ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 257

TABLE 10.6 The Eleven Steps of the Aseptic Machine Filling Process of a
Parenteral Product a

Filling Risk Components

No. Process Step Contributing To Step Risk

1 Filling line setup A, C, D, E

2 Vial transfer from depyrogentation tunnel

to accumulator

C, D, E

3 Conveying empty vials to filling A, B, C, D, E

4 Emptying stoppers into stopper bowl A, B, C, D, E

5 Stopper handling in stopper bowl and

conveying to stoppering

A, B, C, D, E,

6 Filling A, B, C, D, E
7 Stoppering A, B, C, D, E
8 Conveying stoppered vials to accumulator A, B, C, D, E
9 Loading accumulator with stoppered vials A, B, C, D, E
10 Conveying stoppered vials to capping A, B, C, D, E
11 Capping of stoppered vials A, B, C, D, E
a Source: The risk components (see Figure 10.5) contributing to the risk of bioburden ingress are
listed for each step.

risk at each filling step is calculated from the combination of risk components
and the overall risk of microbial contamination to the process determined from
the sum of all process step risks.

10.8 QUALITY BY DESIGN, QUANTITATIVE RISK ASSESSMENT,
AND PRODUCT DISPOSITION

Inevitably, all aseptic processes are vulnerable to varying degrees of risk posed
by extrinsic hazards accessing the product or device across a sterile barrier (or
zone), rendering the product contaminated. Typically, sterility assurance pro-
grams adopt an integrated range of technologies, practices, tests, and monitoring
systems incorporating critical evaluation whose aggregate contributions establish
a level of sterility assurance. Generally, numerous environmental controls are
integrated into a strategy that includes (but is not limited to) facility (design,
finish, materials of construction, cleaning, and sanitization), personnel (number,
traffic flow, movement, dress code), and equipment (design, finish, materials of
construction, operation, maintenance, cleaning, and sanitization/sterilization).

10.8.1 Improving Assessments of Microbial Risks
A successful strategy combines these controls to minimize and measure the num-
ber of microorganisms within the immediate (or extended) vicinity of a product
and must be considered in detail as a fundamental part of any risk assessment.
Whyte [5] and subsequently Whyte and Eaton [24] clearly illustrate the necessity