Batch vs continuous processing and how process intensification can reduce environmental footprint and improve affordability and access of biotherapeutics
Over recent years, targeted biologic therapies have transformed the treatment paradigms and prognosis for many diseases in comparison with previously standard systemic therapies. However, the added complexity of producing biotherapeutics increases the cost of development, and it is estimated that about a third of all current pharmaceutical industry research and development expenditure is on biologics1.
Similarly, a large share of current healthcare costs is related to targeted biologic drugs. The relatively high prices
when compared to small molecule therapeutics is thought to be a barrier to widespread patient access. However, due to their efficacy, demand continues to rise. This puts pressure on the
manufacturers to do more for less.
Bioprocess intensification is all about efficiency, aiming to produce more product per unit, time, volume, cost, and
footprint. Dr. El-Sabbahy states, "increasing efficiency essentially boils down to producing biotherapeutics faster with fewer resources".
Within this, there are a number of different ways to achieve process intensification, including portability/modular systems,bioprocess simplification,improved platforms or materials,better monitoring and control, digital tools, and continuous processing2.
Broadly there are two approaches to increasing efficiency:
Dr. El-Sabbahy explains,“Driving process improvement using existing purification technologies can take you only so far. Advanced materials are really needed to take bioprocess intensification to the next level.”
Prof. Dan Bracewell: “People are looking at where the low hanging fruit might be in terms of investments in new technologies to deliver improvements. They are looking at perfusion technology to intensify the upstream, to give higher titers. Then they look at downstream and ways of improving performance of chromatographic and viral inactivation steps etc. I think, in our small bioprocess community, it is this examination of the process and looking to see…where time can be best spent to get the best return on investment.”
Dr. Hani El-Sabbahy: “I think it's in the nature of scientists and engineers to want to improve their processes. There are really a few ways that you could go about it. One of them is to improve the quality of the product that your process produces. The other one is to make the process more efficient, and I think that's really where the process intensification comes in. Essentially, it's about trying to do more with less, so using fewer resources in order to produce your biotherapeutic. If you look at most of the developments, they're all linked to that idea.”
Prof. Alois Jungbauer: “Improving the dynamic binding capacity in chromatography is something which has been done now for several decades. It's clear it is one of the key parameters to actually intensify the processes, to reduce the buffer consumption, to decrease the footprint of a unit operation or entire manufacturing training.
But I think process intensification goes beyond intensification of a single unit operation. It's actually more about either combining or even interconnecting operations. A prime example is what they call Accelerated Seamless Antibody Purification (ASAP)9 where all unit operations for purification of antibodies are interconnected and by doing so you can avoid all intermediate manipulations between different steps.”
“We have to think about how efficient our industry became through continuous simplification and improvement of processes."
Prof. Dan Bracewell: “If we look at dynamic binding capacity for chromatography resins, which is the key pinch point throughout processing, we will obviously hit a certain point where we can go no further. We get to viscosity problems and then aggregation and proteins will become unstable.
Then, one has to turn to thinking about being a bit more creative to further intensify operations. Obviously one aspect of intensification is the amount we can handle in a single batch, the other aspect is how fast we can go. When we hit natural limits for what the dynamic binding capacity of materials can be, maybe we have to start thinking about how fast we can do the processing to intensify by that means.
We can indeed see people looking at convective materials, membranes and nanofibers to look at intensification of that part of the process by going faster when we start to hit these limits in terms of capacity that the resins can cope with.”
Prof. Alois Jungbauer: “We have to think about how efficient our industry became through continuous simplification and improvement of processes. In the past, an antibody downstream process took a week or so, nowadays, a lot of companies can complete the full purification of an antibody within two days. I’ve even heard of some companies aiming to do it within a single shift. This is a really a prime example of the power of process intensification and process simplification.”
One way of intensifying a process that has long held great promise is continuous processing. The aim of continuous processing is to increase efficiency of the process by reducing its overall size, better utilizing available capacity of chromatography resins, minimizing downtime and reducing footprint of the process.
However, integrated continuous processing adoption has been slow due to its associated complexity and today, other approaches that focus on advanced materials can give many of the same benefits without the complexity3.
Studies such as one by Pollock et al4 have shown that an integrated continuous strategy is optimal for early phase production and small/ medium-sized companies, but for commercial production and companies with large portfolios, a hybrid strategy with fed-batch culture, continuous capture and batch polishing offers a better Cost of Goods per gram. Therefore, adapting the approach based on the production scale, the wider organisational context and operational considerations is critical in terms of realising the benefits of continuous processing.
Prof. Dan Bracewell: “Going completely continuous is a significant technological barrier. We've seen these islands of continuous processing that are entirely possible; you can have certain parts of the process that are appropriate and that are continuous.
When you're trying to improve the speed and then the utilization of chromatography resins, for example, or improve the speed and utilization of the viral activation step, it's not simply one or the other, we can mix and match between continuous and batch processing.”
Prof. Alois Jungbauer: "I think a typical process intensification where you mix and match continuous with batch is like a continuous upstream process with perfusion and then a continuous capture. You then hold everything and continue with batch virus inactivation, a batch-wise intermediate purification and polishing. That's a typical mix and match because you improve the resin utilization. You can also decrease the size of your plant and potentially implement more runs or campaigns in the same plant.
As companies or groups have investigated transferring processes from batch to continuous downstream processing, they thought it is also an intermediate opportunity to improve process intensification by combining different unit operations into one.
I think, currently, a lot of companies are following up on this strategy. It's extremely useful because, when you try to intensify your process, you don't have to make a radical change in your process and you can stay within your regulatory limits.”
Dr. Hani El-Sabbahy: “We've seen papers where research groups look at the economic analysis for adopting continuous or partially continuous or batch processes. The economic case depends on things like the size of the company and the number of molecules that they have in their pipeline.
I think, when it comes to process simplification versus continuous processing, one of the key barriers - and I think maybe this is why we see companies implementing continuous processing for certain parts of their process rather than the whole process - is a perception of complexity. Of course, the antidote to complexity is simplification. I think on that basis, process simplification is a critical tool for intensification.”
Prof. Dan Bracewell: “I think there's also one aspect that's increasing difficulty. If we're using things like continuous chromatography or rapid cycling where we're using materials multiple times in the same batch, there obviously comes a measurement monitoring and control question.
That obviously overlaps with the industry 4.0 agenda and it's certainly not an insurmountable issue. I think automation of these sorts of steps is entirely possible, but does need consideration, particularly on the regulatory aspects - how we're going to show good control of these more intense processes.”
"It's not simply one or the other, we can mix and match between continuous and batch processing."
As environmental awareness grows, the impact of bioprocesses on the environment is becoming a more and more important consideration. One of the ways to make a process more environmentally friendly is to make it more efficient. In this respect, a smaller environmental footprint is often a direct result of process intensification.
To take an example, heating, ventilation and air purification (HVAC) systems that support clean-rooms consume a large amount of energy in the manufacturing plant.
Therefore, moving to smaller clean-rooms can reduce both environmental impact and costs5.
Similarly, for purification unit operations a large quantity of water is needed. New chromatography technology can decrease buffer volume requirements which saves water. This improves sustainability as Highly Purified Water (HPW) has significant energy requirements associated with it.
For example, 3M™ Polisher ST can be used to replace downstream AEX polishing
A comparison of a Reusable AEX Column 80L Vs 3M™ Polisher ST BC16000, with the latter offering a compact, small footprint solution
columns in both fed batch and continuous manufacturing. This technology provides a compact, small footprint, single-use solution. This reduces buffer requirements by eliminating regeneration and sanitisation steps. It has a high capacity which leads to a smaller unit operation and high yield. This can overcome scale limitations and enable cost-efficient manufacturing to support the growing demand for biologics.
Dr. Hani El-Sabbahy: “If you look at efficiency from a sustainability angle, there are two things that you can do in order to reduce your environmental footprint. One is to look at using different single use materials. The other is to reduce the quantity of the inputs you are using. That's really, for me, how process intensification fits with environmental footprint. If you are reducing the amount of energy, water, materials etc that you're using, then you're also making a process more sustainable.”
Prof. Alois Jungbauer: “One of the main benefits of process intensification is to reduce the number of the auxiliary materials and in turn to simplify the supply chain. When you need less material, less resin, less filters, less chromatography buffers and so on, everything simplifies. It is obvious that the process gets more economical, but you also gain flexibility. That is also often overlooked.”
Research & Development in biologics is expensive and time consuming - with costs ranging from $500 million to $3 billion,and long clinical trials needed to evaluate safety6. Specialised facilities and equipment, expert labour and specific material requirements all impact the cost of the manufacture process. Whilst effective and successful, the cost of biotherapeutics is a barrier to accessibility in many parts of the world. Therefore, more affordable biotherapeutics are essential to improve global accessibility.
Affordability is intrinsically linked with efficiency. Improve efficiency and facility,
equipment, labour and material costs will all fall. The most important and arguably the easiest way to improve efficiency is to focus on yield - ensuring that product losses in downstream processes are minimised to drive efficiency.
Whilst reducing costs is essential to expanding access to treatments, it is also important to look at process portability. Developing simple, modular single-use intensified bioprocesses will enable local manufacturing in developing countries, to supply local patients with lifesaving medicines.
Prof. Dan Bracewell: “The COVID vaccines shine a light on affordability and our ability to supply globally as opposed to just wealthy countries. Affordability is a complicated area perhaps because of rights over the products, but I think we can clearly see that the reason we're in the current situation of having further outbreaks of COVID is because we haven't globally vaccinated. So we see the consequences of not being able to resolve the affordability issues very starkly at the moment.
I think the same clearly already applies to mAbs. Many, many parts of the world do not have access to these cancer therapies. That's clearly an unmet need and a challenge to reduce cost of goods for those sorts of therapies to much, much lower than we are now.
There are the charitable organizations like Wellcome and Bill & Melinda Gates Foundation looking at these issues, but clearly, we are quite some distance from being able to resolve them. The solutions come from continuing to improve our processes and new materials, as we hit natural limits with existing materials, looks set to be key to that.”
A wide range of biotherapeutics have obtained regulatory approval, including antibody fragments, single-domain monoclonal Antibodies, Fc-fusions, antibody-drug conjugates, non-antibody protein therapeutics, PEGylated proteins/peptides, mRNA, vaccines and viral vectors to name a few.
This diversity of biotherapeutics and expression systems poses
unique challenges for downstream development. For example, viral vectors are a new class of modality with increasing importance that poses very different purification challenges.
With such a diverse range of modalities, a platform approach may not work7. Therefore, for companies trying to expand their product portfolio and produce both conventional and
emerging biotherapeutics, investing in flexible and modular manufacturing technologies, will help them cater to different product classes and efficiently respond to market fluctuations8.
Prof. Dan Bracewell: “I think the big trend is the diversification of the product modalities that we're seeing in everything from viral vectors through to things like exosomes for delivering to the cell, and lipid nanoparticles.
Opening up the variety of the ways of delivering biological medicines to cells significantly challenges existing technologies that we've been developing mainly for mAbs over the last 20 or 30 years. These are generally much larger products, often more labile, with different measurement challenges and different product-related impurities. That's a major change that presents challenges and opportunities.”
Prof. Alois Jungbauer: “We cannot apply the same downstream processing strategies to vaccine and gene therapy vector manufacturing because they have different, for instance, purity targets, different doses and also a completely different quality profile. That's definitely a challenge.
There is also a challenge for the new modalities of whether we can develop downstream processing strategies which are affordable. What's quite interesting is that some of these newer advanced materials which have been developed, like these fibre and flow-through technologies, really could be a future solution to downstream processing problems of these new modalities.
"Opening up the variety of the ways of delivering biological medicines to cells significantly challenges existing technologies that we've been developing mainly for mAbs over the last 20 or 30 years."
