Advantages and Disadvantages of Different Methods for the Introduction of Artificial Leaks

Leak TypeAdvantagesDisadvantagesAuthor 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