Page 114 - Assurance of Sterility for Sensitive Combination Products and Materials

98 Assurance of sterility for sensitive combination products and materials

significantly from perfect round holes and some may represent a tortuous
path, the defect leak rate is a more reliable measure compared to the dimen-
sion of defects to determine what is critical and what is not. Dana Morton
Guazzo provides an excellent summary in Michael J. Akers’ book “Sterile
Drug Products” [42].
The validation of integrity test methods requires defining the critical
defect size that is detectable, followed by demonstrating it can be measured
with acceptable repeatability. For packaging of solid articles like medical de-
vices, the main concern is to protect against airborne microbial challenges
rather than the ingress of liquids. In the case of a defect or hole of a given
size, the leak rate will be a function of the differential pressure between the
inside and outside of the package as well as the packaging porosity. The
goal of porous packaging is ensuring it remains a microbial barrier while
being permeable to gas. This has enabled gaseous sterilization modalities
to be used extensively and efficiently on a large variety of products while
maintaining sterility. Porous packages are also efficient in reducing differen-
tial pressures while air can penetrate through numerous tortuous pathways
minimizing the impact of a potential defect. Hacket et al. concluded in a
series of experiments in 2000 that “using a material with high permeability in
a well-designed package can provide an effective barrier system even when a hole of
25 μm or smaller is present” [43].
The most used integrity test method is probably visual inspection based
on ASTM F1886 [44]. Extensive round robin data have been documented
with channels of 125 μm being detected at 94% and 75 μm detected at 79%.
Visual inspection has limitations in terms of sensitivity and reliability if op-
erators have to perform the test over longtime periods. For this reason, it is
not always accepted by authorities. Nevertheless, it is an excellent method
for routine checks, but cannot replace other more sensitive methods that are
required for state-of-the-art validation.
Dye penetration testing for porous packaging as per ASTM F1929 [45]
is capable of detecting leaks as small as 50 μm with a probability of 99%.
The bubble test (ASTM F2096 [46]) is a popular test and easy to realize. Its
main weakness is the lower sensitivity with porous materials. Customized
methods have been developed to test porous lidded trays with CO 2 tracer
gas (ASTM F2228) or with vacuum decay methods (ASTM F2338 [47]).
These nondestructive tests have acceptable sensitivities, but they required
customized equipment and are significantly more expensive. Recent de-
velopments in ultrasound testing (ASTM F3004 [48]) or optical tomo-
graphic imaging are also encouraging since these tests can be used online