February 1, 2006 (Vol. 26, No. 3)

Angelo DePalma Ph.D. Writer GEN

Acceptance of Disposable Products is Growing

From their humble beginnings as small-scale media storage and shipping containers, single-use disposable bioprocess systems have grown to encompass ever-larger bag sizes integrated with tubing, adapters, connectors, ports, automation, and sensors.

Acceptance of disposable products is growing among bioprocessors seeking to control costs and enjoy flexible manufacturing. Notable trends include:

Demand for larger disposable systems for mixing, processing, storage, and shipping. The largest disposable bioreactors contain about 2,000 L, although 5001,000 L is more typical.

Mixing, processing, and filling systems with greater functionality (i.e., inlets, connectors) and a high degree of integration.

Greater focus on film purity, especially with respect to animal-derived ingredients and components.

More diversity in designs of all types of bags, particularly for mixing and fermentation/cell culture.

Collaborations, mergers, and acquisitions, with the goal of offering complete, turnkey disposable systems for various unit operations, and, ultimately, for a completely disposable process.

Domination of the disposables marketplace by a few large companies, with perhaps 2030% of the remaining sales going to smaller firms and startups.

Development and sale of standardized bag designs to meet the market demands for predictable, reliable, and cost-effective disposable systems.

Greater focus on supplier agreements to maintain a reliable source of disposables.

Within five years, eighty percent of the disposables business will be held by a small number of large companies with deep pockets, robust R&D capabilities, in-house quality engineers, and large sales and marketing teams already focused on sterile bioprocessing, says Jerry Case, vp of business development at Newport Biosystems (www.newportbio.com).

According to Vijay Singh, Ph.D., president of Wave Biotech (www.wavebiotech.com), as biotech companies incorporate disposable bioprocessing into core manufacturing operations, users become more sophisticated about how equipment is manufactured, inspected, and validated. Vendors have responded by supplying prevalidated equipment, which shifts the regulatory burden away from end-users. For example, Wave Biotech has filed a DMF (drug master file) with the FDA that provides users with regulatory information for product and process registration.

One knock against disposable processing is the apparent upper size limitation for single-use cell culture bags. Disposable bioprocessing began to take off around the time that pundits were warning of dire cell culture capacity shortages and calling for construction of 50,000-L reactor tanks.

The shortages never materialized in any serious way, but perhaps more importantly, cell culture yields, process efficiencies, and product potency have risen steadily, rendering moot the question of bag volumes. Production that once took place in a 10,000-liter tank, in batch mode, can now be done in a 100-liter bag using perfusion culture and better-engineered cells, notes Dr. Singh.

Cost will continue to be a driver for adoption of disposable processing. Dr. Singh estimates that the nondisposable component of disposable system (in his case, the rocker table and instrumentation for the Wave Bioreactor) costs one-fourth to one-third as much as comparable reusable equipments (e.g., installed stainless steel stirred tanks), while the disposables themselves cost significantly less than the cost of cleaning, sterilizing, maintaining, and validating a steel bioreactor.

Paul Priebe, head of product management for disposable technology at Sartorius (www.sartorius.com), observed a distinct trend away from components toward disposable processing systems that can replace traditional process equipment.

This transition is occurring where disposables are being used for actual process steps, Priebe observes. Factors enabling this transition include development of efficient disposable mixing systems, the growing expertise among vendors and end-users alike, and expanded vendor services that routinely include regulatory support.

In other words, vendors of disposable products are catching up, in terms of support and the information they provide customers, with other suppliers. Filter suppliers have long provided the validation services required to implement the use of their products in cGMP processes, notes Priebe.

Product and Service Roundup

In August 2005, bag production began at STC Bio, the new Stericon (www.stericon. com)/TC Tech (www.tc-tech.com) biomanufacturing facility in Maple Plain, MN. The 30,000-sq.ft. facility increases the companies process bag manufacturing capacity sixfold.

Earlier, TC Tech launched a new line of sterile fluid-handling bags utilizing fluid contact components certified to be free of animal-derived materials. These products, developed in response to customer requests, eliminate the need to document identity, traceability, and inactivation of stearates and other bovine-derived materials.

While TC Tech does not believe the use of stearates in polymeric materials poses a significant risk, we are sensitive to the time and expense a manufacturer incurs in documenting safety and compliance, notes John Schmitz, vp of sales and marketing.

TC Tech, in addition to its line of fluid-handling disposables, supplies LevTech (www. levtech.net) with bags for the LevTech Mixing System, which employs a superconducting magnet to levitate an impeller inside the disposable bag. In addition, TC Tech maintains a distribution agreement granting Sartorius (www.sartorius.com) worldwide exclusive distribution rights to all TC Tech bags containing Sartorius filters, and for TC Tech bags outside North America.

In December, Fisher Biosciences (www.fishersci.com) announced its partnership with Alfa Laval (www.alfalaval. com) to provide single-use bioprocessing systems for Haemacures (www. haemacure.com) new Hemasee fibrin bio-adhesives manufacturing facility. The bioprocessing systems are marketed and sold by Alfa Laval under an exclusive agreement with HyNetics (www.hynetics.com), a joint venture between Alfa Laval and HyClone (www.hyclone.com).

The contract with Haemacure marks one of the first major installations of HyNetics technology for large-scale bioprocessing. The principals cited elimination of cross-contamination and cleaning validation, improved costs, and higher efficiency as reasons for switching from stainless steel reactors to disposables. In addition, HyClone will provide Haemacure with its disposable BioProcess Containers for storing and transporting process materials, among them human plasma.

Vaccine Collaboration

Flu vaccine manufacture is one area where disposables can offer tremendous flexibility at research, development, and manufacturing scales. Vaccine batches tend to be small relative to cell cultures for therapeutic monoclonal antibodies.

In October, Wave Biotech entered into a collaboration with vaccine innovator Novavax (www.novavax.com) on a commercial-scale production process for that companys vaccine for pandemic avian influenza virus, as well as other biological products.

The initial focus will be to demonstrate a manufacturing process for Novavax H5N1 avian flu-like particle vaccine at 500-L scale. Wave will provide process and equipment expertise based on disposable equipment, and will help develop the vaccine manufacturing process.

SAFC Biosciences (www.sigmaaldrich.com) marketing manager Denise DeTommaso observed that customers of disposable products are looking for products whose impact on product, facility, and cost management are well-understood. With the disposables industry in its infancy, customers need information to make important process decisions. We, as vendors, need to fill the knowledge gap.

SAFCs BIOEAZE line of disposable process containers and components includes bags, tubing, holders, connectors, filter sets, rigging sets, and bag manifolds for aseptic processing. We have a catalog of off-the-shelf products, but 90 percent of our customers want a design specific to their process, says DeTommaso. SAFC spends a good deal of time assisting customers with process equipment design and the actual fabrication of custom systems. If processes were standard, then disposable process equipment could be too.

As the capacity limit of single-use systems has increased, so has the need for high flow rates via larger diameter tubing and engagements, comments Bob Smith-McCollum, director of marketing at Stedim (www.stedim.com). This lead to larger bag ports with more robust engagements, such as Stedims Tri-Port, which connects one-inch internal diameter tubing to bags through tri-clamp fittings.

In January, Stedim introduced two disposable products: the Flexel 3D Aseptic Mixing System and the Flexel 3D Impeller Mixing System. 3D Aseptic combines a fully integrated recirculation mixing system with Stedims Flexel 3D single-use bags.

According to Smith-McCollum, preconnected recirculation loops, with a capacity of 1,500 L/hr, reduce the risk of contamination by reducing the number of tubing connections. Stedims new Impeller system provides the mixing capabilities of overhead impellers (driven by a 0.25-hp variable speed motor) for liquid blending and powder dissolution.

Broadening the Application Base

Technologic advances have broadened the application base for disposables while providing depth and function for existing applications. Waves Wave Mixer line of process mixers, available at volumes of up to 500 L, now includes options for heating and cooling within disposable mixing bags. FlexMixer, which uses odd-looking but effective mechanical actuation to mix without an impeller, opens the door for processing difficult fluids, such as gels and pastes, in disposable containers.

Sartorius products include the Gammasart Biosystem disposable bags and assemblies for ultrafiltration and diafiltration, the LevTech/TC Tech disposable impeller-based mixing system, the Sartobind SingleSep membrane chromatography series, Sartocon single-use crossflow filtration cassettes, and a non-invasive sensor product for pH, dissolved oxygen, and pCO2.

The sensor systems, developed by Fluorometrix (www.fluorometrix.com), consists of a single-use patch probe that is built into and sterilized along with the bag, and a reusable detector, which operates outside the bag.

Sartorius expanded its Confidence suite of services to include services for implementing disposable technology. Services include gamma sterilization validation, extractables analysis, chemical compatibility documentation, adsorption, and integrity testing.

For truly disposable sensors, bioprocessors should look into products from Scilog (www.scilog.com), which introduced a line of single-use disposable fluid-path products pre-fitted with disposable, pre-calibrated sensors for conductivity, temperature, and pressure. Sensors for additional process parameters are in development.

SciLog also holds several patents on single-use manifolds for automated, aseptic liquid transfer for liquid-intensive separates such as filtration, tangential flow filtration, ultrafiltration, reverse osmosis, sterile dispensing, bioreactor feeding, and chromatography.

These are smart sensors, says product manager Julie Schick. That means the devices contain embedded memory in which they store identification numbers, lot numbers, and calibration data. The sensor transmits this information to the SciLog monitor, which feeds back to the automated equipment and data collectors.

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