Vacuum Decay Container/Closure Integrity Testing Technology. Part 2. Comparison to Dye Ingress Tests

Materials and Methods

Materials

The test packages were 1-mL glass syringes with staked needles and elastomeric nonrigid needle shields manufactured by Becton Dickinson (Franklin Lakes, NJ) and purchased by Amgen, Inc. (Thousand Oaks, CA).

Leaks were artificially created by Lenox Laser (Glen Arm, MD; www.lenoxlaser.com) by laser-drilling a defect through the glass barrel of each positive control syringe. These defects were sized to a corresponding nominal hole diameter by measuring the outlet flow of compressed air applied to the defect at 15 psig. Each defect was assigned an equivalent hole diameter to the nearest 0.1 μm by comparing the hole outlet flow rate to calibrated traceable primary transfer standards. Test samples were grouped into target hole diameter subsets of 5, 10 and 15 μm. Each sample fell within ±2 μm of the target diameter. These same holed syringes used for the current study were also used for the ASTM F2338 precision and bias studies described in Part 1.

Each of the three test sites utilized unique negative control (no-hole) and positive control (holed) test sample populations. Each test site was given a total of 20 test syringes: five negative control syringes plus 15 positive control syringes, five per each hole-size subset (5, 10 and 15 μm). The same syringes were used for both the dye ingress and vacuum decay tests. Holed syringes were not tested across sites to minimize hole clogging risks. All costs for generating these defects were underwritten by PTI.

Methods

Test Site Locations:

The test locations included Amgen, Inc. in Thousand Oaks, CA, Bristol-Myers Squibb Co. in New Brunswick, NJ, and Whitehouse Analytical Laboratories, Inc. in Whitehouse, NJ. Test sites are anonymously referred to as Sites 1 through 3.

Vacuum Decay Leak Test:

Vacuum decay leak tests were performed at each test site on all empty (air-filled), stoppered test syringes just prior to subjecting them to dye ingress tests. All vacuum decay leak tests were performed using a PTI VeriPac 325/LV vacuum decay leak tester, one instrument per test site for a total of three test units. The test results were used to verify each hole's presence and relative size. The vacuum decay liquid leak test method parameter set-points used in the Part 1 precision and bias studies were duplicated for the current study (Table I). The differential pressure reading and the Pass/Fail test results were documented for each sample tested.

Dye Ingress Tests:

After the vacuum decay leak tests were completed, the syringes were prepared for dye ingress testing. The stoppers were first removed from the syringes, each syringe was filled with 1-mL of water, and then the stoppers were slowly reinserted. Syringe stoppering was manually performed by positioning a narrow-gauge wire between the barrel and the stopper to vent the syringe during stopper insertion.

The various dye ingress methods used at the test sites are described in Table II. The USP/Ph.Eur. and ISO tests were performed at Site 1. The only difference between the compendia and ISO methods was the vacuum exposure time (10 min versus 30 min). The USP/Ph.Eur. and ISO methods were modified at Sites 2 and 3 to include greater vacuum conditions (−37 kPa versus −27 kPa). These modifications were attempted to improve dye ingress test method sensitivity and reliability.

Dye Test Visual Inspection Method and Inspector Qualification:

The USP/Ph.Eur. and ISO dye ingress tests all require visual inspection for package dye ingress verification. No compendia or ISO dye leak test method specifies the inspection environment; therefore, each test site utilized readily available lighting and background materials for the inspection area as described in Table III.

No standard dye ingress method imposes inspector capability criteria. Nevertheless, in the current study each inspector participated in a qualification study to demonstrate his or her ability to accurately identify those syringes containing trace amounts of dye. These results only served to characterize each inspector's visual inspection abilities; they were not used as inspector selection criteria.

The qualification study required each individual to inspect a small population of syringes filled with aqueous solutions ranging from 0 to 0.4 ppm in methylene blue dye concentration. The inspector was required to identify each sample as either “containing dye” or “not containing dye”. Samples were blinded to the inspector and were inspected in random order at an inspection pace of no more than 10 seconds per syringe. The inspector was provided known, negative control syringes (no dye) for visual comparison. All inspections were completed within 15 min of test syringe preparation to prevent possible dye fading or package sorption effects. No inspector had been prescreened for visual acuity or formally trained to perform visual inspection.