Page 122 - Assurance of Sterility for Sensitive Combination Products and Materials

106 Assurance of sterility for sensitive combination products and materials

5.3.4.6 Stability studies
The classification of a combination product’s primary mode of action defines
the regulatory pathway. In Europe, the first case will be regulated under the
medical device or active implantable medical device directives [78, 79], the
second case will be under the directive for medicinal products [80]. This is
particularly important for defining the procedures to follow for stability testing
as regulations will not be cumulative. Stability studies tend to take considerable
time and are resource intensive, so it is important to seek advice and support.
ISO 11607-1 “Packaging for terminally sterilized medical devices” Part 1 [1]
requires stability studies of the SBS based on real-time aging to demonstrate
the maintenance of integrity overtime, however, accelerated aging results
are considered sufficient to go to market when real-time aging results are
not yet available. The standard also requires real-time and accelerated aging
tests to begin simultaneously. This ensures that both sample populations
are comparable, facilitating root cause analysis in the event that there are
unexpected results. Accelerated aging duration is typically calculated based
on ASTM F1980 [81] with elevated temperatures while normally staying
below 56 °C or lower. The Arrhenius equation is used to correlate real-time
aging and accelerated aging as a function of temperature. The rate of chem-
ical reactions doubles with every temperature increase of 10 °C, up to ap-
proximately 60 °C. This correlation often decreases at greater temperatures
increasing the risk of failures [81]. For this reason, it is good practice to
proceed conservatively to avoid repeating these time consuming and ex-
pensive studies.
Stability studies for the packaging itself can be leveraged if the same
packaging is applied to different devices and when it is demonstrated that
“the product does not interact with the specified sterile barrier system over time” (ISO
11607-1 paragraph 6.4.7) [36].
For drug products, the requirements for stability testing for products
marketed in the United States are defined in CFR §211.166 [82]:
(a) There shall be a written testing program designed to assess the stability charac-
teristics of drug products. The results of such stability testing shall be used in deter-
mining appropriate storage conditions and expiration dates. …
The European Directive 2001/83/EC [80] requires submission of a de-
scription and the specifications of the container and the closure system(s) for
the active substance(s) and a summary of the detail of the stability studies,
including “information on the analytical procedures used to generate the data and
validation of these procedures.” It requires also to provide a “post-authorization
stability protocol.”