In this podcast, we discuss the challenges facing biotech companies as they move their therapeutic candidates through the clinic and on to commercial manufacturing. The priority of speed to market is often at odds with issues around development resources, facility space, and infrastructure for both development and manufacturing. Continuous bioprocessing provides solutions for many of these challenges in certain applications, but to deliver on this promise we need fit-for-purpose tools and technologies to enable process development and provide reliable transfer to commercial manufacturing.
We began the podcast by discussing manufacturing challenges. Tom shared that among the challenges for manufacturers are high capital costs, both for equipment and expensive clean room facilities and support laboratories required for development and production operations. Additionally, large fixed costs for staffing is needed to support GMP manufacturing of biologics, key areas include manufacturing, quality control and quality assurance, materials management, engineering, process sciences, facilities, project management, and regulatory groups. In addition to the substantial fixed costs, expensive raw materials and consumables are also typically required.
Bert explained why there is a trend toward continuous biomanufacturing, specifically perfusion culture, to address the challenges Tom listed. He explained that because of the continually rising high costs, as well as the increasing variety of biological therapeutics, there is a growing trend towards process intensification and building more flexible facilities. For clarity it was added that, intensification means doing more in less space, for example concentrating the amount of production in a bioreactor. Perfusion and continuous processing are forms of process intensification, with the goal being reduction of equipment size, thereby decreasing facility footprint and ultimately lowering the cost of these expensive biopharmaceutical manufacturing facilities. He went on to say that an additional benefit of reduced equipment and facility size is that it allows for more modular construction and more portable equipment. This enables manufacturing suites to be reconfigured and adapt to changing process requirements. In this way, a company can accommodate various processes in the same facility, providing big savings especially when making different products.
I followed up about the benefits of perfusion culture and how these benefits alleviate some biomanufacturing challenges. Bert stated that since perfusion is a form of intensification, meaning more cells in culture and more product produced per unit time, there is higher volumetric productivity which is a given amount of product can be produced in a smaller bioreactor. Perfusion technology also offers an additional level of control over the culture. A steady state can be achieved in continuous culture where the conditions of product formation remain constant. The FDA and other regulatory agencies have long expounded on the advantages of perfusion/continuous culture to reduce the variability in product quality.
Tom then added that continuous processing operations can be extended to the entire flowpath, as the industry starts to seriously assess continuous manufacturing operations. The improved capital utilization and manufacturing flexibility and portability that Bert mentioned are both drivers, as are the potential benefits from improved control of product quality attributes. Another emerging benefit as the industry has more experience with continuous manufacturing is improved speed of development and speed to market.
Next we discussed how perfusion culture not only benefits manufacturing, but also process development. Tom said that the cost of setting up a process development lab can be quite high with benchtop bioreactors, particularly multiplex bioreactors, being a significant part of the cost. They also take up a fair amount of bench space and require a good amount of labor to support. He went on to say that as his company began evaluating microbioreactor technology, such as the Erbi Breez, they appreciated the labor savings of these devices. They are also quite simple to operate and require less labor due to the smaller scale of operation and automation built into the device.
Bert said that one perceived challenge of perfusion culture in process development is providing sterile medium to every bioreactor unit continuously and then continually harvesting the product. Additionally, bioreactors need to have separate control to run different conditions in each unit separately. Benchtop bioreactor units typically handle the controls well, but struggle to keep track of feeding each individual unit with different media containers, tubing, flow control, etc. A device that would simplify these operations would pave the way for more perfusion in process development.
I then asked about the impact to capital cost when implementing perfusion culture in process development. Bert explained that the benchtop bioreactor has been the workhorse of the industry for the past 15-20 years and has done this well. However, the cost of each unit can be $50,000-$60,000 including all necessary controls. In the case of perfusion, you also need a cell retention device for each bioreactor that can be expensive. If the cost of this set up could be brought down on a per unit basis, it would enable process development groups to obtain higher throughput through perfusion by permitting more test conditions in the same footprint at lower cost and with less people.
Goals for Continuous Bioprocessing
I asked each of our experts what they thought that the goal should be for continuous process at both process development and manufacturing scale? Tom said that the goal for both continuous and batch process should be the same, a robust and reliable process for producing safe and effective products. He went on to say that with any new technology, the industry and regulators are going to need to develop a comfort level with applying the technology before adopting it broadly. This tends to drive applications to cases where continuous manufacturing is enabling, such as poor product stability in culture. For broader application, one of the early goals for continuous manufacturing is to demonstrate that companies can manufacture product of comparable product quality, or at least a well-understood impact, with a continuous process compared to conventional fed-batch. This will reduce the perceived risk of switching between fed-batch and continuous manufacturing. Eventually, as the technology becomes more accepted, this type of comparability will become less important.
Bert pointed out that the need for scale down models is really important for both fed-batch and continuous. Scale down models allow the opportunity to study various conditions by reproducing conditions in a small bioreactor that the cells would experience in a large scale reactor. Those results can then be extrapolated to a larger scale. Since fed-batch technology is well established, scale down models have been achieved using benchtop reactors or multiplex reactors. The problem with existing technology is that it is difficult to get complete independent control of every single unit. Controlling temperature, pH, and dissolved oxygen is one thing, but controlling media flow is another. The Erbi Breez has been designed with that capability in mind from the beginning. As a result, it can it control all the standard parameters on every unit, and it can also control the continuous flow of media and gasses to each of those units independently. Complete parameter control is required to develop processes and characterize them.
Fit for Purpose Perfusion Tools
We then talked about how continuous process development tools are limited and that most scientists are using fed-batch tools instead. Bert explained that this is largely due to the commercial success of monoclonal antibodies and as a result, much of the biopharmaceutical manufacturing infrastructure is dedicated to fed-batch production. Due to this investment in fed-batch, most biopharma companies continue to use the same platform for newer proteins, and thus, the tools available have been influenced by this trend.
Tom clarified that we live in a fed-batch world right now, so most process equipment and scale down model equipment is designed to support fed-batch mammalian culture operations. However, as the market for continuous processing develops, which it is already doing, suppliers recognize that the market is moving in this direction, and are starting to respond with tools that are designed to be more fit for purpose.
I asked Tom, if we are looking at this from a CDMO perspective, how do you implement continuous biomanufacturing when so much of the process development tools are designed for fed batch operations? He said that first, you need to establish a strong team of people who really understand bioprocess operation and have some experience with continuous processes. This includes analytical development, which is becoming so important to the industry as products are becoming better characterized and defined. Next, you need equipment, technology and suppliers designed to support continuous manufacturing. Since the industry is predominantly a fed-batch industry, most equipment and technology is focused on these operations. While they can generally be adapted for continuous, this is not nearly as effective as purpose-built systems and technology for continuous manufacturing. The Erbi Breez is an example of a very promising development system that has been designed for perfusion cell culture process development. Because of this focus, the unit is better adapted for developing continuous processes than conventional process development equipment.
I then asked Bert what process development tools to optimize continuous bioprocessing are available and where is there need for innovation? He said that to be able to support high-throughput cell culture development in the interest of speed to market and speed to development, tools are needed where multiple conditions can be tested in parallel. There are units available on the market that address some of these needs, but they don’t always enable control of every parameter individually on every microbioreactor unit. There are other devices that make use of robotics, in which case feeding media to each of the microbioreactors is done intermittently and not continuously. This is not a true perfusion simulation in every chamber. What is required is something that combines the best of all those things with high throughput, but also control of conditions including perfusion rate in each of the microbioreactor units.
He continued that none of the devices on the market were originally designed with perfusion in mind. Therefore, to control the flow of a sterile medium to every bioreactor unit is sometimes problematic, or it is done on a semi-continuous basis. There are various sizes of microbioreactors that range from 15-20 milliliters up to a quarter liter and then the benchtop bioreactors are somewhere between half a liter to 3-4 liters. This equipment is quite expensive and can take up lab space, thus conducting this work at a smaller scale would be a valuable tool. The Erbi Breez has only 2 ml working volume, which is three orders of magnitude smaller in scale to some of the other devices that are available on the market, and still allows a separate control of every parameter to every individual unit.
The Erbi Breez
I asked if they could provide examples of how the Erbi Breez is truly fit for purpose in modeling perfusion culture. Bert said that the small scale is certainly an advantage in the field of recombinant protein expression. With newer technologies where the cell type and/or the medium itself or the requirement for growth factors can add up to a lot of money, media consumption is even a bigger concern. In continuous mode, you are running for an extended period of time and can run through a lot of media in one experiment. So a smaller device that doesn’t consume a lot of media and still allows testing of many different conditions including media flow rate with an onboard cell retention device is a real advantage.
Tom added that one clever thing about the Erbi Breez is that the design does a good job of mimicking the high gas transfer rates and the mixing with different approaches, which is obviously required for operating at these very small scales. Part of the excitement and opportunity of working with a new technology is developing a better understanding of how processes in this system will translate to the larger scale systems and even how it compares with data from benchtop bioreactors or more traditional approaches.
Bert finished by saying that what is exciting about the Erbi Breez is that cell concentrations well in excess of what is typically achieved in a large reactor have been achieved. The question is why can cells be grown to higher cell concentrations in the Erbi Breez than at large scale. That is the complete opposite of what you want in a scale down model, but it is much easier to optimize a small bioreactor model so it operates more like large scale than the other way around.
I then asked Tom to share why the Breez was important to his process and what it has enabled. He said that when they started using the Breez, they were a small start up with limited resources. One of the really attractive features of the Erbi Breez was that it is significantly smaller and less capital intensive to setup than other microbioreactors. It is very straightforward to operate, so training times are short and a lab can be up and operational very quickly, even with relatively inexperienced operators. Also, because of the small scale of operation, the media costs are limited and maintenance of the systems was very straightforward.
I closed by asking if either Bert or Tom had anything else to add for listeners. Tom said that while we have focused on the use of the Erbi Breez as a scale-down model for perfusion cell culture process development, he would be remiss if he did not also point out that it can be a valuable tool for other process development applications such as media development and cell line screening. It is important to consider its use in a wide range of applications.
Bert said that the very small volume required is a virtue from a number of perspectives, especially in new therapeutic modalities like cell therapy where cells are in short supply or are very expensive and the media is also costly. It is also important to note that some of the companies pursuing newer therapeutics are small companies that don’t have extensive resources and are trying to develop these technologies with limited funds. Thus, being able to buy a device that doesn’t require significant lab infrastructure to support, is not super expensive, doesn’t depend on expensive robotics to operate it, and quick to get and set up are also advantages that shouldn’t be overlooked.