GMP for Sterile Manufacturing

Maintenance of sterile areas is an important task because air, as well as personnel working in sterile classified areas, are major sources of contamination. Below are some good manufacturing practice points that will help maintain a sterile environment.

1. Precautions should be taken to minimize contamination at all processing stages, including the sterilization stage.

2. Preparations containing live microorganisms should not be made or filled into containers in areas used for the processing of other medicinal products; However, vaccines containing dead organisms or bacterial extracts may be dispensed in containers after valid inactivation and valid cleaning procedures on the same premises as other sterile pharmaceutical products.

3. Validation of aseptic processing should include process simulation using a nutrient medium. The form of nutrient medium used should generally be equivalent to the dosage form of the product. The process-simulation test should simulate the routine aseptic manufacturing process as closely as possible and should include all subsequent critical manufacturing steps.

Simulation of the worst expected conditions should be considered. Process simulation tests should be repeated at defined intervals and after any significant changes in equipment and processes. The number of containers used for a medium fill should be sufficient to ensure a valid assessment. For small batches, the number of containers for medium filling should be at least equal to the product batch size.

4. Care should be taken to ensure that no validation process is compromised.

5. Water sources, water-treatment equipment and treated water should be regularly monitored for contamination by chemicals, biological contaminants and endotoxins to ensure that the water complies with specifications appropriate for its use. Records of monitoring results and any action taken should be maintained.

6. Activity in clean areas, especially when aseptic operations are in progress, should be kept to a minimum, and movement of personnel should be controlled and methodical, to avoid excessive loss of particles and organisms due to over-vigorous activity. Ambient temperature and humidity should not be uncomfortably high because of the nature of the clothing being worn.

7. The presence of containers and materials responsible for fiber preparation should be minimized in clean areas and avoided entirely when aseptic work is in progress.

8. Materials, bulk-product containers and equipment should be handled after the final cleaning process in such a way that they are not re-contaminated. Materials, bulk product containers and equipment should be properly identified at the processing stage.

9. Washing and drying and sterilization of ingredients, bulk-product containers and equipment as well as the interval between sterilization and use should be as short as possible and subject to a time-limit suitable for valid storage conditions.

10. The time between the start of preparation of a solution and its sterilization or filtration through a bacteria-retaining filter should be as short as possible. A maximum allowable time should be set for each product that takes into account its composition and prescribed method of storage.

11. Any gas used to clean the solution or blanket must be passed through a sterile filter.

12. Organic load of products should be monitored before sterilization. Contamination of the product immediately after sterilization should have a working limit that is related to the effectiveness of the method used and the risk of pyrogens. All solutions, especially large-volume parenterals, should be passed through a microbe-retaining filter, if possible, prior to the filling process. Where aqueous solutions are kept in sealed vessels, any pressure-relief outlets should be protected, such as by hydrophobic microbiological air filters.

13. Materials, bulk-product containers, equipment and any other items should be sterilized in a clean area where aseptic work is in progress and, wherever possible, should enter the area through a wall-sealed double-ended sterilizer. Other methods that prevent the introduction of contamination (such as triple wrapping) may be acceptable in some circumstances.

14. The effectiveness of any new processing method should be verified, and the validation should be repeated at regular intervals thereafter or when any significant changes are made to the process or equipment.

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