MEP Plans in Construction of Building and Industrial Projects 2024
Pda fda joint conference - 09-2008
1. 1
Connecting People, Science and Regulation
®
Filtration Interest Group
EU ANNEX 1, Paragraph 113
Pre-use Integrity Testing
Minimizing or Increasing Risk ?
Maik W. Jornitz
Group Vice President Sartorius Stedim NA Inc.
Connecting People, Science and Regulation
®
Filtration Interest Group
Disclaimer
Information within the presentation are discussion points
and vary within processes and process requirements.
Some of the process suggestions can be found in existing
processes, but do not represent copies.
All statements made are personal statement and do not
represent any organization.
2. 2
Connecting People, Science and Regulation
®
Filtration Interest Group
Statement within Paragraph 113
113. The integrity of the sterilised filter should be
verified before use and should be confirmed
immediately after use by an appropriate method
such as bubble point, diffusive flow or pressure
hold.
Connecting People, Science and Regulation
®
Filtration Interest Group
Integrity Testing
• wetting of the filter with
appropriate fluid, commonly
water and fluid volumes
• atmospheric pressure on the
filtrate side
All integrity tests listed require at least:
3. 3
Connecting People, Science and Regulation
®
Filtration Interest Group
Statement within Paragraph 113
113. The integrity of the sterilised filter should be
verified before use and should be confirmed
immediately after use by an appropriate method
such as bubble point, diffusive flow or pressure
hold.
Connecting People, Science and Regulation
®
Filtration Interest Group
What Risks are involved, when not pre-use tested ?
• Filter fails post-use test
if possible, reprocessing required
if filled or reprocessing not validated, batch needs to
be discarded
economical burden
• Filter passes post-use test, but has been non-
integral during filtration
hypothetical, personally never experienced in 100’s of
tests
4. 4
Connecting People, Science and Regulation
®
Filtration Interest Group
Statement within Paragraph 113
113. The integrity of the sterilised filter should be
verified before use and should be confirmed
immediately after use by an appropriate method
such as bubble point, diffusive flow or pressure
hold.
Connecting People, Science and Regulation
®
Filtration Interest Group
Why would a filter fail after sterilization ?
• Most common reasons:
ignored filter manufacturer’s
technical specifications
improper end-user training
improper sterilization process
design and/or qualification
temperature
pressure
5. 5
Connecting People, Science and Regulation
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Filtration Interest Group
How to prevent a filter fail after sterilization ?
• Common practice:
design steam sterilization
according to filter
manufacturer’s specification
run Process Performance
Qualification and check the
filter’s:
integrity
integrity test value changes
appearance
Connecting People, Science and Regulation
®
Filtration Interest Group
Implication of the Word - sterilised
The filter has been sterilized by commonly either autoclaving or
in-line steam sterilization
Status: Filtrate Side is Sterile and requires to stay Sterile
Filling
6. 6
Connecting People, Science and Regulation
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Filtration Interest Group
Implications for a Sterilized Process
Hold Vessel
Bulk
Filling
• Wetting fluid reaches the
sterile filtrate side
• Wetting fluid potentially
dilutes product
• Pressure on sterile side
requires to be atmospheric
• Downstream volume
requires to be large enough
• Cooling time to obtain
appropriate temperature
RPN = Severity x Occurrence x Detection = 10 x 1-2 x 8-9 = 80 - 180
Connecting People, Science and Regulation
®
Filtration Interest Group
Process Design Alternatives
Wetting fluid flush diverted via a
3-way valve into a flush
volume tank, followed by the
integrity test with the gas vented
through the vent filter.
Pipe work to equipment stays
overpressure.
Disadvantages:
• Dilution if not dried
• Additional integrity test
• Additional preparation & set-up
Hold Vessel
Bulk
Filling
Hydrophobic
Vent Filter
(requires
integrity
testing)
P > Patm
Patm
Ptest > Patm
Flush Receival
7. 7
Connecting People, Science and Regulation
®
Filtration Interest Group
Process Design Alternatives
Wetting fluid flush diverted via a
3-way valve through a hydrophilic
/hydrophobic filter, followed by the
integrity test with the gas vented
through the h/h filter.
Pipe work to equipment stays
overpressure.
Disadvantages:
• Dilution if not dried
• Additional integrity test
• Additional preparation & set-up
Hold Vessel
Bulk
Filling
Drain
Hydrophilic/
Hydrophobic
Filter
(requires
integrity
testing)
P > Patm
Patm
Ptest > Patm
Connecting People, Science and Regulation
®
Filtration Interest Group
Process Design Alternatives
Redundant filtration system, which
tests filter 1. and leaves filter 2. in
its sterilized form. Filter 1. will be
wetted and tested via 3-way valve
and drain.
Disadvantages:
• Dilution if not dried
• Additional preparation & set-up
• Additional hold-up volume
Hold Vessel
Bulk
Filling
Drain
P > Patm
Patm
Ptest > Patm
8. 8
Connecting People, Science and Regulation
®
Filtration Interest Group
Process Design Alternatives
Product is the wetting fluid
and flushed into the equipment side.
After wetting the 3-way valve is
opened to the vent filter, followed
by the integrity test with the gas
vented through the vent filter.
Disadvantages:
• Potential product loss when failed
• Additional integrity test
• Equipment side under Patm
Hold Vessel
Bulk
Filling
Drain
Hydrophobic
Filter
(requires
integrity
testing)
Patm
Patm
Connecting People, Science and Regulation
®
Filtration Interest Group
Statement Clarification Need
113. The integrity of the sterilised filter should be
verified before use and should be confirmed
immediately after use by an appropriate method
such as bubble point, diffusive flow or pressure
hold.
The question to post is:
Does “should” here has the same meaning as described in Q8 or Q9 ?
“The use of the word should in Agency guidances means
that something is suggested or recommended, but not required.”
9. 9
Connecting People, Science and Regulation
®
Filtration Interest Group
ANNEX 1. Wording Alternative
113. The integrity of the sterilising filter may be
verified before use and should be confirmed
immediately after use by an appropriate method
such as bubble point, diffusive flow or pressure
hold.
Leave the Decision to the End-User
Connecting People, Science and Regulation
®
Filtration Interest Group
Why leave it to the End-User ?
Because a post-sterilization, pre-use integrity test would
not increase process safety (RPN ~ 80-180 vs. 30-60).
It is mainly an economical decision to be made.
And when steam sterilization and filtration processes
are properly qualified, the filters are not adversely
affected by such and users trained the risk of a
failure is minimal (never non-existing).