Deterministic methods

HVLD allows to detect the presence of a leak(s) in the wall of a nonporous, rigid or flexible package (relatively electrically nonconductive), by applying high voltage potential to electrically conductive products. HVLD is non-destructive CCI technique, highly sensitive technology applicable for a wide range of liquid filled parenteral products including protein based products.

Advantages:

• Deterministic
• High sensitivity
• Exploitables for large molecules drug products
• Non destructive

Disadvantages:

• Test limited to liquids (with no combustion risk) more electrically conductive than package
• The varying resistivity of the materials (e.g. glass vials stoppered with a metal crimp cap) may result in loss of sensitivity and reliability of the test

Vacuum and pressure decay techniques exploit quantitative measure of pressure rise/drop within an evacuated/pressurized test chamber with sample inside in order to detect the presence of a leak. Both techniques are non-destructive and are high sensitive for liquid products composed by small molecules. Pressure decay is the test of choice for lyophilized product and it could exploitable for packaging system filled with large molecules products. [riferimento articolo]

Advantages:

• Deterministic
• Good sensitivity
• Exploitable for large category of product: liquid and lyophilized
• Non destructive

Disadvantages:

• For pressure decay the detection of a leak under the surface could be impeded as a function of liquid fill-level
• For vacuum decay package surfaces below the liquid fill-level may be tested only for those liquid products that volatilize at test vacuum without solidifying and blocking leak paths

Helium leak detection is the most common technique belonging to the category of Tracer gas detection in vacuum mode. It is based on the quantitative measure by spectroscopic analysis of tracer gas leak rate emitted from a tracer-flooded test sample positioned in an evacuated test chamber. Sample leakage rate is calculated by normalizing the measured tracer leak rate by tracer concentration in the test sample.

Advantages:

• Deterministic
• The high sensitivity allows to use this leak test technology to determine the maximum allowable leakage limit
• Highly recommended during the development of the packaging system

Disadvantages:

• The test is destructive if the introduction of tracer gas compromises assembled package integrity or if the inclusion of tracer gas may prevent introduction of these packages into commercial or clinical markets.
• Leak paths must be clear of liquid or solid materials that could potentially block tracer gas flow.
• Caution is advised when testing liquid-filled packages, because vapors or liquid drawn into the test system can seriously damage instrumentation.
• Large leaks in the smallest packages may be missed because of the rapid loss of tracer gas

This technique provides a quantitative measure of quantitative, nondestructive measure of oxygen content, water vapor content,  low internal pressure in the headspace and carbon dioxide of a nonporous, rigid or nonrigid package. Frequency-modulated spectroscopy is used to cause a near-infrared (IR) diode laser light to pass through the gas headspace region of the sealed test sample. Light is absorbed as a function of gas concentration and pressure.

Advantages:

• Deterministic
• Non-destructive
• Exploitable for Products that require: low-oxygen or low-carbon-dioxide headspace content, low water vapor content (e.g., lyophilized or powdered product) and low internal package pressure (e.g., lyophilized products)

Disadvantages:

• Package integrity, or absence of leakage, is confirmed by replicating tests on a given test sample as a function of time: headspace analysis at a single time point may not be indicative of package integrity.
• Test samples require a minimum headspace volume and headspace path length