BioProcess International has followed, from the beginning, the ways in which single-use technologies have transformed the landscape of industrial bioprocessing. On 18 March 2009, we organized a panel session at the annual Interphex conference (Jacob Javitz Center, NYC) to drive discussion toward longer-term implications of single-use components and technologies on the future of bioprocessing. Is their use a cost-saving strategy overall? What economic factors are driving their adoption? The panelists were prepared to address such topics as economic considerations in early planning stages, risk management and supply chain issues, the relationships between suppliers and users, factors that determine which processes are good candidates for disposable products, and some implications of wider adoption of single-use technology when considering total life-cycle costing. My comoderator Jerry Martin (see the Panelists box on the next page for participant details) and I each directed questions to the panelists. The following are highlights of the ensuing discussion.

Is the growing trend toward use of disposables in biomanufacturing just a fad, or are they destined to become the standard manufacturing platform for biopharmaceutical products?

Rick Stock: A fad? Absolutely not. When I first got involved in the industry, about 75% of the models I was asked to develop involved disposables on some level. Now it’s 100%. Although most of these models are at least hybrids, we’re starting to be asked to model things that are pretty much 100% disposable. We’re even seeing advances to make it possible for microbial systems. So I don’t believe this is a fad at all.

It’s generally thought that disposables projects are quicker to build than others. Is this true? And if so, what critical activities need to be considered early on?

Miriam Monge: The really important thing is the overall project management. To benefit from a reduced timeline, you need to be able to decouple some operations from the facility build. Some things need to be looked at much earlier than usual, such as vendor prequalification and selection (which need to be looked at in depth to understand a vendor’s manufacturing quality system and supply chain security).

There are two reasons for that. One: If you are going to analyze which products carry high risk, they need to be prototyped and tested before the end of the basic design phase. To do that, you need to have carried out your vendor prequalification, defined which technologies you’re going to work with, and put them on prototyping very well in advance. And to do that, of course, you have to have selected your vendors.

Second: To really reduce your timeline, you need to be able to put products on stability. To do that, you need to have selected who you’re going to be working with. If you don’t start those very early on in concept design, then you’re not going to profit as much from a reduced timeline as you could if you carry out your disposables project implementation the right way.

Jim Robinson: Some general examples that have been cited on timelines is that a stainless steel factory might take a year and a half to two years from initial concept to build, whereas a single-use factory could be done in as little as six months or some time between six months and a year.

Does that differ based on a company’s product and therapeutic focus? How do end users look at these specific drivers?

Lisa Crossley: There are very different drivers depending on a company’s product and therapeutic focus. Certainly there are different drivers if you’re a vaccine manufacturer versus an antibody manufacturer versus a recombinant protein manufacturer. The risk of batch-to-batch cross contamination is a much more significant issue with mammalian cell culture processes. So those end users tend to have more of a sensitivity around that sterility risk. If you have a blockbuster product that’s being manufactured continuously, running batches several times a week, every week over a year — versus a company making a product a couple of times a year — that will significantly affect the way that company looks at the economics of implementing a disposable. If you’re amortizing the cost of reasonable technologies over 100 batches a year or two, you can see a significant impact on economics that drive the processes.

There’s also a difference in predictability of demand. If a company is making a vaccine, for example, and it knows it’s going to require x number of doses a year consistently, it is better able to have hard-plumbed infrastructure, scale the technology including all purification units, and have those fixed. But if demand is likely to differ, and it’s difficult to predict that, then going to a flexible, disposable type of downstream process may really fit the needs of that particular business better.

INTERPHEX PANELISTS: 18 MARCH 2009

Lisa Crossley, president and CEO of Natrix Separations, is involved in chromatography separations with single-use technology. Her background is in biopharmaceutical manufacturing: She worked at Dyax Corp in Boston, MA, where she directed the global manufacturing of two therapeutic candidates that each went into two separate clinical indications.

Girard Gach is a marketing director with GE Healthcare. His team is responsible for ready-to-use and membrane-based products for GE’s bioprocess division. He has >25 years of experience in the filtration and separations industry, where he’s worked in R&D, sales, sales management, and business development.

Jerry Martin is senior vice president of global scientific affairs at Pall Life Sciences and chairman of the board for the Bio Process Systems Alliance (BPSA) trade association for single-use manufacturing. Martin has over 30 years experience in technical support and business development. He is a frequent speaker and author on bioprocess filtration and aseptic processing topics, having coauthored several PDA technical reports as well as ASTM, ISO, and ASMEBPE Standards. He is a recipient of the 2007 PDA distinguished service award and serves on advisory boards for BPSA, IBC, PDA, and numerous publications.

Miriam Monge is vice president of marketing and disposables systems implementation for BioPharm Services, which she joined in 2008. She’s worked in the disposables industry for the past 15 years, 14 of which were with one of its pioneers: Stedim Bio Systems. She is also chair of ISPE’s disposables community of practice.

James Robinson is vice president of technical and quality operations for Novavax, Inc. He’s worked about 25 years in the biopharmaceutical industry, starting with Searle, and spent 20 years with Sanofi Pasteur. By the time he left, that company had made about 600 million doses of egg-based flu vaccine at its US industrial operations.

Rick Stock, an associate consultant working on process economic modeling for BioProcess Technology Consultants, started out doing contract work at World Precision Instruments. After that, he founded a biopolymer company, making what were considered to be medical devices. Returning to consulting, he worked for BioPharm Services on a Millennium Pharmaceuticals disposables project, which eventually led to the formation of a new company: Xcellerex. Stock notes that it has been three or four years since he has developed a process economic model that has not involved disposables.

We’ve definitely noticed, in working with customers, that larger companies (blockbuster types of pharmaceutical companies) would have very different drivers from contract manufacturing organizations. CMOs are very much driven by throughput, facility capacity, the number of batches, and the numbers of customers they can get through in a year. A large biopharma — the Amgens, the Genentechs, the Biogens of the world — can predict demand and are not as driven by the need for flexibility as either a CMO or just some smaller biotechs that aren’t necessarily sure when they’re going to get through phase one, when they’re going to need to scale up. Drivers certainly differ depending on the specific needs of a particular company. But what we’ve found is that there’s a pull for disposables from all arenas. It’s just that the drivers specific to each particular customer differ based on what it’s making and what its needs are.

Jerry Martin: I’m thinking about the talk that Steven Burrill gave yesterday: He said the funding sources from Wall Street (from hedge funds) for small biotechs with market cap <$100 million are completely gone and not coming back. So costs are going to become very critical for small biotechs. And they're really not going to be able to generate the funds to put in a stainless steel factory. So my crystal ball tells me that single-use/disposable technology will be very enabling for small biotech companies because it doesn't require that initial capital investment if they do it right.

What factors determine which processes make good candidates for implementation of disposables? And which would be better served by conventional reusable technologies?

Gerard Gach: I am convinced that the manufacturing floor will look very different from what it is today, and operations will also be very different, the more disposables are discovered. So my answer will change as new techniques and technologies are introduced.

Current disposable solutions are fully feasible in pilot plants and, with some reservations, also in clinical manufacturing facilities. There may be too little flexibility of the mindset as to changing the routines of manufacturing for the clinic as yet, but it will come. In brief, the disposable space is favoring multiple products, CGMP, clinical manufacturing at smaller scale, 2–30 kg per product — or a non-GMP pilot facility, 10–500 g per product. Realistic reactor volumes are currently limited to 1,000 L or a maximum of 2,000 L. Consideration must also be given to batches per year, and the economics for disposables are compelling, up to 50 batches per year with some unique considerations up to 100. Of course, as titers increase the demand for larger-capacity disposable trains will wane, as will the need for the number of batches for orphan therapies.

Jerry Martin: The FDA has issued a guidance on CGMP for phase 1 investigational drugs, which clearly states that the agency sees the use of disposable systems as a recommended pathway for clinical batches because it creates a dedicated system, eliminates cleaning requirements, and provides higher security of safety. Clinical batches are one area where we see the broadest application. As disposables are used more in clinicals, I think people will discover that they can continue into production until they get up to stages that are larger than the technology can address.

SINGLE-USE TRENDS

According to a 2008 survey by Bio Plan Associates, industry proponents of single-use technologies showed an increasing focus on benefits of reducing capital investment and accelerating turnaround of batches — rather than on reducing cross contamination and assuring sterility (the top concern of the 2007 survey and the main reason that the FDA currently cites for going disposable). Other important factors include reduction of cleaning and cross contamination and shortened start-up times. Respondents commented that disposables increase plant capacity, reduce design and modification costs, lessen installation time, and provide modular flexibility. Many new technologies are being introduced including buffer storage, filter capsules, media, bioreactors, and depth filtration.

Miriam Monge: In relation to which processes are good candidates for disposables, you need to consider the impact of scale and titer and batch size to determine the relative cost savings of stainless versus disposables. As titer increases, the relative savings are reduced. [Ed. Note: A figure providing more detail can be found online at www.bioprocessintl.com/bpiextra.] You are going to see the greatest cost savings at the 500-L bioreactor scale with around 1 g/L.

As you move up to larger scales, there are still some relative cost savings, but less. You can still get applications in the later stages of DSP — in innocular sampling, for example. That gives you a very good readout of where it’s going to make sense to use disposables, linked into the type and the scale of process, the number of batches, titer, and so on. Of course, there are a number of other factors. It’s much more difficult to determine the benefits of disposables in a retrofit scenario. But you may have a specific case where a facility is actually constrained in terms of water use so disposables may bring considerable benefits.

In terms of scale, a lot depends on the technology. Hold bags, for example, can go easily up to 3,000-L scale and be well implemented into commercial manufacturing processes. But if you look at the current disposable technology in TFF, for example, it is available at only very small scale, which is useful only in pilot and clinical manufacturing. There are a lot of possibilities for product development improvements. And I know all the suppliers are working very hard to make those new technologies at larger scales available.

Can you list some perceived risks in going to single use?

Miriam Monge: The first thing is a technology maturity analysis, ideally visiting reference sites with a manufacturing team. The next thing is economics. You want to do a life-cycle approach from initial investment through to decommissioning and look at where it’s going to make best sense to use disposables from the economic point of view. I think supply chain security is a real key aspect. You’re effectively outsourcing manufacturing to a third party. You need to go and check out the supply chain security of your supplier. But in terms of managing risk, as an end user you need to design disposable systems to limit risk. The way we’ve found to do that is to design disposable systems that, wherever possible, involve components available from more than one supplier. Of course that’s not always possible. There are some technologies today for which there is no equivalent available from a second supplier. That is an issue because, as we move into strategic biomanufacturing with constant implementation of disposables, then a second source in GMP manufacturing is obligatory. So the suppliers also need to work together to find solutions for that.

The last aspect of risk management is validation. Here you need to really work through your interaction matrix and define early on which process steps and which solutions are going to need to be put on stability. That’s the risk management approach — technology maturity, economics, supply chain security, validation — that we at BioPharm Services have developed for the projects that we work on.

There’s interest in standardization. Do you think that that’s an approach to reducing the supplier chain risk, to allow greater interchangeability? As a single-use manufacturer, how do you look at that risk of being sole-sourced with suppliers?

Jim Robinson: That can be a very deep question. There are a lot of risks in biological manufacturing. And frankly, we’re all using single-use systems today, even if only in small areas. I don’t know whether anyone reuses sterile filters, as an example. I think a lot of the groundwork for how to qualify and have multiple supplies of a sterile filter is pretty much laid out if we model interchangeability around how to change filters. Certainly a bag as a container is much simpler. A liner in a reactor is not all that complex.

As for standardization, in general I think it’s something we can easily overcome. There’s actually more risk staying with the traditional approach where you have all these things that can go wrong, not just your process equipment itself, but also all the supporting infrastructure that has to work to make your process work. By going single use, you simplify that; you can focus all your energy on your process, not on the infrastructure that supports it, much more economically than the current approach.

How are vendors meeting material certification of origin requirements — in particular, things like BSE free or animal component—free? What standards are being adopted?

Jerry Martin: When you’re looking at animal-free components, there are two parts. One is the use of animal-derived materials in manufacturing a component by the supplier. The second is the use of animal components in the raw materials that that the supplier purchases. I’m not aware of any instance where animal derived materials are actually used in manufacturing single-use products themselves. But many plastic materials do have animal-derived raw materials in their formulation — most commonly calcium stearate, which is derived from bovine tallow. As some people see it, the materials are not animal-free because there is an animal-derived component in the plastics formulation. Suppliers of plastic products such as polypropylene that contain calcium stearate can require their suppliers to certify that it comes only from certified BSE-free countries, which include Australia and New Zealand. The FDA has issued a statement saying that tallow-derived bovine products such as stearate are not considered a risk for BSE because processing the material makes it safe. This combination of factors has been widely accepted by users and regulatory authorities without issue. That is somewhat of a standard practice, although it’s not written into any standards yet. That’s one thing some of the organizations are doing.

What types of change control requirements do end users place on suppliers to ensure the consistency of disposable components?

Jerry Martin: I know from my experience working with the FDA that the agency people will expect that end users have good change control with their suppliers.

Jim Robinson: I think it’s one of the biggest fears. Right now, you control your stainless steel plant, but we can’t control our vendors. We still rely on a lot of things from them. It’s expanding what we do now. And I think standards can help in that regard. But from a change-control standpoint, you must understand which critical design factors of a single-use system affect your process — then you can set up specifications. Unfortunately, they’re going to be different for every product and process. So I don’t think that’s an area where standardization will help. But you really need — as a manufacturer, as an end user — to understand what the critical parameters are, how these systems interact with your manufacturing process. And then you design your change control around that.

Lisa Crossley: At Dyax, we did a lot of our clinical trials in Europe during the late 1990s. Although there wasn’t yet a lot of sensitivity in North America about animal-derived products, there certainly was in Europe. So we required that our key suppliers inform us of any changes regarding animal source products being introduced into any materials we were purchasing from them. I agree with Jim: You need to figure out what are the key parameters in your process and require that your suppliers provide change-control notification around those key parameters. But they’re not necessarily just around performance, they can also be around changes in extractables and leachables, animal-source raw materials, as well as any substantial changes in the release specifications for a given product.

Questions from the Audience

Is there any significant effort going on to standardize the use of films? The primary advantage might be in simplifying extractables and leachables studies and validation.

Jerry Martin: BPSA has a subcommittee working among many suppliers to develop a standard approach to generating generic supplier extractables data on various components. Many fluids used in bioprocessing (for example, buffers) fall within a definable range. It’s conceivable that the suppliers could develop generic data for those materials that users could then submit to regulatory authorities without having to repeat those studies. At present, many suppliers already do have such data, but they’ve each generated it under slightly different conditions. In many cases, the differences are not really that significant. Someone may have an extraction for three hours at 40 °C; another may have an extraction for four hours at 30 °C. From a chemistry point of view, those conditions are really not that different, but many end users have said that makes it really difficult for them to standardize. So this is something BPSA is working on to say, “Look, within these ranges, this is what we recommend the suppliers do.” They’ll make the data comparable, and that will start to make it a lot easier for end users to somewhat standardize on it.

Is it worth encouraging suppliers to use the same films?

Jerry Martin: I think each supplier has applied unique conditions in the selection films. Personally, I don’t see use of identical materials ever happening. It certainly hasn’t happened in filters for the past 40 or 50 years. It hasn’t happened in gaskets or tubing, stoppers, or anything else. I don’t think we’re going to see it in bag films, either.

Obviously there’s a lot of motivation to implement single use in the United States. Miriam, do you believe another organization like BPSA will happen in Europe? Is it necessary? Are they moving without this kind of push that companies here somehow need? In Europe, is it moving as quickly as it is here?

Miriam Monge: In many ways, the Europeans have moved very fast in implementation of disposable technologies. I’ve certainly seen facilities in Europe that have gone into very significant implementation of disposable technologies. In fact, many of the associations are global. ISPE has both a European and Asian as well as an American affiliate. I think the BPSA is increasingly active in Europe, as is the PDA and so on.

Lisa Crossley: I found much more of a pull for our disposable technology in Europe than in North America. And I’ve noticed that the EMEA has actually pushed much more aggressively for companies to implement disposables than the FDA has. In the early 2000s, the EMEA pushed Novartis to change over its flu vaccine plant to almost entirely disposable processing technologies. The FDA did nothing comparable with any major manufacturers. I think Europe has actually been ahead of us in terms of a pull for implementation of disposables.

Jim Robinson: Vaccine manufacturers have been early adopters of single use, primarily driven by the flu vaccine incident in the United Kingdom. So the EMEA has been very much in favor of that. Rapra [Smithers Rapra Technology Ltd., a UK consultancy] is primarily a European organization, but they invited BPSA to come and speak at their meeting. So we’re starting to have more interaction. Most end users are global companies. Most suppliers are global companies. So there’s a lot of activity in Europe as well as the United States.

Miriam Monge: I think the vaccine point is very important because the scale of vaccines lends itself extremely well to disposables implementation. Certainly a significant portion of vaccine capacity for a long time was based in Europe. That is, of course, changing now.

Jerry Martin: But those were the first companies to go into significant adoption of disposables within commercial manufacturing. Some other early adopters — both in the European Union and the United States — were biotech companies making proteins that were poisoned by metal ions. They had to make their processes all in plastic.

For mammalian processing, the economics and commercial viability of disposables have been broadly demonstrated. But on the microbial side, have you seen any successful applications with the kind of protein recovery you can get from stainless steel systems?

Jerry Martin: There are many applications for disposable bioreactors using bacterial systems. It’s certainly an area where there’s a lot of research and a lot of development. And I think we’ll see a lot of improvement, also in larger scale. It has started already.

Lisa Crossley: I feel compelled to address that one as a chemical engineer. There are always going to be constraints on single-use technology for large-scale microbial production because it is difficult to get the agitation. And there are issues around the exothermia of reactions with high cell densities. But there has been a lot of disposable reactor technology implemented at smaller scales, <5,000 L. There are fundamental engineering issues that I'm confident the disposable bioreactor companies will address. But that's definitely an area that's still under development.

What are the top three metrics to describe the successful implementation of single-use technologies?

Lisa Crossley: If you’re able to successfully manufacture your biologic and make a transition to a disposable, there are a number of different metrics to look at. Among those are ease of implementation. Part of that will come down to time, then economics, and then performance. Consistency of performance relative to reusable technology is also important.