This is one of the first regulatory documents that specifically recognizes the potential use of alternative RMMs.
- Process Analytical Technologies (PAT) Guidance The concept of PAT is described in FDA's Guidance for Industry – PAT A Framework for Innovative Pharmaceutical Development, Manufacture and Quality Assurance.5
PAT is defined here 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 process."5
PAT expects faster, more accurate test methods capable of producing real-time or near real-time data for process control,
rather than reliance on finished product testing. Traditional microbiological test methods usually cannot deliver these results,
making them unsuitable for PAT applications.
RMMs were included by the FDA PAT subcommittee on PAT in October 2002 following input from industry practitioners.
- EP Proposed Chapter on RMM PHARMEUROPA published a draft chapter 5.1.6. Alternative Methods for Control of Microbiological Quality in 2004.6 This chapter provided an overview of some RMMs available and potentially applicable to pharmaceutical processes, and how
they may be used for microbiological control of products and processes. It also provides guidance on how to choose and validate
an appropriate method.
Does RMM = PAT Application?
In most cases, the definition of PAT includes collection of real-time data, typically in-line, to make decisions about the
quality of a product earlier in the production process. Although there have been great advances in the RMMs in recent years,
most methods developed to date are still conducted on the laboratory bench, off-line. Samples are collected and taken to a
lab for testing. While this may not be as advantageous as many of the chemistry applications developed, it is a significant
improvement over the traditional microbiological methods, where instead of days or weeks to obtain microbiological test results,
they may be available in a period of a few hours to a few days. As such, implementation of these methods makes it possible
to achieve many of the savings available from other systems.
Classical microbiological test methods used are frequently divided into three general categories, based upon the test function
performed, e.g., presence or absence of microorganisms (e.g., pathogen detection, absence of objectionable organisms, sterility
testing), enumeration of microorganisms (e.g., bioburden testing), and identification of microorganisms.
This classification of methods answers three specific questions: "Is something there?" (Presence/Absence); "How much is there?"
(Enumeration); and "What is there?" (Identification)
The classification systems for rapid methods are based on how the technology works, e.g., growth of microorganisms, viability
of microorganisms, presence/absence of cellular components or artifacts, nucleic acid methods, traditional methods combined
with computer-aided imaging, and combination methods.
- Growth-based Technologies These methods are based on measurement of biochemical or physiological parameters that reflect the growth of the microorganisms.
Examples include: ATP bioluminescence, colorimetric detection of carbon dioxide production, measurement of change in head-
space pressure, impedance, and biochemical assays.
- Viability-based Technologies These types of technologies do not require growth of microorganisms for detection. Differing methods are used to determine
if the cell is viable, and if viable cells are detected, they can be enumerated. Examples of this technology include solid
phase cytometry and flow fluorescence cytometry.
- Cellular Component or Artifact-based Technologies These technologies look for a specific cellular component or artifact within the cell for detection and/or identification.
Examples include: fatty acid profiles, mass spectrometry (Matrix Assisted Desorption Ionized – Time of Flight, MALDI-TOF),
enzyme linked immunosorbent assay (ELISA), fluorescent probe detection, and bacterial endotoxin-limulus amebocyte lysate test.
- Nucleic acid-based technologies These technologies use nucleic acid methods as the basis for operation. Examples include: DNA probes, ribotyping/molecular
typing, and polymerase chain reaction (PCR).
- Traditional Methods with Computer-aided Imaging This involves using a classical method for most of the processing of a sample, and using imaging software to detect the growth
earlier than methods requiring visual detection of growth. In most cases, detection of growth using human vision typically
requires growth to 105 or 106 cells. Computer-aided imaging can detect growth at much lower levels of cellular growth.
- Combination Methods This term describes systems that use more than one type of methodology or test to achieve a final result.