Materials used: Sterile placebo inert powder such as Poly Ethylene Glycol PEG 8000, Lactose, sodium chloride and carboxy methyl cellulose, General media such as Tryptic Soy Broth TSB
Interventions: routine and worse case interventions.
If normal production utilizes inert gas, this gas should be replaced by compressed air The use of an inert gas and anaerobic medium (e.g., Alternate Fluid Thioglycollate Medium) would be appropriate where the persistent presence of strict anaerobic organisms has been confirmed in either environmental monitoring or, more likely, during end product sterility testing.
Media fill batch size: For small batch sizes (less than 5000 units), APS (Aseptic Process Simulation) batch size should be at least equal to production batch size. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units (FDA sterile drug products produced by aseptic processing), according newly released FDA Draft guide minimum (10-15) % of production batch size.
Incubation of media fill: Prior to incubation, filled APS units should be inverted or manipulated to ensure contact of the medium with all internal surfaces of the closure system before they are incubated. APS units should be incubated for a minimum of 14 days ( 1st week at 22.5±2.5ºC), the 2nd week at 32.5±2.5ºC), (Starting with the lower temperature)
Growth promotion studies are commonly performed after 14 days of incubation to assure that the media used still support microbial growth.
Frequency: Initial validation (and after major changes) three runs and one run every 6 months.
Examples of such changes that require initial Validation of Media Fill for aseptically filled products:
1. Modifications to the equipment (interchanging identical standard parts does not constitute an equipment modification)
2. Modification to equipment or facilities that potentially affects the air quality or airflow in the aseptic environment
3. Major changes in the number of production personnel or initiation of second (or third) shift production when the facility has been qualified only for single shift operations.
4. Major changes to the aseptic production process and/or procedures
5. Major modification to the equipment preparation or assembly techniques, filling line relocation.
6. The addition of new product containers or container-closure combinations
7. Any significant modification to HVAC
One run required in case of:
- Any product sterility test failure& Breach of asepsis in the aseptic processing area
- Invalid media fill (no growth in positive control growth promotion test failure for TSB media post incubation period).
- Presence of only one contaminated unit after 14 days incubation (for media fill batch size more than 5000 units, this requires repeating media fill run after investigation.
- A confirmatory media fill is recommended for filling line decommissioning.
