One strong take-away message from BPI’s flexible facilities supplement (December 2012) is that there is no single road to achieving a flexible manufacturing process. The ability to quickly modify a unit operation, process line, or entire facility to accommodate change certainly depends on several factors. Flexibility is no longer exclusively linked to single-use systems for one specific operation. It connects facility design, staffing models, and revamped technologies. Vendors and suppliers are hearing first-hand what the industry wants in flexible operations.

“Different customers have different needs,” says Dennis Powers (director of integrated solutions North America at Sartorius Stedim Biotech). “Some want to increase throughput within their facility and reduce turnover time for their manufacturing processes. For others, flexibility means they want to run multiple processes or products within their existing footprint. In other cases, flexibility means being able to rapidly scale up a manufacturing process or scale back based on market demand.”

“The first thing I think of is agility,” says Josh Hays. (marketing manager at EMD Millipore). “Customers want to be agile in how they set up their operations from timing and processing perspectives. Facilities are continuing to shrink, and classified space is very expensive to install and maintain. Titers are increasing, so companies are producing a lot more protein with a lot lower volumes.” That falls right into what Hays refers to as the “sweet spot” of single-use manufacturing. “As we see footprints continuing to shrink, one general trend we will see is the industry looking for ways to expand into getting more unit operations out of less equipment.”

Pulling resources together to establish and maintain a flexible process can be challenge. “The main driver for greater flexibility is doing more with the same number of people,” says Jens Vogel (executive director of process science and technology officer at Boehringer Ingelheim). “The industry suffers from having very long development times, and the most critical problem is the inherently low clinical success rate. You basically have to develop 10 projects to bring one or two molecules to market. So it is really about getting to clinical proof of concept as quickly and efficiently as possible.” Vogel says this strategy also applies to flexible staffing models. “We want to minimize or eliminate interfaces, especially in the early phases of a development program. We are building a flexible development workforce that executes early stage development and then transfers the project into a GMP space to do the actual early phase clinical supply and execute that as well. So you effectively eliminate one technology transfer interface and therefore dramatically increase overall efficiency.”

The Effect of Flexibility on Facility Design

Using a facility for manufacturing multiple products, even at various phases in development, is one way major biomanufacturers are increasing flexibility. According to John Bonham-Carter (vice president of sales and business development at Refine Technology), two major factors are driving this trend. First, increasing market pressure to compete with future biosimilars is forcing companies to reexamine costs. “Many big pharmaceutical companies have biosimilar programs, so when they are looking at a new manufacturing facility for these they need to look at costs. They don’t want the facility to be just about one product as well. There is no point in taking forward an old or inefficient technology that worked well 10 years ago for your best-in-class drug, your unique drug. You want to have today’s advanced and cost-saving technologies instead — and they might well be used for improving an old facility too.” The second push is the presence of multiple drugs for the same indication. “A multibillion-dollar market might have to be shared three, four, or five ways. That means your cost of manufacturing, which might not have been critically important previously, is now important. It could even be a competitive selling point in the market. It’s really a question of, when examining your future production requirements: Can you build a cheaper, smaller, and more flexible facility that can handle different drug products with different production needs? The new technology available today has reduced the barriers and costs to entry significantly, and every company needs to reassess those opportunities and risks themselves.”

Some suppliers are developing solutions to meet flexible facility design needs and take the risk out of capital investments. “A manufacturing facility or process that is bound to one product requires a high demand, long-term product to amortize the facility,” says Maik Jornitz (vice president of business development at G-Con LLC). “When it comes to scaling up or down, increasing or decreasing capacity or repurposing a facility, traditional designs are too inflexible to do so. Furthermore, single-use technologies create process flexibility, but at that point you are still in a rigid facility environment.” G-Con developed self-contained, manufacturing “PODs” that can be implemented into new or existing facilities, up- or downstream (what the company calls podification). “True flexibility means you can use the facility for multiple products, rapidly ramp up and down, plug-and-play unit operations in and out of a process stream. That can only be realized when you have autonomous cleanroom solutions like the PODs, which can be effortlessly moved, reliably decontaminated and repurposed, if needed.”

QbD, PAT, and Continuous Processing

Implementation of quality by design (QbD), process analytical technology (PAT), and continuous processing concepts will undoubtedly play a significant role in extending greater levels of flexibility in biomanufacturing. “We have substantial experience with continuous processing, and it is an area we are actively looking at for the future,” says Vogel. “There is a good reason the bioindustry is dominated by batch processing, but we seek to look into alternative modes of operation, including continuous, in the future. The combination of disposables and continuous processing holds great promise, at least for certain classes of molecules. QbD and PAT are certainly complementary to flexible manufacturing concepts, especially for platform molecules such as antibodies. For nonplatform molecules such as therapeutic proteins, we can not use a protein A downstream platform and therefore use a high throughput development platform to perform early screening of different unit operations quickly.”

“We are hearing more and more from customers that they would like to move away from batch processing and toward continuous types of processes,” says Powers. “Continuous or parallel processing also would help them reduce the footprint of their manufacturing operations.”

“A common question is whether you should go with the continuous processing route, which is very useful for everything from QbD, PAT, cost reductions, and so on,” says Bonham-Carter. “In a manufacturing setting, continuous processing will always win if you need a lot of product, but, strangely people question quality. In fed batch, you are producing multiple batches with inherent variability, which is why many industries from bakeries to automotive factories have made such efforts to move to continuous production performing exactly the same every day, giving a better quality record.” However, making a process flexible and gaining quality and efficiency advantages means you need to ensure that your media preparation and the way you operate your bioreactor and downstream are all fitted together. “Planned well, this can mean your early clinical scales (from phase 1 or 2) are th
e same as your commercial scale, vastly reducing tech transfer risks. Your facility can easily adapt from a clinical to commercial manufacture.” Rather than thinking about the traditional way of flexibility (running a certain number of batches), Bonham- Carter says you would think of needing a certain amount of product, which is a certain amount of time. “So you move from batch to thinking about time and productivity. And for our industry that is a massive step.”

The shift will take time, indeed. As Geoffrey Hodge (vice-president of biomanufacturing services and senior global product manager at Xcellerex) explains, “I’ve heard some interest in continuous processing, but I’m not sure how quickly the industry will move to it. It requires a fairly large shift in logistics and mindset. It will be interesting to see how single use plays out with continuous processing because it will also require changes in some of the single-use process technologies, which have been based mainly on batch processing.”

Evolution in Single-Use Systems

Suppliers are well aware that change has been a constant part of producing single-use systems. Disposable components are easily associated with incorporating greater flexibility. “Start-up companies take on their processes one small piece at a time,” says Hays. “They don’t want to make a massive up-front capital investment. For them, single-use technologies provide some advantages in terms of time to get running as well as time to make changes such as switching production from one molecule to another.”

“When you look at the history of single-use technology — what started out as disposable encapsulated filters and tubing sets for small scale production — you really see an evolution,” says Powers. “We now have 2,000-L single-use bioreactors on the market as well as large-scale single-use mixing systems. Customers are moving to expand single-use unit operations to whole upstream and downstream single-use manufacturing processes. As industry continues to adopt single-use technology, we will see more innovative products become available, allowing customers to expand implementation.”

Boehringer Ingelheim is setting up a global disposables clinic supply platform and in-house development program to address the needs of its diverse range of clients. According to Vogel, the idea is to have a fully disposable flow-path clinical supply capability, meaning single-use bioreactors in the upstream area and fully disposable flow-path chromatography, tangential flow filtration systems, and so on in the downstream area for large drug substance manufacturing. “This will maximize flexibility and will allow us to offer our clients fast and efficient transfer into the same platform on three different continents allow us to offer our clients fast and efficient transfer into the same platform on three different continents, so we have the exact same disposables clinical manufacturing capabilities in Fremont, CA; Biberach, Germany; and Shanghai, China.”

“There are several different levels of flexibility,” says Hodge. “The first afforded by single-use systems was the ability to put equipment on wheels and detach it from utilities so you could move things around and reconfigure them to make flexible use of your space. The challenge then is logistically connecting them together. How do you connect one unit operation with another, making sure to use the right tubing sets and fittings and sensors and filters and manifolds? We have solved a lot of logistics challenges because we have made GMP material in single use, and we share that knowledge with our customers. So some of the flexibility is just how you set up your staffing, your logistics, and material flow. It’s not the equipment per se, it’s how you make the best use of that equipment.” The company’s Marlborough, MA, facility, has developed closed-environment modules that “shrink the cleanroom down around each unit operation and allow the operation of downstream process steps in the same open cleanroom as the upstream process steps.” The manufacturing crew adds a separate level of flexibility. They are cross-trained to work both up- and downstream, moving back and forth between unit operations, which allows more with a smaller crew.

Single-use and stainless steel technologies, as well as other facets of flexibility, still have room for growth. “There are only a few pieces where single use hasn’t reached yet, including large-scale centrifugation and homogenization for microbials,” says Hodge. “I’m not sure if there will be solutions in that area. Probably the next big priority for the industry is to integrate sensors and improve single-use sensors. There has been a lot of success in those areas, but there is still some ground to cover.”

Author Details
Maribel Rios is managing editor of BioProcess International; 1-957-646-8884; mrios@bioprocessintl.com.