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:
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 risk assessment.
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 following: