ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 238

accompanied by uncertainty and variability far exceeding that for the established
mechanics and statistics of spore/cell death inherent in terminal sterilization
processes. Although sterility has been described as an abstract concept [2,3], and
there is merit in this thesis, there remains significant opportunity in the application
of sophisticated, mechanistic, and statistically valid risk assessment to define the
likelihood that one unit of a product is free from microorganisms. Such a strategy
does demand the combination of sophisticated process analytical technology
(PAT) to measure hazard (microorganisms), risk assessment, quality management
systems, and quality by design (QbD). Assessments for the purpose of evaluating
and managing risk in the broad field of aseptic processing (here I include
pharmaceutical manufacturing, healthcare admixing, compounding, and patient
administration) is therefore deserving of special consideration. Risk assessment
in the context of aseptic pharmaceutical manufacture is the principal focus of
this chapter, in particular, with a description and explanation of a quantitative,
statistical tool of risk analysis that permits a more exacting evaluation of risk.
10.2 PATIENT RISK
In the broadest sense, microorganisms represent an extrinsic form of hazard [4]
and may conceptually achieve ingress (contamination) at any number of stages
within the aseptic processing life cycle of a product. At each stage or step, there
may be a variable number of different sources, associated routes of contamina-
tion, and an uncertain magnitude of microbial challenge. At any point post aseptic
pharmaceutical manufacture, the access of microorganisms across the physical
sterile barrier (container closure) of a parenteral product or device also renders the
item nonsterile and has the potential to introduce microorganisms into the patient
during administration. Numerous locations in the aseptic pharmaceutical manu-
facturing process potentially permit the contamination of a product from “resi-
dent” bioburden. Table 10.1 inventories many of the typical locations and orig-
inating sources of bioburden in aseptic manufacturing environments. Although,
there are usually numerous locations from which bioburden might eventually con-
taminate a product, there are usually only a few sources. A technique to generate
comprehensive lists of the locations and origins of bioburden has previously been
described by Whyte [5]. Within the aseptic manufacturing environment opportu-
nities and locations for microbial ingress, post final active (critical) control points
(Fig. 10.1) represent the greatest risk to product “sterility.” Here, the term active
control points describes those purposefully instituted mechanisms that are specifi-
cally designed to address the adverse affects of the hazard. An example would be
a submicron sterilizing grade filter to remove microorganisms from a formulated
product before filling the final sterile container. Within Figure 10.1 the active
control of hazards are the washing process of containers, closures, and equip-
ment to remove endotoxin; sterilization of container, closure, and equipment to
remove bioburden; and sterile filtration of a product to remove microorganisms.