Page 113 - Assurance of Sterility for Sensitive Combination Products and Materials

Package/container closures 97

Package testing has focused on seal integrity for both nonporous and po-
rous pouches, to demonstrate that they protect product from microbial in-
gress. Other key methods are microbial barrier testing of porous materials
and seal strength testing.
ISO 11607-1 annex B [36] includes an informative list of test methods
and guidance documents that may be used to demonstrate compliance with
requirements of ISO 11607-1. ASTM F2097 [37] is another useful guide
for test methods selection. A useful detailed guidance is also provided in
annex A of ISO TS 16775 [38] on “Selection, evaluation and testing of packaging
materials and sterile barrier systems.” Fundamental material properties such as
tensile strength, elongation, puncture, tear resistance, and abrasion resistance
can also be monitored.

5.3.3.1 Integrity test methods
Test methods to assess the integrity of seals and closures are arguably the
most important of the test methods used for the validation of SBSs. Seal
integrity shall “minimize the ingress of microorganisms” into the packaging [1].
For nonporous SBSs, there is an additional requirement to ensure that the
gas surrounding the product is also preserved. USP <1207> [39] defines
package integrity for nonporous packaging as “the ability of a sterile product
container–closure system to keep product contents in, while keeping detrimental envi-
ronmental contaminants out.” Thus, for nonporous sterile containers, integrity
is confirmed if a package allows no leakage greater than the maximum
allowable leakage limit.
The sensitivity of the test is the probability of detection of a given in-
tegrity defect, for example, the critical leak rate or critical hole size. Critical
parameters are dependent on the packaging type, product type, defect type,
and environmental exposure of the package itself. These factors have been
studied and reported in the literature. Morton and Kirsch confirmed that
−5
3
microbial ingress does not occur for leak rates lower than 10 Pa m /s.
3
−4
Kirsch et al. also showed that for gas leak rates of 10 Pa m /s, liquid leak-
age would not always occur, while the probability for microbial ingress
would be even lower. Various articles, like those of Kirsch et al. published in
the PDA Journal from 1997 to 2000, or Burrell et al. [40] and Keller et al.
[41] concluded that in containers for sterile liquids critical defect sizes as
small as 0.3–10 μm may lead to loss of sterility. They further demonstrated
that a liquid must be present for microbial ingress to occur. He concluded
that liquid leakage and microbial ingress are probabilistic events, while gas
leakage is a deterministic event. Since the shape of real defects may differ