TRS 961-annex6-GMP-Sterile Pharmaceutical Products

General considerations

1.1 The production of sterile preparations should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate standard of cleanliness and supplied with air that has passed through filters of the required  efficiency. 

1.2 The various operations of component preparation (such as those involving containers and closures), product preparation, filling and sterilization should be carried out in separate areas within the clean area. These areas are classifi ed into four grades (see section 4).

1.3 Manufacturing operations are divided here into two categories: 

— fi rst, those where the product is terminally sterilized; and

— second, those which are conducted aseptically at some or all stages.

Quality control

2.1 The sterility test applied to the fi nished product should only be regarded as the last in a series of control measures by which sterility is assured. The test should be validated for the product(s) concerned.

2.2 Samples taken for sterility testing should be representative of the whole of the batch but should, in particular, include samples taken from parts of the batch considered to be most at risk of contamination, for example:

• for products that have been fi lled aseptically, samples should include containers fi lled at the beginning and end of the batch and after any signifi cant interruption of work; 

• for products that have been heat sterilized in their fi nal containers, consideration should be given to taking samples from that part of the load that is potentially the coolest. 

2.3 The sterility of the fi nished product is assured by validation of the sterilization cycle in the case of terminally sterilized products, and by “media simulation” or “media fi ll” runs for aseptically processed products. Batch-processing records and, in the case of aseptic processing, environmental quality records, should be examined in conjunction with the results of the sterility tests. The sterility test procedure should be validated for a given product. Pharmacopoeial methods should be used for the validation and performance of the sterility test. In those cases where parametric release has been authorized in place of sterility testing special attention should be paid to the validation and the monitoring of the entire manufacturing process 

2.4 For injectable products the water for injection and the intermediate, if appropriate, and finished products should be monitored for endotoxins, using an established pharmacopoeial method that has been validated for each type of product. For large-volume infusion solutions, such monitoring of water or intermediates should always be done, in addition to any tests required by an approved monograph for the finished product. When a sample fails a test, the cause of the failure should be investigated and necessary action should be taken. Alternative methods to those in the pharmacopoeias may be used if they are validated, justified and authorized.

2.5 The use of rapid microbiological methods to replace the traditional microbiological methods, and to obtain earlier results on the microbiological quality of, for example, water, the environment or bioburden, could be considered if appropriately validated and if a comparative assessment of the proposed rapid method is performed against the pharmacopoeial method.