About 10 years ago, Tom Warf recalls, Merck & Co. introduced a process that used only disposable equipment at its West Point, Pa., vaccine facility. The combination of disposable filters, tubes, reagent and growth media pouches, and bioreactors (which looked like high-tech resealable bags) yielded 5 liters of hepatitis-A vaccine.
It was the perfect process for disposables, says Warf, an engineer now associated with DME Alliance Inc., an engineering firm in Allentown, Pa. At the time, disposables were best suited for low-volume processes. Because Merck could make the vaccine in such high concentrations and required very little product for each immunization, a single 5-liter bag could produce thousands of doses and was worth approximately $1 million.
“It was also a complex process,” Warf recalls. “The scientist in charge of process development decided it was easier to scale up by using multiples of what he had already done than scale everything up to a larger reactor. We were competing with another company and this let us bring a product to market faster.”
Others had made similar decisions. In 1989, biotechnology pioneer Amgen Inc. was rushing to commercialize erythropoietin, a recombinant hormone to treat anemia. It piloted its process using disposable roller bottles, which researchers had to open constantly to add nutrients and turn to encourage cell growth. Rather than reinvent its groundbreaking production route in stainless steel, Amgen saved time by using a robot to handle thousands of roller bottle operations daily.
Since then, disposable equipment has moved into the biotechnology/pharmaceutical mainstream. Only 3% of biopharmaceutical manufacturers use no disposables today, according to the “Third Annual Report on Biopharmaceutical Manufacturing Capacity and Production,” issued in June 2005 by BioPlan Associates, Inc., Rockville, Md..
Filters are the most common disposable. That’s not surprising. After all, such filter capsules have been around for roughly 20 years.
The widest non-filter use involves using disposable bags to add ingredients to a batch or move products between reactors. Yet, fully one-fifth of respondents also uses disposable bioreactors to grow cells or carry out complex reactions.
“Surveys like this often raise more questions than they answer,” says BioPlan president Eric Langer. “Most companies are using dry and pre-filled media and buffer bags, but are they only using them during development or at the pilot stage rather than full production? How many are going to be sold in what capacity?” he asks.
Although Langer plans a follow-up survey, he sees some trends emerging. While no biopharmaceutical manufacturer has replaced existing stainless steel tanks, many have begun to use disposables at certain points in their processes, as well as in process development and pilot plants. Companies racing competitors to market or smaller firms with anxious investors, he says, may opt for disposables to speed commercialization.
Roberta Landon, group product manager for disposable manufacturing at Millipore Corp., Billerica, Mass., agrees. “We’re seeing more and more disposable use in new units to cut the lead time for stainless steel reactor. If you look at the time frame to do all the pipe fitting and welding to fabricate a stainless tank, it takes about six months. Compared with welding, disposable tubing is very forgiving if you need to take off a foot, and that lets you reduce your time frame to about two months.”
Landon says customers are using disposables to prepare media and reagents for existing product lines, taking advantage of disposable convenience without risking active ingredients. Manufacturers also often employ disposables to make drugs for clinical trails rather than invest in expensive stainless reactors prior to regulatory approval. Some multi-product facilities opt for disposables for final fill and finish to reduce the risk of cross-contamination.
The regulatory environment certainly is a major factor in the increasing acceptance of disposables. The U.S. Food & Drug Administration (FDA) must approve every production facility and each process within it. Approval covers everything from materials of construction through validation of each process step through clean-in-place (CIP) procedures after each batch run.
The latter is often a sticking point, says Ted Hutton, a senior business development engineer from polymer supplier Arkema Inc., Wetmore, Colo. “Manufacturers use thousands of gallons of purified water to clean their systems after each batch,” Hutton explains. “They must clean all their tanks and pipes — these are often very large systems — with detergent, then rinse it, then steam it to kill any possible living organisms. They do this continuously throughout the day and must then properly dispose of the water. With disposables, they can buy pre-validated bags, tubing, and valves and eliminate some of the steaming.”
A typical turnaround takes a full day or even longer. By using pre-validated disposables to reduce cleaning time, companies can boost productivity and increase effective capacity while complying with FDA guidelines, he says. Also, because bags take less space to store than drums or other containers, they free up plant floor space for more productive uses.
Proponents claim disposables are economical, even though they can be expensive. For example, disposable bioreactors, which consist of multilayered bags and usually include mixing systems, sampling ports, integral tubing and instrument probes, typically cost $200 to $300 each.
Landon, who often must make an economic case for disposables, notes, “First, you have to look at the high upfront capital investment in stainless compared with the very small investment in consumables, though the cost of consumables goes up over the life of the product.” She cautions, “A lot of existing stainless steel processes use more consumable items than a lot of customers realize. There’s water usage, purification costs, utilities. If you use caustics and chemicals for CIP, how do you dispose of those chemicals? You have to neutralize them and some facilities must then pump them out or cart them away.”