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mostly limited to efficiency improvements. While it could be argued that major manufacturing advancements like isolator and RABS systems are, in part, driven by the microbiologically-derived imperative to separate people and product, the true potential of these new systems is often hampered by old microbiological paradigms (e.g. needing to insert/collect/extract a growth-based settling plate within an aseptic isolator).
To be sure, advancements such as the Analytical Profile Index method of rapid microbial characterization and quantified, lyophilized pure-strain cultures are among notable microbiological milestones. However, the backbone of microbiological analysis continues to focus on methods tied to crude quantification tools and metabolic analysis using stains such as the Gram stain. These methods pioneered by Pasteur, Bergey, and others a century ago play an important part in pharmaceutical microbiology, but the tendency to limit one’s microbiological worldview to what has come before is a major hurdle to the adoption of better microbiological methods.
years ago, isolators were relatively new, and with the exception of larger pharmaceutical firms, most sterility testing was performed in cleanrooms. There was a strong focus on positive rates, and the financial impact of these was significant. While the use of isolators does not guarantee the elimination of false-positive results, in laboratories that understand the practical limitations of the technology (glove integrity for example) and develop procedures to overcome these limitations, positive rates as low as 0.02% and approaching 0 have been demonstrated.
MK:
environment, results are used to make important decisions. Traditional microbiology (culture-based) techniques like morphology, gram staining, and biochemical tests are quite prevalent as a first screening step, followed by other methods to confirm microbes. One of the milestones was the shift to modern molecular methods as the confirmatory method for identification. Modern molecular methods provide quick turnaround, more accuracy and faster results. They enable establishment of robust environmental monitoring programs and rapid tracking of contaminating microorganisms.
PB:
The other milestone was the development of software to support rapid data analyses.
In the past, traditional microbiology determined results by
looking at a plate of bacteria. You would look at morphology and phenotype under a microscope. Then, you allow the bacteria to grow, and record information for identification. Current methods, including phenotypic methods like MALDI and sequence-based MicroSEQ® ID systems, provide sophisticated analyses protocols with reference databases that allow a great deal of information about microorganisms being identified (by either genotype or phenotype). We’ve moved from a notebook recording to an automated workflow, which includes instruments that automate results, match with existing data, and give you quick and accurate output.
RJ:
While science and technology have progressed at an unprecedented pace in the academic area, practices remained relatively stable
within the pharmaceutical industry. Traditional microbiology method still represents the vast majority of tests performed. Microbial techniques have improved with automation, superior packaging, improved formulations, greater precision and enhanced ease of use for the lab but the basic methodologies of microbiology– many of which are manual – remained the same. The early push for more rapid methods began in Analytical Method Development labs. Few projects went live or were implemented in manufacturing. Still, a few pharmaceutical companies pioneered the use of rapid methods in the early 2000s. Genzyme received first FDA approval to
72 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
A lot of changes have been made over past 15 years. In pharmaceutical microbiology, where it’s a more regulated
A major milestone in the area of sterile product microbiology is the use of isolator technology for sterility testing. Fifteen
release one of its key biotech drugs with a rapid microbiology method in 2004. Since then, several companies communicated on implementation of Rapid Methods, including for example GSK, Novartis, Schering Plough and Alcon. The 2008 financial crisis slowed investment in new technologies and equipment. Nevertheless this time of scarcity helped to further reveal areas for improvement in Microbiology leading now to a dynamic trend of “Efficient Microbiology” where Microbiology becomes a tool for Lean operations and science-based decisions rather than being considered as a cost center.
Pharma users are slowly but surely turning to Rapid Microbiological Methods, what are the drivers for this and why the delay in adoption?
are the excitement of implementation and performing our 100 year old methodology in a new and different manner. Yet, our biology conscience tells us to be aware and be careful, and develop a better understanding of the differences in results that may occur with the new methods. We have grown to understand that variation in biology is the norm, and we expect results to show mostly probability in occurrence based on sampling accuracy or representativeness. We also have learned that there are better controls for microbiological contaminants in the formulation, compounding, manufacturing and packaging of every drug product than trusting laboratory tests. So, if we can accept the latter holistic approach to microbiological control, then we can release our tight scrutiny and expectations of the new methods from being ‘equivalent’ to the highly variable classical methods, which can lead to allowing more innovative methods to be used routinely in our labs and manufacturing environments so we can develop the understanding and historical data needed to accept them as improvements to our testing tool box.
DS:
technology and application. Some RMM technologies focus primarily on the “R”, enabling increased manufacturing efficiencies simply by returning traditional, microbiologically-based results more rapidly.
PN: Other RMM
technologies enable gains beyond incremental speed such as improved performance (sensitivity, precision, etc.), real-time situational awareness, lower cost, and higher quality (online, continuous, integrated data, etc.). These RMMs offer the capacity to go beyond simply testing to compendial requirements, driving operational excellence and value-added paradigms (e.g. real-time risk analysis, Parametric Release, etc.).
RMM benefits (and ROI) often appear proportional to the challenges in adoption. Rapid forms of traditional methods produce similar data streams (e.g. units of measure) that fit nicely within existing quality and regulatory paradigms. These same paradigms, however, can pose hurdles for RMMs that produce dissimilar data. Both regulatory authorities and industry experts have stressed the importance and ability to rethink old paradigms during RMM implementation. RMMs have an important role in pharmaceutical manufacturing, and difficulty in replicating or augmenting a compendial test should not dissuade implementation. Having internal end-user champions and a willingness to challenge old perspectives are keys to successfully realizing RMM potential.
methods in the past 20 years. The pharmaceutical industry is conservative, and the potential of delaying product approval due to the use of a new
MK:
A number of factors impact adoption of these technologies. There have been minimal changes to the microbial compendial
The promise of RMM technologies includes many facets of operational excellence, depending largely on the particular RMM
I mentioned a ‘hurdle’ earlier of implementation difficulties. As scientists, we are anxious to use new technologies. Drivers
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