Single-use technology has become an integral part of biopharmaceutical manufacturing. While the industry is aware of the proven benefits of single-use systems compared with traditional stainless-steel technologies, it is only recently that the paradigm shift observed in upstream processing is making in-roads to downstream processing, which is dominated by chromatographic separations and membrane filtrations.
In this roundtable, experts discuss the advances in single use for downstream applications. Participants include Jerold Martin, senior vice-president, global scientific affairs at Pall Life Sciences, Biopharmaceuticals; Michael LaBreck, global product manager at Novasep; Peter Rogge, vice-president, USP production at Rentschler Biotechnologie GmbH; and Uwe Gottschalk, vice-president, purification technologies at Sartorius-Stedim Biotech.
Single use in downstream Processing
BioPharm: How has single-use technology advanced downstream processing?
Rogge (Rentschler): There has been enormous progress during the past five years, for example, the availability of single-use unit operation systems for all relevant process steps such as chromatography systems, filtration systems, and mixing systems, as well as optimization of already available materials such as tubings, connectors, and bags among others. Moreover, the robustness of systems and materials has been improved. Today, even utilization of single use in market campaigns is feasible.
LaBreck (Novasep): Early single-use technologies (1990s through 2000s) were primarily for storage and transportation of buffers and media, which are very simple applications. Next, single use moved into upstream technologies for cell culture. During the past 10 years, single-use technologies have become increasingly popular for downstream applications including filtration, tangential flow filtration (TFF), and chromatography, which are all more complex operations. Of particular interest is the application of single use in TFF. Traditional reusable TFF systems are fairly labor-intensive, with many cleaning and flushing steps required before and after the TFF process. To give you a real-life example, a customer developing a monoclonal antibody purification process came to us looking for a solution for his TFF step. The implementation of single use for this TFF step removed several non-value added steps of cleaning and flushing, thereby, reducing labor by 50% and reducing buffer usage by 75%.
Gottschalk (Sartorius): Perhaps I should start with the bigger picture. In the current competitive environment, the adoption of innovation such as single-use technology is not just a question of efficiency and cost reduction but a question of ultimate success. For smaller companies that want to bring a product to the market without seeking support from big partners or CMOs, a single-use set-up is the only realistic scenario for early-stage manufacturing as costs are shifted from capital to (controllable) variable expenses. Many companies are developing a competitive edge by taking advantage of single-use unit operations and whole facilities and projects are mushrooming around the globe and especially also in economies that have a certain backlog in the commercialization of biopharmaceuticals and vaccines. Meanwhile traditional companies are joining the race as they face the requirement to decentralize manufacturing of new drugs with fast and seamless process transfer and flexible capacity adaption.
Regarding the trend towards disposable and single-use technology, there is little difference between up- and downstream processing and all unit operations are under investigation. With the exception of few unit operations, today’s question is not whether specific steps can be operated under this new paradigm but whether they makes sense in a particular process.
Martin (Pall): Single-use filtration and biocontainer systems have reduced capital costs for buffer preparation whereas single-use membrane chromatography (Q membranes) has become a standard platform along with virus filtration for final polishing (i.e., removal of residual host cell proteins, DNA, and viruses), reducing process time and buffer volumes versus traditional Qresin columns for polishing. We also have single-use TFF for concentration and diafiltration, which reduces process turnaround to improve productivity.
Advantages and limitations
BioPharm: What are the advantages and limitations of single-use systems in downstream processing?
LaBreck (Novasep): A primary advantage of single-use technologies in downstream processing is the reduction of labor, which is a major cost saving. Additional value, however, comes from the reduction in process cycle times and a significant increase in productivity of the downstream process. Higher product throughput is possible with single-use technologies as a result of the shorter cycle times.
In the case of TFF operations, a specific advantage can be the reduced cost of goods compared to reusable equivalent. For example, by optimizing the manufacturing process of our single-use cassettes, we have reduced the cost of each of them by four- to five-folds and maintained excellent performance. Clients looking for single-use TFF solutions are not interested anymore in only having a single-use product or system; competitiveness is also a crucial point.
Another important advantage is found when studying production context. Single-use technologies are of crucial interest for activities implying multi-product manufacturing, with no visibility on when the next batch will be commissioned, or for markets requiring a high flexibility in the process (mainly CMOs and CROs). For TFF operations, the advantage of a single-use, competitive TFF cassette is obvious for clinical-batches production since you have to control costs and move quickly.
To understand the advantages of single-use technologies, people have to look through a multi-face prism implying labor and goods cost reduction, considering also their own activities (clinical-batch production, operation of multi-products facilities, etc.)
A disadvantage in current single-use systems is limitation in the scale of operation. While disposable bioreactors for cell culture in upstream application are available up to 2000L, the current downstream technologies in single-use are struggling to keep up with these capacities. For very large-scale downstream processing, it is difficult to find pumps, piping, and probes that are actually single-use. However when you stay at development-scale, pilot-scale, or for small commercial production, some fully single-use systems (such as the Sius TFF Skid) do already represent good solutions for single-use implementation. This scale-related limitation can also be partially solved when systems are used in continuous mode.
Gottschalk (Sartorius): Single-use downstream processes can be designed and set up in a much shorter time-frame than conventional facilities and for a fraction of the capital expenditure. Individual batches can be run with preconfigured assemblies that come pre-rinsed and even pre-sterilized where necessary and this plug-and-play mitigates the risk of operator errors and adventitious contamination events. Both of these advantages support the manufacturing of clinical material and/or vaccines on demand and are less dependent on local infrastructure--GMP and single use are a natural fit, which therefore provides additional tailwind.
When it comes to large-scale manufacturing and long-term market supply, the considerations may be completely different. Especially for legacy products that are required in multi-ton amounts, stainless-steel facilities provide an economy of scale that will not be met by single-use processes. In this area we will see, however, an increasing trend towards single-use steps such as disposable chromatography in polishing and I would like to remind us that most filtration steps are handled this way for many years.
One area that benefitted from these new capabilities is the manufacturing of antibody-drug conjugates. In this case, it is not only the product that needs protection from the environment but most importantly, the operator also, and single-use assemblies can provide a high level of containment without the need of reliable and, therefore, extensive cleaning procedures.
Martin (Pall): Advantages are reduction of capital expenditures, elimination of cleaning/cleaning validation and sterilization/sterilization validation for increased productivity and facility utilization, reduced energy costs, carbon footprint, and water utilization. Limitations are the increased supply and inventory requirements, lack of clarity on specific regulatory expectations for extractables and leachables data, and risk assessement.
Rogge (Rentschler): The advantages are that single-use systems are easy to implement, they require low capital investment, and can increase turnover rates and reduce maintenance costs. The limitations include size restrictions, remaining risks due to the handling of disposable material, insufficient data for extractables and leachables, enormous efforts needed for training of staff, lack of integrity testing methods for bags, and the logistics.
BioPharm: What are the key considerations when switching to single use downstream processing?
Martin (Pall): You need to consider actual cost factors, especially when switching rather than moving to a new facility. There’s also the greater dependency on supply chain that must be taken into account as well as the potential for dual sourcing. Component selection is important and can be a challenge. And you need to make sure that you have sufficient extractables and leachables data.
Gottschalk (Sartorius): Companies that select technologies with a high degree of exchangeable components, are exposing themselves to a certain risk due to the increasing complexity involved. This risk is, however, only gradually different from any kind of raw material and consumables that represent a critical component of the supply chain. Apart from reliable material clearance procedures, the sustainable security of supply is absolutely crucial for a successful adoption of such concepts. Some of these challenges may be new to the biopharmaceutical industry but they are very well known and professionally addressed in other industries.
LaBreck (Novasep): A major consideration when switching to single use is the adoption in a new facility versus an existing facility. An existing facility may have traditional reusable capital equipment for many downstream operations. Often, a hybrid of reusable and single-use operations is common in an existing facility. The hybrid approach takes advantage of the utilization of the capital equipment in these unit operations. A good example is CMOs and CROs activities, characterized either by a limited visibility on next campaigns or by the treatment of multiple products. The hybrid approach can be a good way to combine high capacities with reusable technologies and strategic flexibility with single-use technologies.
Conversely, in the design of a new facility, existing capital equipment is not a limitation. In this case, single-use technologies can be more fully utilized. Complete, fully disposable downstream processes have been implemented in some of the major biotechnology companies. Often times, the requirements for process utilities (water, buffers, and steam) are significantly reduced in the new facility, single-use design. Reducing the dependency on these energy-intensive utilities can reduce the total carbon footprint of the downstream process.
Secondly, the way the process is operated is not the same. The process itself has to be adapted to single-use and a consistent quality-assurance system should be implemented, for example, do the probes or similar devices meet authorities’ requirements? How do you deal with bio-burden?
Finally, it is crucial to make sure the operators are trained to use single-use technologies. For example, many leaking issues are due to a misuse of the single-use devices. Then, it makes sense to adapt procedures and protocols, including clean-in-place (CIP) procedures, taking account of the specificities of single-use technologies.
Rogge (Rentschler): Companies that intend to switch to single use must consider the logistics, supply chain, supplier qualification and quality agreement with suppliers, extractables and leachables, size limitation of unit operations, purpose of utilization whether for toxicology, Phase II or Phase III or even for market supply, waste logistics, and training of staff.
BioPharm: What aspects of single use need to be further improved for downstream processing?
Gottschalk (Sartorius): Looking at the list of unit operations in bioseparation, not all technologies are currently available in a single-use version, for example, large-scale centrifugation or Protein A chromatography in monoclonal-antibody manufacturing. Protein A chromatography is the gold-standard in antibody capturing and I don’t see this changing in the near future. Providing this in a single-use set up is a big challenge, if not impossible. But before we change this, we have to confirm its relevance. Single-use should not be a mantra that ends in itself. There will always be a process, a scale, a molecule, an application, or a price point where it just does not make any sense.
LaBreck (Novasep): Advance-ments in cell-culture productivity and high-titer output from upstream operations have put a strain on downstream processes to keep pace. Many downstream processes are dependent on flow and pressure. Process-control instrumentation can be limited in availability for single-use applications for larger-scale operations (> 500 L). At present, there has been a limitation of the scale of operation where single-use technologies can be used in downstream processing. Further advancements in pumping and instrumentation technologies (pressure, flow, and measurement) will be necessary to expand the scale of operation in downstream unit operations. Extractables and leachables are of course a subject of high interest nowadays. It is clear that a better understanding of these elements will be required by every stakeholder (vendors, users, and regulatory entities).
Martin (Pall): Areas for improvement include standardization of supplier’s extractables and leachables data packages, quality agreements between users, suppliers and sub-suppliers, increased transparency of supply chain and supply assurance.
Rogge (Rentschler): The robustness of single-use systems needs to be increased. It is important that suppliers deliver more relevant data concerning extractables and leachables. Applications for integrity testing also need to be improved.
—Moderated by Adeline Siew
This article appears in the BioPharm International 2014 Single-use Systems eBook.