In recent years, GEN has reported on single-use bioprocess bags, connectors, sensors, and tubing many times. The benefits of disposables are, by now, well known and do not require repeating. An early knock on disposables was their limited volume, but the debut of 2,000 L bioprocess containers, accompanied by dramatic improvements in protein titers from cell cultures, dramatically expanded the scope of disposables. Yet, Sartorius Stedim Biotech estimates that single-use equipment has penetrated less than 20% of its potential biomanufacturing market.
One GEN reader, T&C Stainless CFO Todd J. Cook, takes issue with the single-use mania, citing environmental and cost issues and arguing—with some justification—that reporting on disposables paints an unduly rosy picture. “I have watched the growth of single-use systems from the beginning, and I do realize they have their place. Stainless does cost more in the startup phase of a [biopharmaceutical] product, but it must be less costly during manufacturing due to the ongoing cost of bags, and their subsequent disposal as hazardous waste.”
Cook recognizes the need for flexibility in one-off processes, in multiproduct facilities, or early in development when the cost of investing in stainless equipment may not be justified. But stainless steel is preferred in single-product plants, particularly immediately post-approval. “I know of stainless systems that have been in use for 20 years or more. The cost of single-use systems during that period would be vast.”
But proponents of single-use equipment point out that bioreactors are just one variable in the cost equation. Cleaning materials used to sanitize steel tanks, including high-purity water, are expensive and carry a significant carbon footprint and time investment that rapidly adds up. The cost of electricity that powers a facility during downtime adds to the environmental impact per batch. Then there are the substantial human resource costs associated with documentation and cleaning/validation operations.
Plastics have environmental consequences as well. Plastics manufacture carries a significant carbon footprint, uses nonrenewable feedstocks, and involves environmentally unfriendly disposal. “I was in the plastics industry for 15 years before my present position,” Cook told GEN, “and have seen the cost associated with producing plastics from crude oil, the production of the product itself, and the cost of disposal. Recycling [of bio-bags] is out; landfills are not an option due to the fact that the bags are biohazards, and even if they could be put into a landfill they never break down. That leaves incineration, which is costly and not environmentally friendly.”
Single-use process bags provide fewer paths for problem recovery, observes George Moyer, director of business development at Broadley-James. For example, if a 1,000 L stainless steel CHO culture foams and fouls an exhaust filter, it is possible to isolate or change the filter. “With a single-use bioreactor, if you foul a filter and you don’t have a replacement read to uncap and install, the game is over. The run is finished.”
Another potential issue arises from contaminated batches, and how to dispose of the culture. “With steel tanks you press the ‘auto-sterilize’ button and run the fluid down the drain,” Moyer says. “Disposables require the use of a chemical disinfectant, which may or may not be effective.”
A Matter of Perspective
In its sixth annual report on trends in single-use bioprocessing, BioPlan Associates put some of the concerns over single-use equipment into perspective. Author Eric Langer notes that the question for most bioprocessors is not whether single-use equipment will be deployed, but where and how (and by implication, when). According to BioPlan’s survey, “concerns over adoption are rapidly becoming less strategic and more operational and commercial,” and “objections to disposables have declined both in quantity and importance.”
For example, worry over leachables and extractables among the 443 production executives surveyed declined from 16.6% in 2008 to 10% in 2009. Moreover, these executives were more concerned with cost-effectiveness than whether single-use equipment would serve their purposes. Larger companies were less likely to be interested in increasing their disposables usage, a fact that reflects the number-one economic issue at play here: investment in capital equipment.
Seventy-three percent of respondents at large companies cited “existing equipment” as a hindrance to adopting disposables, compared with just under half of executives at mid-sized firms. Even so, this objection decreased, from 19% of respondents last year to 14% in 2009. And 13% overall agreed with the statement that “disposables are expensive.” Interestingly, contract manufacturers, the group often cited as prime customers, were 20 percentage points more likely than sponsors to name cost as a key impediment to greater use of disposables.
Michiel Ultee, Ph.D., who heads process science efforts at Laureate Pharma, concurs with BioPlan’s findings, at least on the subject of capital investment. “In my experience, stainless steel bioreactors are favored over disposables whenever a company has already invested in stainless steel tanks, and this equipment is validated and running well. This is especially true for repeated runs of the same process.”
Process volume is another area where manufacturers often have little choice but to specify stainless steel. The largest disposable bioreactor currently available, from Xcellerex, holds 2,000 liters. “And bag costs and handling become an issue when the bags get really large.”