ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 248

different quantifiable risks. Using truly quantitative, formulaic, and systematic
risk assessment to assist product disposition is described in greater detail later.
In contrast to the numerous reasons for executing an analysis of risk, there
are only a finite number of events or triggers (planned, scheduled, or unfore-
seen) which elicit this activity and which should be systematically recognized
within any risk management program. The circumstance, purpose, available data,
and required output associated with a risk assessment may all vary, warranting
judicious choice of the appropriate risk analysis and risk evaluation tools. Risk
analysis and risk management are currently embedded in industry and regulatory
agency expectations, the rational choice of tools, techniques, and their consistent
data-driven application will remain key decisions for exponents of risk assess-
ments. Equally, the manner in which a risk assessment has been performed in
terms of objective and unbiased risk analysis (e.g., the assignment of risk scores),
risk evaluation, and risk management must be beyond contestation. Table 10.5
lists several circumstances and stages within a product or process life cycle
(including those described earlier) with suggested aspects to be considered for
choice of the best tool. A number of tools and techniques are listed on the basis
of their reported and potential application at each life cycle stage. This certainly
is not an exhaustive inventory of tools and techniques, but provides the reader
with benchmark applications.
10.5 ASEPTIC PROCESSING HAZARDS
Any perceived or substantiated existence of risk to an aseptic process or aseptic
manipulation is necessarily contingent upon the presence of a tangible hazard.
The World Health Organization (WHO) has clearly defined a hazard as “any cir-
cumstance in the production, control, and distribution of a pharmaceutical which
can cause an adverse health effect [28]”. Although ISO14971:2007(E) specifi-
cally refers to the risk management of a medical device, it does provide a list of
example hazards that serve not only for illustrative purposes but also provides
an excellent starting point to understand potential hazards associated with aseptic
processes, admixing, or administration [29]. Within this definition, hazards can
be separated into hazards that are either integral or inherent elements of processes
or systems (termed intrinsic) or those entities that originate externally and are
therefore not predesigned constituents of the process, that is, extrinsic [30].
10.5.1 Intrinsic Hazards
Intrinsic hazards are frequently associated with discrete events such as the risk of
equipment, process, systems, or control failures. In addition, chemical, physical,
physicochemical, biochemical, or biological hazards inherent in a therapeutic
and which are not necessarily coupled with such “failure modes” might also be
interpreted as intrinsic hazards. In contrast to inherent intrinsic hazards, extrinsic