Sterility testing attempts to reveal the presence or absence of viable micro-organisms in a sample number of containers taken from batch of product. Based on results obtained from testing the sample a decision is made as to the sterility of the batch¹.

There are two common types of sterility test methods:

Immersion (Direct Inoculation) The immersion (direct inoculation) method requires the test article be inoculated directly into test media.

Membrane Filtration The membrane filtration method requires the test article to first pass through a size exclusion membrane capable of retaining microorganisms. The filter is rinsed and then the membrane is transferred into the appropriate test medium.

The pharmacopoeias and 21 CFR 610.12 recommend using two media for both the immersion and membrane filtration methods. In both test methods the test article or membrane is incubated for 14 days in the test media².

Major factors of importance in sterility testing

* The environment in which the test is conducted

* The quality of the culture conditions provided

* The test method

* The sample size

* The sampling procedure Sterility testing is required on each manufactured FDP lot. Sampling requirements for final drug product are provided in the pharmacopoeias.

The following data outlines the requirements as stated in the current USP³.

Batch Size Minimum Number to be tested in Each Media

100 or less 10%or 4 containers, whichever is greater

101 - 500 10 containers

>500 2% or 20 containers, whichever is less

Bulk - Up to 4 containers Each container

5 - 50 20% or 4 containers, whichever is greater

>50 2% or 10, whichever is greater

Volume / Container Minimum Quantity to Test in EachMedia

Less than 1 mL The entire contents of each container

1 - 40 mL Half the contents of each container, but not less than 1 mL

41 - 100 mL 20 mL

>100 mL 10% of the contents of the container, but not less than 20 mL.

STERILITY TEST^3,4

SAMPLING The number of containers tested per batch and quantity tested from each container should be, as a minimum, in accordance with the pharmacopoeial method followed Samples from terminal sterilisation cycles should be selected from at least the potentially coolest part of the load if such a location was identified during validation studies, and from every load sterilised.

MEDIA TYPES The media used should be in accordance with the pharmacopoeial method followed. Soya-bean casein digest (SCD) and fluid thioglycollate media (FTM) should normally be used.

INCUBATION PERIOD All test containers should be incubated at temperatures specified by the pharmacopoeial method for each test media for at least 14 days, regardless of whether filtration or direct inoculation test methodology is used. If the product produces a suspension, flocculation or deposit in the media, suitable portions (e.g. 2-5 percent) of the contents of the containers should be transferred to fresh media under clean room conditions, after 14 days, and reincubated for a further 7 days.

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REFERENCES

1. FDA Guidelines 2004 "Guidance for Industry Sterile Drug Products by Aseptic Processing, Current Good Manufacturing Practices," September, 2004
2. ISO 11737 ANSI/AAMI/ISO 11737-2 1998 - Sterilization of Medical Devices - Microbiological Methods - Part 2, Tests of Sterility Performed in the Validation of a Sterilization Process
3. ISO 11135 1994 Medical Devices Validation and Routine Control of Ethylene Oxide Sterilization
4. Code of Federal Regulations Title 21/Chapter I/Part 820, "Quality Systems Requirements: General," 2006