Rapid Microbio ROI
Calculating scientific benefits as return on investment dollars
Microbiology testing is an area of untapped potential for many pharmaceutical companies. Many labs still rely on the traditional methods that originated with Louis Pasteur over 100 years ago. But standard, growth-based methods face many limitations; the biggest disadvantage is waiting several days or weeks for results. In a get-it-done-yesterday world, pharmaceutical companies are finding that traditional methods cost them time, money, and opportunity.
Depending on the test, rapid microbiology methods (RMMs) can provide results in hours rather than days. That saved time creates opportunities for quicker response to contamination, lengthened product shelf life, accelerated delivery to the marketplace, reduced warehousing costs, and enhanced quality control.
Despite potential advantages, RMMs are typically implemented after years of detailed evaluation of various technologies and their potential return on investments. RMMs have gained momentum as the technology has proven its benefits and regulatory agencies such as the Food & Drug Administration (FDA) have responded favorably. Even so, microbiology labs wanting to introduce RMMs can face internal barriers, including:
• budget constraints, especially during the current economic recession;
• doubts as to the financial justification for the investment;
• inadequate time to research, learn, and implement new equipment;
• fear of validation and regulatory uncertainty; and
• lack of compatibility with current products and processes.
Scientific Rationale for RMM
Concerns like the ones listed above must be addressed to justify investment in rapid methods. The process for each company will be different, but all must start with a scientific reason for incorporating rapid methods by comparing the processes involved in new technologies with those of traditional methods.
Traditional methods require enough microbial growth over extended periods of time that it can be detected by microscope or eye (106 cells/ml). Cultivation of microorganisms in pharmaceutical ingredients, intermediates, products, and manufacturing environments usually requires a long recovery phase, especially with stressed samples. Microbial detection and enumeration typically range from two to 14 days of incubation. RMMs, on the other hand, offer quicker results—often in real time—that are not only automated but are more sensitive and accurate. RMMs can detect slow growers and/or viable-but-not-culturable microorganisms.
Different technologies are available to detect the presence or absence of microorganisms and to enumerate those that are found. Depending on the technology, the time to results and sensitivity can vary significantly.
Selecting the Best RMM
Amy McDaniel, PhD, director of quality control microbiology for Wyeth Vaccines in Sanford, N.C., began evaluating rapid methods in 1999 and has been using them routinely for several years.
"The initial interest in rapid methods focused on detecting contaminating bacteria in mammalian cell culture systems using the fastest technology with the most accurate results. The cell culture process presented a potential risk because it had to operate without microbiology results, which came retrospectively. So three days later, if a contamination was detected, the batch already would have been downstream, where it would be terminated, and we would have to stop production, take corrective action, and bring the process back up. Even if it’s very infrequent, it has a big impact," said Dr. McDaniel.
"Once we began validating rapid methods for real-time, in-process results, we realized we had more benefits than originally thought," Dr. McDaniel added. "Cleaning validation became an obvious target. If we could release vessels the same day, we could gain flexibility and potentially increase our number of batches. Then we expanded into environmental monitoring. If necessary, we now had the power to pinpoint the source of an event within a day."
Dr. McDaniel’s cost justification process looked at where rapid methods would have the biggest impact (see Figure 1). The process includes:
• evaluating traditional processes and determining where rapid methods would give value;
• assessing vendors and technologies (literature reviews, conference presentations, rapid systems in use, most applicable technology for a process);
• securing technology and validating it on site;
• considering regulatory aspects and understanding necessary filings; and
• outlining cost justifications before purchase (capital costs, validation costs, cost per test, potential return on investment).
"It’s very difficult to calculate how RMMs impact total operating costs per day, because they might only impact a specific area. It’s easier to determine savings of production batches," said Dr. McDaniel. "For example, if the contents of a bioprocessor is valued at $500,000 theoretically, and bioburden results take seven days while the process only takes three, you would not only lose the first batch if contaminated but also the next batch before test results came back. A significant amount of product could be lost before you knew it was even contaminated."
The same is true for cleaning validation, Dr. McDaniel added. "If a tank can not be used for days while quarantined and waiting for micro results, we can estimate theoretically that we could have produced a certain amount of material risk free if we knew the results the same day. If a company intends to use rapid methods for product release, they might estimate how much more product would have been sold if it had been released 13 days earlier using a one-day sterility test."
Dr. McDaniel recommended looking at historical cases of contamination to determine how much time and money could have been saved if a rapid method had been in place. "As you evaluate root causes with increased microbial sampling, you are again either ceasing production or putting it at risk while waiting for results. If a rapid method is available that can give you the results in a fraction of the time of traditional testing, that means you have the potential to close the investigation that much sooner. When you consider how many batches could have been produced during that period of time, that’s when the financial savings start to make a dramatic impact," Dr. McDaniel said. "Depending on the product and the process, even one batch saved could cover the technology and validation costs."
"We calculate the cost justification in many ways," Dr. McDaniel added, "even including softer benefits such as freeing up analysts from manually reading plates, reducing the risk of something happening to the plate during incubation or reading, and certainly improved quality."
Online ExclusiveAdditional Considerations for Return on Investment
Overview of Traditional Microbiology Methods Limitations of Traditional Micro Methods
Impact of Traditional Micro Methods
Overview of Rapid Microbiology Methods Growth-Based Methods
Viability-Based Methods(Viability stains or cellular markers are used/no microbial growth)
Tangible Benefits
Intangible Benefits
Applications of Rapid Microbiological Methods
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Comparing the Technologies
Baxter Healthcare Corporation (Round Lake, Ill.) has been evaluating the benefits of RMMs for over 10 years, said Elizabeth Young, MS, a research scientist and project leader for the Baxter RMM evaluation.
"When the corporate R&D group recently became interested in rapid methods, I polled Baxter facilities worldwide, asking them what features would be important. Then I assessed available rapid technologies and their applications," said Young, who created a decision matrix evaluating nine technologies against 11 criteria.
"Our facilities were mostly interested in how much the new technology would reduce time compared to current testing methods. They also were more interested in nondestructive technologies. They had some pricing limitations, but that was not the main concern," Young said.
"We were most interested in applications for sterility testing, water, bioburden, environmental monitoring, and some biological indicator testing. With Baxter being a global corporation, there was not one technology that would fit everyone’s needs, so we didn’t limit the selection process to a specific technology at that point," Young added. Once the decision matrix showed which technologies were best for specific facilities, Young started the return on investment (ROI) process.
"We looked at the probability of success versus ROI. We ranked four factors for each technology to determine probability of success—technical challenges, validation ease, regulatory acceptance, and uncertainty," she said.
"In calculating the ROI, we looked at capital costs, consumable costs, additional manipulations, the potential savings of not losing a batch, potential savings of reducing inventory days, and saving personnel time. When we determined values for different technologies, the matrix gave us a visual overview to help us determine which technology made good business sense," Young said.
"Saving money was critical. There are several upstream steps in the production process [at which], if contamination were detected early, before reaching the end product, there would be great potential for money and time savings," she added.
Baxter brought several systems in house to determine their full potential, then created thorough, plant-specific ROIs that looked at the price of the system, consumables, and preventative maintenance as well as the number and types of tests run. They calculated the cost of the new system versus current methods in a three-year payback period.
ROI Time Frames and Challenges
"The three-year payback was a desired characteristic; however, if a rapid technology made good scientific sense and there is a solid rationale for moving forward, a longer payback period would be considered," Young said.
According to Dr. McDaniel, determining an ROI in three or five years was not the primary justification path when RMMs were implemented at Wyeth, although a strong business case was essential. Instead, the question was how would Wyeth achieve a rapid result if it was needed and which technology would best accomplish that result.
Jeanne Moldenhauer, vice president of Excellent Pharmaceutical Consultants, helps pharmaceutical manufacturers evaluate which rapid method technology makes sense for their operations. Many of her clients try to calculate a three-year ROI, but most returns do not happen in three years. While justified as three to five years, some companies are realistically looking at five years, and a few companies may need as many as 10 years to realize all of the financial benefits of the system.
"As scientists, we clearly understand the benefits rapid methods have on improved product quality, faster release, and finding contamination faster, but how do we explain that to an accounting person? These benefits don’t really calculate into a number for them," Moldenhauer said.
"It can be very hard to get the accountants to allow you your cost-savings estimates. For example, one of my clients saved $10 million warehousing costs per year, and the accountants allowed it. With another client, the accountants only allowed the interest on money saved on warehousing costs," she said. "If a company can truly get rid of all the warehousing costs, they will get much bigger, undisputed savings. If a client can reduce warehousing to one-third, that’s significant if the accountant will allow the saving to apply to the cost justification."
Moldenhauer added that many of her clients find it easier to justify the cost of rapid methods by calculating the ROI for sterility testing, which is easier to justify than bioburden. Once the system is in place for sterility, the company can expand the use for other tests. She suggests that scientists network with accountants to understand what rules they will allow for cost justification.
Young goes further and recommends putting together a team comprising key players—including but not limited to development, management, regulatory affairs, finance, and manufacturing—to look at every possible cost-justification angle.
Determining ROI for RMMs
A clear statement of the financial benefits is the most critical part of any proposal evaluating the possible implementation of RMMs. Calculating the scientific benefits of RMMs as ROI dollars will be different for each company.
"In our case, it was surprisingly simple to justify the investment. Upper management was enthusiastic about rapid methods," said Garry Schmitt, senior scientist with Catalent Pharma Solutions in Research Triangle Park, N.C. The decision took about a year from concept to getting the purchase order out. Catalent has one RMM system in operation, one in validation, and a third to be placed.
"Being that Catalent is a contract manufacturer, we have to be competitive in different ways than major pharmaceutical companies. We need to be more innovative to be on the cutting edge. It was clear that if we did not get into rapid methods, we would no longer be competitive; we would be obsolete, behind the times," said Schmitt. "How could we afford not to do this? It’s the way things are going." He added that part of the FDA’s process analytical technology (PAT) initiative is looking for real-time process checks and quality assessment.
Catalent’s financial team analyzed direct and indirect costs and savings, with direct costs and savings being day-to-day operating expenses, time savings, the number of samples processed, the number of tests run, and so on. Indirect costs and savings were primarily realized in warehousing.
"Warehousing cost was a huge factor for us. Current sterility testing is the last hold-up before release, which means we have to hold product 14 days in a warehouse. Once all the other tests are done, people begin chomping at the bit come day 10 to release that product because of the cost of warehousing," Schmitt said.
Estimating Potential Savings
Using a five- to seven-year payback period for its cost justifications, Catalent took two approaches for estimating potential savings—the impact of implementing USP chapter tests versus non-USP chapter tests.
According to Schmitt, getting FDA pre-approval to implement alternative tests for USP chapters like sterility testing, microbial limits testing, and preservative efficacy testing could take a year or longer. Using the rapid method instrument for non-USP chapters like water testing, product bioburden, and environmental monitoring, however, could be implemented more quickly and supported by a defendable validation document.
"At Catalent we decided to take the easiest approach first, so we could begin realizing the benefits of the rapid methods more quickly. Then we will begin working on applications requiring FDA approval," Schmitt said. "We estimate that our Illinois manufacturing facility will save $500,000 in the first year and our RTP Contract Analytical Facility will experience $612,000 in increased business and revenue in the first year."
In addition, Schmitt adds, "the analytical basis of rapid technologies is a strong benefit because it takes out subjectivity in testing. There is no variation in incubation times, when plates are pulled, how tests are read. You just press a button and walk away."
Generally, the business case measures costs and savings; it provides information on what personnel and financial resources the project will require and what the project will deliver in return over a predetermined period of time. It is critical to include all applicable costs and possible savings of RMMs and compare them to the costs of current or conventional methods by plugging them into a financial formula favored by the company (see "Costs and Investment Return Compared,").
Once the above elements are reviewed and answered, the project team can determine the value proposition the RMM offers and, finally, calculate whether or not the ROI supports the introduction of rapid methods. There is no one perfect ROI formula for all situations but, rather, several basic formulas that lab managers can use or adapt accordingly (see "ROI Formulas Compared,").
Calculating ROI is critical, but it is by no means the only deciding factor. Intangibles like company reputation always weigh heavily. Lab managers should consider the economic recession but should not be halted by it. "In the current economic environment it’s more difficult to get capital funding. I recommend that companies don’t give up," said Dr. McDaniel "The power of these technologies is worth it. We’ve been at this a long time, and it’s harder, not easier, but we stay at it, because of the benefits to the company and the improved control over the process that can be gained by an accurate, rapid result."
Dr. Gadal is the CEO of AES-Chemunex Inc. For more information, reach him at p.gadal@aeschemunex.com or go to www.aeschemunex.com.
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