LEAKAGE TEST FOR PHARMACEUTICALS (AMPOULES , INJECTABLE AND NON INJECTABLE PLASTIC CONTAINERS)
Ampoules are small glass containers that contain a sterile medicinal liquid intended for parentral use. Presence of capillary pores or tiny cracks can cause microbes or other dangerous contaminants to enter the ampoules or may lead to the leakage of contents to outside. This may lead to contamination of the sterile contents and also spoilage of appearance of the package.
Changes in temperature during storage can cause expansion and contraction of the ampoule and its contents, thereby accentuating interchange if an opening exists. Leaker test for ampoules is intended to detect incompletely sealed ampoules so that they can be discarded in order to maintain the sterile conditions of the medicines.
Tip seals are more likely to be incompletely closed than pull seals.
Open capillaries or cracks at the point of seal result in LEAKERS.
Leakers are detected by this process in a visible manner. Ampoules are placed in a vacuum chamber, completely submerged in a deeply colored dye solution of about 0.5 to 1% methylene blue.
A negative pressure is applied within the ampoule. Subsequent atmospheric pressure causes the dye to penetrate an opening thus making it visible after the ampoule has been washed.
The vacuum, about 27 inches Hg, should be sharply released after 30 minutes. Detection of leakers is prominent when ampoules are immersed in a bath of dye during autoclaving cycle as this has the advantage of accomplishing both leaker detection and sterilization in one operation.
Capillaries of 15 micron or smaller diameter cannot be detected by this test.
Vials and bottles are not subjected to such a leaker test as the rubber closer is not rigid.
Fill about 10 containers with water and fit with an appropriate closure.
Keep these containers in an inverted position at room temperature for about 24 hrs. Check for any leakage from any container.
Take five containers and fill them with nominal volume of water. Heats seal these containers with an aluminium foil - polyehtylene laminate or other seal. Weigh the containers accurately and allow to stand for 14 days at a relative humidity of 55 - 65% and a temperature between 20 to 25@C. Reweigh the containers. The loss in weight in each container should not be more than 0.2%.
Above mentioned test are specific for certain types of material. Some other approaches also available to detect the leak in various types of container based upon different mechanisms. Let's see one by one.....
This is done by leak test using methylene blue dye what I mentioned for ampoules.
This calculated by plotting a graph with loss or gain versus time under specifically defined condition (what I mentioned in water vapour permeability test).
By the application of pressure and/or vacuum under defined conditions can help detect any leaks to external atmospheres like gases in the form of bubbles. Detection by visual inspection are limited to around 1 cm3 per minute with the possible detection of pinholes up to 20-25m.
Pressure decay systems are operated to a specified pressure and then monitored for pressure drop by which leaks down to 10-3 cm3/sec.
Pressure increase method can also be used in which leakage from a pack under vacuum is detected as a positive pressure change.
Flexible packs generally intend to extend (or indent) when the pack is under vacuum or pressure in sealed condition. A grossly leaking pack does not show any such movement and a slightly leaking one shows less movement. By assessing these movements the leak can be analyzed with the help of transducers or spring loaded sensors.
The sense of deflection and force changes can be detected with typical instruments like blister testers.
Both these methods are more sensitive than the older conventional vacuum with dye tests and can detect pinholes down to 10m. These tests are also non destructive and the time period is as small as 0.5 to unit second in order to minimize temperature effects.
This test makes use of gases associated with the product or a gas which is specifically introduced for the leakage detection process. The commonly used gases are:
Helium uses mass spectrometry which enables leakage to be detected down to 10-12 Pa m3s. This test needs high vacuum that may not be ideal for the component being tested. Other halogens are also used for gas detection.
Oxygen, i.e. Mocon Ox-tran: It uses a stream of dry nitrogen whereby presence of oxygen is detected coulometrically.
Carbon dioxide, e.g. Mocon Permatran C used to detect carbon dioxide in another dry gas using infrared technique.
Moisture vapour, e.g. Mocon Permatran W or Dynamic water vapour tester measures moisture by a photoelectric sensor.
Radio isotope tracer gas, e.g. using krypton 85 where a high sensitivity is reported.
The strength of the seals can be estimated by tensile tests as seal or peel tests or the air pressure that is sufficient to create rupture.
This test is carried out by placing a hypodermic needles arrangement and pressurizing the pack against it at a specific rate until the pack bursts. Depending on the nature of the seal the rupture may arise in the body of the pack or at the seal.
An alternative to this can be done by applying steadily increasing mechanical compression on a pack placed in a jig.
Different methods have been developed under normal pressure and vacuum in order to check whether highly contaminated liquid, gel or media based material will grow back or penetrate closure systems. Alternative methods of leak detection are more preferable as variable results been observed with this method.
The old conventional dye/vacuum immersion tests were used earlier to check the seal efficiency in ampoules. These methods have been replaced by electrical conductivity and capacitance type tests.
Typical equipments include NIKKA DENSOK AMPOULE INSPECTION MACHINE.
This machine employs a high frequency and high voltage. It distinguishes between good glass (a non conductor) and areas of cracks or pinholes where current will flow between the inner and outer glass surfaces.
There are other machines that make use of capacitance and dielectric constants where a material with defects will display a higher dielectric constant.
These make use of a thermistor bridge that is balanced against air and is subsequently upset if another gas leaks into the leak.
CHEMICAL TRACER TESTS:
This test follows the principle of interaction between material i.e. ammonia on one side and hydrochloric acid on the other forms a white cloud of ammonium chloride indicating leakage. Pinhole can be well detected by this method.
This technique based on the mechanism of temperature change. These are mainly used to detect a drop in temperature when a solvent type systems escape under vacuum. It is also used to detect the presence of warmer gases.
 Lachman L, Lieberman H, Kanig J. The Theory and Practice of Industrial Pharmacy, 3rd Ed. Mumbai, Varghese Publishing House: Page-673.
 Indian Pharmacopoeia. Govt. of India, Ministry of Health and Family Welfare. 1996: Page- A129-A130.
 Dean DA, Evans ER, Hall IH. Pharmaceutical Packaging Technology, 1st ed. London, Taylor & Francis; 2000: Page-335.