OVERVIEW OF THE VALIDATION MASTER PLAN
As described above, several modifications have been introduced compared with the classical glass-vial technology. To ensure
that these modifications meet regulatory requirements and expectations, they have been tested according to the US and European
pharmacopeas and to the guidelines published by the International Conference on Harmonization (ICH), and compiled in the validation
The tests performed are listed in Table I. They can be split into four parts: the container–closure materials, the behavior
of the container closure in various conditions, the specific filling operations, and the overall process.
Table I: Overview of the tests performed in the validation master plan.
One crucial aspect of the container–closure is that the container has to be treated by gamma-irradiation to ensure its overall
sterility, and not only asepsis. Gamma-irradiation may have physico-chemical effects on the materials. Therefore, to be robust,
validation must be performed using worst-case conditions regarding the irradiation dose. To that end, a dose-mapping experiment
on the densest pallet (1-mL vials) showed that to ensure a minimum of 25 kGray at the coldest point, the hottest point can
receive up to 46 kGray. Therefore, the decision was made to irradiate all the test material at minimum 50 kGray.
VALIDATION OF THE CONTAINER MATERIALS
Different chapters of the pharmacopeia are applicable to closed-vial materials, as indicated in Table I. Of course, these
tests must be conducted only on materials in direct contact with the pharmaceutical drug (i.e., the TPE stopper and the COC
The toxicity test described in
<87> Biological Reactivity Tests,
has been conducted on both vial body and stopper materials. Extract of materials are subjected to the elution test in which
L-929 cells are incubated for 48 hours with media used to extract materials. This test was repeated on three batches of each
material and did not show any sign of reactivity.
The toxicity test described in
<88> Biological Reactivity Tests,
is directly linked to the USP Class VI classification. It combines systemic injection, intracutaneous injection, and intramuscular
implantation tests with extracted materials or strips of materials. Based on the results obtained, the material can be classified
from Class I up to Class VI. According to the application, a certain level of classification is mandatory (e.g., USP Class
VI is mandatory for permanent implantation such as prosthesis). For injectable containers, Class IV is acceptable. Nevertheless,
as most of container materials meet the most stringent conditions (i.e., class VI), this one became a recommended standard.
To perform a complete range of tests, the products must be extracted with four different solutions: 0.9% sodium chloride,
1:20 alcohol solution in sodium chloride, 0.9% polyethylene glycol 400, and vegetable oil. For both vial body and stopper
materials and with all extraction solutions, the test was performed on three different batches and no toxicity was recorded,
showing that USP Class VI requirements are met.
Other tests were performed regarding material physico-chemical properties. The
requires a series of tests on polymers in
General Chapter <661>. These tests are limited to nonvolatile residues, residues on ignition, heavy metals, and buffer capacity.
Some polymers such as polyethylene require specific tests but these are not applicable to COC. In the
3.1.3 Polyolefines, is dedicated to polyolefin. Although COC does not fall in that category, because the definition of polyolefin
is limited to "polyethylene or co-polymer of ethylene with less than 25% of another organic compound," it was still decided
to conduct that series of tests on COC. The vial body passed all these tests.
Concerning the tests to be conducted on the elastomeric closure, because
<381> Elastomeric Closures for Injections contains the
tests described here as well as other tests harmonized with those described in
3.2.9 Rubber Closures for Containers,
3.2.9 for single-dose container was selected. This chapter describes mixing chemical tests on elastomeric closure extracts
and mechanical tests such as fragmentation and penetrability on the whole stopper. The TPE stopper successfully passed all
these tests for single-use container.