Sterilizing Grade Filtration Validation & QualificationThe Difference between Being in Control & Fear

Maik W. Jornitz, Sartorius Stedim North America Inc.

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 higherthe fear factor and utter reliance on so called “experts”.

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)

“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)

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-culturableorganisms 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”

“Fear Factors”

Most are either driven by lack of knowledge or marketing !

Corrective action:Training Scientific discussionsOpen dialogue

Corrective action:a critical educated end-user

Most commonly:• Regulators

• Consultants

• Inexperienced vendor staff

Motivation: cover all bases

Most commonly:• Experienced

vendor staff !

Motivation: sell more

Let’s get into Control

“0.2 µm filters are penetrated, the industry requires to switch to 0.1 µm rated filters”

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%)

True ?

Let’s get into Control, cont.

“redundant 0.2 µm filtration is necessary and should be used”

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.

True ?

Let’s get into Control, cont.

“diffusive flow integrity testing is better than Bubble Point”

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.

True ?

Let’s get into Control, cont.

“the maximum bioburden in front of a sterile filter should be 10 cfu/100 ml”

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.

True ?

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-culturableorganisms or L-forms or nano-bacteria in our processes”

Organisms adapt rapidly, however there is no scientific evidencefor 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

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

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

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

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 !

Thank you for your attention !

“Control your destiny or somebody else will.”Jack Welsh

maik.jornitz@sartorius-stedim.com