Rapid Microbiological Methods and the PAT Initiative - Numerous new RMM systems are available to replace traditional testing methods - BioPharm International

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Rapid Microbiological Methods and the PAT Initiative
Numerous new RMM systems are available to replace traditional testing methods


BioPharm International
Volume 18, Issue 12

Solid-Phase Cytometry

Type of Technology: Viability-based.

Premise of Technology: Solid-phase cytometry uses membrane filtration to separate potential microbial contaminants from filterable samples before labeling the captured cells with a universal viability substrate. Once within the cytoplasm of metabolically active microorganisms, the non-fluorescent substrate is enzymatically cleaved to release free fluorochrome by a ubiquitous hydrolytic enzyme esterase. Only the viable microorganisms with membrane integrity retain the marker used in the assay. A laser-based detector then automatically scans the membrane, and the number of fluorescently labeled cells is immediately reported. Solid-phase cytometry eliminates the need for cell multiplication. Sensitivities to the single cell level are possible, independent of the volume of sample filtered. In addition to vegetative cells, the technique also can detect spores (bacterial and fungal), stressed organisms, and fastidious organisms. Near real-time results are obtained, typically within two to five hours of sample preparation. Solid-phase cytometry was accepted for pharmaceutical-grade water testing by the FDA in February 2004, and in the United Kingdom in 2000.

Commercial Systems Available: ScanRDI (AES-Chemunex).

Other: Several articles have been published on the topic of viable but not culturable microorganisms. Using a viability-based technology may require changes to existing limits or levels.

Turbidimetry

Type of Technology: Growth-based.

Premise of Technology: As microorganisms grow, one can detect changes in the opacity of the growth medium. Optical density measurements can detect differences in opacity at specified wavelengths, using a spectrophotometer (usually in the range of 420-615 nm). Another version of this methodology uses microtitre plate readers with continuous detectors, to detect organism growth earlier.7 A common use for this type of test is to determine microbiological suspension or inoculum sizes.

RMM APPLICATIONS

Table 1 provides a table of some of the ways rapid microbiological methods can be applied in a pharmaceutical environment.

When evaluating a system, one should consider a variety of factors, such as the following:

  • Type of technology considered and the type of microbiological test being performed
  • Cost for purchase of the initial system
  • Cost per test on an ongoing basis
  • System's ability to handle the type of products manufactured, e.g., filterability, sample size, detection limits appropriate for the test
  • System throughput
  • Level of automation required and available

DISCLAIMER

There are reports of thousands of systems that are in some stage of development for use in place of traditional microbiological methods. This article introduces some of the technologies available. Inclusion or exclusion of available methods is not meant to confer credibility, endorsement, or acceptance of some methods over other methods.

ACKNOWLEDGEMENTS

Special thanks to Casey Costello and Vicky Strong for their aid in compiling this information.

Jeanne Moldenhauer is a senior quality assurance and regulatory affairs professional and pharma consultant at Vectech Pharmaceutical Consultants, Inc., 24543 Indoplex Circle, Farmington Hills, MI, 48335, 248.478.5820, fax: 248.442.0060,

REFERENCES

1. Parenteral Drug Association. Technical Report 33: Evaluation, validation and implementation of new microbiological testing methods. J Pharm Sci Technol. 2000; 54(suppl):TR33.

2. <1225> Validation of compendial methods (2nd supp to USP 27). Pharmacopeial Forum. 2003; 29.

3. Proposed Chapter <1223> Validation of alternative microbiological methods. Pharmacopeial Forum. 2003; 29:256-264.

4. US Food and Drug Administration. Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach: Final Report, Fall 2005. Rockville, MD: Department of Health and Human Services; 2004. Available at: http:// http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm


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