ASEPTIC PROCESSING: ONE - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 233

• Environmental monitoring generally requires interventions as well, and their
impact must also be considered.
• All interventional activities should be carefully defined, practiced, and exe-
cuted using proper aseptic technique.
• Particular consideration should be given to corrective interventions with the
goal of reducing their impact and frequency. ‡‡
• There is no “safe” intervention; contamination potential is a part of each [35].
9.4.7 Personnel
The aseptic operator is the primary source of contamination in aseptic processing
[36]. In large part, the concerns identified previously for the other contributing
factors in aseptic processing are intended to reduce the impact of the operator on
the materials being produced. Concerns relating solely to personnel include the
following:
• Operators must be trained in a variety of relevant subjects including micro-
biology, aseptic processing, CGMP, gowning, and any job-related tasks.
• Operators must demonstrate proficiency in aseptic gowning (where nec-
essary) and aseptic activities such as equipment assembly, inherent and
corrective interventions (including environmental monitoring).
9.5 STERILITY (SAFETY) BY DESIGN
Proper consideration of the preceding elements constitutes the design phase for
an aseptic processing operation. As described, it is clearly quite different from
the quality by design (QbD) expectations that are becoming prevalent in drug
substance or drug product process development [37]. In those areas, correlation
between the independent and dependent variables can often be established with
some degree of certainty. The goal is to establish operational controls for the
independent parameters, which will ensure that the dependent quality attributes
associated with the process can be appropriately controlled. The lack of suffi-
ciently sensitive metrics for what is in effect “sterility” precludes the application
of conventional QbD thinking to aseptic processing. The linkage between the
independent variables and successful outcomes resulting from the aseptic pro-
cess is much less distinct and subject to variations for which there are no means
of detection. Risk assessment, as described earlier in this effort, is perhaps the
only effective means for objective evaluation of the suitability of many of the
various design decisions.
‡‡ Corrective interventions as defined in PDA TR#22 are those utilized to correct faults in the equip-
ment, components, or procedures requiring operation correction. In theory, a process could operate
without the need for corrective interventions. It is inappropriate to consider any corrective interven-
tion as a 'routine' activity necessary in every batch.