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Microbiology Consultants LLC - Articles and news items
The recent revision to USP General Informational Chapter <1223> Validation of Alternative Microbiological Methods that became official on December 1, 2015 contained a section discussing the limitations of the colony-forming unit (CFU) in terms of enumerating only those microorganisms that readily grow on solid microbiological media. The section highlights its inappropriateness as a gold standard for method validation when there are many signals available other than CFUs for the detection, enumeration and identification of microorganisms in water, air, pharmaceutical ingredients and drug products…
The Encyclopedia of Rapid Microbiological Methods: The new fourth volume discusses technologies, regulatory acceptance and validation case studies
This is the second paper in our continuing series on Rapid Microbiological Methods (RMM) that will appear in European Pharmaceutical Review during 2013. As the editor for the Encyclopedia of Rapid Microbiological Methods, I provide a summary of the latest volume, which was published earlier this year. New case studies, regulatory guidance and novel technologies are highlighted, and encourage our industry to adopt new ways of performing microbiology assays across a wide range of applications.
Improving the quantitation of live antigens used to produce rabbit generated serotype specific antiserum
This is the first paper in our continuing series on Rapid Microbiological Methods (RMM) that will appear in European Pharmaceutical Review during 2013. Flow cytometry represents one of a variety of viability-based RMM technologies that are currently available to the pharmaceutical industry. In flow cytometry, individual particles are counted as they pass through a laser beam in a very narrow flow cell.
Hot topics in rapid methods: revisions to validation guidance and real-time environmental monitoring
This is the sixth and final paper in our continuing series on Rapid Microbiological Methods (RMM) that have appeared in European Pharmaceutical Review during 2012. As many of you already know, I am keen on staying on top of recent developments in the world of rapid methods, and have used my own blog (http://blog.rapidmicromethods.com) to communicate technology advances and changes to regulatory and validation practices and expectations. In my final article of the year, I am providing an overview of two very interesting topics that have sparked additional discussions within the professional community: the proposed changes to USP’s informational chapter on the validation of alternative microbiological methods and real-time environmental monitoring.
Revision to USP Chapter <1223>: Method validation is the process used to confirm that an analytical procedure employed for a specific test is reliable, reproducible and suitable for its intended purpose. All analytical methods need to be validated prior to their introduction into routine use, and this is especially true for novel technology platforms such as RMMs.
Because many RMM technologies consist of a combination of instrumentation, software, consumables and reagents, in addition to specific detection, quantitative or identification methodologies, it is important to develop a comprehensive and holistic approach to the validation process to ensure that the entire RMM system is suitable for its intended use.
This is the fifth paper in our continuing series on Rapid Microbiological Methods (RMM) that will appear in European Pharmaceutical Review during 2012. As many of you know, I am always on the lookout for the next generation of rapid microbiological method (RMM) technologies and solutions. In this article, I have invited Noe Miyashita, a researcher from Hitachi Plant Technologies, to describe a novel ATP bioluminescence technology platform that she and her colleagues are currently working on. But in order to frame this discussion, it is appropriate to provide some background material on the fundamental basics of ATP bioluminescent methods.
ATP bioluminescence is the generation of light by a biological process, and is most recognised in the tails of the American firefly Photinus pyralis. First discovered in 1947 by William McElroy, he described the ATP bioluminescence reaction in which ATP (Adenosine Triphosphate) is enzymatically consumed to produce light. Specifically, in the presence of the substrate luciferin, the enzyme luciferase will use the energy from ATP to oxidise luciferin and release photons (light at a wavelength of 562 nanometres). The photons can then be detected and measured by a luminometer equipped with a photomultiplier tube. Figure 1 provides an illustration of this chemical reaction.
This is the fourth paper in our continuing series on Rapid Microbiological Methods (RMM) that will appear in European Pharmaceutical Review during 2012. Over the past few years, a number of professional meetings have focused on strategies and case studies for the validation and application of rapid microbiological methods (RMM). If you were able to attend one of these meetings, you probably found it encouraging and worthwhile listening to and speaking with end-users, regulators and vendors of the technologies. This year and next are no exception; scheduled conferences and training sessions within Europe and the US will provide the industry with a comprehensive overview and guidance on how to successfully implement RMMs. To give you a feel for what’s in store, this edition of our RMM series will highlight upcoming PDA and ECA RMM sessions. In addition, the last section will provide more information about the overall October 2012 PDA Global Conference on Pharmaceutical Microbiology, of which a number of RMM presentations will be delivered.
European Compliance Academy (ECA) Annual RMM Conference (December 2012):
This two-day conference offers you a unique opportunity to evaluate the new developments in RMM systems, to extend the current experi – ences in validation, as well as implementation of these systems within the pharmaceutical industry. Attendees will also learn about the expectations of the regulatory authorities and new developments with regard to regulatory requirements.
This is the third paper in our continuing series on Rapid Microbiological Methods (RMM) that will appear in European Pharmaceutical Review during 2012. Rapid sterility testing is one of a number of applications that novel microbiological technologies afford the pharmaceutical industry. RMM technologies have already been validated and implemented for both small and large molecule pharmaceuticals and ophthalmic products, in addition to cell therapy and tissue culture products, as an alternative to pharmacopeial sterility tests, and company success stories have been presented and published at numerous professional meetings and in a variety of scientific journals (please see the reference page at http://rapidmicromethods.com for the full titles). However, the industry as a whole has not embraced the use of rapid sterility testing as much as other microbiological applications, such as in-process bioburden, environmental monitoring and Microbial Limits testing. The reasons are varied, and have included concerns regarding return on investment, the extent of the validation plan and regulatory acceptance. Fortunately, recent changes in regulatory policy make it clear that RMMs for finished product sterility testing have a place in our industry, and it is the FDA that is leading the motivation for change.
In February 2008, the FDA published their draft guidance on the validation of growth-based RMMs for sterility testing of cellular and gene therapy products. The guidance addressed considerations for method validation and determining equivalence of an RMM to sterility assays described in Title 21 Code of Federal Regulations (CFR), 610.12 (21 CFR 610.12).
This is the second paper in our continuing series on Rapid Microbiological Methods that will appear in European Pharmaceutical Review during 2012. In my last article, we discussed a number of myths or misconceptions associated with the validation and implementation of rapid microbiological methods (RMMs). In fact, most RMM myths that have been circulating throughout our industry are not true or have been exaggerated to the point that many companies continue to be hesitant in exploring what RMMs have to offer.
One of the most prominent myths is that the regulators do not understand, accept or even encourage the use of rapid methods. I submit to you that the regulators want to see RMMs implemented, as their use is directly aligned with the future state of pharmaceutical manufacturing, QbD, PAT and continuous process and product improvement. Further – more, recent changes to regulatory guidance and proposed policy have made it easier to implement RMMs than ever before. In my last article, I introduced a relatively new process that the European Medicines Agency (EMA) launched that allows for the review and approval of RMM validation strategies before testing is initiated. A more thorough review of this process, better known as the Post Approval Change Management Protocol (PACMP), is presented herein.
This is the first of many articles in our continuing series on Rapid Microbiological Methods that will appear in European Pharmaceutical Review during 2012. For the past two years, I have enjoyed sharing with you a broad range of topics associated with the validation and implementation of rapid microbiological methods (RMMs), including:
– A review of the history of conventional micro – biology and the benefits of using RMMs
– Validation strategies
– Perspectives from the regulatory authori – ties, including FDA and EMA
– Overviews of currently available tech – nologies, including those based on the growth of microorganisms, detection of cellular targets, optical spectroscopy, nucleic acid amplification and gene sequencing, viability staining and laser excitation, as well as micro-electro-mechanical systems, or MEMS.
In addition to my articles, numerous companies have published their success stories of RMM selection, validation and implementation, for a variety of applications including, but not limited to, sterility testing, bioburden analyses, water testing, environmental monitoring and the detection of Mycoplasma and other micro – organisms.
This is the sixth and final article in our series on Rapid Microbiological Methods (RMMs) that have appeared in European Pharmaceutical Review during 2011. In our last article, we reviewed the world of nucleic acid amplification technologies, including PCR-DNA amplification, RNA-based reverse-transcriptase amplification, 16S rRNA typing and gene sequencing for the detection, identification, and in some cases, the enumeration of microorganisms. In our last article of the year, we will explore one of the most exciting areas in microbiological detection and miniaturisation: Micro-Electro-Mechanical Systems, or MEMS.
Imagine, for a moment, a machine so small that the human eye cannot see it and thousands of these machines are manufactured on a single piece of silicon. Imagine a future where gravity and inertia are no longer important, but atomic forces and surface sciences dominate. This is the world of Micro-Electro-Mechanical Systems (MEMS), and the future is now.
MEMS is the integration of mechanical, electrical, fluidic and optical elements, sensors and actuators on common silicon or other solid substrate through microfabrication technology. This is one of the fastest growing segments in the diagnostics and biomedical applications area, particularly for drug discovery and delivery, DNA testing and diagnostics, biotelemetry and genomics. And now, these same technologies are being introduced into the pharmaceutical sector for the rapid detection of contaminants. Examples of MEMS that have already been developed include Lab-On-A-Chip and microfluidics devices, microarrays, biosensors and other nanotechnology platforms.
This is the fourth in a series of articles on rapid microbiological methods that will appear in European Pharmaceutical Review during 2011. Previously, we discussed a number of cellular-component rapid microbiological methods (RMMs), such as ATP bioluminescence, fatty acid analysis, MALDI and SELDI time of flight mass spectrometry, Fourier transform-infrared (FT-IR) spectrometry and technologies that rapidly detect the presence of endotoxins. In the current article, we will review a relatively new set of rapid methods that are based on optical spectroscopy. These technologies are quite exciting, as they do not rely on microbial growth for a response and the time to result can be instantaneous.
Optical spectroscopy is an analytical tool that measures the interactions between light and the material being studied. Light scattering is a phenomenon in which the propagation of light is disturbed by its interaction with particles. There are a number of light scattering principles that may be utilised in rapid method technologies; therefore, it is appropriate to quickly review some of these principles in order to understand the scientific basis for the RMMs that will be discussed later in this article.
This is the third in a series of articles on rapid microbiological methods that will appear in European Pharmaceutical Review during 2011. In my last article, I provided an overview of viability-based rapid microbiological methods (RMMs), such as flow and solid-phase cytometry. In this article, we will review some of the currently available RMMs that fall under the category of cellular-component based technologies. These RMMs rely on the analysis of cellular markers or the use of probes that are specific for microbial target sites of interest. Examples include ATP bioluminescence, the detection of endotoxin and the use of MALDI-TOF mass spectrometry for microbial identification.
ATP bioluminescence is the generation of light by a biological process, and is most recognised in the tails of the American firefly Photinus pyralis. First discovered in 1947 by William McElroy, he described the ATP bioluminescence reaction in which ATP (Adenosine Triphosphate) is enzymatically consumed to produce light.
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