In biomanufacturing, innovative new technologies continue to provide cost and time improvements. Several contract manufacturers, in an effort to offer customers cost effective biomanufacturing services with quick turnarounds, are exploring the use of disposables. Disposable bag technologies, used for media storage, process development, seed inoculum, and as the actual bioreactor vessel itself, may develop into an important tool in the quest for ever increasing efficiencies in bioproduction.
Many pharmaceutical and biotechnology companies are already using disposable bag technologies for in-house bioproduction. In the latest report by HighTech Business Decisions, Biopharmaceutical Contract Manufacturing 2005: Improved Processes and New Capacity for Pipeline to Commercial Production, 51 directors of biomanufacturing at pharmaceutical and biotechnology companies worldwide were surveyed. More than half of these directors are either using, or are interested in using, disposable bags in-house or through a contract manufacturing organization (CMO). In addition, of those reporting on the size of the disposable bags expected to be used in the next few years, nine expect to be using bags of 500L to 1,000L.
As with any technology used in bioproduction, there are a host of advantages and challenges. The most prevalent issues identified by the biomanufacturing directors interviewed for the survey are listed in Table 1. The primary advantages cited by respondents stem from the avoidance of the cleaning process, whereas the perceived disadvantages include an unproven new technology, unavailability of larger bags, and repetitive purchases that may be expensive. It should be noted that suppliers of disposable bags are increasing bag sizes to accommodate customers' needs. Bag sizes of 1,500L to 2,500L are becoming available and HyClone reports offering a 10,000L bag through its HyNetics option.
|Table 1: Pharmaceutical and Biotechnology Company Perceptions: Top Advantages and Disadvantages of Disposable Bag Production Technology|
Figure 1: Baxter's single-use components in use at the Hayward facility
Several CMOs interviewed for the survey use disposable technologies for their customer projects. Some providers, like PacificGMP, specialize in the development and manufacturing of biologics using disposable technology. Leigh N. Pierce, chief operating officer, says, "We have chosen this type of processing over 'traditional' modes of production for the advantages that disposable technology offers. From the client's perspective, benefits include a shorter time to market, which is crucial for smaller pharmaceutical and biotech companies. The capital investment is reduced and the cost of goods sold (COGS) is substantially lower. All of these factors lead to increased flexibility, which is actually good for both the CMO and the client. These factors alleviate issues pertaining to a shortage in capacity that some clients face."
PacificGMP uses disposable bag technology for material transfer, reagent storage, reactor feed solutions, and product storage. In addition, they currently use this technology exclusively for all production in bioreactors.
At Xcellerex, Inc., disposable bags are used in media prep, buffer prep, product intermediate processing, and storage. Parrish M. Galliher, president and chief technology officer at Xcellerex, says, "Current bag-based bioreactor technology is not scalable. We have developed and are marketing scalable disposable stirred tank bioreactors (Xcellerex disposable reactor, XDR™) up to the 1,000L scale using bag liners, and we will expand their use in our manufacturing. There are major advantages with disposable stirred tank bioreactors, such as no clean-in-place (CIP) or steam-in-place (SIP) requirements, and fast turn-around."
Disposable bag and tubing technologies were originally used at Laureate Pharma during purification processes, as storage and collection vessels, for storage of buffers and solutions, and for collection of product and chromatography side and waste fractions. Disposables have been routinely used in Laureate's manufacturing facility since the early 1990s in the manufacture of clinical and commercial monoclonal antibody products.
Laureate's chief executive officer, Robert J. Broeze, Ph.D., says, "We presently use disposables throughout our manufacturing processes, including cell culture media storage vessels and protein production in bag bioreactors, protein purification vessels, and aseptic filling product vessels. Our aseptic filling process uses all disposable product contact parts, including pump tubing. The main benefits to our clients include decreased cleaning requirements, decreased potential for cross-contamination, availability in a wide variety of sizes and configurations, and ease of storage before use."
At AppTec, disposable bag technology is used extensively for solutions make-up and hold, buffer-media-supplement additions, and both in-process and bulk drug substance hold. Currently, disposable bioreactor systems are used only for smaller scale processes. Larry Thomas, AppTec's executive vice president, business development, says, "It is likely that the migration towards disposable bags and other disposable technologies will continue as unit pricing becomes more favorable as a function of volume. Single-use systems are especially beneficial for multi-product operations. Most, if not all, customers are pleased to learn that our approach of using disposable bag technology eliminates any cleaning or validation concerns. Clients are often concerned that the preceding client had a similar product, say, an IgG1 Mab, so they want assurances that the former product is not creating cross-contamination issues."
Photo courtesy of Pacific GMP
>At the Baxter Hayward facility, disposable bags are used in sizes ranging from 1L to 600L for storage of cell media, buffers, process intermediates and final products in both manufacturing and process development. Kurt T. Kunas, Ph.D., senior research scientist at Baxter says, "In the future, we plan to incorporate newly available stirred tank versions of Single-Use Bioreactors (SUB™) into process development and manufacturing processes. Prototype single-use stirred tank bioreactors, which were jointly developed between Baxter Healthcare Corp. and HyClone Laboratories have been successfully tested at our facility."
Although Baxter has established a traditional manufacturing suite containing stainless steel vessels of various sizes, the company will create a single-use manufacturing suite in which media transfer, bioreactor operation, and product collection are accomplished using single-use systems exclusively. Dr. Kunas says, "A major benefit of using disposable technologies is that they are closed systems that require no cleaning or sterilization in-place. The capital and operating costs of systems and utilities, such as clean steam required for SIP and CIP, are eliminated. " Figure 1 shows the single-use components that are currently in use at the Hayward facility, from thaw of cells through collection of cell culture supernatant from the bioreactor.
Contractors also identified the benefits and drawbacks of working with disposable systems from a CMO perspective. Dr. Kunas at Baxter explains, "Because they are closed systems, the capital expenditure required to accommodate multiple products simultaneously in single use containers is quite low compared to the cost of traditional systems. The costly design elements of traditional stainless steel vessels that are dictated by CIP and SIP requirements are eliminated." One drawback to disposables identified by Dr. Kunas is that data regarding compatibility of the disposables' construction material with the product must be generated. However, as more single-use containers are being used in the industry, standard materials and methods for demonstrating compatibility are being adopted, and this drawback is being mitigated.
For some CMO customers, moving from single-use bioreactors into stainless steel may raise process comparability issues. Dr. Kunas explains, "Stirred tank bioreactors produce a well-characterized hydrodynamic environment that can be readily scaled. We propose that a need exists in the industry for a single-use bioreactor that is also a stirred tank bioreactor, and is scalable to and from traditional stirred tank bioreactors currently in operation."
Figure 4: Cell Concentration and Viability
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Figure 5: Antibody Concentration
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For AppTec's Mr. Thomas, drivers to use the disposable bags as a CMO include (1) the elimination of cross-contaminants from cleaning and operations, be it residual or additive; (2) the operational flexibility in adjusting to process changes and scale, which allows one to build a plant based on process technology rather than product requirements at the moment; and (3) the reduction in capital costs associated with reduced cleaning space and stainless steel equipment when building a plant. Mr. Thomas says, "Where one saves in capital cost there is an associated cost per run that is typically passed on in some portion to the customer. For both the contractor and client, this becomes a cost trade-off, which is well worth the protection against contaminants. In addition, the use of disposables allows for the flexibility to deal with process improvements at production levels because one does not need to worry about fixed tank volume requirements. There is only a slight increase in variable costs per run."
However, Mr. Thomas explains the limitations, "With today's technology, it is more difficult to justify disposable bag systems for dedicated product or greater than 10,000L bioreactor scale processes. Most of the larger scale facilities already have the investment in the ground for the tanks and the required cleaning validations to support multiple product use."
At Laureate Pharma, customers frequently ask about disposable technologies in use. Michiel E. Ultee, the company's senior director Biopharmaceutical Operations, says, "Our clients are pleased by the fact that we have integrated disposables throughout our manufacturing processes. As a CMO, the benefits include decreased cleaning validation as well as decreased use of WFI and cleaning solutions, ability to make aseptic connections using tubing welders, ease of installation, ease of moving when empty, and reduced capital costs." Mr. Ultee also identified some of the drawbacks, which might include compatibility, leachables and inability to store hot liquids, potential for puncture, difficulty in moving when full, pressure and temperature sensitivity, and disposal costs. He adds, "Also, some customer's mammalian cells are difficult to grow in disposable bag technologies."
"Our clients expect us to use disposables in our bioreactor runs because of our scalable stirred tank bioreactor technology," says Mr. Galliher from Xcellerex. "The only drawbacks are possible leachables and occasionally costs, but these are minor concerns."
Some of PacificGMP's clients are currently using disposables and need assistance with scaling up their process, while others wish to make their process a "closed" process with as few manipulations as possible. Still other clients wish to take advantage of the flexibility of disposables to improve their process efficiency and yields. Ms. Pierce explains, "One of the reasons that our clients seek us out is for our expertise in single-use disposable platforms for manufacturing."
She continued, "From our perspective, there are many benefits for the CMO. These include outsourcing the cleaning and sterilization of bioreactors, process tanks, etc. to the supplier. Validation is reduced as systems are less complex. This decrease in complexity saves on engineering costs and shortens the lead time on equipment manufacture and delivery. Utilities, space, and labor requirements are also reduced with disposable technology, which decreases costs for the manufacturer as well as for the client. Quality and regulatory requirements are reduced since there is no chance for cross-contamination or resistant bioburden to persist in process tanks. As a CMO, we save on our facility start-up costs, decrease operating costs and capital investment, increase our flexibility with quick turn-around time between process runs, and we are able to perform many different types of processes in the same facility. This in turn increases the number of clients that we can serve."
A summary of the advantages and disadvantages of disposable systems for CMOs is shown in Table 2.
|Ability to accommodate multiple products simultaneously, each in single use containers, for a low capital expense. Many types of processes can be performed in the same facility, increasing the number of clients served.|
|Elimination of cross-contaminants from cleaning and operations be it residual or additive; quality and regulatory requirements are reduced because there is no chance for cross contamination.|
|Decreased operating costs and capital investment: savings on start-up capital costs as well as utilities, space, and labor requirements.|
|Cost savings from reduced cleaning needs: less space and stainless steel equipment needed; decreased cleaning validation and decreased use of WFI and cleaning solutions; cleaning and sterilization of bioreactors or process tanks can be 'outsourced' to disposable bag suppliers.|
|Elimination of the design elements of traditional stainless steel vessels that are dictated by CIP and SIP requirements: validation is reduced because systems are less complex.|
|Less complexity saves on engineering costs and shortens the lead time with quick turn-around time between process runs.|
|Operational flexibility in adjusting to process changes and scale; flexibility to deal with process improvements at production levels because fixed tank volume requirements are not a concern|
|Ease of installation|
|Ease of moving when empty|
|Ability to make aseptic connections using tubing welders|
|Compatibility must be proven: data on compatibility of the disposables' construction material with the product must be generated. Some customer's mammalian cells are difficult to grow in disposable bag technologies.|
|Slight increase in variable costs per run|
|Disposable bag systems difficult to justify for dedicated products or greater than 10,000L bioreactor scale processes.|
|Most of the larger scale facilities already have the investment in the ground for the tanks and the required cleaning validations to support multiple product use.|
|Leachables and inability to store hot liquids|
|Potential for puncture|
|Difficulty in moving when full|
|Pressure and temperature sensitivity|
In the study, Biopharmaceutical Contract Manufacturing 2005: Improved Processes and New Capacity for Pipeline to Commercial Production, CMOs identified the use of disposables as one of many important developing technologies that will help increase biomanufacturing efficiencies for the industry. Disposables are increasingly being used by CMOs, primarily in small-scale applications, but there is potential in the larger sizes as well.
Dr. Broeze says, "We believe that disposables will be used in the CMO industry more frequently at all processing steps. Disposables may serve as a suitable alternative to stainless steel process vessels at even the largest scales. At those scales, disposable bags may serve as liners for less expensive solid wall vessels that do not require electro-polished 316 stainless steel."
The advantages from technical, operational, and liability standpoints are significant. Mr. Thomas believes there are too many benefits to be had compared to the downside, indicating a continuing migration to disposables. He remarks, "One impact we expect to see is a decreasing need for early stage non-cGMP material to be manufactured at a CMO as disposable technology continues to improve. Its impact on outsourced cGMP manufactured material should be less because a significant portion of the ongoing costs and required expertise in cGMP are the systems, the people, and the maintenance, not the installed equipment."
Ms. Pierce at PacificGMP sees the utilization of disposables as a revolution in the CMO industry. She says, "CMOs that have already invested in the traditional infrastructure will continue to use traditional systems while integrating the use of disposables into their processes over time or as requested by clients. In addition, as processes become more efficient with higher yields, smaller volumes will meet client needs. New CMOs entering the industry will begin by utilizing disposable technology from the start, saving on start-up costs, decreasing operating costs, and increasing flexibility."
Xcellerex's Mr. Galliher agrees, "Major cost, quality and schedule advantages are available to the industry if CMOs convert to the use of disposables. In the future, CIP and SIP operations can be completely avoided."
Disposables may one day be the industry standard for early cell culture production inclusive of Phase I and II production according to Dr. Kunas at Baxter. He says, "We expect that single-use technologies will continue to increase the safety, flexibility, and efficiency of the CMO industry."
Starting with small-scale production, and possibly developing as an important option for some larger scale manufacturing, disposable technologies will foster biomanufacturing improvements at CMO facilities. These technologies will also allow CMOs to bring capacity online more quickly. Disposables have the potential to shorten lead times, provide schedule flexibility and flexibility as regards process and scale changes, reduce complexity and validation requirements, reduce the chances of cross contamination, and possibly reduce some costs for CMO clients. The CMO industry is developing a toolbox of technologies to increase bioproduction efficiencies, and the use of disposables is proving to be one of the important tools.