Page 79 - Assurance of Sterility for Sensitive Combination Products and Materials

Aseptic processing 65

10L Sterile holding vessel
Autoclaved
Seven day hold
Grade C environment
Media fills to validate hold

Fig. 4.6 Holding vessel.

the ailure during the requalification aseptic process simulation, it did not
f
explain why the initial aseptic process simulations passed. A further investi-
gation of the failure was conducted to uncover a key variable and resulting
weakness in the aseptic process.
The initial successful aseptic process simulations took place during a pe-
riod when there was very low activity was occurring, except for validation.
Normal manufacturing had not started yet. The Grade C environment was
exhibiting environmental microbial loads closer to Grade A or B environ-
ments. During the initial aseptic process simulations, the Grade C area in
which the vessel was held was also much cleaner than it would be during
normal operations. When normal production began, activities were occur-
ring in the Grade C area and the environment exhibited normal levels of
activity and microbial loading. The control system to protect the interior
of the vessel from contamination was adequate for the cleaner premanu-
facturing Grade C environment, but not for the more routine Grade C
environment.
The validation study assumed that the Grade C environment was a con-
stant if it met Grade C specifications, but the Grade C environment was
a variable. This case study illustrates two important points. First, a careful
analysis and evaluation of process variables and the risk they may pose on
product quality are needed when designing the process and the validation
study. The second point is that aseptic process simulations were not sensitive
enough to pick up these weaknesses.
If a properly performed risk assessment was performed, it would likely
have identified the wrapped opening on the vessel as potential process weak
points as the vessel cooled and the wrapping became wet in the Grade C
area. Those designing the system would then have had an opportunity to
mitigate that risk with further process controls, such as closing the valves
placing the vessel under positive pressure or storing in a more controlled area.