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Objections Overruled!

Mon, 02/09/2009 - 9:08am
Single-Use Components in Biopharmaceutical Manufacturing: Opportunities Outweigh Objections


Contract manufacturers (CMOs) are continually looking for ways to improve and optimize the biotherapeutics manufacturing process, especially technologies that can reduce turn-around time and simplify multi-product processing.

This article presents our perspective as a CMO, on applications of disposable technology in the biopharmaceutical production process, from bioreactor production through purification.

Single-use technology continues to gain followers, as disposables make the biopharmaceutical manufacturing process safer, faster and easier. While some challenges remain, newer technology and the promise of higher throughput outweigh earlier concerns about cost, environmental impact and questionable efficiencies. Disposable technology is an attractive way to cut production costs for both biopharmaceutical companies and contract manufacturers.
Traditional Stir Tank Bioreactor Systems vs. Disposable Plastic Bag Systems

Most bioprocess equipment is made of stainless steel. Stainless-steel tanks used in bioreactor systems must be cleaned, sterilized and validated, readying the system for the next product run. While stainless steel is very cleanable, the processes for doing so and validating the cleaning process are time and resource consuming.

One type of disposable systems is a Wave bioreactor (GE Healthcare), a customized system that uses rocking rather than a stirring motion to provide the agitation needed to suspend the cells and ensure good mixing. These types of bioreactors are frequently used for scale-up of cell-culture inocula, where they represent a convenient and simplified system easily integrated into an existing facility. Their rocking motion, however, is different from the industry standard of stirred-tank bioreactors, which, combined with their limited scale, limit their application in primary production.

Another type of disposable bioreactor is the Single-Use Bioreactor (S.U.B) (HyClone), which features a design similar to conventional stirred tank bioreactors. The S.U.B. consists of a permanent stainless steel outer support container and a specially designed plastic bag designed to fit inside the steel outer container. The disposable bag contains an impeller agitation system, resulting in a cellular environment similar to stainless steel bioreactor systems. This makes the S.U.B. a flexible, rapid and economic option to update or increase the bioreactor capacity. Similar but more complex types of disposable stirred-tank bioreactors are available from Xcellerex.

Pre-assembled, pre-sterilized disposable plastic bags eliminate the need to clean the stainless steel bioreactor tanks in preparing the changeover from one product to another. Rather than sterilizing the stainless steel tank, which involves clean-in -place (CIP) and steam-in-place (SIP) techniques and significant time in a clean room environment, the disposable plastic bag is simply drained and discarded.

Using a disposable bag also means reduced cost of operations, because it requires less purified water, fewer chemicals and reduced use of supporting utilities. By using a disposable plastic bag the contract manufacturer not only eliminates the risk of cross-contamination, a huge benefit, but also saves time and man-hours.

Additional benefits include greater flexibility in bringing a new product online which results in higher throughput. Due to the reduced turn-around and easier set-up time, using disposables can increase the number of runs per year in a facility by 25-40%, depending on the scale.

A third type of disposable bioreactor is based on hollow-fiber cartridges (BioVest), in which the cells grow in a perfusion process. Cells grow inside the cartridges around the hollow-fibers, through which nutrients pass and waste products exit via the semi-permeable membrane structure of the hollow-fibers. Proteins made by the cells are retained and concentrated in such a system, and are harvested continuously once the process is well underway. This type of disposable bioreactor facilitates a plug and play approach to cell culture and has the advantage of concentrating the product produced by the cells.
Single-Use Mixing Systems

Single-use mixing systems for media and buffer preparation are widely used, allowing manufacturers to reduce man hours as well as purified water, detergents and other caustic solutions used in cleaning. Often the disposable system's container, typically a bag within a rigid liner, can be used for the final storage container as well.
Downstream Disposables

Newer technology has also been designed for downstream processing or protein purification.

In separation chromatography, glass or acrylic tubes are filled with small chemically modified charged beads (resins), equilibrated in an aqueous buffer and then a solution containing the target protein is run over the resin. Different components in the solution interact to different extents with the resin and buffers flowing through the column. The result is separation of the target protein from by-products and process impurities, resulting in purification.

At least one supplier has introduced pre-packaged, pre-sanitized, ready-to-use columns, eliminating the need and man hours to pack new resin and assemble the traditional columns. These are not really disposable, but pre-packed columns that offer convenience and save time. Ready-to-use chromatography columns do have a downside, however, in that the column packing volume is not customizable. Instead, one is restricted to the sizes offered for the pre-packed columns, which are limited. Nevertheless, this limitation may be acceptable given the time savings and throughput advantages. Contract manufacturers are still comparing costs but believe that ready-to-use columns offer great promise.

Another newer filter technology in the purification process is the use of membrane absorbers, which are intended to be used instead of columns. The filters are chemically modified in a similar way to the resins used in columns. Filters offer much more rapid kinetics of binding due to their thin structure, and come ready to use. They are typically disposable as well, reducing set-up and utility costs and saving time. Membranes are most commonly used in polishing steps in a purification, however, since they have lower capacity than columns with resins.
Visualization in Plastic Bags

Plastic bags used in biopharmaceutical production are translucent or transparent, giving the added advantage of being able to see what is inside them. For example, in preparing solutions in plastic bags, the solid contents can be observed going into solution. In plastic-bag bioreactors, foam and other aspects of the culture can be readily observed without needing sight-glass observation ports.
Disposable Connectors

Even the connectors that are used between the hoses and the plastic bag are disposable. In clean-room aseptic applications, there is concern for microbes and bacteria in the air, requiring the air to be filtered and the equipment sterilized. Disposable pre-sterilized connectors are reducing the risk of contamination and making the process easier. For example, single-use plastic bags often come fully assembled with pre-sterilized ready-to-use connectors that allow more robust aseptic connections.
Environmental Impact

While disposables make the biopharmaceutical manufacturing process very convenient and mean a higher throughput in the facility, some have expressed concern for the impact disposables have on our environment, including adding plastics to landfills and carbon load. Recent studies have, however, shown that disposals are "greener" than using stainless steel tanks1. Reduced purified water and steam generated for sterilization mean considerable energy savings. In addition, disposables can be turned into energy sources through co-generation, if incinerated properly. Nevertheless, proper disposal is important is working with disposable components.2
Weighing The Costs

Significant investment capital is needed to build a manufacturing facility.

Because of their customizable design, disposables allow for faster design, construction and manufacturing flexibility, which results in significant reduction in capital needed. This factor plus the reduced processing time and operating costs are benefits that are driving market demand for single-use technology. Their increasing availability and application, plus the well-known dramatic increases in cell-culture titers, may allow future biopharmaceutical plants to become smaller and more versatile.
Challenges

One challenge in using single-use technology in bioreactors is that not all cell lines are compatible with disposable bioreactors. For example, we have found that cholesterol-dependent cells bind to the plastic of the bag, resulting in poor growth3.

Another challenge in implementing disposable technologies is that the biggest disposable bioreactor commercially available is 2000 L in size. If a process needs to be scaled up to a higher volume, then it must be transferred to a stainless-steel bioreactor.

Concerns about leachables or extractables from the plastic bags reaching the product have been expressed, especially in Phase III clinical-trial or commercial production. Product-specific validation is expected for these types of materials. However, the USP Class VI plastics used in biopharmaceutical disposables have been extensively tested for biocompatibility, both in vitro and in vivo, minimizing these concerns. Furthermore, such plastics are used in the medical device industry for patient-implantable applications.

Sterilized disposable plastic bags must be stored and do take significant warehouse space. But disposables mean that experienced and more highly paid staff do not have to clean stainless steel tanks in the clean room space, reducing man-hours and improving productivity.
The Future For Disposables

Thanks to their convenience, potential to reduce cross contamination, and elimination of many of the cleaning procedures, single-use systems will continue to grow in importance and demand. Indeed, vendors of these technologies are expanding their product range and developing new applications for them. Disposables are a valuable tool in this undertaking. As more and more applications for disposable technology are identified, the demand for disposables will grow. An entire truly disposable manufacturing process is still not possible at this time and will be the focus for the next generation of disposable technology.
References

1 A.. Sinclair, L. Leveen, M. Monge, J. Lim & S. Cox. The environmental impact of disposable technologies. Biopharm Intl. Nov. 2008 Supplement, p 4-15. 2 H. Pora & B. Rawlings. Managing solid waste from single-use systems in biopharmaceutical manufacturing. Bioprocess Intl. Jan. 2009, p18-25. 3 M.E. Ultee. Single-use technologies in biopharmaceutical manufacturing from cell culture through aseptic filling. IBC Conference on Antibody Development and Manufacturing, Carlsbad, CA, 2/28-3/2/07.

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