Disposable Manufacturing Coming to Biotech

Cleaning, sterilizing, and validating pharmaceutical manufacturing equipment are as inevitable as death and taxes. Bioprocess equipment cleaning has borrowed extensively from the larger pharmaceutical industry in this regard, plus developed its own set of protocols to deal with biocontaminants such as pyrogens, DNA/RNA, and infectious agents. To reduce the cleaning and validation burden bioprocessors are moving towards plastic storage systems as alternatives to glass and stainless steel. These vessels, referred to as flexible carboys or bioprocess container systems, are essentially high tech plastic bags that are discarded after use. Bag materials are chosen for inertness, strength, and barrier properties to prevent carbon dioxide from entering the carboy and moisture from exiting.

Implementing flexible carboys in a sterile manufacturing environment requires a high level of integration among the components of these systems - primarily bags, tubing, and filters. Systems must be available in different sizes with custom designed inlet/outlet ports, tubing, and fittings to work seamlessly within an existing manufacturing process. The challenge has been to ensure a practical, reliable method of maintaining the sterility of fluids filled into and stored in these containers.

"Especially for handling non-critical fluids," says Millipore Corp. marketing manager Stephen Tingley, "companies are looking to replace glass and stainless steel tank at sizes ranging from one liter up to 1000 liters. When this has been possible, cleaning and validation issues - at least as far as those vessels are concerned - go away."

For several years now, Millipore has touted its Millipak and Opticap filter units (Figures 1 and 2) as "enabling technology" for disposable manufacturing. "Constructing a completely disposable manufacturing environment takes more than just assembling the parts," Tingley said. "Typically, end users first go to bag manufacturers and tell them what they need: so many bags of 500, 100, 50 liters, etc. Then they come to Millipore for filters. The bag companies assemble the bags, filters, tubing - and gamma sterilize them. They then deliver exactly what the customer needs, in the proper sizes and quantities."

Tingley stated that flexible carboys took off after Millipore introduced its Millipak and Opticap filters sterilizing grade capsule filters, since now the entire process, including fluid transfers, may easily be carried out under sterile conditions. The company offers sterile filter modules for both bacterial (0.22 micron) and mycoplasma (0.1 micro) removal in a range of surface areas from 0.1 ft² to 7 ft². The wide surface area ranges allow easy costing and matching of all equipment, especially during scaleup.

Surface areas up to 1 ft² are supported by the Millipak line, which are made from Durapore PVDF membranes and polycarbonate housings. Both materials hold up very well to gamma sterilization. For larger volumes Millipore offers the same membranes in disposable 5 inch and 10 inch Opticap formats, in 3.5 and 7 ft² membrane area sizes. Opticap is constructed from gamma-stable polypropylene and polyethylene.

Opticap is available only in a non-presterilized option while the Millipaks come in either non-sterile or gamma presterilized. Validation guides are available for both Millipak and Opticap products.

The Future: Disposable Reactors and Columns
Today flexible carboys are used in about 50 percent of large volume applications for non-critical fluids (media, buffers). "The industry has readily accepted flexible carboys as storage vessels," said Tingley. "Truly disposable manufacturing is still only a goal, but definitely within reach."

Tingley described this trend, which includes disposable reactors and columns, as "futuristic."

"Think of a contract manufacturer making ten to twenty different products, or a small biotech startup that needs to make one or more different batches of clinical-grade material but does not have the capital to invest in all-stainless or stainless/glass equipment for each product. More and more biotech firms are in this category, and this is where the greatest immediate opportunity lies for disposable equipment. These manufacturers will be happy to fill 50 liter plastic bags rather than invest in 50 liter vessels. Similarly, disposable plastic reactors and chromatography columns will give them advantages of flexibility, control, and timeliness."

Millipore has been working with Peter Dunill at University College (London), British Biotech, and Pharmacia to develop products and standards for disposable products.

Angelo DePalma

For more information: Stephen Tingley, Director of Marketing, Millipore Corp., 80 Ashby Rd., Bedford, MA 01730. Tel:781-533-2559.