Development of a Dye Ingress Method to Assess Container-Closure Integrity: Correlation to Microbial Ingress

Lana S. Burrell; Mary W. Carver; George E. DeMuth; William J. Lambert

Abstract

To demonstrate maintenance of parenteral product sterility, container-closure integrity over the shelf life of the product is critical. In the past, sterility testing has been used to ensure closure integrity. However, because of the limitations associated with sterility testing, there is a need for an improved method for evaluating containerclosure integrity. This article describes the development of a physical test method (dye ingress) for the evaluation of container-closure integrity. FD&C Red No. 40 dye was used in dye ingress studies. The dye solution visual detection limit was similar to the spectophotometric detection limit. This limit was approximately 0.0025 μL of dye/mL, which corresponds to an absorbance of approximately 0.002 absorbance units at 506 nm. Breached vials with various sizes of microtubes were utilized to correlate the dye ingress method with a microbial ingress method. The inner diameter of the microtubes ranged from 2 to 75 μm. The dye ingress and microbial ingress methods had similar sensitivity to breached vials. One advantage of the dye method over microbial ingress is that it may be utilized with vials containing formulations that are cidal or static to microbes. Thus, the dye ingress method is considered an excellent test method for evaluating container-closure integrity.

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