Disposable process equipment, once a tiny niche market, has seen dramatic growth in the past few years, as drug manufacturers adopt single-use systems to reduce cleaning, sterilization and their associated validation costs. A recent study by Stedim and Biopharm Services  found that shifting from traditional stainless steel to disposable process equipment can reduce biopharma manufacturing costs by 8-9% per batch, and overall capital costs by 21%.
Converts to single-use systems are now demanding larger and integrated systems; some vendors even offer prevalidated process systems, and others are joining forces to design new systems. However, some drug makers who haven’t made the switch to disposables are concerned about the plastic materials leaching into product or contaminating solvent, and want to avoid getting locked into one source of the materials .
To address these concerns and develop standards for disposable equipment, the Bio-Process Systems Alliance, a division of the Society for the Plastics Industry, was established last year. The organization, which came together at last year’s Interphex conference, has 40 members, all manufacturers of single-use bioprocessing systems, according to Jerold Martin, a Pall Corp. executive who is on the Alliance’s executive board and who chairs its Guidelines Committee. Martin expects that number to increase to 50 by the end of this year.
The organization’s standards subcommittees are focusing on specific components — films and containers, filter capsules, tubing and connectors — to review quality tests and methods, and establish a matrix of quality tests and references. The Alliance expects to publish qualification test methods this month, in time for Interphex 2007.
Throughout the world’s biopharmaceutical manufacturing facilities, disposable systems are being used as bioreactors to prepare and store buffers and cell cultures, filter virus, harvest cells and handle bulk sterilization. In January, Lentigen, Inc. selected Wave Biotech’s Cellbag disposable bioreactors and ancillary mixers, tube sealers and fusing devices, for the manufacturing of its gene delivery systems.
Materials consultant Don H. Miller, Ph.D., has outlined a systematic methodology for evaluating the risks of extractables or leachables in disposable equipment, which is accessible via the Alliance’s web site (www.bpsalliance.org). Test criteria must satisfy 21CFR211.65 as well as the ICH API Good Manufacturing Practices 5.11.
- Sinclar, A. and Monge, M. “Quantitative Economic Evaluation of Single-Use Disposables in Bioprocessing,” Biopharm Services.
- Monge, M., “Successful Project Management for Implementing Single-Use Bioprocessing Systems,” Biopharm International, November 2006.
Following is a small sampling of new disposable biopharmaceutical process equipment systems that some Alliance members have developed for pharma applications.
Based on a joint venture equally owned by HyClone and Alfa Laval Biokinetics Inc., Alfa Laval has developed a single-use mixing system based on the HyNetics mixing technology. This patented technology incorporates single-contact process surfaces with a complete stand-alone hardware platform. Capacities range from 30 L to 10,000 L. The mixers can be used to prepare media, buffer, final formulations, IV solutions, intermediate solutions and homogenous suspensions for adjuvanted vaccines.
Alfa Laval Biokinetics, Philadelphia, Pa.
Tel: (215) 656-2511; www.hynetics.com
This manufacturer offers a wide variety of biomedia containers that can be used to contain pH-sensitive sterile liquid cell-culture media, salt solution, serum products, cell cultures, buffers and artificial nutrient liquids. Standard sizes are offered using Class VI medical grade materials ranging from 250 mL to 2,500 L.
Advanced Scientifics, Millersburg, Pa.
Tel: (717) 692-2104; www.advancedscientifics.com
Tubing and Connectors
This manufacturer specializes in connectors for single-use process equipment. They may be customized, using Ys, Ts, cross Ts, reducers, mini and standard Tri-Clamps, bottle stoppers and sealers, and tubing. The tubing and connectors are designed to eliminate entrapment issues and leaks that have been associated with barbed fittings. Components are permanently bonded into one single-use unit, reducing the risk of cross-contamination.
AdvantaPure, Southampton, Pa.
Tel: (215) 526-2151; www.advantapure.com
AppliFlex is the result of an alliance between Applikon and Stedim. The combination of the bioreactor with sensors and control system offers opportunities for cGMP applications. The AppliFlex bioreactor is made of Stedim 7.1 film, with the bag and pH, dissolved oxygen and temperature sensors designed for single use.
Applikon Biotechnology, Foster City, Calif.
Tel: (650) 578-1396
Aseptic Sampling Device
This manufacturer’s aseptic sampling device was designed to sample ultrapure biopharma process fluids safely and efficiently. The ergonomic device comes fully assembled and ready to use in any closed system. The device is designed to minimize the chance of cross-contamination, and can be customized.
Amesil, Oak Ridge, N.J.
Tel: (973) 697-4100; www.amesil.com
Disposable Fermentors and Bioreactors
Last year, ATMI Life Sciences and Pierre Guerin SAS formed an alliance to design, make and sell a full line of disposable fermentors and bioreactors. The alliance joins ATMI’s ultraclean film manufacturing and single-use mixing technology with Pierre Guerin’s expertise in control equipment, software and fermentation vessel and bioreactor design. Managing Director Mario Philips said, “Our initial focus has been to establish our scalable single-use mixing technology. Now, in our alliance with Pierre Guerin, we are extending our mixing technology platform to fermentation and cell culture applications.”
ATMI Packaging, Hoegaarden, Belgium
Tel: +32 (0) 22.214.171.124; www.atmi-lifesciences.com
According to this manufacturer, its Steam-Thru Connections (STC) are making the process cleaner, faster and easier. With the STC, steam passes directly through the connection, creating a one-step steam-in-place process. By eliminating unnecessary connection points, the STC prevents “dead legs,” reduces chances of contamination and minimizes validation concerns. The process is used in flexible bag and media manufacturing applications.
Colder Products Co., St. Paul, Minn.
Tel: (651) 645-0091; www.colder.com
The NovaSeal crimping solution is designed for use with single-use assemblies. As part of the Mobius family of disposable bioprocessing technologies, the NovaSeal solution is used for sampling, transporting or transferring fluid, while ensuring sterility is maintained and the fluid is securely protected from the outside environment.
Millipore Corp., Billerica, Mass.
Tel: (800) 645-5476; www.millipore.com
The WavePOD instrument module integrates all instrumentation associated with the Wave Bioreactor: dissolved oxygen, pH and CO2/O2 gas mixing controls. The instrument connects via a digital link to a Wave Bioreactor base, allowing access to all parameters, including data from the bioreactor. Multiple POD configurations are available to meet individual cell culture needs, for insect cell, mammalian cell, perfusion or cell therapy applications.
Wave Biotech LLC, Somerset, N.J.
Tel: (732) 302-3100; www.wavebiotech.com
Pall supplies a range of disposable filter assemblies and filtration sets, such as capsule filters with customized tubing systems attached. The company also supports the use of filters attached to disposable bag-based processing systems. Disposable capsule filters of all sizes with surface areas from a few cm2 to as much as 4.8 m2 (50 ft2) are available. Disposable filters can be offered with a wide range of filter media for: prefiltration and clarification; sterilization; and virus removal.
Pall Life Sciences, East Hills, N.Y.
Tel: (800) 717-7255; www.pall.com
Disposable Spinfilter System
The Spinfilter P system is primarily used for medium perfusion in cell culture processes. It is constructed from woven open-mesh PETP polyester fabric on a polycarbonate body. This specialized monofilament fabric is characterized by precisely controlled pore sizes with tight tolerances. Standard pore sizes are 10, 20 and 40 micron. The disposable Spinfilter P line is available for vessels ranging from 1 to 500L
Sartorius North America, Edgewood, N.Y.
Tel: (631) 254-4249; www.sartorius.com
Silicone Tubing Substitute
Tygon 2275 I.B. high-purity pressure tubing is plasticizer-free, is hydrophobic and will resist the absorption/adsorption of aqueous fluids. This reduction in sorption minimizes the risk of fluid alteration in single use applications. The smooth inner surface inhibits particulate entrapment on the tubing wall and reduces the potential for bacterial growth and contamination.
Saint Gobain Performance Plastics, Mickelton, N.J.
(856) 224-7811; www.biopharm.saint-gobain.com
3D Open Bag System
The Flexel 3D Open Bag is an open, single-use bag designed to fit in plastic cylindrical drums. The bags were developed to enhance open-tank fluid processing, such as mixing that can be carried out using an overhead agitator. The bags are available in a wide range of sizes to suit the Nalgene range of plastic tanks or equivalent. Volumes available include: 50L, 100L, 200L, 300L, 370L, 560L and 1000L.
Stedim, Inc., Concord, Calif.
Tel: (925) 689-6650; www.stedim.com