Vacuum decay container closure integrity leak test method development and validation for a lyophilized product-package system.

A leak test performed according to ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method was developed and validated for container-closure integrity verification of a lyophilized product in a parenteral vial package system. This nondestructive leak test method is intended for use in manufacturing as an in-process package integrity check, and for testing product stored on stability in lieu of sterility tests. Method development and optimization challenge studies incorporated artificially defective packages representing a range of glass vial wall and sealing surface defects, as well as various elastomeric stopper defects. Method validation required 3 days of random-order replicate testing of a test sample population of negative-control, no-defect packages and positive-control, with-defect packages. Positive-control packages were prepared using vials each with a single hole laser-drilled through the glass vial wall. Hole creation and hole size certification was performed by Lenox Laser. Validation study results successfully demonstrated the vacuum decay leak test method's ability to accurately and reliably detect those packages with laser-drilled holes greater than or equal to approximately 5 µm in nominal diameter. All development and validation studies were performed at Whitehouse Analytical Laboratories in Whitehouse, NJ, under the direction of consultant Dana Guazzo of RxPax, LLC, using a VeriPac 455 Micro Leak Test System by Packaging Technologies & Inspection (Tuckahoe, NY). Bristol Myers Squibb (New Brunswick, NJ) fully subsidized all work. LAY ABSTRACT: A leak test performed according to ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method was developed and validated to detect defects in stoppered vial packages containing lyophilized product for injection. This nondestructive leak test method is intended for use in manufacturing as an in-process package integrity check, and for testing product stored on stability in lieu of sterility tests. Test method validation study results proved the method capable of detecting holes laser-drilled through the glass vial wall greater than or equal to 5 µm in nominal diameter. Total test time is less than 1 min per package. All method development and validation studies were performed at Whitehouse Analytical Laboratories in Whitehouse, NJ, under the direction of consultant Dana Guazzo of RxPax, LLC, using a VeriPac 455 Micro Leak Test System by Packaging Technologies & Inspection (Tuckahoe, NY). Bristol Myers Squibb (New Brunswick, NJ) fully subsidized all work.

Vacuum decay container/closure integrity testing technology. Part 1. ASTM F2338-09 precision and bias studies.

ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method is applicable for leak-testing rigid and semi-rigid non-lidded trays; trays or cups sealed with porous barrier lidding materials; rigid, nonporous packages; and flexible, nonporous packages. Part 1 of this series describes the precision and bias studies performed in 2008 to expand this method's scope to include rigid, nonporous packages completely or partially filled with liquid. Round robin tests using three VeriPac 325/LV vacuum decay leak testers (Packaging Technologies & Inspection, LLC, Tuckahoe, NY) were performed at three test sites. Test packages were 1-mL glass syringes. Positive controls had laser-drilled holes in the barrel ranging from about 5 to 15 microm in nominal diameter. Two different leak tests methods were performed at each site: a "gas leak test" performed at 250 mbar (absolute) and a "liquid leak test" performed at about 1 mbar (absolute). The gas leak test was used to test empty, air-filled syringes. All defects with holes > or = 5.0 microm and all no-defect controls were correctly identified. The only false negative result was attributed to a single syringe with a < 5.0-microm hole. Tests performed using a calibrated air leak supported a 0.10-cm3 x min(-1) (ccm) sensitivity limit (99/99 lower tolerance limit). The liquid leak test was used to test both empty, air-filled syringes and water-filled syringes. Test results were 100% accurate for all empty and water-filled syringes, both without holes and with holes (5, 10, and 15 microm). Tests performed using calibrated air flow leaks of 0, 0.05, and 0.10 ccm were also 100% accurate; data supported a 0.10-ccm sensitivity limit (99/99 lower tolerance limit). Quantitative differential pressure results strongly correlated to hole size using either liquid or gas vacuum decay leak tests. The higher vacuum liquid leak test gave noticeably higher pressure readings when water was present in the defect. Both the ASTM F2338-09 test method and the precision and bias study report are available by contacting ASTM International in West Conshohocken, PA, USA (www.astm.org).

Vacuum decay container/closure integrity testing technology. Part 2. Comparison to dye ingress tests.

Part 1 of this series demonstrated that a container closure integrity test performed according to ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method using a VeriPac 325/LV vacuum decay leak tester by Packaging Technologies & Inspection, LLC (PTI) is capable of detecting leaks > or = 5.0 microm (nominal diameter) in rigid, nonporous package systems, such as prefilled glass syringes. The current study compared USP, Ph.Eur. and ISO dye ingress integrity test methods to PTI's vacuum decay technology for the detection of these same 5-, 10-, and 15-microm laser-drilled hole defects in 1-mL glass prefilled syringes. The study was performed at three test sites using several inspectors and a variety of inspection conditions. No standard dye ingress method was found to reliably identify all holed syringes. Modifications to these standard dye tests' challenge conditions increased the potential for dye ingress, and adjustments to the visual inspection environment improved dye ingress detection. However, the risk of false positive test results with dye ingress tests remained. In contrast, the nondestructive vacuum decay leak test method reliably identified syringes with holes > or = 5.0 microm.