The answer depends on the resourcefulness and creativity of the end user. Many studies have focused on cost of goods savings (COGS), but development companies, contract manufacturing organizations (CMOs) and large pharmacuetical companies all have their own specific accounting to report these costs. Minimal COGS savings but a significant value realized in flexibility is becoming prevalent with large pharma, while smaller biotech companies are realizing direct cost benefits from single-use technology. Advances in cell culture have increased product titers to make 1000L to 2000L single-use bioreactors a viable option for commercial manufacturing. But there needs to be real value in switching from stainless steel at these larger scales. Issues with extractables/leachables are still a significant barrier to overcome in clinical and commercial manufacturing. While there may be cleaning, validation and labor savings by switching, those savings may be significantly less after regulatory concerns are addressed. The most costly and time-consuming stainless steel unit operations need efficient single-use technology solutions. Single-use systems need more complex controls and functionality to handle current stainless steel processes without limitations.
Currently single-use technology has moved on from small-scale bioreactor runs, media & buffer preparation and product hold to a completely single-use upstream process with many downstream options in use at the clinical scale. Many biomanufacturing pipeline development approaches favor single-use bioreactor technology mainly due to flexibility, product safety, capital investment advantages and reducing time to market. Companies can take advantage of reduced costs and high plant utilization rates to produce multiple products at the same site. The flexibility advantage with single-use systems can reduce downtime between same product batches to mere hours and different product changeovers to days. In stainless steel facilities, the high level of validated procedures that need to be in place for both same product and multiproduct changeovers to address safety concerns of cross contamination and sterility are costly and time consuming. Stainless steel facility product changeovers can take up to half a day for the same product and potentially weeks for different products. And, contamination of a stainless steel cell culture facility can be devastating with lost production capacity until the contamination is removed. Contract manufacturing organizations have been quick to implement single-use technology for these exact reasons. These clear advantages over stainless steel options make single-use technology at the clinical production scale a growing industry providing a good business decision to make in-house biomanufacturing available to both large and small biotech.
Even with a growing acceptance of single-use manufacturing technology across the biotech industry, there is a surprisingly high aversion to the risk associated with disposables due to leachables and extractables, concerns of bag integrity, high consumables costs and materials of construction incompatibility with process fluids. The materials of construction (MOC) are characterized by the vendors for the transfer of trace contaminants from the product contact surfaces, but every case will likely need additional testing under actual processing conditions. The contaminants arise from the degradation of the MOCs due to the sterilization procedure (gamma irradiation) and additives used to make the polymer films. The product residency time within the single-use material can become a critical factor. This is most evident in the sometimes detrimental effect on cell growth due to plastic film properties of the single-use containers used in the bioreactors. These issues will have to be overcome by vendors in order to gain a wider acceptance. Development of new inert materials of construction and in-depth understanding of their interaction with biologics processing fluids and products will be critical to gain new customers. Part of this problem will be addressed as regulators become more receptive to single-use applications in clinical and commercial production. This could be expedited with collaboration from vendors and their customers with a large amount of supporting data to provide a broad understanding of the appropriate process conditions compatible with the MOCs and technologies. Although single-use technology reduces a significant amount of cleaning and product change-over validation and procedures, from a regulatory standpoint there will be issues with leachables, sterile integrity and process robustness. Product companies will have to manage this with more diligent risk assessment and analytical testing.
Companies with large investments in stainless steel capacity will hold off on converting to single-use technology. Companies with established stainless steel capacity usually run processes as similarly as possible from process development to commercial production to mitigate issues with tech transfer and scale-up. But even these companies often invest in single-use technology for facility expansions. A discrepancy exists between scale-up factors between development-sized, single-use rocking platform bioreactors and large-scale stainless steel bioreactors. This has essentially been overcome with the introduction of the stirred tank single-use bioreactors. Stirred tank single-use bioreactors have similar scale-up parameters and mixing attributes as their stainless steel counterparts, adding value in areas of tech transfer and scale-up compared to single-use rocking platforms.
At the commercial scale, companies invested in stainless steel equipment have another significant factor to consider. Whereas validation and fixed capital costs are reduced for a single-use facility design, the overall consumables waste costs are increased. At large scales, the consumable costs will outweigh the savings contributed by single-use technology. Another problem at large scale is that the media/buffer preparation time is not significantly reduced because of increased transfer time due to the current pump/tubing configuration of single-use technology. Once buffers have been prepared, the pumps provided with most disposable systems take significant time away from the time saved from cleaning. Only hypothetical data exists for large-scale, single-use facilities. It will be interesting to determine the true utilization rate of a single-use facility comparing the quick turnaround versus the extra risks associated with bag integrity and process robustness.
The critical activities at larger scales are affinity chromatography and any ultrafiltration/diafiltration (UF/DF) steps. The reduction of cleaning and steaming in other process steps such as cell culture and media/buffer prep is nearly insignificant if these critical steps are still bottlenecks. The protein A step takes a huge amount of processing time and expense. The solutions for this appear to be cheaper single-use media or a faster more efficient process alltogether, like membrane absorbers. The solution is developing an inexpensive material for single-use that works as well as Protein A. Currently, there is a particular single-use affinity resin that promises double the capacity of Protein A at a lower cost. Membrane absorbers have found single-use success in the removal of trace contaminants (polishing) with a flow through process. Membrane absorbers for bind and elute applications are being developed for both cation and anion exchanges. Assuming these membranes are about five times as efficient in binding capacity compared to what is currently available, membrane chromatography can be a viable single-use option. The available UF/DF single-use systems do provide minimal set-up and cleaning times and reduce the risk of cross-contamination between runs. But the issues with fluid transfer at larger scales keep the usefulness of these systems to small volumes. A surprising relatively new technology was single pass tangential flow filtration (TFF). A company was able to demonstrate 30x purified MAb concentrations, in-process volume reduction, in-line salt reduction and high concentration formulations all with single pass TFF. This technology is particularly useful for quickly concentrating a feed stream to Protein A chromatography because the higher the MAb concentration in the feed the higher the dynamic binding capacity of the Protein A and the lower the residence time of the product in the column. This enables Protein A unit operations to be run more efficiently. Although this technology is not available as a disposable option currently, it is planned.
The 1,000L to 2,000L scale certainly has challenges for single-use technology to be comparable to stainless steel. Single-use storage vessels and bioreactors at and over the 1,000L scale become limited in portability and have an added risk of the disposable container’s materials of construction sensitivity to pressure and temperature which can lead to the bag being compromised. This, coupled with increased fluid transfer times, suggests that large-scale, single-use systems may not yet be appropriate for replacing fixed-tank buffer/media preparation and seed cell culture systems in large volume manufacturing facilities. More precise process control in single-use systems is needed compared to the controls available in stainless steel. The responsiveness of process controls has a big impact on cellular behavior. Disposable in-line process monitoring is essentially limited to pH, dissolved oxygen and temperature. Anything more complex such as substrate monitoring becomes more of a custom specification. Reliance on suppliers for consistent supply especially with customized design and validation support is strongly needed.
Single-use technology has some very good niche commercial markets to expand into. A good market for single-use systems is the small-scale production of cytotoxic products.The intense containment, cleaning and validation associated with these products can be mitigated with single-use technology. Another good space is vaccine production. The concept of setting up a vaccine production line nearly anywhere in the world is very appealing. Some companies have created partnerships to provide emergency vaccine production for outbreaks. These modules are supposed to house up to 2000L bioreactors and are fully customizable for both upstream and downstream processes. The models are designed to be completely contained for use in unclassified spaces. The modules were also designed for easy retrofitting to make them useful after emergency use. This concept has value for both responding to an emergency crisis and for enabling access to biomanufacturing for smaller companies to help develop their pipeline. The models will be more affordable, quicker to build and easier to maintain compared to building a new facility or renovating an existing one.
Single-use bioreactors are in use at the commercial scale (i.e., erythopoietin & capromab pendetide), but getting from using a fully single-use upstream to a fully disposable single-use process is another challenge. One certainly could produce a product in a completely disposable format. But does the current single-use technology provide the necessary value? There are many options for cell culture but not many for UF/DF and chromatography. Basing a decision solely on capital and cost of goods savings seems inappropriate. The focus should be on options to move products through the pipeline. Single-use options can certainly do this at the clinical level but if commercial scales require use of stainless steel there may be issues with scale-up and process reliability moving from single-use technology. Expediting products to the market place should be viewed as more valuable than reducing cost of goods. Clinical and commercial biologics manufacturers need to work with vendors to address these issues and understand what needs to be accomplished for single-use technology to achieve commercial GMP manufacturing.
Author Biography
Rick Stock has worked as a specialist in biomanufacturing and process cost modeling for over 14 years. Prior to joining BioProcess Technology Consultants, he performed computer modeling of biological and biomanufacturing systems at BioPharm Services, Inc, working on a variety of bioprocesses including recombinant proteins and biopolymers. Dr. Stock has assisted both early stage biotechnology companies and large pharmaceutical companies. He was Assistant Director of a pilot manufacturing facility at Worcester Polytechnic Institute responsible for the contract development and manufacturing of a variety of products for biotechnology clients. He was also an Instructor in the Bioprocess Lab at Worcester Polytechnic Institute (WPI) where he taught and advised graduate students for more than two years. Dr. Stock also founded, and later sold, Natural Biopolymers, LLC, a company that developed a process for producing a novel pharmaceutical grade biopolymer for drug delivery. He holds a B.S. from The Ohio State University and an M.S. in Chemical Engineering and a Ph.D. in Biochemical Engineering from WPI.
This article was printed in the April 2011 issue of American Pharmaceutical Review - Volume 14, Issue 3. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.