Filter Integrity Testing

Dr. Mathias Siebner, Product Specialist Separation Technology

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Agenda
Integrity test regulatory requirements
Bacterial Challenge Test (BCT) and correlation to IT
Integrity Test Methods
• Diffusion
• Bubble Point
• Water Intrusion Test (WIT)
Integrity Testers
• Quality Risk Management
• Data Integrity
• Usability
• Health, Safety and Environment (and Contamination Control Strategy)
Trouble Shooting of Integrity Tests

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What is Integrity Testing?

A non-destructive physical test to determine the presence of oversized

pores or other defects that may compromise a given filter’s retention
capability.

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Regulations for Integrity Testing

EU GMP (Annex 1, Filtration of medicinal products which cannot be sterilised in their

final container, (June 2001))

85. “The integrity of the sterilised filter should be verified before use and should be
confirmed immediately after use by an appropriate method such as a bubble point,
diffusive flow or pressure hold test. The integrity of critical gas and air vent filters
should be confirmed after use. The integrity of other filters should be confirmed at
appropriate intervals.“

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Regulations for Integrity Testing

FDA Guideline on sterile drug products produced by aseptic processing,

September 2004

“Integrity testing of the filter(s) can be performed prior to processing, and should be
routinely performed post-use. It is important that integrity testing be conducted after
filtration to detect any filter leaks or perforations that might have occurred during the
filtration. Forward flow and bubble point tests, when appropriately employed, are two
integrity tests that can be used. A production filter´s integrity test specification should
be consistent with data generated during bacterial retention validation studies.”

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Regulations for Integrity Testing

PDA Technical Report No. 26 Sterilizing Filtration of Liquids

“It generally is regarded as a GMP requirement that filter or filter systems routinely
be integrity tested both prior to and after use.

If one filter has been validated to achieve sterilization with a specific product, then
the single sterilizing filter must satisfactorily pass integrity testing before and after
use.”

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Pre-use Post-sterlilization I-Test

Annex 1 : Manufacture of Sterile Products (DRAFT, 2020)

“It is recognized that pre-use post

1492 sterilization integrity testing (PUPSIT) may not always be possible after
sterilization due to process
1493 constraints (e.g. the filtration of very small volumes of solution). In these
cases, an alternative
1494 approach may be taken providing that a thorough risk assessment has been
performed and compliance
1495 is achieved by the implementation of appropriate controls to mitigate any risk
of non-sterility.”

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Agenda
Integrity test regulatory requirements
Bacterial Challenge Test (BCT) and correlation to IT
Integrity Test Methods
• Diffusion
• Bubble Point
• Water Intrusion Test (WIT)
Integrity Testers
• Quality Risk Management
• Data Integrity
• Usability
• Health, Safety and Environment (and Contamination Control Strategy)
Trouble Shooting of Integrity Tests

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Correlation to Bacterial Challenge

Test (BCT)

• A physical integrity test is only meaningful when it can be related to specific filter
retention characteristics.
• For sterilizing grade membrane filters, the industry standard test is a micro-
organism challenge using B. diminuta.
• Since bacterial challenge tests (BCT) are destructive, they cannot be used on
filters intended for production usage.
• Therefore, a correlation is established between bacterial retention and physical
integrity testing.

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BCT Organism:
Brevundimonas diminuta

▪ Diameter: 0.3 - 0.4 µm

▪ Length: up to 1µm

▪ Concentration level greater

than 107 CFU/cm2

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Bacterial Challenge Test (BCT)

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Diffusion / BCT Correlation

Safety Margin
Diffusion (ml/min)

Sterile Non-Sterile

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Agenda
Integrity test regulatory requirements
Bacterial Challenge Test (BCT) and correlation to IT
Integrity Test Methods
• Diffusion
• Bubble Point
• Water Intrusion Test (WIT)
Integrity Testers
• Quality Risk Management
• Data Integrity
• Usability
• Health, Safety and Environment (and Contamination Control Strategy)
Trouble Shooting of Integrity Tests

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Principle of Diffusion

Test pressure (e.g.

Atmospheric
2.5 bar): good solubility
pressure:
of compressed air
degassing
in the wetting medium

Henry 's Law:

The solubility of gases in liquids is dependant upon pressure
(and temperature).

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Diffusion Formula

D·H·P·F
N =
L
• N: Diffusive flux of the test gas
• D: Diffusivity of the test gas through the wetting fluid
• H: Solubility coefficient of the test gas through the wetting fluid
• P: Differential pressure applied
• F: Contact area between liquid and gas
• L: Thickness of the wet layer (membrane thickness corrected
by a “tortuosity” factor)

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Principle of the Bubble Point

compressed air

compressed air

wetted membrane surface tension and capillary liquid forcibly removed from
effect resist liquid expulsion the largest pores first, resulting
from pores in bulk air flow

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Flowrate vs. Pressure

Increasing Flowrate

BUBBLE POINT REGION

Increasing Pressure

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Bubble Point Equation

4 · k ·  · cos 
P =
d
• P: Differential pressure at which largest pores will open
• k: Correction factor for the shape of the largest pores
• : Surface tension of the wetting fluid
• cos : Contact (“wetting”) angle between the liquid and the membrane
• d: Diameter of the largest pores

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Integrity Testing a Hydrophilic

Membrane

compressed
gas

wetting liquid:
aqueous solution

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Integrity Testing a
Hydrophobic Membrane

Water Intrusion Test

water Water under pressure is forced

to intrude into the pore matrix.
The greater the overall
porosity, the higher the rate of
the intrusion.

leading edge
The water vapor travels from
the leading edge downstream
through the filter membrane.
air

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Water Intrusion Test

V1 Water under pressure

V2
evaporates through the
membrane and causes an
increase in the headspace
volume above the filter
(V1 → V2).

The resulting pressure drop

from the volume increase is
converted into a water flow
Water Water rate.

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Water Intrusion Test (WIT)

Formula

∆ p (mbar) • Volume (ml)

Intrusion (ml/min) =
Test Time (min) • Test Pressure (mbar)

The limit values for intrusion are directly correlated to the Bacteria Challenge Test
(ASTM F838).

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Agenda
Integrity test regulatory requirements
Bacterial Challenge Test (BCT) and correlation to IT
Integrity Test Methods
• Diffusion
• Bubble Point
• Water Intrusion Test (WIT)
Integrity Testers
• Quality Risk Management
• Data Integrity
• Usability
• Health, Safety and Environment (and Contamination Control Strategy)
Trouble Shooting of Integrity Tests

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Surpass the Requirements of

Quality Risk Management (QRM)

ICHQ9
Annex1
EMA
US FDA
WHO
PIC/S

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Quality Risk Management –

Some hard Facts
• The regulatory focus on QRM is greatly increasing by the arrival of the new Annex1, expected to
become effective in 2022
• “QRM” and “Risk Assessment” are mentioned already in the §-Scope and §-Principle
• The word "risk(s)" is used 101 times throughout the latest draft version (Feb 2020)
• QRM also applies to filter integrity testing:
• "2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with
QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling
potential risks to quality.“

• False passed and false failed integrity test results are indeed a risk to quality:
• False passed test results puts the health of the patients in danger
• False failed test results generate costly QA deviation and a risk for drug shortage
• The new Annex 1 was written by EMA and reviewed by US-FDA, WHO and PIC/S.
• It should be applied virtually worldwide

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Filter Integrity Tester – QRM

• Traditional QRM methods are essential

• Operator training
• Standard operating procedures
• Possibility to use barcode scanner for program selection
• Rare but regular end-user complaints of false passed and false failed test results prove that
traditional QRM methods are not enough

• Integrity Tester with improved QRM:

• Possibility to make the barcode scanner mandatory
• Automatic detection of operator errors by program specific safety parameters
• QRM Handbook & FMEA documentation
• Identifies hazards, calculates the RPN and suggests measures for Risk Control
• Guidance for setting of safety parameters reduces the Likelihood and improves the Detectability

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Data Integrity from a regulatory perspective

• There is a high focus on data integrity from regulatory bodies (cf. frequency of regulatory texts
hare below)
• The number of FDA warning letters related to data integrity has greatly increased over the last
years
• The vulnerability of computerized companies have been understood by recent ransomware
attacks (cf. “WannCry” and “NotPetya” malware outbreak 2017 - $10 billion total damages
(https://www.apextechservices.com/topics/articles/435235-notpetya-worlds-first-10-billion-malware.htm#)

Data integrity - FDA 483 Warning

US FDA – Dec 2018 Letters
Data Integrity and Compliance with Drug CGMP Questions and
80
Answers:
Guidance for Industry 60
MHRA – March 2018
‘GXP’ Data Integrity Guidance and Definitions 40

ISPE – March 2017 20

GAMP Guide: Records & Data Integrity
0
US FDA – April 2016 2014 2015 2016 2017 2018
Data Integrity and Compliance with CGMP: Guidance for Industry
https://govzilla.com/blog/2019/05/pharma-medical-devices-data-integrity-breaking-down-
keywords-and-citation-trends-from-the-fda/

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ALCOA / ALCOA+ Principle

FDA: “For the purposes of Attributable Legible Contemporaneous

this guidance, data
• Who did it? • Can I read it? • When is it recorded?
integrity refers to the
completeness,
consistency, and accuracy
of data. Complete, Original Accurate Complete
consistent, and accurate • Has it been modified? • Is it contextually • Is it a full set?
data should be correct?
attributable, legible,
contemporaneously
recorded, original or a true
Consistent Enduring Available
copy, and accurate • Is it contextually • Is it durable? • Is it easily accessible
consistent? for review?
(ALCOA).”

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Integrity Tester– Data Integrity

• Internal Double Data Backup

– All generated data is instantly backed up on the
internal inaccessible memory
• Encrypted Data
– Efficient protection against misuse
• Audit Trail and NTP
– Reliable time stamps in the audit trail of all events
– Export as digitally signed write-protected PDF
• User Matrix to generate individual user roles
– Freely define user roles according to the matrix of all
existing features for a maximum of flexibility
• Four eyes principle with electronic signature
– Enhance test result reliability and data validation
– Combined with automatic detection of faulty setups
it enhances the reliability of the operator's evaluation

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I-Testing with Alcohols

HSE / OSH – Explosion proof

• The only filter integrity tester device on the

market to be explosion proof
• This allows safe re-testing of alcohol
wetted filters according to recommended IECEx, ATEX Zone 2 Groupe II-B
procedures (cf. PDA Technical Report 26 FM (USA) Class 1 Zone 2 Group II-B
and Points To Consider part 2).

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HSE / OSH – External Cleanability –

Contamination Control Strategy
• External cleaning can be made with most of the commonly used chemical agents thus allowing
rotating use of disinfectants e.g.
• Spor-Klenz® Ready-To-Use Cold Sterilant
• 3% Hydrogen Peroxide WFI Sterile Solution
• Septihol® Sterile Alcohol Solution 70% IPA
• Water for injection
• Sodium hydroxide (NaOH) 10%
• Quaternary ammonium compounds 0.2%

• The Sartocheck® 5 / 5 Plus is designed to be compatible to

VHP and can therefore be left in the cleanroom during fumigation

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HSE / OSH – Internal Cleaning –

Contamination Control Strategy

• The internal pneumatics of the Sartocheck® 5 / 5 Plus can be cleaned with up to

0.5M NaOH @ 50 °C
• 0.1M NaOH at room temperature is mostly enough (c.f. cleaning study)
• Fully automated cleaning, rinsing and drying – plug and play without intermediate steps or
disconnection during the process (fully risk assessed)

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HSE / OSH – Backflow protection and

protection against cross cont.
• The optional Accessory Kit for External Venting Prevents Unwanted
siphoning of liquid
• Prevents cross contamination between product-soaked filters being
post-use tested and new filters being pre-use tested (e.g. PUPSIT)
• Is complementary to the cleaning kit to reach the highest level of CCS
• A specific CCS datasheet is available

The ATEX classification of the AKEV

• IECEx, ATEX Zone 1 Group II-B
• FM (USA) Class 1, Div. 1, Zone 1 Group II-B

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Agenda
Integrity test regulatory requirements
Bacterial Challenge Test (BCT) and correlation to IT
Integrity Test Methods
• Diffusion
• Bubble Point
• Water Intrusion Test (WIT)
Integrity Testers
• Quality Risk Management
• Data Integrity
• Usability
• Health, Safety and Environment (and Contamination Control Strategy)
Trouble Shooting of Integrity Tests

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Failure Analysis / Troubleshooting

(from PDA Technical Report No. 26)

If a sterilizing filter fails an integrity test, it could be damaged, but there may be
other causes for the failure that include incorrect assembly (incomplete sealing)
and incomplete wetting. Any investigation of filter failure or retesting should be
described in the operating procedure.

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Filter Damage or Test Problems?

• To distinguish between filter damage and possible test problems or
artifacts, the following verification steps may be taken —
• The appropriate integrity test has been selected.
• The correct test parameters have been used.
• The correct wetting fluid and wetting procedure have been used.
• There are no leaks in the test system.
• Filter assembly temperature has remained stable and within specification during testing.
• Equipment has been properly calibrated.
• Test setup has been properly assembled and functions properly.
• Correct filter has been installed.

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Retesting Protocol

To confirm corrective action has been effective, the following retesting step may
be taken —
• Rewet the filter according to the specifications and repeat the test

If the filter integrity test fails again, the following step may be employed —
• Apply more aggressive wetting conditions by increasing flush volume / time,
increasing pressure differential and / or applying back pressure

If the filter integrity test fails yet again, the following step may be employed —
• Perform the integrity test in a lower surface tension reference fluid to assess filter
wettability changes independent of filter integrity
• If the filter fails using the reference fluid, the filter fails the test

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Failure Analysis Decision Tree (Step 1)

Verify System Setup Verify Test Parameters

• Ensure test setup is assembled and • Ensure appropriate integrity test has
functions properly been selected
• Ensure test equipment has been • Ensure correct test parameters are
properly calibrated being used
• Ensure there are no leaks in the system • Ensure correct wetting fluid and wetting
procedure are being used
• Ensure correct filter has been installed
• Ensure temperature has remained within
specified range during test

Rewet filter and repeat integrity test

Pass/Fail

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Failure Analysis Decision

Tree (Step 2)

Pass Pass/Fail Fail

Filter Wetting (Stage I)

• Increase flush volume / time

• Increase differential pressure
• Apply back pressure

Record Pass result.

Filter is integral
Pass/Fail

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Failure Analysis Decision

Tree (Step 3)
Pass Pass/Fail Fail

Filter Wetting (Stage II)

• Flush filter with a low surface tension reference

wetting liquid to enhance wetting per
manufacturer’s instructions
• Repeat integrity test using appropriate test
parameters and limits for low surface tension
reference wetting fluid

Record Pass result.

Pass Pass/Fail
Filter is integral

Fail

Record Fail result.

The filter fails the test

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Membrane Wetting
• Membrane polymer: Some polymers are easier to wet than others, depending on the
critical surface tension of the membrane material.

• Pore size: The smaller the pore size, the more difficult the pores are to wet.

• Wetting fluid: Some wetting fluids may interact unfavorably with the polymeric matrix.
• Product residues or contaminants: Product residues or contaminants can alter the
hydrophilicity of the membrane polymer and repel the wetting fluid or lower the surface
tension.
• Pressure conditions: Manufacturer’s pressure recommendations should be followed to
completely wet the membrane.

• Temperature conditions: Temperature influences the surface tension of the wetting fluid.

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Key Factors Affecting

Diffusion Tests
Wetting liquid:
• Complete wetting / thickness of the wetting layer
• Temperature consistency / range throughout test
Test gas:
• Solubility coefficient of the test gas in the wetting liquid
• Diffusivity of the test gas through the wetting liquid
• Applied differential pressure
• Temperature consistency / range throughout test
Membrane:
• Porosity
System:
• Stabilization and test time
• Leak tightness
• Temperature equilibrium

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Key Factors Affecting

Bubble Point Tests
Wetting liquid:
• Surface tension
• Wetting angle
• Temperature consistency / range

Test gas:
• Applied differential pressure (incremental)
• Temperature consistency / range during any pressure decay increment

Membrane:
• Complete wetting
• Diameter of largest pores

System:
• Leak tightness

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Key Factors Affecting Water

Intrusion Tests
Wetting liquid:
• Fill level / headspace
• Wetting angle
• Temperature consistency / range during entire test
Test gas:
• Applied differential pressure
• Temperature consistency / range during entire test
Membrane:
• Contamination (e.g. hydrophilic spots / hydrophobic interaction)
• Porosity
System:
• Leak tightness
• Stabilization time
• Test time
• Thermal equilibrium

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Automated Integrity Test Musts

• Use calibrated integrity tester

• Maintain constant temperature throughout entire test
Tsystem = Tair = Tfluid = Tfilter = Thousing
• Thoroughly wet membranes
• Ensure system leak tightness
• Use proper integrity test parameters for filter being tested

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Integrity Test Troubleshooting Guide

(from TR26, Appendix D, Table D-2)
No Test Pressure • Filter system leakage (i.e., damaged sealing, valve open, clamps improperly closed, damaged
Buildup filter)
• Improperly wetted filter
• Inappropriate wetting medium (e.g., solvent instead of water)
• Filter contains traces of product solution or extraneous material from wetting fluid
• Incorrect filter pore size rating
• Gas supply to the unit blocked
• Inlet tubing to the housing improperly installed
• Excessive temperature drifts
• Improper valve function within unit
• Internal pneumatic leaks

Continuous Venting of • Internal valve contamination and improper function

the Unit

Abortion of Test • Filter system leakage (i.e., damaged sealing, valve open, clamps improperly closed, damaged
During Stabilization filter)
Phase • Insufficiently wetted filter
• Contaminated filter
• Incorrect filter pore size rating
• Excessive temperature drifts
• Internal pneumatic leaks

Measured Volume is • Incorrect input of the reference volume

Wrong • Internal pneumatic leaks

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Integrity Test
Troubleshooting Guide (cont.)
Failure of Bubble Point • Damaged filter
• Insufficiently wetted filter
• Inappropriate wetting medium (e.g., solvent instead of water)
• Incorrect filter pore size rating
• Filter contains traces of product solution or extraneous material from wetting fluid
• Internal pneumatic works improperly
• Inlet tubing to the housing improperly installed
• Incorrect test gas
• Incorrect test parameter setting
• Incorrect test code
• Large multiple-cartridge assembly
Failure of Diffusive Flow • Damaged filter
• Insufficiently wetted filter
• Inappropriate wetting medium (e.g., solvent instead of water)
• Incorrect filter pore size rating
• Filter contains traces of product solution or extraneous material from wetting fluid
• Internal pneumatic works improperly
• Inlet tubing to the housing improperly installed
• Incorrect test gas
• Incorrect test parameter setting
• Temperature shifts during the test time
• Insufficient stabilization time
No Pressure Decay • Inlet tubing to the housing improperly installed
• Downstream valve closed
• Blocked connector
• Blocked internal pneumatic
• High temperature during test time

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Integrity Test Troubleshooting

Guide (cont.)
Failure of Pressure • Filter system leakage (i.e., damaged sealing, valve open, clamps improperly closed,
Decay damaged filter)
• Insufficiently wetted filter
• Inappropriate wetting medium (e.g., solvent instead of water)
• Incorrect filter pore size rating
• Filter contains traces of product solution or extraneous material from wetting fluid
• Internal pneumatic works improperly
• Inlet tubing to the housing improperly installed
• Incorrect test gas
• Temperature shifts during the test time
• Insufficient stabilization time or incorrect test time
Inappropriate • Damaged filter
Diffusion Test • Insufficiently wetted filter
Result • Inappropriate wetting medium (e.g., solvent instead of water)
• Incorrect filter pore size rating
• Internal pneumatic works improperly
• Inlet tubing to the housing improperly installed
• Incorrect test gas
• Incorrect test parameter setting
• Temperature shifts during the test time
• Insufficient stabilization time or incorrect test time
From Appendix D, Table D-2. PDA Technical Report No. 26, Sterilizing Filtration of Liquids, Revised 2008

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Failed integrity test

Pre-use

WIT Trouble Shooting Check system setup

(Pre-use)
• leaks in filtration system
• correct installation
• water quality / IPA concentration
• integrity tester

Check test parameters

• correct filter / test program
• net volume
• water or gas flow / diff. / BP
• stabilization and test time

Check temperature conditions

• enviroment & filtration system
• test gas and liquid

Integrity test using WIT IPA/water wetted integrity test

Pass/Fail Pass/Fail

fail fail
pass
Test WIT
Increase flush
volume / time

Pass/Fail opt. Test IPA/water wetted

pass

pass
pass Pass/Fail

allow
fail 1x re-test
fail

Passed result Failed test result,

filter integral optional further investigation. e.g. BCT

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Failed integrity test

Post-use

WIT Trouble Shooting Check system setup

•
•
leaks in filtration system
correct installation

(Post-use)
• water quality / IPA concentration
• integrity tester

Check test parameters

• correct filter / test program
• net volume
• water or gas flow / diff. / BP
• stabilization and test time

Check temperaturel conditions

• enviroment & filtration system
• test gas and liquid

clean Choice of test possible

filter method contamination

Integrity test using WIT IPA/water wetted integrity test

Pass/Fail Pass/Fail

Clean product residues with suitable Increase flush

solvent, e.g. IPA volume / time

If the filter was cleaned, If contaminant is not soluable with

dry the fiter IPA use suitable solvent

Re-test WIT Test IPA/water wetted

Pass/Fail
Pass/Fail
allow
1x re-test
Passed result
filter integral
Failed test result,
optional further investigation.
e.g. Aerosol Test or BCT

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