Rapid Microbiological Methods and the PAT Initiative

The methods used in most microbiological test laboratories originated in the laboratories of Koch, Lister, and Pasteur. While numerous changes have occurred in the chemistry laboratory, there have been limited improvements in methods used for microbiological testing.

In the past decade, many researchers have focused on the study and implementation of improved methods for isolation, early detection, characterization, and enumeration of microorganisms and their products. This translates into better methods, automated and miniaturized methods, methods that require less time or those that are less costly. All of these changes are collectively grouped into the category known as rapid microbiological methods (RMM). In some compendia, these are also called alternative microbiological methods. Although these methods are called rapid microbiological test methods, many of them have their roots in other sciences, e.g., chemistry, molecular biology, biochemistry, immunology, immunochemistry, molecular electronics, and computer-aided imaging.

RMMs provide significant advantages for pharmaceutical companies to obtain data that may be significantly better than traditional methods, may be more cost effective, may provide marketing advantages, and may allow for coordinated process analytical technologies to be fully integrated within a facility.

Slow to Adopt New Methods

While science moved forward in the development of new microbiological methods, industry was slow to accept and implement them. One fear originates from a concern that regulators would not recognize these methods as superior to traditional methods. Another concern was that companies would not be allowed to change test limits based upon the test method, i.e., they would use a superior method that was likely to detect more organisms and not be allowed to adjust the limits to accommodate the sensitivity of a new method.

A concern among other companies was that the first company to submit a new technology for regulatory approval would face a much more difficult time obtaining approval than companies that submitted later.

Regulatory Framework

In recent years, a variety of documents have been issued or drafted to aid the microbiologist in selection, purchase, implementation, and regulatory submission of RMMs.

Industry Guidance PDA TR No.33 The Parenteral Drug Association (PDA) was one of the first organizations to develop guidance for the evaluation, implementation, and validation of RMMs. Guidance information was published as Technical Report Number 33.1 This document was developed by a committee of individuals from industry, regulatory agencies, compendial groups, and instrument vendors. This guidance provided definitions in microbiological terms for validation criteria similar to the information in USP <1225> for chemistry methods.

USP Proposed Chapter <1223> on Validation of Alternative Microbiological Methods The USP proposed a draft monograph <1223> that defines various validation criteria to be used for RMMs, along with definitions of these criteria in terms of microbiology. The proposal also identifies how to determine which criteria are applicable to different technologies, based upon the type of testing being performed.2

GMPs for the 21st Century The Food and Drug Administration (FDA) initiated a program to modernize requirements for pharmaceutical manufacturing and quality. This modernization included encouraging early adoption of new technologies, facilitation of industry application of modern quality management technologies, encouraging implementation of risk-based approaches in critical areas, ensuring that policies for review of a submission, compliance, and facility inspection are based upon state-of-the-art technologies, and enhancing the consistency and, coordination of FDA regulatory programs.3 This resulted in an initiative entitled Pharmaceutical cGMPs for the 21st Century – A Risk-Based Approach in 2004.3

FDA Guidance on Aseptic Processing 2004 In 2004, FDA published a guidance document on aseptic processing of pharmaceutical products.4 It includes a provision for the use of alternative microbiological test methods:

"Other suitable microbiological test methods (e.g., rapid test methods) can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e.g., USP)."