Many in the pharmaceutical industry consider aseptic processing to be among the more difficult activities to execute properly.
A substantial number of variables affects the safety of sterile products manufactured aseptically. The design and operation
of an aseptic production facility must minimize the risk to the patient. This article presents a new approach to risk assessment
for aseptic processing that emphasizes the contributions of personnel.
In September 2004, the US Food and Drug Administration issued the long awaited guidance on sterile drug products produced
by aseptic processing (1). That month, FDA also published Pharmaceutical CGMPs for the Twenty-First Century—A Risk-Based Approach. (2) Each of these documents refers to the other, but there is no substantive information offered in either to assist the
practitioner in establishing a risk-based approach for the design and control of aseptic processing operations.
Numerous pre-existing risk-analysis methods have been adapted for the pharmaceutical industry, including:
- Fault Tree Analysis (FTA);
- Failure Mode and Effect Analysis (FMEA);
- Hazard Analysis and Critical Control Point (HACCP);
- Hazard and Operational Studies (HAZOP);
- Failure Mode, Effect, and Criticality Analysis (FMECA).
These commonly used methods have proven successful in a variety of applications. None, however, was ever specifically intended
for application to aseptic processing, which relies on a large number of variables and has the lowest tolerance for failure
of any process in the entire industry. Simply put, failure in aseptic processing is unacceptable, and a suitable risk-analysis
method must incorporate all of the factors affecting product sterility and patient safety. The risk-analysis approach used
must incorporate the recognition that there is no acceptable level of risk associated with sterile products, regardless of
the manufacturing method. The goal is, and must always be, perfection in all elements of sterile product manufacturing, especially
when products are made using an aseptic process (3). With this in mind, the authors embarked on an evaluation of previously
established risk-evaluation methods as applied to aseptic processing.
Risk and risk-evaluation methodologies
The risk-analysis method that is chosen must focus clearly on the manufacturing activities that are essential for success
in aseptic processing. This normally is manifested by a concern for criticality. Not all of the constituent activities of
a process being evaluated have an equal effect on the end result. Risk, as defined within FMECA, is a multiplication of the criticality of an occurrence by its frequency. This definition seemingly
can be applied directly to aseptic processing. Determining what constitutes an "occurrence," however, is generally difficult
in aseptic processing. One could argue (perhaps incorrectly) that environmental monitoring results can provide a measurement
of occurrences, but this assumption is theoretical at best. Environmental monitoring, especially in the ISO 5 environments
commonly used for aseptic processing activities, hardly can be considered a quantitative or fully effective tool. In the typical
ISO 5 environment, microbial contamination is detected only rarely, and even the most aggressive sampling plans only sample
a limited amount of air or surfaces* (see endnotes). Another drawback of viable environmental monitoring is that results are
unavailable in real time when using common growth and recovery methods. Nonviable particle monitoring, which is available
in near-real time, has never been correlated sufficiently to viable data. The authors consider it of limited value in aseptic
The authors believe that there is a straightforward way to analyze risk in aseptic processing. Risk is by general agreement a function of the release of human-derived contamination into the operating environment. The full
extent of human contamination risk is substantial: a gowned operator may release as many as 10,000 colony-forming units (cfu)
or more per hour (4, 5). The estimated value is derived from operators performing controlled and defined movements immediately
after donning sterile gowns. These methods merely provide a way to estimate the intensity of the contamination source from
activities substantially different from those performed during aseptic processing. Direct application of these data to aseptic
processing unfortunately is not possible, given the differing environments and activities.
Whyte developed a risk-assessment model based on his research on microbial deposition, which was an extension of his earlier
efforts with settle plates (5–8). The premise behind this approach is the recognition that personnel are the primary source
of contamination. It assumes the mechanism for dispersion of that contamination is airborne deposition. Whyte's model is the