Position Paper Pre Use It Mwj 01 11 1

BiioProcess Resources LLC
B oProcess Resources LLC
Scientific Support for Peak Performance

To whom it may concern

The enclosed Position Paper Pre-use/Post-sterilization Integrity Test is
segmented in an Introduction, Executive Summary, Analysis and
Recommendations.

Please do not hesitate to contact me, if additional questions arise. I hope the
information meets the requirements.

Sincerely,

Maik W. Jornitz
Founder
BioProcess Resources LLC

www.go-bpr.com, bioprocessresources@hotmail.com

–1– January 28, 2011

–2– January 28, 2011

Position Paper

Pre-use/Post-sterilization Integrity Test

• Introduction

• Executive Summary

• Analysis

1. Implications

2. Assumptions versus Data

• Recommendations

• References

BiiioProcess Resources LLC
B o Process Resources LLC
B oProcess Resources LLC www..go-bpr..com
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–3– January 28, 2011

Introduction
Sterilizing grade filtration has been used for decades with success,
reliability and accuracy. The reliability of this particular aseptic processing
step increased with filter stability improvements, robust integrity test
methodologies and especially process validation requirements, which
evaluate the performance of a particular sterilizing grade filter under process
conditions utilizing either the actual fluid or a placebo, if the fluid is
bactericidal or bacteriostatic (1, 2, 3).
To verify that the sterilizing grade membrane filter is unflawed, integrity
tests, like Bubble Point, diffusive flow or pressure decay, are used. The
integrity test of a sterilizing grade filter has to be and most commonly is
performed after the filtration process (post-use) (1, 2). Some filter users test
the integrity before the filtration process (pre-use) and before the filter is
sterilized. Extremely rare are integrity tests pre-use, post-sterilization, as
such test would require downstream, filtrate side manipulation and therefore
is considered precarious.
EU Annex 1 (4), paragraph 113. states now “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 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.” The paragraph, in its first sentence,
recommends the rare and risk attached pre-use, post-sterilization integrity
test, which we believe is undesirable.

Executive Summary
Performing a pre-use, post-sterilization integrity test has only justification
due to a) possible damage to the filter during the sterilization process or b) a
minor damage of the filter might be blocked resulting in a integrity test pass
due to the blockage. Justification a) has its merits as most commonly filter
fail due to excessive steam sterilization parameters, although these damaged
filters will be detected by the post-use test. This would mean that the risk
within this process is an economical and not a drug quality risk. The batch
will be either discarded or reprocessed, if validated so. Justification b), a
damaged filter becomes integral during the filtration process is highly unlikely
and so far has not been yet established by any major filter manufacturer.
These manufacturers have thousands of high burden challenge tests of
damaged filters, just failing the integrity pre-use, which still fail the integrity
test post-use, even with such high blocking fluids as experienced in bacteria
challenge testing (5, 6, 7). This justification does not have any merit nor
scientific evidence.
A risk based analysis shows that the risk of performing a pre-use, post-
sterilization integrity test is higher than not to perform such test. The
potential contamination risk to a sterilized filtrate line, downstream of the
filter, causes far more concern to drug quality than the lack of a pre-use
integrity test.

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–4– January 28, 2011

Therefore the recommendation is to leave such decision to the filter user,
as the risk not performing a pre-use test is a sole economical risk and does
not enhance the drug safety. Contrary it creates a potential drug safety risk,
which might not be detected. The ICH guidelines (8) state “The use of the
word “should” in Agency guidances means that something is suggested or
recommended, but not required” and therefore support the notion to leave
the final decision to the filter user.
It would be advisable to rather utilize the FDA Guidance (2) approach,
which recommends “Integrity testing of the filter(s) can be performed prior
processing, and should be routinely performed post-use.” This again allows
the end-user to make the decision on a risk basis.

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–5– January 28, 2011

Analysis
In this section, the implications of the enforcement of a pre-use, post-
sterilization integrity test are analyzed. The balance of benefits versus risk
will be described in detail. There have also been assumptions made, which
will be considered against a scientific data base.
The detailed analysis of all implications and data will support the
recommendations following this section.

1. Implications
Currently filter users are either in-line steam sterilizing filters or utilize
gamma irradiated Capsule filters connected to a filtrate bag or manifold.
When filters are in-line steam sterilized, the filtrate side is kept under
positive pressure after the steam sterilization process to assure that the
filtrate line is leak tight and no potential microbial ingress can happen.
Any down-stream manipulation or additional attachment commonly raises
the risk of flaws, mishandling, leaks or secondary contamination,
therefore should be avoided.
The pre-use, post-sterilization test either performed manually or with
an automated integrity test system would require manipulation of the
downstream side, as the filtrate side requires being under atmospheric
pressure. There are different process designs scenarios possible, which
are evaluated below, not meaning of being complete, but considered as
review point.

Process Scenario Description Evaluation
A 3-way valve is The design adds
installed to separate connections to the
the sterilized downstream side,
downstream process the vessel/ vent
from the mani- filter assembly
pulation. The wetting needs to be
fluid is flushed into sterilized, the vent
the blue retainer filter needs to be
vessel, which has pre-use integrity
vent filter attached. tested, the product
The vent filter filter needs to be
assures atmospheric dried to avoid
pressure conditions. dilution of the
filtered product

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–6– January 28, 2011

Process Scenario Description Evaluation
Instead of a hold The design adds
vessel with a vent connection points
filter, the system to the downstream
utilizes a 3-way valve side, the filter
and a hydrophobic/ requires to be
hydrophilic filter steamed and
combination. The integrity tested pre-
wetting fluid is use, post-steaming,
drained through the which is not
hydrophilic section of possible, since the
the filter and the filter is a hybrid of
hydrophobic section hydrophobic/
assures atmospheric hydrophilic sections
pressure conditions and it needs to be
wetted with
solvents.
Redundant sterilizing The design adds
grade filtration is downstream
used, both filters are connection, the two
validated to retain sterilizing grade
organism according filter mean possible
to ASTM 838-05 (9). increase in hold-up
Filter 2 acts as a volume, unspecific
barrier to the adsorption and
downstream process leachables. Both
and Filter 1 is the filters require to be
sterilizing grade filter validated and
pre-use tested. bioburden in front
of Filter 1 needs to
be <10cfu/100ml.
(10)
In this scenario, the If the filter fails the
actual product is product would be
used as wetting lost on the
agent, flushed into downstream side
the downstream side or, if validated
equipment (vessel, requires to be
fill hopper). Then the reprocessed. The
filter is tested using downstream side is
product wet integrity under atmospheric
test limits. The vent pressure
filter assures conditions, which
atmospheric pressure elevates the risk of
conditions. ingress, if there is a
connection leak.
The hydrophobic
filter requires
integrity testing.

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–7– January 28, 2011

It can be clearly seen that any pre-use, post-sterilization process
design is complex, requires elaborate set-up and therefore might elevate
the risk of human error. In addition, the steaming process of the new
designed process becomes more complex and requires re-qualification.
Since the steaming process is critical in regard to pressure/temperature
conditions a new set-up requires careful evaluation of the p/t conditions to
achieve sterility, but also to avoid any excessive differential pressure
conditions. This new set-up would also require re-training of the end-user.
The first three of the design scenarios will also require the re-
validation of the filtrate quality as wetting fluids will dilute the filtrate. In
case of redundant filtration, the unspecific adsorption might be elevated
and again yield requires being determined. The hydrophobic vent filters
required in the design schematics also need to be integrity tested and
since critical to the process, the integrity test needs may meet the liquid
filtration needs.
Overall, pre-use, post-sterilization integrity testing means more
complex and therefore risk elevated filtrate designs. The questions
required to be posted: “Does the pre-use, post-sterilization integrity test
increase drug safety in comparison to the higher complexity of the sterile
downstream side ?”. We believe not. We believe from a risk management
standpoint and evaluation, that the risk of a downstream manipulation
error is by far higher than the lack of a pre-use, post-sterilization integrity
test.

2. Assumptions versus Data
Multiple technical assumptions probably led to the current paragraph
113. and the claim that pre-use/post-sterilization integrity tests is
necessary. Within this section, we analyze the assumptions and compare
these to available data.

a) In-line steam sterilization damages the filter and the failure
can only be found during the post-use integrity test.
Data: In fact steam sterilization (in-line, especially in reverse
direction) is probably the most stressful situation for the filter element
and failures have been experienced (Figure 1.). Having said this, most
of the time these failure situations were found when the steam
sterilization qualification was insufficient or not performed or when the
filter user was not trained properly. Steam sterilization cycles require
appropriate qualification to establish the efficiency, but also the
parameters to avoid any excessive pressure/temperature profile. If the
differential pressure over the filter is too high at elevated
temperatures, the filter will be damaged, most commonly
substantially. The failed filter would be picked up by the post-use
integrity test and the filtered product either needs to be discarded or
reprocessed, if validated so. The failure effect is a commercial one, but
not a undetected drug safety problem, since the post-use test will
detect such damaged filter.

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–8– January 28, 2011

Figure 1.: Damaged filter due to excessive steam sterilization
pressure/temperature condition

b) Enlarge pore or defect after the sterilization process is covered,
plugged, self-repaired or masked and will not be detected by
the post-use integrity test.
Data: The theory of defect or enlarged pore plugging during the course
of the filtration has been discussed many times within the filtration
expert group. So far there is consensus that such occurrence has not
happened, neither in the industry nor in the filter manufacturers in-
house tests. Pre-use failed filters always failed post-use and any defect
has to been covered that the post-use test passed. These evaluations
are supported by rigid bacteria challenge tests performed by the filter
manufacturers during the correlation of integrity test limits to the
bacteria challenge test. These correlation tests use a hundreds of filter
of different integrity test ranges, are pre-use tested, bacteria
challenged at a high level (up to 108 cfu/cm2) and afterwards post-use
tested (Figure 2.). The integrity test value might shifts slightly, but a
pre-use failed filter always failed post-use. In addition the given
integrity test limits have safety margins, which cause a filter integrity
rejection even when retentive according to the bacteria challenge test.
The integrity test limits are set to include such safety margins to avoid
any borderline passes. Furthermore, literature searches in regard to
any pre-use fail, post-use pass test results have not shown any merit.
There has never been an occurrence of such scenario reported, neither
in the scientific field nor anecdotal.

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–9– January 28, 2011

Figure 2.: Typical bacteria challenge/integrity test limit correlation
(courtesy of Sartorius Stedim)

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– 10 – January 28, 2011

One has to understand that the described bacteria challenge test of
>108 cfu/cm2 is in most case not found within filtration processes.
Excessive filter fouling or blockage of the sterilizing grade filter has to
be avoided to process the defined batch. The sterilizing grade filter
cannot be exchanged during the filtration process; therefore the
scaling of the filter to process scale allows a safety margin for the
effective filtration area. Filters are not excessive used and blocked, but
remain rather less challenged. This also means that a solid blockage of
a filter and therefore defect coverage or masking does not happen in
real life processes.
Furthermore, guidances (1, 2) recommend evaluating process
parameters, which have been utilize for the process specifications and
validation. These parameters are differential pressure over the filter,
flow rates, total throughput or filtration time. If these parameters fall
out-of-specification, the filtration process requires to be investigated.
This also means that a flawed filter would show unusual process
parameter behaviors, as the flaw would result in higher flow rates,
contaminant penetration, lower differential pressures etc. A flawed
filter would probably even be recognized by an out-of-specification
event.

c) The risk to drug safety and quality is higher, when a pre-use,
post-sterilization is not performed.
This is not the case. First of all, pre-use, post-sterilization integrity
testing is not a common practice, but rather a rare event. This means
that many sterilizing grade filtration application perform very
successful, processing a sterile filtrate. Incidences of post-use filter
failure were detected and the filtered product either discarded or
reprocessed. Nevertheless, utilizing the PQRI (11) risk assessment
process, the actual risk of a pre-use, post-sterilization activity is higher
than the lack of this activity.

According to this document the level of risk is calculated as:

Risk = (S) x (F) x (D)

(S): Severity of the event (consequence)
(F): Frequency estimation (likelihood of event occurring)
(D): Level of detectability

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– 11 – January 28, 2011

The three categories are measured as:

Value Severity
1 Negligible: Has no potential to have an adverse effect on identity,
strength, quality, purity or potency of a drug product
2 Minor: Has minimal potential to have an adverse effect on identity,
strength, quality, purity or potency of a drug product
3 Moderate: Has moderate potential to have an adverse effect on
identity, strength, quality, purity or potency of a drug product
4 Major: Has a substantial potential to have an adverse effect on
identity, strength, quality, purity or potency of a drug product
Value Frequency
1 Highly unlikely: The probability of the event occurring is so low
that it can be assumed that the event will not occur
2 Unlikely: Event not expected to occur, but theoretically possible
3 Likely: Event may occur and/or has occurred in the past
4 Highly likely: Event expected to occur
Value Detectability
1 Readily detectable: Will be detected
2 May be detectable: May be detected
3 Not detectable: No mechanism for detection

The scenario of the pre-use, post-sterilization integrity test
performance and the lack thereof are now compared side-by-side:

Category Test No Test Rational
Severity 4 4 If the filter fails or microbial ingress
happens, it has a major effect in both
cases
Frequency 3 2 Microbial ingress into the downstream
side has occurred, for this reason the
downstream side is commonly held
under pressure after steam
sterilization. This overpressure is
replaced by atmospheric pressure
during the pre-use test (3).
Since steam sterilized downstream
processes are commonly held at
overpressure the likelihood of ingress is
low (2).
Detectability 3 1 If there is a microbial ingress due to
downstream manipulation, when the
test is performed, it will not be
detected (3).
If the filter is flawed due to the steam
sterilization process it will be readily
detected by the post-use test (1).
Risk Level 36 8 Risk assessment would not recommend
a pre-use, post-sterilization test.

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– 12 – January 28, 2011

Recommendations
The recommendations resulting from the analysis of the implications and
data are to either reword paragraph 113. to ”The integrity of the sterilising
grade 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...”. The other option would be to utilize the approach of the
FDA, which defines the word ”should” as a suggestion or recommendation,
leaving the decision to the end-user in the first place. Since post-use testing
is of importance to confirm the filters separation performance during the
process, the paragraph might be changed to ”The integrity of the sterilised
filter should be verified before use and must be confirmed immediately after
use by an appropriate method such as bubble point, diffusive flow or
pressure hold...”.
Both alternatives leave the decision to the filter user, who has the
unquestionable desire to produce and deliver a safe drug product. It might be
that the end-user is performing only a post-use test or a post and pre-use,
pre-sterilization test or a post and pre-use, post-sterilization test. The
important fact is that any of these tests have to show a safety improvement
to the drug, not to the process. If the drug is compromised due to a lack of
process safety it is undesirable and the inability to detect a possible microbial
ingress due to filtrate manipulation receives an elevated risk level.
As many times stated “you cannot test quality into your product, you have
to produce it”.

References

1. PDA Technical Report 26, Liquid Sterilizing Filtration, Parenteral Drug
Association, Bethesda, MD, 2008

2. Food and Drug Administration (FDA), Guideline on Sterile Drug
Products Produced by Aseptic Processing, Division of Manufacturing
and Product Quality, Office of Compliance, Center for Drugs and
Biologics, Rockville, MD, 2004

3. ISO 13408-2:2003(E), Aseptic processing of health care products –
Part 2: Filtration, ISO copyright office, Geneva, 2003

4. EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use, Annex 1,
Manufacture of Sterile Medicinal Products, Brussels, 2008

5. Jornitz, M.W., EU Annex 1, Paragraph 113, Pre-use Integrity Testing,
Minimizing or Increasing Risk ?, PDA/FDA Joint Regulatory Conference,
Washington, DC, 2008

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– 13 – January 28, 2011

6. PharmTech, The Debate over Pre-use Filter-Integrity Testing: Making
Assurance Double Sure ?, PharmTech.com, 2009

7. Martin, J., Current Topics in Sterilizing Filtration, ISPE Aseptic
Processing Course, Tampa, 2009

8. ICH Q8, Q9, Q10 Guidance for the Industry, FDA, Rockville, MD, 2006,
2006, 2009

9. ASTM, Standard F838-05, Standard Test Method for Determining
Bacterial Retention of Membrane Filters Utilized for Liquid Filtration,
American Society for Testing and Materials, West Conshohocken, PA,
1983, Revised 1988, 2005

10.EMEA, Committee for Proprietary Medicinal Products (CPMP), Note for
Guidance on Manufacture of the Finished Dosage Form, London, 1996

11.PQRI, Post Approval Changes for Sterile Products Working Group, 2007

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Position Paper Pre Use It Mwj 01 11 1

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