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


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

BioPharm International
Volume 18, Issue 12

GMPs for the 21st Century

FDA has initiated a program to modernize requirements for pharmaceutical manufacturing and quality. This modernization includes several objectives: encouraging early adoption of new technologies; facilitating 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 facilities inspection are based on state-of-the-art technologies; and enhancing the consistency and coordination of FDA regulatory programs. This program resulted in the 2004 initiative, Pharmaceutical cGMPs [current Good Manufacturing Practices] for the 21st Century — A Risk-Based Approach.4

FDA's 2004 Guidance on Aseptic Processing

In 2004, the FDA published a guidance document on aseptic processing of pharmaceutical products. This document includes the following 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)." This was one of the first regulatory documents that specifically recognized the potential use of alternative rapid microbiological methods.5

Process Analytical Technologies (PAT)

Table 1. Applications of Rapid Microbiological Methods
The concept of process analytical technologies (PAT) is described in the FDA's Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacture, and Quality Assurance. PAT is defined in this document as: "Systems for analysis and control of manufacturing processes based on timely measurements, during processing, of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the processes."6 Rather than relying on finished-product testing, PAT allows manufacturers to use faster, more accurate test methods capable of producing real-time or near-real-time data for process control. Traditional microbiological test methods usually cannot deliver real-time or near-real-time results, making them unsuitable for PAT applications. Nonetheless, RMMs were included as PAT applications by the FDA PAT subcommittee in October 2002, following representation from industry practitioners.

European Pharmacopoeia Proposed Chapter on RMM

PHARMEUROPA, the official forum for communicating general policies of the European Pharmacopoeia, published a draft chapter 5.1.6. "Alternative Methods for Control of Microbiological Quality" in 2004. This chapter provides an overview of some of the RMMs available and potentially applicable to pharmaceutical processes, and describes how they may be used for microbiological control of products and processes. This chapter also provides guidance regarding how to choose an appropriate methodology and how to validate the method.7


In most cases, the definition of PAT includes collecting real-time data, typically in-line, to make decisions about product quality early in the production process. Although there have been great advances in RMMs in the past few years, most methods developed to date are still conducted on the laboratory bench, off-line, i.e., samples are collected and taken to a laboratory for testing. While this may not be as advantageous as many of the chemistry applications developed, it is a significant improvement over traditional microbiological methods, because results may now be available in hours to a few days — instead of days or weeks. As a result, implementing these methods makes it possible to achieve many of the savings available from other systems.

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