Container Closure Integrity (CCIT)

Client Background and Details of the Request

The client requested Container Closure Integrity Test acc. USP requirements for an injectable product.

Proposed Service by Intertek (Switzerland) Ltd. Container Closure Integrity Test acc. USP <1207>

The integrity of prefilled syringes or vials needs to be accessed according to USP guidance.

Intertek offers diverse tests. Most common tests are Blue Dye and Microbial ingress test as probabilistic tests and O2 headspaces as deterministic test.

Typically, FDA requests both probabilistic and deterministic test.

Dye ingress method / microbial ingress method / Oxygen Headspace method

1. CCCI-Test with the dye ingress method

Test principle:

Blue dye is exposed to the vials or prefilled syringes while external overpressure is applied.

The dye will colorize the solution after penetration of the internal syringe volume. The coloration is evaluated at different pressure conditions by visual evaluation or photometric methods.

2. CCI-Test with the microbial ingress method if feasible

Test principle:

A microbial test germ is exposed to the vials or syringes while external overpressure is applied. Please note that the syringes have to be filled with microbial culture medium before the tests. The customer needs to fill the vials or syringes with the medium. Intertek can recommend a suitable type of medium.

The microbial germ will contaminate the medium in the vial/syringe after penetration of the internal syringe volume. The microbial growth in the medium is evaluated.

3. CCI-Test with the Oxygen Headspace method if feasible

Test principle:

Syringes and cartridges need to be a barrier to oxygen ingress. Container Closure Integrity (CCI) is the main measure of a packages ability to maintain stability and sterility over the intended shelf life. We develop laser headspace analysis for assessing oxygen ingress rates into syringes or vials.

The recently updated USP 39 <1207> chapter on Package Integrity recommends a move to deterministic analytical methods for assessing container closure integrity of sterile product packages. We recommend the utility of laser headspace analysis for studying oxygen ingress into syringes over a continuum of oxygen ingress rates from permeation to leakage through micron size defects.

USP <1207> defines a maximum allowable leakage limit (MALL) as “… the greatest leakage rate (or leak size) tolerable for a given product–package that poses no risk to product safety and no or inconsequential impact on product quality.”

Product sterility and stability requirements have to be understood and a maximum allowable leak limit (MALL) has to be established that will protect the product over the intended shelf life. From a sterility point of view studies have shown that a diffusive leak rate equivalent to effusive leak rate of 10-6 or 0.2-0.4 micron diameter capillary is the limit for worst case microbial ingress. From a stability point of view gas ingress rates must be much smaller in order to keep oxygen below atmospheric levels in a syringe over a 2 year shelf life.

Syringes are more complicated packages than ampoules or vials and have more pathways for gas and microbial ingress. Gas can ingress through and around the plunger or through and around the tip. Here we develop Laser Headspace Analysis for studying oxygen ingress through specific parts of a syringe.

Intertek recommends analyzing the Oxygen leak rate in a feasibility first. Afterwards the method should be validated and applied routinely during stability in order to check if the O2 leaking or penetration behavior of the packaging changes over storage time.