Sunday, July 10, 2011

Validation of efficacy of membrane filter in sterile filtration, Membrane filter integrity testing

Bubble point test for validation of efficacy of membrane filters for injectable dosage form

Parentral dosage forms is required to be sterile as it is directly administered in to the blood stream of a patient, and the sterilization is a process which eliminates or removes all viable micro-organisms including their spors through the process of destruction by heat and elimination by the process of filtration.

Both processes of sterilization have their unique advantages and disadvantages, sterilization by filtration if of great value when the drug can not be heat treated, the process of sterilization by filtration is carried out by using membrane filters, membrane filters not only make the solution sterile but also removes particulate matter if it is present in the solution.

Mebrane used for filtration process is made of cellulose acetate, mixed cellulose esters, and polytetrafluoroethylene (PTFE) PTFE which are also available as hydrophilic and hydrophobic grades. In sterile filtration the of membrane filter used is of 0.2 micron

Each and every unit of a sterile dosage form of your product is required to be sterile , and it is not possible to test all 100 percent units for test for sterility , therefore one should have a validated process which will ensure that the units produced are sterile, and it is rather bit complicated when the final sterilization process is carried out by filtration and when product can not be heat sterilized.

One of the popular method of validation of  efficacy of membrane filters being used is buble point , the test can be applied before and after the process or while the filtration process is going on as an in process check, Other tests are also used to validate online filters are diffusion testing and forward flow test

Bubble point test for filter integrity testing:

Definition of bubble point of a membrane filter:
It is a pressure at which a steady stream of air bubbles flow through wetted filter from down stream when applied with air pressure from upstream, the down stream point is usually connected with tubing which can be immersed in to beaker containing sterile water for injection for observation of steady stream of bubble, the bubble point pressure is not same for all filter rather it is different for different filter and also changes with the type of liquid being filtered.

Principle behind bubble point test:
When gas pressure is applied over wetted membrane filter, the air passes through membrane pores with steady stream, and there is a pressure head maintained up to certain point of applied upstream air pressure, at a particular pressure a steady stream of bubble is developed downstream, the pressure point reading at which this steady air bubble stream is observed is characteristic of a particular membrane, and the a lower bubble point pressure reading at which a steady stream of bubble is observed could be an indicator of the damaged filter.

If membrane filter fails the bubble point test, the earlier filtered liquid should be filtered again, after replacing the old failed filter in bubble point test with new filter.

How bubble point test is conducted:
A bubble point assembly can be made indigenously by connecting filter stand with ducts for upstream air pressure and a beaker filled with sterile water for dipping the down stream end, there are some assembly also available in market which can be used by placing the filter unit to be tested in to it.

Important tips for conducting accurate bubble point test:

1. Filter should be wetted properly and uniformly with the liquid being tested.
2. A steady stream of bubble should be noted as the reading.
3. Assembly should be properly fitted otherwise might give wrong results.
4. A SOP for all types of filters and their bubble point readings for different types of products should be maintained.

Also see

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Aspects of Validation of Aseptic Process and Sterilisation , Sterilization of Equipment, Containers, and Closures

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21 cfr part 11 FDA guidelines .

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