By James Netterwald, Ph. D.
Single-use technology has been used in the biotechnology industry for almost a decade, yet not every manufacturing facility has switched or retooled its facility to solely single-use equipment. Some of the most common reasons why biotechnology companies resist switching to single-use are listed below. Many of these reasons are no longer valid.
Companies with existing, conventional infrastructure in stainless steel and associated asset depreciation are resistant to changing to single-use equipment. “For existing conversions, without a driver for a change, no one in our industry will undertake a change for the sake of change, so conversion to single-use has to have some real value behind it,” says Paul Priebe, director of fluid management technologies at Sartorius Stedim Biotech North America, who adds that “there do not seem to be too many companies left that do not at least consider single-use when making process decisions.”
There is also a lack of familiarity with the renovation and the cost of building a new facility. “With stainless steel, the resistance occurs with facilities that already have stainless steel equipment that is validated; they don’t want to implement disposable-type operations,” says David Serway, VP of business development at Spectrum Laboratories. “If there are validated preexisting stainless steel systems within a facility where some process operations could go completely disposable (e.g. chromatography steps, tangential flow filtration, sterile filtration, etc.), there is more resistance to change to disposables steps. The fear of the transition is also fueled by myths and fallacies about the robustness of single-use material and the need for scalable performance.”
There are several business decisions that need to be made when deciding to retool an existing stainless steel manufacturing facility into a single-use facility. First, the company must account for the type of products being produced. “The single biggest driver for retooling an existing facility using single-use is that the facility design no longer supports what is required of it,” says Priebe. “A simple example is in facilities with primarily multiuse equipment that is capacity-limited due to clean-in-place [CIP] and steam-in-place [SIP] facility limitations. Often, a targeted single-use implementation can allow a facility to increase its throughput without any invasive and costly facility upgrades.”
Second, a company must consider whether to retrofit its facility or install a completely new facility. “Revalidating an existing product is less likely than implementing single-use for a new product. However, an existing facility that has reached the end of its service may cost as much or more to retrofit than it does to design something new, state-of-the-art, in single-use methods and techniques,” says Ken Clapp, senior director of global marketing and product management at Xcellerex. Finally, the company must also calculate the cost per dose and predict the likelihood of numerous competing products.
Options For Old Stainless Steel Equipment
So, when traditional stainless steel users decide to switch to single-use, what happens to the stainless steel? “There are many stories of perfectly serviceable equipment being scrapped. This is true whether the equipment is to be replaced with another piece of multiuse [stainless steel] equipment or a single-use alternative. Often, a hybridization of existing multiuse equipment may allow for a relatively inexpensive repurposing,” says Priebe.
There are a number of other options for used stainless steel equipment. “If a company is willing to invest in repurposing the old stainless, including the costs associated with revalidation [including cleaning validation] and upgrading the automation/instrumentation, it can be used for a new process. It is often cheaper, too, to buy new single-use equipment and scrap the old. The second-hand market is full of decommissioned stainless equipment,” says Clapp.
According to Barbara Paldus, CEO of Finesse Solutions, “Most of the companies that decide to retool will try to sell their existing stainless steel equipment to other companies. For example, many small companies or companies in India or China are looking to buy used stainless steel equipment. And then, the seller will basically retool in the same space, upgrade by first ripping out the SIP and CIP infrastructure, as well as any other infrastructure associated with the operation of these stainless steel bioreactors, and then install the equipment. Furthermore, because the single-use equipment does not really require as much water or electricity to run as do the stainless steel systems, its use is more economical, which makes retooling an attractive business decision.”
Types Of Facility Renovations
The facility renovations that need to be made to accommodate the new single-use equipment in a renovated facility are as follows. To understand the typical types of facility renovations that need to be made to accommodate the single-use equipment, Priebe gives the following example. Suppose there is a downstream suite that now needs to process 50% more mass of antibody due to improvements made upstream. In this case, the columns, tankage, and CIP/SIP are all undersized. Supplemental, portable single-use bag stations can easily be added to solve the capacity problems with the CIP/SIP and tankage. The use of bags can increase facility capacity by reducing turnaround times. Wait times associated with CIP/SIP of stainless steel tanks because of facility bottlenecks can be easily eliminated. That wait time becomes production time, increasing capacity with little or no capital investment. The bags may reside in clean, nonclassified space, if the facility allows for it, essentially making the change invisible within the suite.
A major change due to a retooling to single-use is the increase in space. Paldus illustrates this point by saying, “If you look at greenfield facilities, and specifically the upstream process, you need to consider that cell culture titers have gone up over the last decade by almost a factor of 10, and therefore the bioreactors that are used for the same production of protein or vaccine require a volume that is 1/10 the size of 10 years ago. What that basically means is that companies can now run a 1,000-liter bioreactor instead of a 10,000-liter bioreactor, which opens up the possibility of using a single-use bioreactor.”
Clapp confirms that single-use equipment takes up less space by saying, “When thinking about conventional approaches to clean room space, there will still be a large space to condition. However, in our FlexFactory concept, less clean room space is necessary for many equivalent processes. The result is smaller space per train or process, meaning more capacity can be built into the former space for the same product or multiple products.” According to Serway, development of a sterile disposable system takes between four and six weeks from conception to completion. In contrast, development of a stainless steel facility can take four to six months and occasionally as long as 10 months, depending on the level of automation.
Kinds Of Savings Reaped
Experts agree that following a renovation to a single-use system, there are several kinds of savings a facility will reap, but the typical breakdown is between 50% and 60% on operating costs and up to 90% on facility construction. The following statements contain savings statistics in more detail. “If you look at the economics of single-use versus stainless steel, you can reduce the capital expenditure by up to 65%, which is strong motivation for making the change to this new technology platform,” says Paldus. “That is offset by somewhat higher operating costs but, nonetheless, if you do the full financial analysis and include labor, energy, and water savings, the overall result is a 30% to 35% savings over an equivalent stainless steel reactor at around the 1,000 to 2,000 liter volume. So, there is a strong economic motivation for moving toward using single-use technology.”
Switching to single-use improves efficiency and further assists with savings on cleaning and increasing capacity/flexibility when compared to stainless steel facilities. “Some of the cost analysis data we have produced shows that a company can produce 1,000 to 2,000 liters of product in a single-use system for less than a dollar per liter, whereas this quantity would cost three to four times as much with a stainless steel operation,” says Serway.
However, Priebe adds that, generally, a facility retooling would not be justified as a cost-savings effort, but only for repurposing or for capacity increase. “Because of that, it is very difficult to quantify savings, since no apples-to-apples comparison is available, and the alternative to retooling would be a greenfield facility build,” he states.
Average Payback Time
Paldus estimates that the average payback for upstream single-use equipment is three years or less. For downstream facilities, though, a company might not see an ROI for up to seven years, mostly because of the need to construct and validate the cell culture single-use components. Paldus also says that with single-use equipment, the company will pay a lot less in capital equipment up front but will have slightly increased consumables than with stainless steel equipment. A company will save a lot on labor, which is a primary economic driver of operating expenses in most facilities.
Economics is not the main reason for making this change; there is also ease-of-use. “Single-use requires much less facility infrastructure. Companies can put it into a much simpler clean room design. You don’t need to have autoclaves. There is a lot of parental equipment that you really don’t need to buy,” says Paldus. “Looking at the overall savings of the new facility, it is actually substantially lower, and therefore, smaller or midsize companies can actually afford to do their own manufacturing, which was not the case 10 years ago. So, for a small to midsize company there is strong motivation.”
Does Size Matter?
Single-use technology has faced many obstacles to acceptance in the biotechnology industry. One of those obstacles is the fear that large (1,000 to 3,000 liter) single-use bags are not ideal for many applications. Large, single-use bags can serve as bioreactors and mixers and for processes such as media hold, reactor/fermentor harvest, and buffer hold. Despite this diverse array of applications, there are still misconceptions about the usefulness of large bags. Some of the common misconceptions regarding large bags are bag integrity and carbon footprint. For example, companies conceive that a plastic bag cannot hold 3,000 liters of fluid weight. And although this is completely true, “properly matching the dimensions of the large bag with the dimensions of a stainless container results in a completely safe and integral fluid management system,” says Derek Masser, life sciences sales manager at Advanced Scientifics, Inc. “The better bags today are produced with a repeatable, more automatic process.”
Ken Clapp, senior director of global marketing and product management at Xcellerex, explains that some companies feel there will be failure in the material or in the seams of the bag and that single-use bag technology just will not perform as well as conventional systems. Single-use bioprocess bags undergo a significant design process and adhere to strict quality standards. In many cases, “the performance is the same, or even better [than their stainless counterparts], and without the other downsides of stainless sterilization and cleaning,” he says.
There is also the misconception by end users that using all of the plastic needed for a complete single-use system cannot be good for the environment. “This is completely untrue,” says Masser, who adds that “there have been several studies which compared the total carbon footprint of a traditional stainless/steam process with that of a single-use process. When taken as a whole, the single-use system commits a much lower impact on the environment.”
Despite these challenges and misconceptions, “large, single-use bags are becoming more prevalent as end users get more accustomed to the single-use technology and its use and applicability to their processes,” says Clapp. And as end users become more educated on their design, it appears that large bags will be used even more.