Advantages and Disadvantages of Different Methods for the Introduction of Artificial Leaks
| Leak Type | Advantages | Disadvantages | Author Experience |
|---|---|---|---|
| Micro-pipettes, ⪆0.1 μm ID (e.g., glass) (19) | • Easy sample preparation | • Fragile and broken tips may not be easily detected • Difficult to determine hole size • Difficult to handle | • Too fragile for routine use • High risk of false sensitivity after preparation of a positive control • Complete seal around micropipette is required • Silicone oil can cause clogging • Pinhole type defect • Material matches primary packaging if glass pipettes are used |
| Laser-drilled holes, ⪆0.5 μm ID (16, 40) | • Wide range of orifice sizes • Better resembles natural defects in glass (cracks) and polymer (pinholes) • State-of-the-art laser drilling processes result in defined holes (e.g., holes are drilled with the cold ablation process, showing fewer cracked pathways). This new technique is, however, more expensive. | • Cost • The size of laser-drilled void needs to be calibrated and represent a defined path • Small holes can clog easily, e.g., silicone oil or highly viscous liquids • Holes can increase size in glass materials from a crack under tension or when exposed to large temperature changes in a short period of time • Can get wide a variability in hole size. May differ according to material and wall thickness • Holes can be irregular shape • Positive controls cannot be prepared directly on the product (e.g., for stability testing purposes) | • Non-negligible risk of alteration of void post manufacture and/or calibration • Requires a specialized external supplier with shipment or prepared and calibrated units • A small hole (≤5 to 10 microns) may not show product leakage when laser drilled are situated in product filled region • Many materials can be used, e.g., glass container, steel plates/tubings • Leaks are closer to real-world defects (no defined geometry) • Holes typically do not increase significantly over time due to lab-based controls of temperature • May reuse positive control samples, but this must be verified • Can get wide variability in hole size and may differ according to material and wall thickness • Drilling and shipment may not be in a clean environment, so dirt or particulates could impact the quality of the holes created • The service is offered by few companies |
| Capillaries (e.g., fused silica capillaries), ⪆0.2 μm ID (21, 49) | • Robust • Easy preparation directly at the testing location • Possibility to prepare positive controls in a specific packaging format and for multiple products (e.g., syringes and lyophilized vial products) • Can be prepared in a flexible way (e.g., may contact liquid and headspace) | • The length of the microtube defects is usually longer than that of typical real-life defects, which may affect the flow pattern • Typically nominal diameters >2 μm available and high uncertainty with respect to the actual diameter • In regard to flow rate, capillary diameter and hole diameter are not comparable • Care should be taken if glue is present as blockage can occur | • Robust, wide size range, and different materials available (fused silica, glass, nickel) • Leakage rate can be fine-tuned through length of capillaries, not only by using different internal diameters (IDs) • Consistent dimensions/leaks • Due to defined dimensions, no need to calibrate each individual leak • Injection needles are not an adequate substitute because ID is too wide |
| Micron wires (e.g., uncoated copper), ⪆10 μm OD (14) | • Low cost • Robust | • Handling of the micron wires can be difficult and the size of the void needs to be calibrated and represent an undefined path • The holes can close up over time depending on the relaxation of the materials (e.g., stopper) • No direct measurement of hole size exists (15) | • Reproducible leak size with defined capping parameters and wire diameter (15) • Leak size only defined when measured relative to a physical phenomenon • Need to consider actual copper wire diameter and elastomer behavior for repeatability • Actual size depends on many parameters (diameter of wire, elasticity of rubber, press fit forces) • Handling of the micron wires can be difficult and the size of the void needs to be calibrated |