Conference presentation about process validation of sterilizing grade filters and possible misconceptions

1. Sterilizing Grade Filtration Validation & Qualification
The Difference between Being in Control & Fear
Maik W. Jornitz, Sartorius Stedim North America Inc.

2. Fundamentals: Being in Control & Fear
“Sandman’ s “control” principle might explain why most people are more
scared of flying in an airplane than driving a car.
Their thinking goes like this: since I control the car, I am the one
keeping myself safe; since I have no control of the airplane, I am at
mercy of myriad external factors.” (Car death 11x higher/miles)
Freakonomics, Levitt & Dubner (2005)
Same principle is at work, when sterilizing grade filtration is used,
discussed or promoted. The higher the lack of control the higher
the fear factor and utter reliance on so called “experts”.

3. What is “Being in Control”
Control = archaic : to check, test, or verify by evidence or
experiments (Mirriam-Webster)
“Being in Control” is equivalent to Validation in Drug Processing
Validation is"Establishing documented evidence that provides a high
degree of assurance that a specific process will
consistently produce a product meeting its pre-
determined specifications and quality attributes.“
(FDA 1987)

4. “Being in Control” in Sterilizing Filtration
Determine the appropriate filter for the application
• Flow rate
• Throughput
• Unspecific adsorption
• Compatibility
• etc.
Perform process validation
• Viability test
• Bacteria challenge test with product under process conditions
• Extractable/leachable test
• etc.
Integrity testing of the filter
Routine control of up-stream bioburden (species/level)

5. Being in “Fear” in Sterilizing Filtration
“0.2 µm filters are penetrated, the industry requires to switch
to 0.1 µm rated filters”
“increasingly, there are detectable, but non-culturable
organisms or L-forms or nano-bacteria in our processes”
“redundant 0.2 µm filtration is necessary and should be used”
“I need an absolute 0.1 or 0.2 µm filter”
“diffusive flow integrity testing is better than Bubble Point”
“flawed filters will not be detected by a post-use test, as the
flaw will be plugged during filtration”
“the maximum bioburden in front of a sterile filter should be
10 cfu/100 ml”

6. “Fear Factors”
Most are either driven by lack of knowledge or marketing !
Motivation: cover all bases Motivation: sell more
Most commonly: Most commonly:
• Regulators • Experienced
• Consultants vendor staff !
• Inexperienced
vendor staff
Corrective action:
a critical educated
Corrective action: end-user
Training
Scientific discussions
Open dialogue

7. Let’s get into Control
“0.2 µm filters are penetrated, the industry requires to switch to
0.1 µm rated filters”
True ?
Yes, in some specific process, fluid and organism settings 0.2
µm are penetrated. This is not new, but has been addressed by
regulators and filter suppliers alike. (PDA/FDA Special Forum 1995)
This possibility has to be eliminated by Process Validation !
However, that does not mean the entire industry has to switch,
as experience shows that such instances are rare.(~0.005 – 0.01%)

8. Let’s get into Control, cont.
“redundant 0.2 µm filtration is necessary and should be used”
True ?
Not necessarily, again proper Process Validation will show
whether a single filter will do the job or not !
However, there are some specific applications, which utilize a
second (redundant) filter as “insurance” filter, i.e. the first filter
fails the second compensates. Though only when both filters
have been validated to show specified retentivity.
Be aware redundant filtration increases costs, extractables, hold-
up volume and unspecific adsorption. This requires evaluation.

9. Let’s get into Control, cont.
“diffusive flow integrity testing is better than Bubble Point”
True ?
No, both tests are valid, well exercised integrity tests !
In some applications, but especially in dimensional aspects the
individual integrity test has its benefits or need of use. For
example, Bubble Point testing should be used on small filter
areas.

10. Let’s get into Control, cont.
“the maximum bioburden in front of a sterile filter should be
10 cfu/100 ml”
True ?
Yes, if one wants to export to Europe and fulfill the Note for
Guidance CPMP/QWP/486/95, which states such limit in front of
a sterilizing grade filter.
But does it make sense – No – as Process Validation commonly
challenges the filter at a higher level (107/cm2 or 1010/10” filter)
and determine the retentivity at process fluid and parameter
conditions.

11. Let’s get into Control, cont.
“I need an absolute 0.1 or 0.2 µm filter”
“Absolute should solely be used for vodka” (Dr. Cooney, 2001)
“increasingly, there are detectable, but non-culturable
organisms or L-forms or nano-bacteria in our processes”
Organisms adapt rapidly, however there is no scientific evidence
for an increase and especially nano-bacteria
“flawed filters will not be detected by a post-use test, as the
flaw will be plugged during filtration”
So far we have not experienced this case, in thousands of
challenge tests and throughput studies

12. Are we in Control ?!
Yes, we are ! by the use of appropriate Process Validation !
Appropriate Process Validation determines:
Fluid influences on the organisms
Fluid influences on the membrane polymer
Fluid influences on the retention mechanism
Process parameter influences on the organisms
Process parameter influences on the membrane polymer
and filter construction
Process parameter influences on the retention mechanism

13. Ultimately
We determine that the specified sterilizing grade filter works in
the process and fluid product specifications set.
“Works” means, the filter:
retains the targeted organism and creates a sterile filtrate
is thermal and mechanically stabile
does not alter the product filtered (leachables, particulates,
unspecific adsorption)
performance as specified (flow rate, throughput)
is readily available

14. Helpful Guidances
PDA Technical Report #26, 2008
FDA Aseptic Processing Guidance, 2004
FDA Changes to NDA/ANDA, 2004
EC GMP Guidance, Annex 1, 2008
EMEA CPMP/QWP/486/95, 1996
ISO 13408 Part 2, 2003
PQRI PAC, 2007
Warning Letters

15. Having said this...
Process validation is just one part of “Being in Control”.
The other, even more essential, as it could eliminate
everything done is the validation efforts, is...
TRAINING !

16. Thank you for your attention !
“Control your destiny or somebody else will.”
Jack Welsh
maik.jornitz@sartorius-stedim.com