost reductions are too low – sometimes people just see what they want to see! When people are sceptical about the data, all we can do is reiterate what we have done and provide more detail as necessary. The only way to counter scepticism is through transparency regarding data, methods and assumptions, which either leads to a “aha!” moment, or an even stronger model.

Future: progress will be continuous
The continuous process of the future will be a highly automated and very efficient process based on real-time analysis and feedback. Instead of testing the drug product at the end of the process, prior to release, future manufacturers will rely on operating within a design space according to quality by design principles, resulting in only minimal testing requirements at the process end. Maintaining operations within certain critical parameters throughout the process will be sufficient to ensure a high quality product. This is already a reality for small molecule drug manufacturing.
Given the current dearth of experience with continuous bioprocessing systems, many manufacturers would benefit from partnering with a supplier that has real-world expertise in the field. Pall is now very well positioned to offer advice in this area – and our recent process economics study has generated a body of knowledge that, going forward, will allow identification of specific cost-containment solutions in the context of the constraints associated with a client’s specific bioprocess. This is important, because every bioprocess is different, and each is impacted in different ways by the capital and consumables costs associated with biomanufacturing.
So the evolution of bioprocessing towards continuous systems is well underway, but has not nearly reached its full potential. More and more continuous technologies will be brought to the market and processes will become more streamlined to bridge the gap between the current and the future state. The cost-saving potential of continuous manufacturing has only just started to be exploited.

Mark Schofield is Senior R&D Manager and Jonathan Hummel is Bioprocess R&D Engineer, both at Pall Biotech.

Reference
1. J Hummel et al., “Modeling the downstream processing of monoclonal antibodies reveals cost advantages for continuous methods for a broad range of manufacturing scales,” Biotechnol. J., Epub ahead of print (2018). PMID: 29341493

Originally published by The Medicine Maker

www.pall.com/biotech

 



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