The authors take a broader view of the contamination potential in aseptic processing and recognize that contamination comes
from various sources. Table I presents a vision of risk assessment that has been used for many years (11). This vision draws
upon that broader view and incorporates concerns that affect each of these tasks and the others that affect sterility assurance
for aseptically produced sterile materials.
Table I: Validation of aseptic processing.
There are several basic concepts that result from this conception of aseptic processing. The effect of personnel on the aseptic
process is all-important, and one must define risk to sterility predominantly in terms of the human activities required to
execute the process. Other factors can be included, but focus on the contribution from personnel must be paramount. Risk is
directly related to the number of human interventions required during the process: the fewer interventions required, the lower
the risk of contamination. Interventions can be scaled relative to criticality. The type of interventional activity performed
and the proximity of that activity to sterile materials suggest that some form of weighting of the intervention's influence
Other factors in contamination exposure include:
- the container-opening diameter (smaller diameters are preferred, following the deposition models described previously);
- the length of time the container is exposed to the environment, from its initial entry until its closure;
- the length of time the closure is exposed to the environment before the container is sealed;
- lyophilization, which can increase the exposure risk as a result of extended exposure time of the unsealed container and a
need for additional interventions;
- container type, (e.g., ampuls versus. vials, sealed versus. unsealed);
- automation that significantly reduces the need for operator interaction with sterile equipment and materials;
- complex assembly activities, which depend to a large extent on operator skill and thus increase risk;
- novelty of personnel, equipment, or procedures, which increases risk.
One of the authors' fundamental premises is that all ISO 5 environments are not equivalent in their ability to support successful aseptic processing. Limitations to microbial detection in these clean environments make distinctions among them subjective. Nevertheless, the
authors acknowledge that some technologies are superior to others in their ability to limit microbial intrusion and contamination.
The environmental conditions in which the aseptic process is performed were included as a major factor in risk assessment.
Environmental conditions are an overall factor in the present model. The application of these general principles and others
of similar intent form the basis for the authors' risk-assessment model.
The pharmaceutical industry seems to give little consideration to risk mitigation during equipment selection. Only slightly
more consideration of risk mitigation is given during the choice of container or delivery system. Ease of assembly and operation
can make a substantial difference in risk exposure. Reducing the number of required aseptic connections is beneficial. Automated
component handling is helpful in reducing risk. Low in-process adjustment and maintenance requirements should be key specifications.
Equipment that can operate with minimum accumulation time also is desirable because it reduces exposure.
Akers–Agalloco method for risk assessment
The objective of this effort is a method that is:
- easy to use;
- based on real-world risk factors rather than more theoretical concepts;
- based on an occurrence and criticality model;
- focused on the effect of personnel;
- inclusive of fatigue as a factor;
- prone to reward processes in which interventions are reduced to a minimum.
Occurrence in the present model includes the quantity and criticality of interventions as well as other elements of process
risk that are indirectly related to the core activity of aseptic filling. It includes:
- background environmental risk, which is distinct from the filling environment;
- aseptic compounding risk, which is heavily dependent on interventions;
- aseptic setup risk, which is heavily dependent on interventions;
- aseptic-filling risk, which is heavily dependent upon interventions and calculated separately for manual and machine processes;
- lyophilization risk, which is included where present.