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GMP for Sterile Pharmaceutical Manufacturing

How to operate the sterile or aseptic pharmaceutical manufacturing process with good manufacturing practices?
Maintenance of sterile area is a critical task because of air, as well as the personnel working in the sterile classified area, are the main source of the contamination. Following are some good manufacturing practice points those shall help in the maintenance of sterile area.

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

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

Cleanroom area3. The validation of aseptic processing should include simulating the process using a nutrient medium. The form of the nutrient medium used should generally be equivalent to the dosage form of the product. The process-simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. 

Consideration should be given to simulation of the worst expected condition. The process simulation test should be repeated at defined intervals and after any significant modification to the equipment and process. The number of containers used for a medium fill should be sufficient to ensure a valid evaluation. For small batches, the number of containers for the medium fill should be at least equal to the size of the product batch.

4. Care should be taken to ensure that any validation does not compromise the processes.

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

6. Activities in clean areas, especially when aseptic operations are in progress, should be kept to a minimum, and the movement of personnel should be controlled and methodical, so as to avoid excessive shedding of particles and organisms due to over-vigorous activity. The ambient temperature and humidity should not be uncomfortably high because of the nature of the garments worn.

7. The presence of containers and materials liable to generate fibers should be minimized in clean areas and avoided completely when aseptic work is in progress.

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

9. The interval between the washing and drying and the sterilization of components, bulk-product containers and equipment, as well as between sterilization and use, should be as short as possible and subject to a time-limit appropriate to the validated storage conditions.

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

11. Any gas that is used to purge a solution or blanket a product should be passed through a sterilizing filter.

12. The bioburden of products should be monitored before sterilization. There should be a working limit on the contamination of products immediately before sterilization that is related to the efficiency of the method to be used and the risk of pyrogens. All solutions, in particular, large-volume parenterals, should be passed through a microorganism-retaining filter, if possible immediately before the filling process. Where aqueous solutions are held in sealed vessels, any pressure-release outlets should be protected, e.g. by hydrophobic microbiological air filters.

13. Components, bulk-product containers, equipment and any other articles required in a clean area where aseptic work is in progress should be sterilized and, wherever possible, passed into the area through double-ended sterilizers sealed into the wall. Other procedures that prevent the introduction of contamination (e.g. triple wrapping) may be acceptable in some circumstances.

14. The efficacy of any new processing procedure should be validated, and the validation should be repeated at regular intervals thereafter or when any significant change is made in the process or equipment.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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