Editor’s Note: The following excerpt is republished from: Saghee, M.R., Sandle, T. and Tidswell, E.C. (Eds.) (2010): Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons. Further circulation is prohibited. The book may be purchased at www.businesshorizons.com.
For another chapter from the book, read The New Microbiological Technology Wave.
Within microbiology, a shift is taking place from simple laboratory studies toward greater use of risk assessment and management . Sometimes these approaches form part of a drug company's total quality system, sometimes they exist as standalone techniques. The most important guidelines for pharmaceutical microbiology are described in ICH Q9, including the tools of FMEA (Failure Mode and Effects Analysis); FTA (Fault Tree Analysis); and HACCP (Hazard Analysis Critical Control Points).
The two most commonly used within microbiology are HACCP (which originated in the food industry) and FMEA (which was developed for the engineering industry). This article explores these two approaches, first with a description of HACCP, followed by a description and case study of FMEA in sterility testing.
HACCP: Risk Based Approach in Environmental Monitoring
Hazard Analysis and Critical Control Point (HACCP) is a risk assessment approach that addresses physical, chemical, and biological hazards . HACCP is designed so that key actions, known as Critical Control Points (CCPs) can be taken to reduce or eliminate the risk of the hazards being realized. HACCP involves focusing on where the control points in a process are. Once these are established critical limits are set. The critical limits are then monitored and the process is verified as being in control (or not) . There are different variants of HACCP. The “Lifecycle Approach” is similar to that contained in the FDA “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach” .
There are two key components of HACCP:
• Hazard Analysis: Determining what microbiological, physical, or chemical risks are associated with a process.
• Critical Control Point: A point, step, or procedure at which control can be applied.
In general HACCP involves the following:
1) Conducting a hazard analysis. This involves listing all potential hazards associated with each step, conduct a hazard analysis, and consider any measures to control identified hazards. For this process flows are useful. For example, see Figure 1.
2) Determining the Critical Control Points (CCPs).
3) Establishing critical limit(s).
4) Establishing a system to monitor control of the CCP.
5) Establishing the corrective action to be taken when monitoring indicates that a particular CCP is not under control.
6) Establishing procedures for verification to confirm that the HACCP system is working effectively.
7) Establishing documentation and record keeping.
The general methodologies of HACCP are also similar to the principles used in qualification and validation, and the critical control points, are often the same as critical process parameters. This allows for several synergies with other aspects of pharmaceutical quality systems.
There are, nonetheless, some limitations with HACCP. It often has to be combined with other risk assessment tools, like FMEA, in order to allow risks to be prioritized and quantified.
HACCP is also less useful for complex processes and it is less useful if the process is not well known.
FMEA: Risk Based Approach in Sterility Testing
A failure modes and effects analysis (FMEA) examines potential failure modes within a system for classification by severity or determination of the effect of failures on the system. Failure modes are any errors or defects in a process, design, or equipment. Such modes can be potential or actual.
Effects analysis refers to studying the consequences of those failures. FMEA looks at the risk of failure at each process step by evaluating the potential failure modes for the process. It then proceeds to evaluate and document the impact of the failure upon product quality or the next stage in the process. Once the process has been mapped, the emphasis is on eliminating, reducing or controlling performance failures through the use of risk reduction techniques.
Although FMEA can be a powerful tool, it is better applied to equipment, where complex items can be broken down to their key components or operational steps, rather than to process manufacture (where HACCP arguably has the advantage in spotting potential microbiological risks). It also relies upon a detailed process understanding; if the process is not well understood then key steps can be easily missed. Some organisations have attempted to combine both HACCP and FMEA together to overcome the disadvantages with both models.
An example of the application of FMEA is outlined in the case study below.
FMEA was applied to assess risk in a barrier isolator system  used for sterility testing. The following steps were taken:
a) Setting the scope;
b) Defining the problem;
c) Setting scales for factors of severity, occurrence and detection (see below);