The growth of single-use process technologies has exceeded many early expectations, as the experiences of Thermo Fisher Scientific and GE Healthcare Life Sciences show. This now is prompting more-traditional equipment manufacturers such as Emerson Automation Solutions to enter the market, too.
Several drivers account for the wide acceptance of single-use technologies today, according to Surendra Balekai, senior product manager, single-use technologies, Thermo Fisher Scientific, Logan, Utah. First, such devices reduce capital investment by 50–75%. Also, a fully validated plant can be up and running in 18 months — a year quicker than with conventional manufacturing technologies. Moreover, the single-use devices can provide greater than 90% savings from decreased demand for water for injection, energy, cleaning in place and sterilizing in place.
“In addition, the industry is changing. No company can survive by manufacturing a single molecule; multi-product facilities are what’s needed and this is ideal for single-use manufacturing technologies,” he notes.
So, for example, a manufacturer that currently uses a stainless-steel 12,000-L bioreactor is replacing it with six 2,000-L single-use bioreactors suitable for a mix of different products. “This is why so many biosimilar manufacturers opt for the single-use, multi-product solution. Assurance of supply is one of their key issues and having multiple capacities ensures this,” says Carsten Lau, global market development manager, single-use technologies, Logan, Utah.
An early adopter of this “six pack” strategy is CMC Biologics, a firm that provides contract process development and manufacturing of biopharmaceuticals with operations in Seattle, Wash.; Berkeley, Calif.; and Copenhagen, Denmark.
The company, which has worked with Thermo since 2009, installed a six pack of bioreactors into an existing space at its Seattle site. This not only allows CMC to manufacture any volume of product from 2,000–12,000 liters but also cut capital investment, while speeding up turnaround, validation and cleaning protocols.
Project teams at both companies now work closely together to meet the tight production timelines and ensure all supplies needed for bioreactor campaigns — which are planned 2–3 years ahead — always are in place.
Balekai points to two other important drivers over recent years. First, very significant advances in cell culture and growth media optimization have hugely increased expression rates. Just seven to eight years ago, expression rates were a couple of mg product/L but today they reach 6–8 g/L. “This has significantly reduced the capacity of the bioreactors required. So typically, one or a multiple of 200-L bioreactors is sufficient. Scale-out is a preferred option to scale-up,” he notes. In fact, since the company introduced its largest size bioreactor, a 2,000-L unit, in 2010, it hasn’t found customers clamoring for larger capacities.
Second, customers are looking to the future and the prospect of the whole process being single use: “With the advances in single-use mixers, heat exchangers, connectors etc., and their acceptance in compliance areas, this is possible.”
Lau points to advances in bioreactor turndown ratio. What was 2:1 not long ago is now 5:1, so fewer bioreactors are needed when scaling up from laboratory to commercial scale (Figure 1).
“Originally, you would move from the 2- to10-L flask then 50-, 250- and 1,000-L bioreactors. Now, you can scale up directly from the flask to the 50-L bioreactor and from there straight to the full 1,000 liter. Reducing the number of bioreactors reduces the initial plant cost but also reduces the consumables needed during the life of that plant. It also significantly decreases the footprint of a plant,” he explains.
The company continues to innovate. For example, its single-use mixer technology has moved from top mixing to bottom mixing. This gives a 100% mix-to-drain (i.e., mix until the last drop of liquid) option that is the only one of its kind on the market, says Balekai. Meanwhile, its single-use heat exchanger technology, which can heat or cool process fluids in non-jacketed tanks — both stainless steel and single use — is gaining increasing take-up.
The company also has introduced a twin-option integrity testing system. The first option involves manufacturer integrity testing, in which Thermo uses helium to check single-use bags before they ship. Second is point-of-use integrity testing at a customer’s production site. It is a qualification process that operates across single-use bag sizes from 1–5,000 liters.
Even so, regulation remains a concern for the industry. Suppliers originally qualified their single-use products on extractables and leachables (E&L) to Bio-Process Systems Alliance standards. Now, they must comply with the standardized extractables testing protocol introduced by the BioPhorum Operations Group. Guidelines from the United States Pharmacopeia are due out soon, too. “Testing to all these standards and to any others emerging in the next couple of years costs lots of money and time to suppliers. Not all can afford these costs. Standardization of E&L protocols will help suppliers,” explains Balekai.