Guidelines -
1. PDA Technical report No.: 22- "Process Simulation Testing for Aseptically Filled Products".
2. PDA Technical report No.: 44- "Quality Risk Management for Aseptic Processes".
2. PIC'S (Pharmaceutical inspection convention or Pharmaceutical inspection co-operation scheme)
3. USFDA Guidance to industry (Sep/2004)- "Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004"
4. European guideline to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products, (corrected version) November 2008.
1. PDA Technical report No.: 22- "Process Simulation Testing for Aseptically Filled Products".
2. PDA Technical report No.: 44- "Quality Risk Management for Aseptic Processes".
2. PIC'S (Pharmaceutical inspection convention or Pharmaceutical inspection co-operation scheme)
3. USFDA Guidance to industry (Sep/2004)- "Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004"
4. European guideline to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products, (corrected version) November 2008.
Aseptic Media fill Simulation Study necessary to-
*Qualify the process line
*Qualify the personal
*Qualify the container- closure system
Media fills may be used to:
1. Support new or revised aseptic processes are operating under the desired state of control.
2. Periodically confirm the aseptic process remains capable of producing sterile drug product.
3. Detect and correct weaknesses in the aseptic process, in line with continuous improvement and Quality Risk Management principles.
*Qualify the process line
*Qualify the personal
*Qualify the container- closure system
Media fills may be used to:
1. Support new or revised aseptic processes are operating under the desired state of control.
2. Periodically confirm the aseptic process remains capable of producing sterile drug product.
3. Detect and correct weaknesses in the aseptic process, in line with continuous improvement and Quality Risk Management principles.
- Interpretation of result
A) for batch size up to 5000 units
If 01 contaminated unit found, revalidation and investigation required.
B) for batch size 5000 to 10000
If 01 contaminated unit found repeatation and investigation required.
If 02 contaminated units found re-validation and investigation required.
C) for batch size more than 10000 batch
If 01 contaminated unit found investigation required.
If 02 contaminated units found re-validation and investigation required.
Concentration of Media (SCDM) for preparation of Media solution will be 30 gram/ 1000 mL of WFI (3% W/V).
Critical Zone: The entire area where product, containers, and closures are exposed to the environment in aseptic processing. Also known as the aseptic core.
Total Particulate Monitoring- Room classification is based on total (non-viable and viable) particulate counts per unit volume of air (cubic meter, m3) of different particle sizes as defined in ISO 14644-1. During room classification a minimum of 1 m3 of air should be collected per sample location.
Ready to use (SCDM- Agar Plate)-
Critical Zone: The entire area where product, containers, and closures are exposed to the environment in aseptic processing. Also known as the aseptic core.
Total Particulate Monitoring- Room classification is based on total (non-viable and viable) particulate counts per unit volume of air (cubic meter, m3) of different particle sizes as defined in ISO 14644-1. During room classification a minimum of 1 m3 of air should be collected per sample location.
Ready to use (SCDM- Agar Plate)-
- 55
mm Rodac- Replicate organism detection and counting (Surface monitoring)-
Ready to use available
- 90
mm (Settle plate and air sampling)- Ready to use available
- 75 mm (For compressed air)- To be prepared
Inherent interventions: An intervention that is an integral part of the aseptic process and is required for set-up or routine operations and / or monitoring.
Corrective interventions: An intervention that is performed to correct or adjust an aseptic process during its execution.
Growth Promotion Test: Test performed to demonstrate that media will support microbial growth.
Number and Frequency of Media Fills-
For a new facility, filling line, or production process, media fills are performed as part of the initial performance qualification.
The initial performance qualification should consist of at least three consecutive media fills and will be carried out before the start of routine commercial production.
For routine performance qualification, perform media fills on at least a twice per year basis with appropriate documented justification for scheduling of each qualified line or process.
Performing media fills prior to the scheduled routine performance qualification intervals should be considered for the following situations-
1. Facility, utility, equipment, and process changes
2. Addition of new product container configurations
3. Major changes in the number of production personnel or initiation of additional production shifts
4. Planned maintenance shutdowns
5. Trends or anomalies in environmental monitoring results
6. Breach of asepsis in the aseptic processing area
7. Final product sterility test failure
8. Media fill exceeding acceptance criteria
When using a bracketing / matrix approach:
*Conduct at least three media fills at each “end” of the bracket. It may also be desirable to perform media fills in the “middle” of the bracket.
*Bracketing decisions must be documented in the assessment and is only applicable with products having the same process.
*Conduct initial performance qualification whenever the bracket is re-established due to the introduction of new product configurations or change in process (may only be required at one “end” of the bracket).
To accurately design and plan the media fill, the following minimal factors are considered-
1. Duration
2. Number of Units
3. Equipment Set-Up
4. Container/ Closure Configuration
5. Line speed
6. Fill Volume
7. Hold times
8. Personnel
9. Interventions
Aseptic Intervention: An aseptic manipulation or activity performed by qualified personnel that occurs within the critical area. (commonly referred to as an intervention).
Interventions must be carefully controlled to ensure they do not compromise the sterility of the materials being produced.
A consistent and systematic approach to intervention management must be employed-
1. Proper identification and assessment of interventions
2. Implementation of procedural controls
3. Periodic review of current interventions in accordance with risk management and continual process improvement principles. Any new intervention must be performed as part of a media fill.
Failure investigation of media fill-
Initiate following checks (but not limited to) if the media fill results show failure due to growth of microorganism.
1. Inspect the contaminated unit thoroughly for any defect or damage.
2. Carryout integrity test of the contaminated unit as per SOP
3. Identify the contaminants up to species level. preferentially by genotypic analysis.
4. Compare the identification details with available database.
5. Investigate all possible source of contamination.
6. Evaluate if the contamination is correlated to any specific intervention (routine or non-routine)
7. Review process record as applicable
8. Review the down times, repairs, etc. indicating anomaly.
9. Review filter integrity procedures / records
10. Review sterilization records
11. Review hold periods of sterilized items
12. Review cleaning and sanitization records of aseptic areas
13. Review environmental monitoring records
14. Review validation documents of equipment’s, utilities including HVAC qualification details
15. Review of changes made since previous media fill validation, including participation of new personnel in media fill if any.
To accurately design and plan the media fill, the following minimal factors are considered-
1. Duration
2. Number of Units
3. Equipment Set-Up
4. Container/ Closure Configuration
5. Line speed
6. Fill Volume
7. Hold times
8. Personnel
9. Interventions
Aseptic Intervention: An aseptic manipulation or activity performed by qualified personnel that occurs within the critical area. (commonly referred to as an intervention).
Interventions must be carefully controlled to ensure they do not compromise the sterility of the materials being produced.
A consistent and systematic approach to intervention management must be employed-
1. Proper identification and assessment of interventions
2. Implementation of procedural controls
3. Periodic review of current interventions in accordance with risk management and continual process improvement principles. Any new intervention must be performed as part of a media fill.
Failure investigation of media fill-
Initiate following checks (but not limited to) if the media fill results show failure due to growth of microorganism.
1. Inspect the contaminated unit thoroughly for any defect or damage.
2. Carryout integrity test of the contaminated unit as per SOP
3. Identify the contaminants up to species level. preferentially by genotypic analysis.
4. Compare the identification details with available database.
5. Investigate all possible source of contamination.
6. Evaluate if the contamination is correlated to any specific intervention (routine or non-routine)
7. Review process record as applicable
8. Review the down times, repairs, etc. indicating anomaly.
9. Review filter integrity procedures / records
10. Review sterilization records
11. Review hold periods of sterilized items
12. Review cleaning and sanitization records of aseptic areas
13. Review environmental monitoring records
14. Review validation documents of equipment’s, utilities including HVAC qualification details
15. Review of changes made since previous media fill validation, including participation of new personnel in media fill if any.
Filling area-
Temperature = 15 to 25 degree Celsius
RH= NMT 60%
DP= NLT 10 Pas
Media Selection-
In general, a microbiological growth medium capable of supporting the growth of a wide range of microorganisms, such as soybean-casein digest medium or equivalent media should be used for routine media fills. The media should meet the USP <71> Sterility test growth-promotion requirements.
Media Selection-
In general, a microbiological growth medium capable of supporting the growth of a wide range of microorganisms, such as soybean-casein digest medium or equivalent media should be used for routine media fills. The media should meet the USP <71> Sterility test growth-promotion requirements.
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