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.