Discussion of Annex I, paragraph 113, pre-use integrity testing and its risk implications

1. ®
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EU ANNEX 1, Paragraph 113
Pre-use Integrity Testing
Minimizing or Increasing Risk ?
Maik W. Jornitz
Group Vice President Sartorius Stedim NA Inc.
Filtration Interest Group
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Connecting People, Science and Regulation
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.
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2. ®
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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.
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Integrity Testing
All integrity tests listed require at least:
• wetting of the filter with
appropriate fluid, commonly
water and fluid volumes
• atmospheric pressure on the
filtrate side
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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.
Filtration Interest Group
®
Connecting People, Science and Regulation
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
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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.
Filtration Interest Group
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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
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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
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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
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Implications for a Sterilized Process
• Wetting fluid reaches the
sterile filtrate side
• Wetting fluid potentially
dilutes product
• Pressure on sterile side Hold Vessel
requires to be atmospheric
• Downstream volume
requires to be large enough
• Cooling time to obtain Bulk
appropriate temperature
Filling
RPN = Severity x Occurrence x Detection = 10 x 1-2 x 8-9 = 80 - 180
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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 Ptest > Patm
through the vent filter. P > Patm
Pipe work to equipment stays Hold Vessel
overpressure.
Patm
Hydrophobic
Vent Filter
(requires
integrity
testing)
Disadvantages: Bulk
• Dilution if not dried
• Additional integrity test Flush Receival
Filling
• Additional preparation & set-up
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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. Ptest > Patm
Pipe work to equipment stays Hold Vessel
P > Patm
overpressure.
Patm
Disadvantages: Hydrophilic/
Hydrophobic
• Dilution if not dried
Filter
Bulk
(requires
integrity
testing)
• Additional integrity test
• Additional preparation & set-up
Drain
Filling
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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.
Ptest > Patm
Hold Vessel
Disadvantages:
P > Patm
• Dilution if not dried Patm
• Additional preparation & set-up
• Additional hold-up volume
Bulk
Drain
Filling
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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 Hold Vessel
vented through the vent filter. Patm
Patm
Disadvantages: Hydrophobic
Filter
• Potential product loss when failed
(requires Bulk
integrity
testing)
• Additional integrity test
• Equipment side under Patm
Drain
Filling
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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.”
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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
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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).
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Thank you !
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