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
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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
DOES RMM = PAT APPLICATION?
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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