ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 255

One or several risk components may be perceived for each stage, process,
step, circumstance, or scenario under evaluation; risk components are likely to
vary in number and type. Each risk component is quantified from risk factors that
interdependently influence and impact each other; therefore, it is the numerical
product of risk factor values that define each risk component. Typical risk factors
commonly adopted have included the following [31,48]:
• amount of equipment transfer into a critical area;
• equipment setup complexity;
• complexity of a critical area;
• number of personnel interventions;
• type of interventions;
• number of personnel in the area;
• environmental conditions; and
• surface contamination levels.
Irrespective of the risk hierarchy, risk components must always include risk
factors that represent the likely occurrence of an event (causing harm) and severity
of the harm imparted; choice of salient risk factors and components is ulti-
mately discretionary based on expert opinion to genuinely represent the model
and mechanisms of ingress risk. This is most easily illustrated through a previ-
ously reported example application [19]. In this application, all likely contributors
(risk components and risk factors) associated with the overall risk of microbial
contamination of an 11-step parenteral filling process were determined; a fish-
bone diagram succinctly illustrates these (Fig. 10.5). Risk components and risk
factors participating and contributing in the risk for each of the individual 11
steps of the parenteral filling process were listed; note that the combination of
risk components vary from process step to step (Table 10.6). The parenteral fill-
ing process manufactured a liquid, biological, protein-based product presentation
filled, stoppered, and capped by machine-based processes. Sterile, depyrogenated
empty vials are transferred from a depyrogenation tunnel onto an incoming accu-
mulator table. Vials are then conveyed to a filling head and filled with the liquid,
biological, parenteral formulation before being transferred to stoppering and sub-
sequently to a second accumulator before capping. The sterile vial stoppers are
initially emptied into a stopper bowl from a sterile container before being trans-
ferred to the stoppering equipment. These operations are performed in a qualified,
controlled, and classified environment maintaining bioburden and particulate lev-
els to Grade A [38] and ISO class 5 requirements. A clean room environment
controlled to Grade B [38] and ISO class 5 requirements surround this critical
zone. For a convenient and meaningful analysis of risk of bioburden ingress
throughout the filling process, the filling line is divided into individual sections
or steps. These divisions are representative of the main functional tasks and
activities of the filling process, designated 1-11 and listed in Table 10.6. Overall