March 1, 2012 (Vol. 32, No. 5)

An Exclusive Q&A with Our Expert Panel

In the Biomarket Trends column in the January 15 issue of GEN, Eric Langer from BioPlan Associates reported that about one-third of bioprocess equipment manufacturers are investing their R&D dollars into the development of single-use/disposable equipment. This is another clear indication that single-use bioprocess systems are increasingly being adopted by biopharmaceutical drug manufacturers.

The benefits of single-use include more favorable manufacturing costs and less complicated validation requirements. Size and scale issues remain as limits to the greater adoption of disposable systems, but equipment manufacturers are working to overcome these barriers.

The bottom line is that single-use technology is here to stay. This month’s special “Tech Tips” feature on Single-Use Technology drives this point home. Interviews with scientists and business professionals from biopharmaceutical companies and contract manufacturing firms discuss why they have gone the disposable route, how they use the technology, and what hurdles need to be overcome to make single-use manufacturing operations even more efficient and economical.

Scientists interviewed for this special feature included Mike Jenkins, Ph.D., general manager of Catalent Pharma Solutions; Timothy Matthews, founder and CEO of Pristine Bioproduction; Morten Munk, vp, business development of CMC Biologics; Serge Runser, Ph.D., head of global biopharmaceutical operations at Novartis Pharma; Stefan Schlatter, Ph.D., associate director of cell culture development at Boehringer Ingelheim; Matthew P. VonEsch, manager of manufacturing, fill-finish at United Therapeutics; and Mark F. Witcher, Ph.D., consultant at IPS—Integrated Project Services.

We believe our Tech Tips section on single-use will help you decide on how to best use this technology for your own specific needs.

How long has your company been involved with disposable bioprocess equipment?

Dr. Jenkins: We currently operate 100 L process development and 200 L stainless steel cGMP trains, but are expanding our capabilities for more lines and a larger scale.

We have used Wave bioreactors (GE Healthcare Life Sciences) for seven years for non-cGMP production and for five years as part of our cGMP bioreactor trains in scale-up vessels. During our expansion planning, over a year ago, we undertook a thorough evaluation of single-use bioreactor systems.

After evaluating several units and integrators, we decided to work with Thermo Fisher/Hyclone SUBs using Finesse Solutions as the integrator. Today we have one unit onsite, and decided to build our new facility with multiple SUB trains and no stainless steel vessels.

Catalent’s biotech facility uses disposable technology throughout our Phase I/II mammalian cell culture operations. We use Wave reactors and SUBs to produce recombinant proteins, as well as pallet tanks and other “bag” technologies throughout our purification processes. We do not work with nonmammalian systems, primarily because we have a gene insertion technology (GPEx®) to engineer mammalian cells to express biopharmaceuticals.

Matthews: We have not yet begun production, but our company intends to be truly end-to-end disposable. Major disposable unit ops include mammalian (CHO) seed train, inoculation train, production bioreactor, depth filter, buffer and media dissolution, chromatography, TFF formulation, and freezing of bulk drug substance.

Munk: We have gradually increased the use of single-use equipment over the last eight years, with a very steep increase over the last four years. The main applications are buffer and product storage, filters, SUBs, buffer mixing, membrane processes, sampling, and development activities. We try to apply single-use for as many applications as possible, from the seed train to final fill of the API for both microbial and mammalian projects. The only exceptions are microbial fermentations, harvest of microbial products, and limited single-use for chromatography.

Dr. Runser: Our large-scale cell culture facility for recombinant protein production, located in Huningue, France, started using disposable equipment in 2005 when it began operations.

The Huningue plant is fully GMP compliant. Its main disposable solutions include bags for media and buffer storage, and fully disposable filter systems incorporating disposable connectors and tubing. We use disposable bags for intermediate storage of product and for final storage of the drug substance.

Dr. Schlatter: We have been using disposable bioprocess equipment for more than 10 years, since 2007 for cell culture. The equipment we use consists of Wave bioreactors, media and buffer bags of up to 1,000 L, shake flasks, harvest filters, filter capsules for downstream processing, the ATMI media formulation system, 100 L/500 L SUBs, and bags for intermediate and bulk drug substance storage (up to 1,000 L). We employ disposable process equipment for mammalian cell culture, and downstream processing up to fill and finish.

VonEsch: Our company began using disposable technologies for mammalian upstream and downstream processing in 2006. In 2009, with the footprint of our sterile filling process under way, we began exploring the possibilities of bringing these technologies further down the line to our sterile fill-finish production.

Dr. Witcher: Disposables have been used for cell culture inoculum development for many years. The use of disposables for large-volume cell culture systems is increasing. Many companies are exploring using disposable bioreactors up to the 1,000 liter scale, although skepticism remains regarding volumes above 500 liters.

Disposables are most attractive for operations that require a small number of low- to medium-volume lots, such as clinical manufacturing, or very high-yield commercial processes such as some vaccine manufacturing.

Does adopting disposables require “buy-in” from top management?

Dr. Jenkins: Substantial buy-in was required as we had already purchased and possessed larger stainless steel tanks for cell expansion. However, since GPEx provides advantages in speed from cDNA to master cell bank, we needed to continue to foster that concept as we built out our expansion. This ultimately led us to single-use manufacturing.

We had several additional factors to build the case with management to adopt a single-use manufacturing strategy:

  • Facility cost based on the infrastructure required for a fixed system
  • Speed of installation of a single-use system vs. stainless steel reactors
  • Increased efficiency with the elimination of cleaning in between runs
  • Increased flexibility

Additionally, we demonstrated that our fed-batch manufacturing processes were easily reproduced in SUBs with no change in key product or process parameters.

It was critical to our initiative to obtain a “loaner” SUB for process evaluation and to familiarize ourselves with its operation. We were then able to make a more informed decision. We have already begun training our staff in this new manufacturing strategy.

Matthews: No, particularly when it provides the luxury of designing the facility and processes from the ground up, as is the case with our company.

Munk: The main concerns for a CMO are controlling risk of cross contamination and minimizing changeover times and activities, such as cleaning and equipment setup. Our technical management group has extensive experience and provides a high level of support.

CMC has also applied appropriate project-management tools for all single-use projects, including stakeholder management and focus on establishing good relationships with all partners. Suppliers are key partners, and close collaboration with them has been crucial to successful implementation of single-use processing.

Dr. Runser: Integration of disposable solutions requires approval within our standard business processes. However, as a company we are continuously investing in advanced disposable technologies, which will help enhance and further improve overall manufacturing processes and outcomes.

Dr. Schlatter: At our company, we needed to address whether a disposable system fit into our current facilities, the costs, and the likelihood of regulatory acceptance (especially for leachables and extractables). We initially performed a non-GMP technology evaluation and implementation at a small scale. With growing experience and increasing acceptance in biomanufacturing, we finally adopted single-use bioprocessing as standard.

VonEsch: Before proposing these technologies, we sat down and performed a thorough cost vs. benefit analysis, which made convincing top management much simpler. The flexibility and cost savings of disposable technologies ultimately won them over.

Dr. Witcher: Buy-in is typically required from top engineering management when disposables are considered for new process development projects. I think resistance increases as you get up the management ladder. However, the advantages of disposable systems are evident, and resistance should drop as usage continues to increase.

I do not perceive buy-in as a problem for future applications in most companies. In some of the more progressive companies, buy-in would be required if nondisposable processing equipment were to be considered.

What types of economic analysis should one conduct before adopting single-use equipment?

Dr. Jenkins: We determined that we would incur lower infrastructure costs—for example the use of less steam and water, lower capital expenses since we would not require clean-in-place, lower risk of cross contamination, and improved safety. However, the higher consumable cost of bags and assemblies partially offsets the positives gained by the reduction of fixed costs.

Matthews: The major advantage of adopting disposables is facility cost reduction. One simply needs to compare the cost of a traditional stainless steel facility to the disposable facility and the answer becomes clear. Expenses of disposable equipment are far outweighed by reduced capital depreciation.

Munk: We conduct a thorough economic evaluation of all single-use projects, including risk analysis and opportunity costs during reconstruction of our facilities to better take advantage of single-use technologies. We only engage in projects where the ROI is double-digit percent.

Dr. Runser: Integrating any new disposable solution requires a successful and thorough evaluation. If the available disposable solution meets internal and external technical and regulatory criteria, it usually has a superior outcome compared to standard stainless steel equipment. However, large-scale GMP biomanufacturing still has a lot of technical limitations that slow down wider use of disposable solutions.

Dr. Schlatter: Whatever analyses are done, one should consider factoring in flexibility and customer attractiveness. Disposable technologies are becoming more and more economically attractive, especially for facilities producing multiple products and with many changeovers.

VonEsch: A simple cost vs. benefit analysis based on the cost of traditional CIP/SIP systems against fully disposable technologies showed that the up-front costs of disposables would be slightly greater, simply because of order quantities to take up gaps in lead times. However, a true savings in time and money, especially with regard to use with multiple products, quickly became evident.

In our situation we currently fill three different products with volume ranges of 10x from one another using a single disposable assembly configuration. The flexibility these systems provide gave us the ability to conserve continuous costs by the elimination of cleaning validation, development work, while reducing changeover times from each production batch.

Dr. Witcher: For small-scale clinical and commercial manufacturing, the cost savings are relatively obvious and little economic justification is required. For manufacturing a large number of lots, an economic analysis is useful to justify the higher variable costs associated with disposables versus amortizing the cost of fixed stainless steel CIP/SIP systems and validation costs.

Economic considerations tend to start the disposable discussion, but when decision time comes, reliability of the components and the ability to reliably get the necessary components tend to become important factors.

What are the limits for adopting disposables?

Dr. Jenkins: I think there will always be scale issues. The handling of large units becomes difficult, for example a 20,000 L bag. I am not sure how much that will actually limit the use of single-use systems given the drive toward higher titers and smaller batches.

But the higher titer does cause downstream bottlenecks. Today this will be one of the more limiting factors in terms of speed and cost of goods. There has been substantial improvement in upstream processing but the development activities will need to improve in purification to exploit all these improvements fully.

Matthews: If the same product is being produced frequently at scales greater than 2,000 liters, the economics for disposables start to lose their advantage. If 2,000 liters isn’t enough capacity for commercial production, one could consider perfusion cell culture. But this decision needs to be made early on because the switch from fed batch to perfusion is substantial, affecting many areas such as process development, regulatory filings, and with the risk of changing product characteristics, the potential need for new clinical trials.

Munk: The major limitations for single use are technical, mostly with processes that represent extreme conditions from the perspective of the disposable equipment.

Some related factors include volumes over 3,000 L, high temperatures, high pressure, high flow, aggressive chemicals, or high physical power input. Plus vendors still have difficulties offering cost-effective solutions for chromatography.

Dr. Runser: Today, the appropriate use of bags without stirring systems is still limited to maximal volume of approximately 2,500 L. Additionally, stirred bag systems are still cost-intensive and relatively cumbersome to operate in an industrial GMP environment, even below 2,000 L.

To be more precise, stirred systems frequently need the use of online pH and conductivity probes. However, the available probing systems are currently not robust enough for routine usage.

Also, disposable filtration systems partially still have pressure limitations. And nonsterile filters cannot always be sterilized in place by steam or a caustic solution, which prevents their use in a fully closed manufacturing environment.

Dr. Schlatter: One limit is the scale of bioreactors, currently around 2,000 liters, and the economic appeal of stainless steel for supplying larger volumes of a single product.

VonEsch: The major limitation I see with disposables with regard to sterile filling will remain tubing compatibility and pump life.

Another will be the prices vendors may look to charge for such systems. “Frontier” users will incur expenses greater than might be expected before these systems become more widely adopted. But unfortunately, it appears that baseline pricing only increases over time, without correlation to widespread adoption. Vendors could possibly out-price themselves before the industry recognizes the true benefits.

Dr. Witcher: The obvious limit is the scale. About 1,000 liters seems to be the practical limit, although larger volumes may be possible. The major advantage of disposables comes from their use in portable, skid-mounted systems that can facilitate the change-out of process equipment that can be used to bring new processes into an operating area quickly and efficiently.

As processes become lower volume and more efficient, for example at higher yields, disposables will become more attractive. Another obvious limitation is fermentation, where heat transfer and mixing are major issues.

What are the key hurdles to overcome in adopting single-use processing?

Dr. Jenkins: Managing bag inventories can be challenging. A greater focus is needed throughout our supply chain. Sourcing and quality need to re-align to handle the change in manufacturing strategy. Auditing and partnership with our suppliers is a crucial function in ensuring quality and supply. Hence, supplier selection becomes significant in the overall single-use strategy. Vendors have satisfactorily addressed such issues as leakage, extractables, and leachables.

Matthews: The major hurdles are the investment cost in existing infrastructure, and the characterization of extractables and leachables. Also important are status quo (general fear of change) and supply chain security.

Manufacturers are concerned whether disposables are truly capable of replicating validated processes in disposable format. This relates to material of construction changes, and the ability to reproduce process control inside of the customer’s characterized and validated operating limits, especially pertaining to critical process parameters.

Munk: We believe the regulatory concerns to be the dominant hurdle industry-wide. The lack of experience by the regulators makes it difficult to address the most important risks, both real and perceived.

Furthermore, suppliers must realize that the end-users are actually outsourcing part of their quality system to them. Thus, the suppliers have to prepare for more audits, for which they must demonstrate GMP-compliant quality systems, including CAPA systems, change control, etc.

Additionally, how suppliers control their raw materials is of great concern, as changes in raw materials might lead to changes in extractables and leachables, which could affect process performance (for example cell growth) or the patient risk profile.

Dr. Runser: Routine use of today’s available disposable solutions still requires a lot of manual handling by well-trained operators, which limits single-use equipment in high-throughput facilities.

The risk of failure, caused either by material deficiency or by operator errors, is still higher compared to standard stainless steel systems. Therefore, the use of disposable systems in a large-scale facility is still preferred for process-supporting activities such as buffer and media storage, rather than for usage of product-containing solutions.

Dedicated disposable solutions still require a long lead time before first use in a GMP environment. In addition, dedicated bag configurations can show more deficiencies than off-the-shelf products. Novartis and its partners have worked to improve inspection and handling procedures to assure a smooth use of disposables in our large-scale manufacturing facility.

Dr. Schlatter: Second supplier concepts are one key challenge: the systems of different manufacturers need to become interchangeable. Regulatory acceptance and experience with the equipment are additional hurdles.

VonEsch: The biggest hurdle to overcome is legacy equipment, and the fact that drug and equipment manufacturers tend to push and develop what they know. Once vendors and manufacturers adopt these technologies and offer simpler implementations, they will grow.

There are five key components to adopting single-use equipment: educated drug companies, educated equipment vendors, educated disposable manufacturers, educated building design/engineer firms, and lastly regulatory oversight buy-in.

Today we have a mix of these components. But wider adoption of single-use will require that stakeholders understand the favorable applications in all aspects of drug manufacturing.

I would say that the smaller drug manufacturers are driving most of these efforts currently, companies that understand the costs, benefits, and flexibility of not just the systems but the manufacturing plants as a whole once these systems are in use.

Dr. Witcher: The reliability of single-use systems is of concern. The possibility of leaks and broken bags are perceived to be a problem. In addition, the ability to get special single-use items from vendors is also a concern.

How can vendors of disposable bioprocessing equipment improve their products or expand their applications?

Dr. Jenkins: They could do a better job providing sterile quick connects, and in linking upstream and downstream production in essentially a single, closed, disposable system with enough flexibility to support a variety of sizes and purification technologies. Complete flexible cGMP manufacturing in gray space would take this technology to the next level.

Supporting customers through the SUB learning curve is important. The adoption of single-use processes is about more than just ordering a system. Since adopting this technology involves a complete change in manufacturing strategy, a higher level of customer service is essential.

Even though the multisourcing of bags is a big issue from a business continuity perspective, parts availability, and having access to a top-tier service group, are vital.

Matthews: Competition is needed in all major unit operations to allow for second sourcing. Having suitable second sources of supply in GMP manufacturing is critical. There is still room for suppliers to innovate and obtain market share from the suppliers that feel they have a monopoly on their respective industry-leading equipment. This is particularly true with single-use bioreactors, chromatography skids, TFF skids, and fabricators of disposable sensors.

Munk: They should work even further together to ensure that different suppliers’ components may be easily assembled for the final manufacturing solution. This includes the connectors, but also that the components they use have similar properties, including extractables and leachables profiles.

Dr. Runser: In addition to the improvements I have already mentioned, disposable equipment is often based on proprietary standards that prevent interchangeability. However, commercial GMP manufacturing needs the availability of back-up solutions to assure its supply chain in case of issues. Therefore, the industry needs to define a set of basic standards to allow further adoption of disposables in commercial GMP environments.

Dr. Schlatter: The products can be improved by performing detailed studies on leachables and extractables, offering customization and compatibility with other vendors, and improving the accuracy of disposable sensors.

VonEsch: While drug manufacturers ultimately need to accept new technologies before implementing them, I feel it is up to the disposable equipment vendors to demonstrate that their products are viable and effective alternatives to stainless steel processing. The more involved and educated equipment and disposable manufacturers become, the better they will serve their clients’ current and future needs.

Dr. Witcher: The most important point is to assure the reliable supply of high-quality disposable components. Financial stability and the size of a disposable vendor is important in selecting a supplier of disposables.

Quality control and assuring that all components meet performance requirements is also very important. A broken bag or two goes a long way to making development people hesitant to use disposable systems. In addition, incorporation of new sensor technology for measuring critical outputs will help in the future.

Mike Jenkins, Ph.D., is general manager of Catalent Pharma Solutions. Timothy Matthews is founder and CEO of Pristine Bioproduction. Morten Munk is vp, business development of CMC Biologics. Serge Runser, Ph.D., is head of global biopharmaceutical operations at Novartis Pharma. Stefan Schlatter, Ph.D., is associate director of cell culture development at Boehringer Ingelheim. Matthew P. VonEsch is manager of manufacturing, fill-finish at United Therapeutics. Mark F. Witcher, Ph.D., is a consultant at IPS—Integrated Project Services.

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