QUALITY CONTROL OF STERILE PRODUCTS (1)

The in-process quality control test includes the leak and clarity testing. The quality control of finished product required the pyrogen and sterility testing.

Leakage test

Leakage test is employed to test the package integrity. Package integrity reflects its ability to keep the product in and to keep potential contamination out”. It is because leakage occurs when a discontinuity exists in the wall of a package that can allow the passage of gas under pressure or concentration differential existing across the wall. Leakage differs from permeation, which is the flow of matter through the barrier itself.

Followings are the leak test methods.

A) VISUAL INSPECTION

Visual inspection is the easiest leak test method to perform. But this method is least sensitive. The method is used for the evaluation of large volume parenterals. To increase the sensitivity of the method, the visual inspection of the sample container may be coupled with the application of vacuum to make leakage more readily observable. This method is simple and inexpensive. However, the method is insensitive, operator dependent, and qualitative.

Sometimes, the method is used in combination with pressure and /or temperature cycling to accelerate leakage to improve sensitivity.

B) BUBBLE TEST

The test package is submerged in liquids. A differential pressure is applied on the container. The container is observed for bubbles. Sometimes, surfactant added liquid is used for immersion of test package. Any leakage is evident after the application of differential pressure as the generation of foaming in immersion liquid. The method is simple and inexpensive. The location of the leaks can be observed in this method. However, it is relatively insensitive and the findings are operator dependent and are qualitative. The optimized conditions can be achieved using a surfactant immersion fluid along with the dark background and High intensity lighting. Generation of a differential positive pressure of 3 psi inside the vial and observation of any leakage using magnifying glass within a maximum test time of 15 minutes.

C) DYE TESTS

The test container is immersed in a dye bath. Vacuum and pressure is applied for some time. The container is removed from the dye bath and washed. The container is then inspected for the presence of dye either visually or by means of UV spectroscopy. The dye used may be of blue, green, yellowish-green color. The dye test can be optimized by use of a surfactant and or a low viscosity fluid in the dye solution to increase the capillary migration through the pores. The dye test is widely accepted in industry and is approved in drug use. The test is inexpensive and is requires no special equipment required for visual dye detection. However, the test is qualitative, destructive and slow. The test is used for ampoules and vials.

D) VACUUM IONIZATION TEST

Vacuum ionization test is useful for testing leakage in the vials or bottled sealed under vacuum. This test is used for online testing of the lyophilized products. High voltage, high frequency field is applied to vials which to cause residual gas, if present to glow.

Glow intensity is the function of headspace vacuum level. The blue glow is the indicative of vacuum while the purple glow indicative of no vacuum. The sensitivity of the method is not documented. This test is on-line, rapid and is non destructive test. However, the proteins present in the test sample may be decomposed. This method is used for the lyophilized vials of biopharmaceuticals.

CLARITY TESTING

Clarity testing is carried out to check the particulate matter in the sample.

Particulate matter

Matter of biological or non-biological origin and with observable length, width, and thickness, e.g., bacteria, fungi, dust, dirt, fibers, plastic, rubber, lint etc. It may be any matter, mixed accidentally during manufacturing in the parenteral product which does not belong to the product. Particulate mater may be tiny pieces of lint, glass, dust, rubber, metal fibers, hair, microbes or unidentified and can make the product impure, unclean or unfit for use.

Sources of particulate matter

Particulate contamination particularly of cellulose fibers, dust, cotton fibers, hair, dandruff and loose skin from human origin as well as microbial contamination may arise from the following main sources.

1. Material arising from the drug: undissolved substances and trace contaminants etc.

2. Material arising from vehicle or added substances: These may include those material not filtered out during a clarification process before to filling the final container.

3. Materials present in the final container: Material already present in container and which were not removed by rinsing prior to filling

4. Materials falling by chance into the final container during the filling process

5. The container or closures which may be deposited in the produce during sterilization, e.g. carbon black, whiting, zinc oxide and clay

6. Packaging components: Including glass, plastic, rubber, I/V administration sets, etc.

7. Environmental contaminants: Including air, work tops, insects’ parts

8. Processing equipments: Including glass, stainless steel, rubber, or filter fiber, etc.

9. Personnel: Including skin, hair, and clothing etc.

Particle size

Particles present in injectable are non-reactive, apyrogenic, sterilized. However, by virtue of their size may biologically hazardous. The particulate matter may be capable of blocking the blood vessels with severe results on induction into body with injection.

A person with 20/20 vision under inspection conditions is able to detect particles of size range 40 – 50 μm. However, it is universally accepted that the particles size of 50 μm is detected visually by an unaided eye.

Particle size greater than 7 μm diameter is considered to be more threatening. Pulmonary capillary are approximately 7 μm in diameter, thus particle of this much size entrapped in vascular bed resulting in multiple pulmonary infarction.