ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 240

processes executed before aseptically combining the container, drug/solution, and
closure and regarded as active critical control points. In this case, critical control
points are authentic critical control points that genuinely adhere to established
hazard analysis and critical control point (HACCP) criteria, that is, those points
with no subsequent risk-mitigating control points downstream, and which if they
were to fail would result in loss of product quality (loss of sterility). Evidence
from sporadic field alerts, product recalls, and adverse events would suggest that
the control of microbial hazards, analysis, evaluation, and management of the
risk of microbial contamination remains an area for improvement. One analysis
notes that nonsterility of pharmaceutical products accounted for almost 8% of
215 product recalls in 2006, [6] and between 1998 and 2006 there were a total
of 115 recalls of sterile products because of the lack of sterility assurance [7].
The potential for wide-scale impact to patient health from nonsterile product risk
is exemplified by the 40,000 adverse reactions (infection) noted in 2002-2003
from the administration of contaminated vaccine. Over 200,000 contaminated
units of vaccine entered the Spanish market [8] as a consequence of microbial
contamination during manufacture; in this event, the vaccine was an animal health
product administered to ruminants.
Aside from microbial contamination of sterile products during aseptic
manufacture, the ingress risk of microorganisms during subsequent admixing,
compounding, preparation, and administration of parenterals is significant
and represents a substantial risk to patient health. Fundamentally, a single
microorganism is the minimum numerical amount of a microbial agent which,
when accessing a sterile product, has the potential to elicit a potentially deadly
infection. In 2002, bloodstream infections accounted for approximately 14% of
1.7 million hospital-acquired infections; such healthcare-associated infections
continue to have dramatic impact with significant morbidity and a mortality rate
as high as 27% [9]. The attendant cost equates to an additional 3.5 million patient
days, costing an additional $3.5 billion as it works out to approximately $29,000
per episode [10]. There has been some conjecture that up to 5% of blood stream
infections are due to intrinsic sources of microbial contamination from the
parenteral infusate, that is to say contaminated products [11,12]. The preliminary
conclusion here is circumspect; contamination from the infusate is likely not
intrinsic per se but rather originates from identifiable opportunities for microbial
ingress, most often aseptic interventions and during any manual admixing
preparation [13]. Regardless, there is and remains an acute need and attendant
benefit of applying risk assessment and risk management in aseptic manufacture.
10.3 RISK ASSESSMENT AND RISK MANAGEMENT
This chapter seeks to address risk assessment in aseptic pharmaceutical manufac-
turing. In this context, risk assessment encompasses risk analysis and evaluation
of those determined risks by applying objective and quantitative methods. This,
of course, is only a fraction of the complete risk management process, which