The current state of the world economy, drug pricing control and stricter quality and regulatory standards, are forcing large and emerging biotech companies to change their overall approach to risk compared to a decade ago. This has led to a focused demand for improved process optimization and more efficient overall operations as a way to keep expenses down. This has created an opportunity for bringing disposables from the current growth at the clinical scale to potential implementation of single-use technologies in the commercial landscape.
Disposable or single-use systems have widespread acceptance by the biotech industry as a key part of producing a safe, regulatory compliant product with robust, efficient processes. There is a demand for the technological benefits offered as the biotech industry integrates disposable systems into new and existing processes. Many single-use solutions are available for upstream processing such as cell culture seeding, media preparation, aseptic sampling, aseptic connection/disconnection, and depth filtration. The number of users of disposable technology is increasing and the steady growth of industrial suppliers of disposable goods offer great opportunity to reduce the risk of handling critical process operations, reduce contamination risks and save time. Despite plenty of brilliant innovation, the majority of disposable processes are still limited to cell culture and vaccine processes.
The most widely integrated disposable systems are for mixing media and buffers and for holding media, buffers and product intermediates. These single use bioprocess container (BPC) systems are provided pre-sterilized for GMP use. There are no pre or post-use cleaning procedures required. Benefits have already been demonstrated for reductions in utilities, manufacturing space and water usage. A wide range in size options up to 1,000L offers flexibility in volumes prepared. Significant reduction in both solution preparation time and required resources are realized. Solution storage has become easier and more flexible especially with stackable configurations. Integrating fluid filters into the BPC systems has eliminated the need for filtration units at each process intermediate stage. The process of creating or adding buffer or media capacity has been simplified compared to stainless steel tank expansion. The implementation and use of BPCs is not a completely perfect to implement. The cost of the disposable portion of the BPC will eventually overcome the capital cost of a stainless steel tank. The impellers used in the mixing systems can easily breach the disposable tank liners. Validation of leachable and extractable contaminants becomes a serious problem due to dissimilar plastic films used by vendors in the BPCs if a supplier change must be made. Supply chain issues can cause inventory supply and storage logistical troubles if wide range of volumes is used.
The most developed and advanced unit operations are the bioreactors available for cell culture. The options available consist of temperature, mixing, pH and aeration control, fed batch capabilities, aseptic addition/sampling and aseptic harvest. These systems have been designed with electronic batch records in mind. Manufacturing floor space footprints, hardware, disposable portions, validation, and custom options vary considerably between offerings in price and availability. The available disposable bioreactors been made with a specific expectation of the type of customer to attract. Most systems are very comparable in cell culture capabilities. Some systems can be put into operation very quickly, a result of their full GMP turnkey package, by reducing the time needed for IQ and OQ. This is not a significant advantage if a company has the resources and time to complete the necessary validation work for GMP compliance. The ceiling height clearance and floor space footprint difference between vendor offerings may allow for more flexibility in the cell culture suite or retrofitting existing facilities. Some disposable bioreactor systems have a lower operating volume requirement which will allow flexibility in production volumes that can be increased over time as demand or downstream capacity is increased. Single-use modular processes also allow for a new way to expand capacity by building out gradually in phases as needed.
An extensive spread of disposable technologies for downstream processing is emerging: stacked depth filters, membrane adsorbers, tangential-flow filtration (TFF) cassettes, and filling equipment. There are also a sufficient number of different disposable unit operations to allow for handling of different process requirements. The accessibility of these disposables technologies has spurred some thinking outside of the box with regard to facility design and downstream process development [1].
The advances in disposable depth filtration technology can now replace the multi-stage stainless steel harvest systems with all disposable filter capsules. One of the big advantages is the elimination of the extensive preparation time for the stainless steel system. This saves materials and resources along with providing flexibility to harvesting. Instead of building in a huge over sizing factor to compensate for unexpected filter clogging the disposable capsules provide a simpler solution to increasing the filter are.
The disposable depth filtration capsules can be used to harvest the cell culture directly eliminating a concentration step. This will lead to a potentially undesirable dilute purification stream. There is a risk implementing a disposable step early in the process such as the harvest step by causing an economic burden by creating the potential for high consumables cost.
Disposable membrane adsorbers are the latest answer to the problems upstream advances are presenting to the downstream purification arena. The advantages of membrane adsorbers over equivalent resin-packed columns are a very small area footprint compared to chromatography skids, the elimination of packing, qualifying, cleaning and validation costs, very high flow rates (short process time) and low buffer usage [2]. Functional groups are available for anion exchange, polyallylic ligands and phenyl groups. They are primarily used for contaminant removal such as host cell proteins, nucleic acids, endotoxins, viruses and DNA [3]. The high flow rates allow removal of concentration steps and allow direct processing of some processing streams without a buffer exchange step such as the eluent from a cation exchange step. Traditional chromatography resins typically have a higher binding capacity, but the advantages, simplicity and reliability of the membrane adsorbers outweigh the expense of extra membrane area needed to compensate. Disposable membranes have already become an integrated part of some platform antibody processes [4].
The use of disposable technology has a positive impact on the success rate of processes by reducing the risk of losses to contamination. As a closed system, it prevents the need to disassemble, transport, clean, validate, and reassemble components in a clean room environment. Disposable products are supplied pre-sterilized to eliminate the need for steam-in-place (SIP) or autoclaving. Adding a single-use device or multi-component disposable system into a product train offers a simplification to process development that otherwise must develop cleaning protocols. The physical translucency of disposable products provides personnel with visibility into unit operations like never before. Operators can observe fluid and foaming levels, air pockets and mixing issues immediately. This increases successful batches by significantly reducing on-site contamination events and other process specific failures.
The flexibility of the disposable options available on the market makes their implementation relatively seamless since they can be suited to meet the requirements of an existing facility. Disposables are well suited for a multiproduct clinical manufacturing setting with frequent product change over. This is important for CMOs in order to provide the flexibility to respond to the many different process requirements inherent in the business. This is an excellent opportunity to reduce capital costs and risk for both the CMO and the client. Reducing costs and overhead should be the primary goal for the CMO and often only minor investments in hardware and facility modifications are necessary to implement the rewards of disposable technology. Together, these benefits show that disposable technologies can be a good fi t in existing facilities for quick, simple and successful cell culture processes.
Everything about manufacturing biologics with single-use disposable systems is not perfect [5]. There are certainly some ongoing challenges. There is a heavy dependence of supplies for the required flexibility in customizing the systems and maintaining the supply chain for the disposable portions. Keeping up with changes in disposable technologies and proper validation (in-house and supplier side) under GMP regulation will not be a trivial task. Although materials, labor and time are often a significant expense savings, this must be balance with a sizable increase in consumable costs. Installation qualification for the setup of each disposable system is required. Often implementing disposables shifts the bottleneck to downstream processing. Disposable technology does not meet the needs of every process. The biology may not translate well to the engineering as with microbial processes. There may be significant restrictions for running scale down processes. Compromises may need to be made that may sacrifice titer or yield for time and material savings. Another issue is the potential to manage data with integrated electronic batch records and data logging.
The idea or belief of overcapacity will likely result in a low uptake of single use systems for commercial bio-pharmaceutical drug manufacture seems a bit optimistic for those that hold the large scale capacity. There is a trend toward fewer blockbuster, capacity draining drugs as patient populations become smaller for target indications and more personalized medicines begin to become prevalent. With the high titer processes in development there will certainly be a high level of overcapacity in the industry [6]. This potential overcapacity of commercial manufacturing space is not effecting the production, development and sales of single-use fermentation systems. Demand for costly high-volume stainless steel tanks will drop for some products as process yields grow following advances in protein expression, cell culture and purification techniques. This trend will continue to push bioprocessing toward single-use technology. Many companies are adopting the use of single-use bioreactors and downstream processing unit operations earlier in process development and for production of clinical material. Presently that is where the value for single-use systems has been realized. The likely path of least resistance to product approval is to continue using similar equipment. And in some sense this approved disposable process is portable and will allow manufacturing anywhere within reason. This can create a market for using disposables in commercial manufacturing of these products in development currently using a high percentage of disposables. Availability of disposable technologies for large scale upstream and downstream processes is reshaping the way biopharmaceuticals are made by providing an efficient path to market for emerging biologic products.
As with anything that is made with the intent to be disposable there is concern from an environmental stand point that these disposable systems are more wasteful. Without a close look, the production and disposal of large amounts of plastics to produce biologics seems wasteful. But in truth the regulations used to make stainless steel systems safe and reusable to produce biologic products is less environmentally friendly. Eliminating cleaning, sterilization and the associated validation creates substantial cost and time benefits. The result is not only material and labor savings, but also a shift in facility design toward less stringent HVAC design for fewer clean rooms and therefore a reduction environmental monitoring requirements. The concern over the potential carbon footprint of a disposable facility versus a stainless steel facility for biologics has been show to be moot [7]. More relevant carbon emissions are produced from employees of the facilities commuting to work than burning the disposable plastic waste even without capturing some of the energy for heat. Carbon emissions are higher from burning disposable plastics for waste or energy for a disposable facility, but the net carbon footprint is easily overcome with a very slight reduction in staff disposables can afford. This coupled with the savings in water usage make the use of disposables a somewhat unexpected positive impact on the environment. There are some arguments that the savings and environmental impact may not scale well for 10,000L and above, but with increasing titers, more efficient downstream operations and lower targeted patient populations these scales may not be needed in the future.
Single-use technologies are not only available for an increasing range of applications and are also expanding from stand-alone devices to multicomponent systems. With this growing trend, comes a great number of benefits and implementation considerations.
Contract manufacturing organizations (CMOs) and biotech start-ups were the first users of disposable technology. CMOs saw them as a way of minimizing the risks of cross contamination in a multi-product facility, whereas new biopharmaceutical companies enjoyed a considerable reduction in the need for raising capital funds. CMOs manufacture multiple products, so this new ability to increase flexibility and reduce the time line gives a competitive advantage.
Disposables have become a benefit to a multiproduct facility with rigid scheduling tied to a need for rapid operational turnaround between projects. A reduction in time taken to clean and prepare stainless steel and suite turnaround allow the reduction in cost for the CMO to be passed directly on to existing clients and attract new ones. The reduced campaign time line has allowed CMOs to gain more projects and offer more services. Some CMOs have developed processes based on the use of sterile disposable technologies at nearly all stages of manufacturing. In the biotech marketplace, this creates a paradox of both opportunities and risks for CMOs. Biotech companies with a deep product portfolio often had no choice but to outsource due to capital and time restrictions. Now this sweet spot market segment to the majority of CMOs, will be able to set up their own facilities more readily. The introduction of disposables has lowered the bar for smaller biotech companies to enter the manufacturing realm. This reduction in the cost to manufacture biologics is also a benefit for CMOs to reach more clients that previously could not afford their services. The biotech industry is experiencing an increase in research and development and production of biosimilar products. Disposable technologies can provide the reduced the cost of manufacturing solutions to producing a competitive biosimilar product. Disposables can also simplify transfer of the drug production processes to other manufacturing sites, such as CMOs, or other facilities within a company. This option provides these companies with more control over the development process and enables production to be accelerated as needed. This new flexibility enables companies to better manage their own manufacturing expenses and investments during later development stages, when greater drug supply requirements for advanced clinical trials can still carry considerable risk of product failure.
The idea of a fully or partially disposable facility currently provides a cost friendly strategy for reducing the amount of time for the production of clinical material. The advantages of single-use technology have been proven to be a reality. The advantages are covered in the flexibility, low risk of contamination or cross contamination, deferring capital risk, lower facility overhead, smaller facilities, reduced labor, reduced allowance for depreciation and environmentally favorable. A financial justification is not difficult to develop when comparing the cost of disposables with capital expenses, with advantages such as low risk, reduced validation and quick deployment of product [8]. As further experience in using disposable system is gained throughout the industry, companies will start to capture them in their strategic plans and implement them in clinical manufacturing with commercial processes soon to follow.
References
1. F Low, D, et al Future of Antibody Purification. Journal of Chromatography B. 848. p 48-63, 2007.
2. Thömmes J, Gottschalk U. Alternatives to Packed-Bed Chromatography for Antibody Extraction and Purification. Process-Scale Purification of Antibodies. Ed: Gottschalk U. Wiley, NY, 2009.
3. Zhou, J. Tressel, T. Basic Concepts in Q Membrane Chromatography for Large-Scale Antibody Production. Biotechnol. Prog. 22, p 341-349. 2006.
4. Glynn J et al. The development and application of a monoclonal antibody purification platform. Biopharm Intl Supplement. p 15-9 Oct. 2009.
5. Gottschalk U. Bioseparation in Antibody Manufacturing: the Good, the Bad and the Ugly. Biotechnol Prog. 24, p 496-503. 2009.
6. Langer, E. 7th Annual Survey of Biopharmaceutical Manufacturing and Production. BioPlan Associates Inc. Nov. 2010.
7. Sinclair, A. et. al. The Environmental Impact of Disposable Technologies. BioPharm International Supp. P 9-11, 2008.
8. Cardona, M., Allen, B., “Project Management: Incorporating Singe-Use Systems in Biopharmaceutical Manufacturing” BioProcess International 4, p 10-14, 2006.
Author Biography
Rick Stock has worked and consulted for the biopharmaceutical industry specializing in biomanufacturing for 10 years. Prior to joining BioProcess Technology Consultants, he was a modeler of biological and biomanufacturing systems at BioPharm Services, Inc. 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.