ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 254

10.7 RISK HIERARCHY

Although the conceptual bioburden ingress model is intrinsically simplistic, the
precise mechanisms by which microorganisms access a product during asep-
tic pharmaceutical manufacture is a complex and multifactorial process. Any
risk assessment must therefore adequately account for and incorporate consid-
eration of all participating factors within a structured architecture or hierarchy.
Risk hierarchies (of varying design) have been successfully incorporated into
contemporary formulaic and quantitative assessments of risk in aseptic manufac-
ture [23,48]. Irrespective of the preferred process or system of risk assessment
adopted, a common hierarchical description of overall risk can be envisioned,
which satisfies all risk scenarios and the model for bioburden ingress (Fig. 10.4).
This hierarchical relationship is fundamental to any assessment of risk and
is suitable for application of any type of the recognized risk assessment tools
and techniques including FMEA, HACCP, and quantitative risk modeling. This
hierarchy can be applied at each step, circumstance, or more simply encompass
the entire assessment of risk. The overall quantitative estimate for risk is derived
from the numerical sum of individual risk components that are generated from
individual risk factors. Risk factors have some level of interdependency in that
their magnitude may directly affect other risk factors and which combine to a
value contributing to the overall risk. Risk factors that affect each other are there-
fore multiplied together. The assignment of numerical values for each risk factor
can be achieved by the means previously described (via arbitrary surrogate but
representative relative values) or by actual empirically derived measurements (see
quantitative risk modeling, later). Risk components (and therefore their numer-
ical value) have no interdependency; they have no influence or propensity to
influence each other's contributors to the overall risk. Typical examples of risk
components include the following [31,48]:

• facility contribution to risk;
• transfer of equipment to filling area;
• equipment setup; and
• personnel interventions.

H

R

C ++ C C

F

XXX

F F F

Figure 10.4 A risk hierarchy describes the relationship between hazards [H], risk [R],
risk components [C], and risk factors [F] [30].