MEDIA FILL STUDIES

1.0 OVERVIEW
-Major interest in the last 15 years.
-Formidable task than any other validation activity
since personnel are involved.
-Assures the sterility assurance of the system.
-Applicable to sterile API & Formulation.
-Current trends in the Pharmaceutical industry.
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2.0 PRE REQUISITES TO MEDIA FILL TRAILS
2.1 Validation of Sterilization processes - vendor details
for the items,SIP,SHS,DHS,Filter validation-Bio
challenge.
2.2 Sanitization of APA - Aerosol fogging,establishment of
cleaning schedule & frequency.
2.3 Validation of Disinfectants.
2.4 Sanitization of other items.
2.5 Validation of HVAC system-DOP test,Non Viable
trend,air flow patterns,air changes.
2.6 Personnel qualification – training of the aseptic
operations-Videography presentations.
2.7 Validation of water systems.
2.8 Validation of utilities-Nitrogen,compressed gases.
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3.0 SELECTION OF PLACEBO MATERIAL
e.g -Lactose,Mannitol,Polyethylene Glycol.
3.1 Pyrogen free Mannitol / lactose readily available in
the market.
3.2 It shall be easy to handle, easy to flow and easy to
clean off / decontaminate.
3.3 Sterilizable by gamma radiation.
3.4 It shall have adequate solubility so as to allow easy
filterability through 0.2 micron Sterilizable grade filters, in
WFI and easily cleanable.
3.5 Have growth promotion properties for the normal
microflora of the environment.
3.6 The medium is tolerant to the actual processing
conditions and does not undergo alterations,
transformation and decomposition.
3.7 The medium shall be non-corrosive to process
equipment.
3.8 Inhibition testing of the placebo material.
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4.0 FORMULATION
4.1 Liquid fills
4.1.1 Verification of Medium sterility.
4.1.2 Aseptic filling operations.
4.1.3 Challenge unit incubation.
4.1.4 Evaluation of results.
4.2 Dry powder fills
4.2.1 On-line powder fill followed by on –line liquid
fill.
4.2.2 Container size[Bracketing approach5mL to
100mL vials]
4.2.3 Filling speed.
4.2.4 Media fill size.
4.2.5 Incubation conditions-14 days[In inverted
condition at 20 –25 o C for 7 days,followed by 30-
35 oC for 7 days]
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5.0 ACCEPTANCE CRITERIA FOR VIAL FILLING
5.1 When filling fewer than 5000 units, no contaminated units
should be detected.
One (1) contaminated unit is considered cause for revalidation,
following an investigation.
5.2 When filling from 5,000 to 10,000 units:
One (1) contaminated unit should result in an investigation,
including consideration of a repeat media fill.
Two (2) contaminated units are considered cause for
revalidation, following investigation.
5.3 When filling more than 10,000 units:
One (1) contaminated unit should result in an investigation.
Two (2) contaminated units are considered cause for
revalidation, following investigation.

Ref-”Guidance for Industry Sterile Drug Products”

Produced by Aseptic Processing —Current Good Manufacturing Practice
Sep. 2004
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6.0 Media fill trials in Bulk API.
6.1 Wet Phase operations:
Non sterile placebo material filtered and processed
upto Crystallizer.
6.2 Dry phase operations:
Gamma sterilizer placebo material processed from
ANFD,blender,auto filling machine and again to
Crystallizer.
6.3 Qualitative method:
Direct inoculation into SCDM & incubating for 20 –25 o
C for 7 days,followed by 30- 35 oC for 7 days.
6.4 Quantitative method:
Plating the membrane into SCDA plate for quantifying
the organism.Incubation for 20 –25 o C for 7
days,followed by 30- 35 oC for 7 days.
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7.0 ACCEPTANCE CRITERIA

7.1 The Process Simulation Validation of Sterile

Crystallization Process can be considered valid if the
contamination rate projects to not more than the chosen
limit of NMT 0.0002 CFU / unit dosage form.

7.2 For computation of acceptance limit the formula

explained in “PDA Technical Report No. 28, Process
Simulation Testing for Sterile Bulk Pharmaceutical
Chemicals, August 1998” is taken into consideration.
 
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7.3 Calculation for the acceptance criteria
Minimum batch size :75 Kgs
Maximum finished product fill weight : 1 gm
Chosen growth promotional media batch size :75 Kgs
Number of dosage forms produced from the production
batch:75,000 g/batch / 1 gm dosage form = 75,000
dosage unit /batch.
Calculate the maximum CFU/unit [X]and compare to the
limit of NMT 0.0002 CFU/unit.
5000 units =1
75,000 units =X
If the projected contamination rate Y CFU/unit[Dry & wet
phase operations] is less than the acceptable
contamination level of 0.0002 CFU/unit the Process
Simulation Validation Process passes.
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8.0 Types of Media fill trials in API
8.1 Fresh run Media fill trails.

8.2 “Piggy back”-Post campaign Media fill trials-No

CIP & SIP.

9.0 Frequency of Media fill trials:

9.1 Three consecutive runs every 6 months in case of
Formulation.

9.2 Three consecutive runs of wet phase & Dry phase

operations every 6 months in case of bulk API.

9.3 Three consecutive “Piggy back” at the end of three

campaigns once in the facility.
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10.0 WORST CASE SIMULATION
10.1 Power failure & AHU,LAF trip.
10.2 Disturbance of differential Pressure below
standard.
10.3 Entrance of maintenance personnel with tool
box in working zone during critical aseptic
operation.        
10.4 Extended period of critical aseptic operation.
10.5 More number of personnel for critical aseptic
operation.
10.6 Usage of growth promoting medium in place of
the APIs manufactured is in itself a worse case
condition.
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11.0 CONCLUSION

11.1 Greater reliance on CIP/SIP.

11.2 Dramatic changes in Facility designs

concepts/equipment features/clean rooms.

11.3 Application of robotics and barrier technology

by the year 2010.
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Future Sterile API & Formulation --??????