Taking the Mystery out of
Media Runs
Robert J. Pallo, MA
Manager, Pharmaceutical Sciences Operations
Fill and Finish Operations
Allergan
Any views or opinions presented in this presentation are solely those of the
author and do not necessarily represent those of Allergan
OVERVIEW
The Second Law of Thermodynamics
In time, any system will change from order
to disorder
Entropy has often been loosely associated
with the amount of order, disorder, and/or
chaos in a thermodynamic system
OVERVIEW:
OBJECTIVE OF THE MEDIA
RUN
1.
To Validate aseptic Processes
used to produce sterile product
2.
To Assure Processes, Facilities
and Personnel remain within a
State of Validation
3.
To meet cGMP requirements
OVERVIEW
Factors to be Considered
1.
2.
3.
4.
5.
6.
7.
8.
9.
Study Design
Frequency and Number of Media Runs
Filling Durations
Operating Speeds
The Environment
Duration of Media runs
Type of Media
Incubation and analysis
Results
OVERVIEW
Hot Topics
Media run my simulate aseptic
manufacturing operations
– Must represent actual conditions during batch
operations
– Shall not used enhanced procedures that
provide superior conditions than would be
present during normal batch operations
OVERVIEW
Hot Topics
Must closely simulate aseptic
manufacturing operations and provide a
worst case set of procedures and
conditions to provide a challenge to the
aseptic system
An SOP that describes actual conditions
must be clearly defined.
OVERVIEW
Hot Topics
Media Run must address:
– Line Setup Operations
– Normal interventions
– Operator fatigue
– Machine fatigue
– Number of personnel involved
– Line Speed
– Weight checks and adjustments
Study Design
Study Design
Your longest Filling Operation (elapsed
time)
Study Design
Your longest Filling Operation (elapsed
time
Common Interventions
Study Design
Your longest Filling Operation (elapsed
time
Common Interventions
Participants
Study Design
Your longest Filling Operation (elapsed
time
Common Interventions
Participants
Aseptic Connections
Study Design
Your longest Filling Operation (elapsed
time
Common Interventions
Participants
Aseptic Connections
Line and weight check rejects
Study Design
Your longest Filling Operation (elapsed
time
Common Interventions
Participants
Aseptic Connections
Line and weight check rejects
An SOP for each Intervention
SECTION 1: NUMBER AND FREQUENCY
OF RUNS
SECTION 1: NUMBER AND
FREQUENCY OF RUNS
New Filling Lines
SECTION 1 : NUMBER AND
FREQUENCY OF RUNS
New Filling Lines
New Equipment
SECTION 1 : NUMBER AND
FREQUENCY OF RUNS
New Filling Lines
New Equipment
Closeout of failure investigations
SECTION 1 : NUMBER AND
FREQUENCY OF RUNS
New Filling Lines
New Equipment
Closeout of failure investigations
Semi Annual Media Runs
SECTION 1 : NUMBER AND
FREQUENCY OF RUNS
Startup simulation tests
– New Filling lines
– New Equipment
Closeout of failure investigations
Semi Annual Media Runs
Employee Qualifications
SECTION 2: MEDIA RUN DURATIONS
AND RUN SIZES
SECTION 2: MEDIA RUN
DURATIONS AND RUN SIZES
How many hours should you run?
SECTION 2: MEDIA RUN
DURATIONS AND RUN SIZES
How many hours should you run?
How many units should you run?
SECTION 2: MEDIA RUN
DURATIONS AND RUN SIZES
What to do if your batch sizes are
N < 3,000?
– Perform this simulation test at the maximum
batch size
SECTION 2: MEDIA RUN
DURATIONS AND RUN SIZES
What to do if your batch sizes are
100,000 > N > 3,000?
– Current industry practice appears to indicate
that many firms are performing these tests
with 5,000 to 10,000 units
SECTION 2: MEDIA RUN
DURATIONS AND RUN SIZES
What to do if your batch sizes are large
(>100,000 units)?
– Fill 3,000 units; switch to WFI; Fill 3,000 more
– Fill 3,000 units; simulate filling; Fill 3,000 more
– At the completion of a production batch,
disassemble/reassemble and Fill 3,000
– Fill WFI for an extended period; then Fill 3,000
– Simulate filling for an extended period; then Fill 3,000
Ludicrous Speed
SECTION 3: LINE SPEEDS
SECTION 3: LINE SPEEDS
Pitfalls of filling at a slow speed
SECTION 3: LINE SPEEDS
Pitfalls of filling at a slow speed
Pitfalls of filling at a fast speed
SECTION 3: LINE SPEEDS
Pitfalls of filling at a slow speed
Pitfalls of filling at a fast speed
How should you run your media run?
SECTION 4: VIAL/FILL SIZES
SECTION 4: VIAL/FILL SIZES
Pitfalls of larger fill volumes
SECTION 4: VIAL/FILL SIZES
Pitfalls of larger fill volumes
Pitfalls of smaller fill volumes
SECTION 4: VIAL/FILL SIZES
Pitfalls of larger fill volumes
Pitfalls of smaller fill volumes
What to do if you run various sizes
SECTION 5: OTHER CONSIDERATIONS
Setup and Assembly Activities
 Simulation should be designed to detect
potential contamination during setup
Interventions
 Perform each standard intervention
during the media run
 Have these interventions documented in
an “Intervention SOP”
Process Gasses
 If inert gas is used during production,
replace it with sterile compressed air.
SECTION 6: A WORD ABOUT MEDIA
SECTION 6: A WORD ABOUT
MEDIA
Soybean casein digest medium
SECTION 6: A WORD ABOUT
MEDIA
Soybean casein digest medium
Must demonstrate growth promotion
– Gram positive
– Gram negative
SECTION 6: A WORD ABOUT
MEDIA
Soybean casein digest medium
Must demonstrate growth promotion
– Gram positive
– Gram negative
Fill with enough media to contact all inner
surfaces (when the unit is inverted or
swirled
SECTION 7: WHAT SHOULD BE
INCUBATED?
SECTION 7: WHAT SHOULD
BE INCUBATED?
Everything!
SECTION 7: WHAT SHOULD
BE INCUBATED?
?
Everything!
– Except vial or closure defects that are culled
out as part of your normal inspection process
SECTION 7: WHAT SHOULD
BE INCUBATED?
Everything!
– Except vial or closure defects that are culled
out as part of your normal inspection process
– Except units STANDARDLY removed during
interventions
SECTION 7: WHAT SHOULD
BE INCUBATED?
Incubate initial flush units
SECTION 7: WHAT SHOULD
BE INCUBATED?
Incubate initial flush units
Incubate weight check units (if unopened)
SECTION 7: WHAT SHOULD
BE INCUBATED?
Incubate initial flush units
Incubate weight check units (if unopened)
Incubate cosmetic defects
SECTION 7: WHAT SHOULD
BE INCUBATED?
Incubate initial flush units
Incubate weight check units (if unopened)
Incubate cosmetic defects
All units must be reconciled and
accounted for
SECTION 8: TEST RESULTS
SECTION 8: TEST RESULTS
Shoot for NO POSITIVES
– Any positive unit is an indication of potential
lack of sterility assurance, regardless of the
run size.
– Modern aseptic processing operations
conducted using current state of the art
procedures should normally yield no media fill
contamination
SECTION 8: TEST RESULTS
Filling Fewer than 5,000 units
– 1 positive requires an investigation and performance
of three revalidation media runs
SECTION 8: TEST RESULTS
Filling Fewer than 5,000 units
– 1 positive requires an investigation and performance
of three revalidation media runs
Filling 5,000 to 10,000
– 1 positive requires an investigation and consideration
of a single repeat media run
– 2 positives require an investigation and performance
of three media runs
SECTION 8: TEST RESULTS
Filling Fewer than 5,000 units
– 1 positive requires an investigation and performance
of three revalidation media runs
Filling 5,000 to 10,000
– 1 positive requires an investigation and consideration
of a single repeat media run
– 2 positives require an investigation and performance
of three media runs
Filling of more than 10,000 units
– 1 positive requires an investigation
– 2 positives require an investigation and performance
of three media runs
SECTION 9: INVESTIGATING A MEDIA
RUN FAILURE
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Follow Your Media Run Failure SOP
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Follow Your Media Run Failure SOP
What units were contaminated? All?
Beginning?
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Follow Your Media Run Failure SOP
What units were contaminated? All?
Beginning?
Look at your EM. Did you find the same
bugs in your EM data?
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Follow Your Media Run Failure SOP
What units were contaminated? All?
Beginning?
Look at your EM. Did you find the same
bugs in your EM data?
Look at your morphology. Water born?
Human born?
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Guideline if human born bacteria
– Look at training records
– Look at video tape to watch technique
– Look at facility EM data
– Look at individual EM data
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Guideline if spore former
– Look at autoclave, dry heat, EtO, or Radiation
charts or certifications
– Look at bio burden of the component
preparation area
SECTION 9: INVESTIGATING A
MEDIA RUN FAILURE
Guideline if pseudomonad
– Check filter integrity data
– Look at compounding bio burden
□
Compile data from batch records on this form to indicate the maximum number of hours, units, personnel and hold time
validated in media runs.
ROOM
EQUIPMENT
ACTIVITY
100
FILTRATION STATION
ASEPTIC
FILTRATION
100
FILLING MACHINE 1
PF SYRINGE
FILLING /
STOPPERRING
200
300
FILLING MACHINE 2
FILLING MACHINE 3
IV SERUM VIAL
FILLING/
STOPPERING
SEALING
OPHTHALMIC
FILL, TIP, CAP
400
FILLING MACHINE 4
OPHTHALMIC
FILL, TIP, CAP
500
FILLING MACHINE 5
IV SERUM VIAL
FILLING/
STOPPERING
MAXIMUM
No. of HOURS
MAXIMUM
No. of UNITS
MAXIMUM No.
PERSONNEL
MAXIMUM BULK HOLD
TIME
□
1H
_________ □
2H
_________
REF
LOT
Other
________________
RUN DATE
BY
DATE
INTERACTIVE SESSION
INTERACTIVE SESSION
Under what circumstances could you
invalidate a media run?
What if your product is filled under a
nitrogen blanket?
What if your media run is negative, but
your bulk product container is positive?
Your media run has pseudomonas
throughout the entire batch. What is a
possible route of contamination?