Using Positive Controls to Define the Defect Detection Range for CCIT Method Development and Validation.

Abstract

In recent years, the pharmaceutical industry has moved towards using quality by design (QbD) principles to ensure safety and efficacy in parenteral products. Developing and validating container closure integrity test (CCIT) methods that can be used to confirm inherent package integrity - as well as batch-release and stability sample testing - is an essential aspect of this more holistic approach. To do so, both positive and negative controls are required, both of which should ideally be assembled with container components in a manner mimicking the production samples that are to be tested. The performance of these controls enables the accuracy, precision, limit of detection (LoD), and range of the CCIT method to be defined per the ICH Q2 parameters [1]. The negative controls should contain no known defect. The positive controls should differ from the negative controls only in that they have a well-characterized defect that creates a quantified breach in the container closure integrity (CCI) of the package assembly. When appropriate, "type controls," as defined in USP <1207>, can also be included during CCIT method development [2]. Type controls are intended to qualitatively evaluate the ability of the CCIT method to identify defects that better mimic "real-world" defects, including the potential of the product to inhibit the identification of such defects.The first objective of this study was to present a theoretical framework that links the flow-effective size [3] parameterization with the observed gas flow rates for a defect. The second objective was to demonstrate the use of microcapillaries to create defects with a flow-effective size much smaller than the current 2 μm limit of laser-drilled defects. The third objective was to reveal that the flow-effective size associated with 5 and 10 μm laser-drilled defects in glass vials decreased significantly when submerged below a liquid 0.2 μm filtered-water fill.