Pharmaceutical companies implementing barrier isolation technology usually do so for one reason: regulatory concerns.
“The economics are there,” says Hank Rahe, director of technology at Contain-Tech Inc. (Indianapolis). “But because pharmaceutical is a regulated industry, the return really comes from a whole different set of assumptions.”
Baxter International (Round Lake, IL), which has more than a dozen isolators for sterility testing and manufacturing, pursued the technology “not from the point of view of cost reduction, but from the point of view of improved sterility assurance. The real issue here is not isolators, but a higher level of process control,” says Archie Woodworth, principle engineering specialist. Return on investment (ROI) is “just not looked at very closely. We are certainly concerned about product cost, and we try to reduce internal costs, but that's not the issue with isolators,” Woodworth says.
Inside a formulation isolator tray at Haupt. Photo courtesy of TPC Microflow.
Another user, who requested anonymity, says his company's “decisions to use isolation manufacturing were never founded in financial return. If they had been, we would never have undertaken the projects. We went to isolation technology as a way to address what we thought would be future concerns with aseptic processing and to get us out of a bind with European regulatory officials. It is as simple as that.
“But we are satisfied with our decisions. We are expanding our isolator manufacturing area and adding a syringe filler isolator. We are committed to isolator technology. Isolators provide us with more control over our manufacturing process and decrease the likelihood of introducing microbial contaminants to our product since people are 'isolated' from the process.”
For these companies, cost is secondary to investing in a technology that offers a higher level of sterility assurance and containment. Others go through a formal process to financially justify isolators before committing to them.
Manufacturing personnel at Monsanto (St. Louis) took four months to justify isolators, says Ken Weerts, manufacturing technology manager. The life sciences company is building a facility with multiple isolators, including a syringe filling line isolator.
“The main thing is to show a solid ROI and make sure management is supportive of the technology. The more you can justify the project to management, the more they buy into it,” says Weerts.
“Any time you are building a facility now, you have to be prepared to look at where the FDA is currently and where the regulatory requirements will go over the next five years,” Weerts says. “You have to be proactive to some extent when building a new facility. You want to be on the cutting edge, but not the bleeding edge.”
The view from the regulators
Processing improvements driven by isolation technology give the industry “more confidence in the safety of the final drug product, and my position is that that is always worthwhile from a public health standpoint. I don't know what that means from a dollar and cents point of view to the companies,” says Dr. Peter Cooney, associate director for microbiology in the Office of New Drug Chemistry within the FDA's Center for Drug Evaluation and Research (CDER).
The Office of New Drug Chemistry now views isolators as demonstrably superior to cleanrooms, Cooney says. “The drug applications we have received that use barrier isolation for aseptic processing have media fill results that appear to be superior to those obtained in conventional cleanrooms.”
Cooney told attendees at a June International Society for Pharmaceutical Engineering (ISPE) barrier isolation conference that reviewers do not look favorably upon placing isolators in unclassified or uncontrolled environments. When pressed to name a specific cleanroom classification for isolators, he told the group that Class 100,000 “would usually be considered OK.”
He also said that in the review process of new drug applications that use barrier isolators, “the rigor we use to do those reviews is not significantly different than it is for conventional cleanrooms. Therefore, the reviewers will not institute artificially higher standards simply because barrier systems are installed.”
Although reviewers won't demand a higher standard for a barrier system, the validation data already obtained do imply improved sterility assurance – but not the 10-5 or 10-6 levels claimed by early adopters. During the development phase for barrier isolators, those first groups performing original validations would run media fills and then add the results, Cooney says, which led to claims of sterility assurance levels that were scientifically incorrect.
This vessel, connected to the formulation isolator at Haupt, maintains aseptis during manufacture. Photo courtesy of TPC Microflow.
However, any improvement in sterility assurance levels will likely lead to higher aseptic processing requirements, which can only be met with isolators. “When regulators find there is a demonstrably better manufacturing method, the pressure is on to use that technique,” says Julian Wilkins, vice president for sales and marketing for TPC Microflow (Andover, UK), an isolator manufacturer. “We have already seen European inspectors encouraging clients to adopt isolators.”
While “the FDA will never come out and tell you that you have to manufacture in an isolator,” the industry will increasingly turn to the technology to meet continually improving manufacturing requirements, Weerts says.
“Is a cleanroom a viable alternative anymore? That's what it amounts to,” Rahe says. Users can make the choice by “looking at the sterility assurance levels you can achieve with people in the environment. It's well accepted that that's the single greatest advantage of isolators – taking people out of the environment from an aseptic and containment standpoint.”
Apart from regulatory concerns, manufacturers can justify isolation technology through decreased capital and operational costs, a lower rejection rate and a project's overall ROI. (For one company's isolation justification checklist, see accompanying article.)
The mistake some companies make is to compare only the capital costs of the two approaches instead of analyzing all costs involved, Rahe says. In some cases, capital costs may be slightly higher with isolators than cleanrooms. Moreover, comparing the two is like comparing the proverbial fruits, Rahe adds. “They're taking existing technology that has incremental improvements and doing a comparison to something that has a quantum leap to it.”
Overall, a new-build isolator line typically costs the same or slightly less than a conventional cleanroom build, but the long-term operational costs are substantially cheaper. By eliminating the need for Class 100 space, segregated rooms for each product, changing rooms and airlocks, isolators reduce the floor area of a facility by 15 to 35 percent and drastically cut air handling requirements, Wilkins says.
“If you can take out even half of that quality space, it certainly saves money on utilities and enhances turnaround efficiency. Because the facility requires less clean-up and sanitization, you get more use out of it,” says Rahe.
The technology also saves on clothing operators, which can run $10 to $20 per day per operator, and the time spent gowning and degowning. And by replacing segregated cleanrooms with isolators, fewer personnel are needed to man the lines.
But there may be a trade-off, Weerts says. “How much more are you willing to spend to get something running to gain those manufacturing costs? It is harder to start up an isolation system than a cleanroom.”
Retrofitting isolators into an existing building may not result in capital cost savings. “But if you are building a facility from scratch, there are significant savings, because you need smaller cleanrooms, less air handling and less piping,” Weerts says.
One hopeful sign: As the technology matures, its cost will come down, Rahe says. “Like anything when it is new, it costs a lot because [suppliers] are trying to recover their development costs.”
Another consideration is the number of lots normally rejected in a year and how that number might be decreased with a successful isolation system. “If the isolator is not going to decrease the rejection rate, the justification for it drops dramatically,” Weerts says. “But if you have one additional rejected lot per year for the next 15 years, what does that cost your company?”
To determine the rejection rate savings, Weerts suggests that companies identify the cause of failures. If related to cleanroom activities, some simple adjustments there might offer more payback than investing in isolators. It's a “soul-searching exercise” when weighing rejection rate savings, Weerts says. For a company manufacturing lots worth $1 million each, avoiding one rejected lot a year may be all the justification necessary. But the answer will vary for each manufacturer.
Decreased lot loss was the primary rationale for using isolators in the new Monsanto filling line, Weerts says. “In a cleanroom the risk of contamination goes up, so we made the assessment that given the long fill time associated with the process, it warrants the investment in isolation technology.”
Weerts also advises companies to consider the project's overall ROI – regardless of whether isolators or conventional cleanrooms are used. If the total project itself has a high justification, there's more leverage to go with a higher technology. But it's not a good idea to use state-of-the-art manufacturing processes for projects with marginal ROIs. An unforeseen delay could wipe out potential returns.
That's why when calculating ROI, it's important to adjust for risks, Weerts says. “If the project took six months or a year longer, people need to factor in what this does to the ROI. If it is a good investment now, but not with a one-year delay, you have a weak ROI.”
When deciding to invest in isolators, “begin with the end in mind,” says Rahe. “You have to decide where you want to end up. Are you looking at something from an economic standpoint? Then look at the total economics. Are you looking at quality issues? Then consider all the quality data that is out in the industry. If you are looking at something to satisfy the regulators, then go to the conference meetings, read articles to see what they are thinking, then emulate it. Decide what your endpoint is. It is usually the latter.”
When regulators look upon a new technology favorably, there's a rush to implement it. “Nobody wants to be there first but everybody wants to be there second,” Rahe says. “That's where barrier isolators are.”
Isolation justification checklist
Many variables affect the decision to invest in isolators. Based on their experience with isolators, and as part of a course, Dr. Frank Kohn, director for manufacturing, and Dr. Carmen Wagner, director of quality control and quality assurance at Wyeth-Lederle Vaccines (Sanford, NC), developed a justification checklist for implementing isolation technology.
“The checklist tries to capture not only the higher level of regulatory compliance afforded by isolation technology, but also the economic evaluation of isolators versus conventional manufacturing approaches,” Kohn says. The checklist includes:
Financial analysis. To make any capital expenditure today, most companies have to go through a detailed financial analysis, examining potential ROI or cost savings that might result from the expenditure.
“We usually sit down with a good financial person, look at a number of cost items and compare isolators versus traditional cleanroom systems. Then we do some simple math to determine the cost differences,” Kohn says. “Some people feel the initial capital investment for isolation technology is the same or slightly higher than a traditional cleanroom capital investment. However, issues such as labor savings, indirect materials, utility operating costs and preventive maintenance frequently offer a way to cost-justify isolators.”
The financial drivers considered during this process include capital investment; cost savings; reduction of labor; capacity increases; cash flow; net present value; payback period; and ROI. “Generally, companies like to see an ROI in less than two to three years,” Kohn says.
FDA regulations. FDA compliance expectations and the enhanced security that results from isolators can easily justify the technology. Isolators are worth the investment if they help avoid false positive sterility results and lot rejection due to sterility issues. Production considerations are more complex, but can also be justified by using several European and U.S. successful examples.
Facilities and expansion issues. A facility expansion, capacity increase or new product launch will often facilitate the introduction of isolators. In this category, Kohn and Wagner compare isolators versus traditional cleanroom construction and installation timelines, consider hazardous control issues, and the potential for retrofitting. Instead of tearing out walls, floors and ceilings, companies can consider upgrading a facility with a portable isolator.
Product issues. New products can often provide an opportunity to consider an isolator; in some cases, old or existing products requiring process or yield improvements can also help justify isolation technology.
Controls. Modern isolators have integrated computer controls that monitor a controlled environment. The expenses of automated controls in a production application should be considered early in the project, during initial cost assessment.
Also in their checklist, Kohn and Wagner consider three major expense categories: startup and inventory purchases; direct operating expenses, including supplies, materials and labor; and indirect expenses, such as HEPA filter integrity testing, gowning changes and utility costs.
Quantifying the cost savings of isolators is not a simple task even for companies following a rigorous justification process. But using a structured checklist makes the investment decision a little easier, Kohn says. –SG