Editor's Note: See the end of this article for data from our recent RMM survey, a list of vendors and their rapid method technologies, and links to related resources.
The past few years have seen a wide array of rapid microbial methods (RMM) reach the market. Designed to reduce the time required for traditional microbiological testing, these newer methods (Box, below) are based on widely different technologies but they can reduce plant downtime significantly, and cut testing time from weeks to days or hours.
At this point, more pharmaceutical manufacturers are using RMM’s, as demonstrated by a growing number of new drug approvals (NDA’s) specifying use of the technology, but there has been no mass stampede to convert existing operations.
Concerns about cost, validation and acceptance by global regulatory agencies are all tempering enthusiasm.
Apart from one method that was commercialized last year by Battelle Laboratories (Box, below), there is no single RMM that can detect and count microbes. In many cases, testing is considered destructive because samples cannot be stored or analyzed after testing.
Despite FDA’s affirmed support of use of RMM, and numerous guidance documents and requirements from agencies around the world, there are lingering concerns about European regulatory approval.
Spectroscopy, REBS and the
Optical spectroscopy is becoming a more viable technique for rapid microbial identification and monitoring. Infrared spectroscopy is being studied for analysis of bulk materials, but Raman is being applied to detect individual cells. Last year, researchers at the Electronics, Sensors and Information Systems division of Battelle Memorial Laboratories commercialized the REBS, the Rapid Enumerated Bioidentification System, based on Raman spectroscopy.
The technology is nondestructive, and detects, counts and identifies microbial particles larger than 300 nm in diameter. The system takes about five minutes to analyze each particle, and less than $10 per sample. A major advantage is that it allows for sample archiving and secondary confirmation of results. Each device is modular and weighs less than 100 lbs.
To get some idea of the impact that RMM’s are having within the drug industry, Pharmaceutical Manufacturing recently surveyed readers on their use of rapid methods. Professionals at 34 drug companies responded (results are summarized on below). Only 18% of respondents say they are not interested in the technology. Over half of those who responded to the survey say they are already using RMM, and another 30% are evaluating these technologies.
Survey respondents say they are using RMM mostly for non-sterile process applications such as WFI, for sterile product testing and environmental monitoring. However, 77% said they are interested in applying RMM for sterility testing, while 36% are exploring use of RMM in endotoxin screening.
To put survey results in perspective, we asked two PDA Committee experts on RMM for their comments and views: Jeanne Moldenhauer, VP of Excellent Pharma Consultants (Mundelein, Ill.), who wrote a chapter dedicated to RMM’s in “Priciples of Bacterial Detection,” published in September 2008 by Springer, and and Michael J. Miller, Ph.D., President of Microbiology Consultants, LLC (http://microbiologyconsultants.com; Tampa, Fl.), and the editor of the “Encyclopedia of Rapid Microbiological Methods,” published by DHI Publishing in 2006.
PhM: Pharma is notoriously conservative about applying new technologies. Is there a mindset that is preventing more manufacturers from using RMM, and is perceived cost an issue?
JM: Cost is definitely an issue. Most companies use ROI to approve new investments, and its not always easy to prove that RMM’s will pay for themselves within a few years, particularly for sterility testing. One can expect to pay between $150,000 and $400,000 for the typical system alone. Validating the systems will cost about the same.
Accountants don’t typically assign a dollar value to controlling risk, so quantifying the benefits of what may be a good investment can be difficult. Generally, it is done based on projections of reduced inventory, hold time or headcount.
MM: You have to weigh costs for many things—automation, higher throughput, and elimination of headcount.
PhM: Many of our survey respondents expressed concerns about validating RMM’s. Aren’t there many guidance documents already out there that support their use?
JM: Several guidance documents are available. Yet, there are some points that may remain unclear. For example, compendial requirements dictate that statistically-based tests be used to validate RMM’s. Basically, the industry took chemistry-based tests and applied them to microbiology, and the methods can be difficult to use when working with low counts. In sterility tests, for example, you’re dealing with 0 or 1 levels. Statistics need to be “debugged,” since there was no general acceptance at the time the requirements were published.
MM: These issues are being addressed by the PDA Committee on Technical Report No. 33. The document came out in 2000, but is being revised to clarify validation and to provide more guidance on use of statistics. Revisions are expected by the end of this year, or early next.
The USP Chapter <1223> and European Pharmacopoeia Chapter 5.1.6, which are similar, also provide guidance on how to qualify rapid methods. Another resource is FDA’s guidance on aseptic processing, which contains language that specifically mentions “methods such as RMM”.