Examples of pCCI Techniques for Consideration for CCS Qualification, Manufacturing Process Control, and/or Quality Control
| Technique | Measuring Principle | Advantages (literature, instrument manufacturer) | Disadvantages (literature, instrument manufacturer) | Author Experience and Area of Application |
|---|---|---|---|---|
| High-voltage leak detection (electrical conductivity and capacitance) (33, 34) | Deterministic. Based on quantitative electrical conductance measurements. The presence of a leak path in the proximity of electrically conductive liquid results in a drop in test sample electrical resistance, shown as a spike in current above a predetermined pass/fail threshold. | • Non-destructive • Feasible for 100% online testing • High testing speed • No sample preparation required • Accuracy not dependent on operator skill • Testing performed under normal atmospheric pressure | • Pass/fail result, no quantitative result • Product must be more conductive than the package • Potential for damage to the product (e.g., protein degradation) • The formulation must not be flammable • Ozone generation • Special fixtures are required for a specific CCS • Electrodes must be within a certain distance of leak for detection • Product liquid needs to be in contact or close to the leak • Product clogging could lead to incorrect results • Does not work for lyophilized products | • High throughput on commercial production line • Need to assess product quality after exposure to voltage • Limitations for use in long-term stability testing due to clogging (drying out) of liquid residues in the voids during prolonged storage • Risk that conductivity of the drug product is not sufficient to detect a defective syringe • A 100% online module can be integrated with the automated visual inspection • Has limited sensitivity in 100% online testing because only larger leak sizes, i.e., visually leaking cracks, are detected • Limited applicability for cracks in the vial head region under the crimp cap given lack of product liquid contact |
| Laser-based headspace analysis (14, 18, 19) | Deterministic. Assessment of package headspace via laser-based analysis techniques provides a quantitative, non-destructive measure of oxygen, nitrogen, carbon dioxide, water vapor, or internal pressure in a non-porous, rigid or non-rigid package's headspace. A near-infrared diode laser light is passed through the gas headspace region of the sealed package. Light absorption, measured using frequency-modulated spectroscopy, is indicative of gas concentration and pressure. | • Non-destructive • Quantitative • Feasible for 100% online testing • High testing speed | • The container must be transparent • Requires modified atmosphere in the headspace • Requires a certain minimum volume of headspace with a certain size window for detection • Will take an extended period of time to detect small leak sizes • Change parts need to cover different container sizes and types | • Could take weeks of gas exchange to detect micron-sized leaks (low throughput) • Easy to use • Can be used to evaluate transient leaks (e.g., for products stored under cryogenic conditions) • Risk of false results, particularly during stability testing due to gas permeation or absorption of the tracer gas into the liquid product phase • Large leaks may not be detectable (e.g., for studies under cryogenic conditions) because of fast equilibration with ambient air • Difficult to discriminate between different leak sizes • Difficulties or even inability in detecting leaks located in the liquid solution area, thus limited applicability for filled syringes or cartridges • Potential for clogging in lyophilisate products • Partial pressure is temperature-dependent |
| Helium leak test (18, 33) | Deterministic. Helium-filled or flushed samples are placed in a test chamber, where a vacuum is created by the instrument's internal pumps. Fixtures may be required to isolate particular package areas of interest. Leaking samples allow helium to escape, enter the test system, and be detected by an analyzer cell. The stream of helium ions hitting the analyzer cell target is proportional to the partial pressure inside a sample. | • Quantitative • High testing speed • Wide range of CCS sizes can be analyzed • A specific leak rate can be calculated • Accurate and reproducible results • Very sensitive (if flow rate is determined by a mass spectrometer) • ASTM available | • Destructive • Low throughput • Off-line use only • Product clogging could lead to incorrect results | • Reproducible and easy to use once tooling has been qualified • Cannot be performed on intact product containing packages unless under artificial helium atmosphere (e.g., via bombing), i.e., destructive test • Detection sensitivity to 2 μm and possibly far lower • Can be used for testing samples for frozen drug products/at low temperatures (16, 36, 37) |
| Mass extraction, mass flow (16, 36) | Deterministic. A vacuum is drawn on a sample enclosed in a chamber. Once a vacuum is established, the instrument monitors the amount of airflow required to sustain a specific vacuum level. The amount of flow required to keep the vacuum steady is proportional to the amount of flow escaping from leaks in the sample under test. | • Non-destructive • Quantitative • 100% testing feasible • Flexible, can be used on liquid and lyophilized samples and plastic bottles/IV bags • Sensitive | • Product clogging could lead to incorrect results | • Detection sensitivity to 2 μm leak size is possible • It has long cycle times with large packages • Good repeatability for testing the same packages multiple times • Labeled packaging can induce false positives due to off-gassing; testing unlabeled samples mitigates this potential issue |
| Pressure decay (36, 38) | Deterministic. A test package is placed into a custom-designed test chamber that is subsequently exposed to overpressure. Sensitive pressure transducers monitor changes in chamber pressure. A pressure drop indicates a leak. | • Non-destructive • Feasible for 100% online testing • ASTM method available | • Typically only a pass/fail result • Product clogging could lead to incorrect results | • Less sensitive than vacuum decay test • High throughput on commercial production line |
| Vacuum decay (33, 36, 39, 40) | Deterministic. A test package is placed into a custom-designed test chamber that is subsequently exposed to vacuum. Sensitive pressure transducers monitor changes in chamber pressure. A pressure increase indicates a leak. | • Non-destructive • Feasible for 100% online testing • High testing speed and throughput • No time lapse between manufacture and testing necessary • ASTM method available • Can be used on liquid and lyophilized samples • Can be used on colored CCSs and labeled samples | • Expensive equipment that requires specific instrumentation/tailored test chambers for each CCS • Product clogging could lead to incorrect results • Vacuum chamber preparation is critical (humidity can impact on measurement results) | • Versatile and can be used on primary and secondary packaging in support of development, manufacturing, and stability testing • Suitable for liquid and lyophilized products • Can be used for device testing and for products with labels; however, test sensitivity is reduced compared to unlabeled primary packaging • Limitations for online use, generation of false positive results (e.g., due to potential for air entrapment within a crimped cap or humidity fluctuations) • Development studies have shown equivalent sensitivity for lyophilized product and liquid-filled syringes and vials • Rapid clogging observed for positive controls that contained laser-drilled holes in contact with the liquid product (viscosity limitations) or clogging by proteins or silicone oil in prefilled syringes • Magnitude of pressure change can be correlated with size of leak or leakage rate, however, no distinction between multiple small leaks or single breach or gap in CCS can be made |
| Corona discharge testing (41) | Deterministic. A high-voltage frequency electrode is applied to the outside of the sample. Gas molecules in the sample's headspace are ionized followed by a Corona discharge (glow) measured as a current/ discharge pattern. | • Non-destructive • 100% testing feasible • High testing speed and throughput • No sample preparation required • Accuracy is not dependent on operators skill • Testing is conducted under ambient atmospheric pressure | • Headspace required • CCS has to be closed under a vacuum • There is a threshold for minimum detectable vacuum level • Potential ozone creation, thus potential for damage to the product | • Does not work for a CCS closed under atmospheric pressure • Reliable detectable vacuum range is limited • Currently not widely used and a lack of published data specific to CCIT |
| Bubble emission (42) | Probabilistic. The test package is submerged into an immersion fluid and inflated by applying a defined vacuum or an overpressure. Evidence of bubble emission through the package is considered a failure. | • Widely used for decades • ASTM method available • Inexpensive • Convenient and easy to use • Good for flexible packaging • Leak location can be confirmed | • Destructive • Pass/fail result, no quantitative result • 100% testing is not possible | • Easy to train the operator and perform the test. However, the results can depend on operator technique and can take several minutes per sample • Limit of detection may be too high to assess microbial contamination risk |
| Dye ingress (liquid tracer test) (21, 33, 43–45) | Probabilistic. In its most common form, a package is placed in a bath of water with a dye and perhaps surfactant within a test chamber and a set vacuum is drawn on the package. The method attempts to draw air out of the package cavity. The vacuum is then released from the test chamber. If the package cavity leaks air the package cavity will have a reduced pressure drawing dye into the package cavity. Subsequent exposure to increased pressure can enhance dye penetration if leak is present. An operator (or instrument) will then inspect the package for any degree of coloration, i.e., dye ingress. | • Widely used for decades • ASTM and ISO methods available (24, 46–48) • Industry and regulatory familiarity • Basic and efficient • Flexible, can be used for several different CCSs (types and size and products) in same run • The leak location can be specified • The leak can be in the liquid phase | • Pass/fail result, no quantitative result • Destructive • 100% testing is not possible • The test samples need to be transparent, for visual assessment • In larger volume products ingress of small amounts of tracer liquid may be more challenging to detect • Detection is probabilistic for small size defects | • Versatile and can be used on primary and secondary packaging in support of development, manufacturing, and stability testing • Detects directly relevant leaks of concern • Different dyes can be used to tailor the method • Improved sensitivity when optimized vacuum/pressure cycles are used. Limit of detection varies depending on the leak size, materials, dye concentration, and challenge conditions • The tracer liquid must be miscible and not chemically reactive with the product • Correlation to microbial ingress can be established using the same challenge conditions • Has been seen to work well for liquids but depending on the dye it may not be suitable for lyophilized products |
| Microbial immersion or aerosol challenge (mCCI) (20, 24, 36, 49) | Probabilistic. The sample is filled with sterile nutritive media, then the outside of the container is challenged with an actively growing motile micro-organism in order to assess CCI. Any microbes detected in the sample after a defined period of storage time are classed as a failure. Vacuum and/or overpressure are frequently applied to samples. | • Widely used for decades • Industry and regulatory familiarity • Readily incorporated into media fill runs • Direct assessment of relevant property (i.e., maintenance of integrity with respect to microbial contamination) | • Destructive • Pass/fail result, no quantitative result • 100% testing is not possible • Can take weeks • Labor intensive • Media-filled CCS only • Potential for false positives and false negatives; the level of detection is partly related to operator technique • Detection is probabilistic for small size defects • No harmonization on media and organisms and method specifics | • The limit of detection varies with leak size, materials, organisms, media, and challenge conditions • Historically used to establish a critical leak (rate or size) • The submersion method is more common and easier to set up and more reproducible than the aerosol method • Long-term checks over a period of weeks without using vacuum or overpressure can be more representative of actual storage conditions • Short-term checks over a period of hours with applying vacuum and/or overpressure can be more representative of transport conditions and reduces test time |