Pda fda joint conference - 09-2008

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Connecting People, Science and Regulation ®

Filtration Interest Group

EU ANNEX 1, Paragraph 113Pre-use Integrity Testing

Minimizing or Increasing Risk ?

Maik W. Jornitz Group Vice President Sartorius Stedim NA Inc.



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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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.



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:

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hold.



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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hold.



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:

integrityintegrity test value changesappearance



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

Hold Vessel

Bulk

Filling

• Wetting fluid reaches thesterile filtrate side

• Wetting fluid potentiallydilutes product

• Pressure on sterile siderequires to be atmospheric

• Downstream volume requires to be large enough

• Cooling time to obtainappropriate temperature

RPN = Severity x Occurrence x Detection = 10 x 1-2 x 8-9 = 80 - 180



Process Design AlternativesWetting fluid flush diverted via a3-way valve into a flushvolume tank, followed by theintegrity test with the gas ventedthrough 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

HydrophobicVent Filter(requires integrity testing)

P > Patm

Patm

Ptest > Patm

Flush Receival

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Process Design AlternativesWetting fluid flush diverted via a3-way valve through a hydrophilic/hydrophobic filter, followed by theintegrity test with the gas ventedthrough 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

FillingDrain

Hydrophilic/HydrophobicFilter(requires integrity testing)

P > Patm

Patm

Ptest > Patm



Process Design Alternatives

Redundant filtration system, whichtests filter 1. and leaves filter 2. inits sterilized form. Filter 1. will bewetted and tested via 3-way valveand drain.

Disadvantages:• Dilution if not dried• Additional preparation & set-up• Additional hold-up volume

Hold Vessel

Bulk

Filling

Drain

P > Patm

Patm

Ptest > Patm

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Process Design AlternativesProduct 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

FillingDrain

HydrophobicFilter(requires integrity testing)

Patm

Patm



Statement Clarification Need113. The integrity of the sterilised filter should be




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




hold.

Leave the Decision to the End-User



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 !

Pda fda joint conference - 09-2008

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