Sterile Filter Handling PDF

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Training Handbook
Sterile Filter Handling & Troubleshooting
Maik W. Jornitz and Joachim Weisse-Blanke
Training Handbook : Sterile Filter Handling & Troubleshooting; M. W. Jornitz and J. Weisse-Blanke @ 2006
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Training Handbook
Sterile Filter Handling & Troubleshooting
Maik W. Jornitz and Joachim Weisse-Blanke
Table of Contents
INTRODUCTION
Acknowledgement
HANDLING OF FILTERS
TROUBLE SHOOTING – FILTER FAILURES
• Steam Sterilization
• Chemical Compatibility
• Handling
• Protection
REGULATIONS
• Out-of-Specification (OOS) Situations
• Validation
ADDITIONAL READING
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INTRODUCTION
This Training Handbook was meant to be called Complaint Handbook.
Nevertheless, the human individual always combines complaint with a negative
connotation, instead of taking complaints as the opportunity for improvement. The
wording filter failures, as such, has a similar negativity, but commonly finds a wider
acceptance than complaint. In any case, independent from the wording, due the
complexity of biopharmaceutical filtrations, the large variety of filter types that are
available, and the many different purposes for which they may be employed make
necessary the careful training of those who would engaged in filtration operations.
Appropriate explanations of filter properties, of causes and effects in their
management, and instructions in their manipulations, gained from experience,
would be an ideal first step in such training. The regulatory authorities endorse
training as being necessary for individuals working in filtration. Indeed, there is an
obligation, so stated by the FDA, to train those who are assigned such work.
Most commonly presentations are utilized as an appropriate tool of lectures
by those relatively expert in filtration techniques, and knowledgeable in the
underlying science are a common and useful way of training. Those being trained
are equipped with lecture notes, hard copies of the slide presentations that
illustrate the specific instructions or informational points being discussed.
Presentations have the advantage that photos, charts, figures and tables can be
utilized as examples.
The purpose of this writing is to present an illustrated lecture series directed
to experienced filter failures, an explanation why these filter failures occurred and
a possible corrective action path, which should be taken to avoid such failures.
When a complaint or filter failure occurs, most important is a fast reaction time to
resolve the issue at hand. In situations like this a fast track support will assure
success and also will also fulfill the support demand by the filter users. This
handbook shows explicit examples of filter failures and damages. The first visual
inspection can show very distinctive reason for the failure. The explanation of this
failure by looking at the failed filter or the process will comfort the filter user that
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the complaint is in proper hands and that the filter manufacturer will do everything
to find the root cause and eliminate such.
The authors do not claim that the filter failure list presented is complete, as
the industry and the filter technology evolves, different failures may be
experienced. This handbook can be used by filter vendors and users to perform a
first analysis, what the potential failure could be, what could potential caused it and
what needs to be done to resolve the issue.
Nevertheless, the authors also want to emphasize that this book cannot be
meant as a replacement of necessary detailed analysis, which may be performed
to find a root cause of a process or handling problem. Commonly, such detailed
analysis has to be performed within our technical service laboratories, by specially
trained and highly experienced staff.
A list of reference readings is included. It is based primarily upon technical
papers forthcoming from peer-review journals. It reflects the scientific principles
relevant to liquid filtrations as validated by experimental experiences.
May this handbook also console many sales people that filter failures most
of the time are not the reason of an inappropriate quality, but often of inappropriate
handling. Whatever the cause is, experiences and knowledge are the most
comforting aspects in a critical situation as this.
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Acknowledgement
We wish to acknowledge our colleagues and friends within all filter

manufacturers, our clients within the biopharmaceutical industry, and regulatory
agencies for their consideration and collegiality in sharing their experiences and
findings over the years. These individuals have been our mentors and supporters,
spending many hours of patiently explaining specifics of filtration processes and
circumstances. Without them explaining to us why things happen, we would not be
able to accomplish this handbook. Their technical experiences included in this
book will now become even more widely available to the common good.
We specifically would like to express our gratitude to Dr. Theodore H.
Meltzer who shared his experiences, which cover over 40 years activities within
the filtration industry, generously with us. He most certainly is the role model of
training, support and advise to the biopharmaceutical and filtration industry.
We dedicate the handbook to our wives, Petra Weisse-Blanke and A.
Dorette Jornitz, for their continuous support and understanding. Many hours were
spent writing, instead of private ventures together. Without them, we also would
not have found the encouragement to finish such work.
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HANDLING OF FILTERS
Appropriate handling of a filter, which means to install, treat and use the
filter according to filter manufacturers instructions, is the key for a stable and
uneventful filtration process. As soon as instructions are not followed, filter failures
might occur. Interestingly enough, written instruction one receives for a home
computer or television are read by us with elaborate interest, even this equipment
is by far more robust than a sterilizing grade filter. Most often instructions of use
for filter cartridges are not thoroughly regarded and in instances ignored by
overruling Standard Operation Procedures (SOP´s). This could lead to a trial and
error basis, than a stabile process. Therefore handling of filters starts by reading
and taking in the instructions how to use the filter.
Handling Filtration Systems

Out of the Box to Production
 Note part number, lot number, and description

on box.
 The Certificate of Conformance is in the box.
 The filter is sealed in a protective bag. The
bag & box labels should be the same.
 Cut the bag at the adapter end. Remove the
filter partially from the bag, holding the filter
with the bag still in place.
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The next step would be to describe and instruct how the filter should be
checked before it enters a production. Visual inspections should be performed,
when the filters is unpacked from its outer (most commonly card board) packaging.
Any rough failures or damage to the package will be determined in this inspection
step. The documentation relative to the identity of the selected filter comes with
the filter package. The filter choice should be confirmed by the documentation.
The cartridge should be installed into the holder under conditions that avoid,
or at least minimize, contamination; under aseptic conditions when sterile filtrations
are the goal. The cartridge should not be touched by the bare hand during its
removal from its package and while it is being installed. Partially removed from its
plastic wraps, enough to permit its insertion into the holder, it is handled and
protected by way of the wraps. (Please see the following photograph). The use of
gloves is considered even more advisable, as the handling of the filter via the filter
bag could potentially be difficult to handle.
Filter Cartridge Installation
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Water (sterile) or alcohol, if not inappropriate, should be used as a lubricant

to facilitate the insertion of the cartridge into the housing. Otherwise the filter may
be damaged by using too great a direct or angular force to effect its insertion.
O-rings and gaskets should be checked to ensure against cuts or nicks that
would compromise tight seals. Indeed, it is a common practice to replace O-rings
whenever cartridges undergo change outs.
Handling Filtration Systems

Out of the Box to Production
 Wet any filter cartridge o-rings with water

before installing into housings.
 Assemble filter housing with filter cartridge in
place. Flow through a cartridge is always from
outside to inside.
 Flush filter according to SOP’s for integrity
testing, sterilization, & use.
Cartridges should be flushed to prepare them for the initial integrity testing.
Complete wetting of the membrane is required for a successful testing. Given the
variety of polymer types, pore size ratings and filter constructions, wetting
procedures can vary. The smaller pores are more difficult to wet out. One
recommendation is for a water flush of 20-30 L per 10 inch cartridge containing 5
ft2 (0.5 m²) of membrane to achieve complete wetting. Wetting of the filter has also
been found advisable as the total throughput of a wetted filter can increase by up
to 30 % in comparison to a dry filter membrane.
Depending on the system design, once installed, the cartridge is sterilized
as by steam and is then integrity tested. The testing confirms the filter choice and
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attests to its not having been damaged by the sterilization process. Alternatively,
the cartridge can be steam autoclaved, installed aseptically, and then be integrity
tested. Integrity testing follows steam sterilization because heating the filter may
serve to relieve casting stresses. Pore distortions and pore size alterations are a
possible consequence. Some believe that initial integrity testing is not essential;
that the drug processor may rely upon the GMP mandated final integrity testing to
sanction the filter action. Prudence would seem to demand initial as well as final
integrity testing. Additionally, initial integrity testing may detect an imperfectly
sealed system, as possibly caused by a damaged O-ring. Pressure drop integrity
testing is often used for this purpose.
The filtration exercise can be summarized as consisting of the following
sequence of events: Filter cartridge receive à unpacking of the filter cartridge à
documentation and lot number check à transfer of the filter à documentation of
the filter type and lot number into the batch record à cartridge installation à
aqueous flushing of cartridge à steam sanitizing in place à if possible, perform
initial integrity test à proceed with the filtration of the drug preparation à conduct
the final integrity testing à documentation into the batch record.
Before we even install…
Any filter system installed requires evaluation at the start. Premature
blockage, fouling and excessive unspecific adsorption fall into the category
complaint or filter failure. To prevent the above, filterability trials are of importance.
The filter performance requires to be determined with any individual drug product or
fluid to be filtered. Commonly such filterability trials are performed with automatic
equipment as shown in the next chart. A manifold of filter combinations are utilized
to find the optimal filter solution.
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Filterability Trials
The test fluid is forced from a vessel to the filtration rig via a specified
differential pressure. The filtration rig commonly utilizes 47 mm filter composites
and can be of multiple steps and of different retention ratings and pore sizes. The
throughput is commonly measured by sort of weighing or volumetric.
There are three concerns that figure in any filtration:
- The particle retention level.
- The rate of flow.
- The throughput volume.
Within the bounds consonant with the proper degree of particle retention,
filterability is usually measured in terms of throughput volume. Compaction of the
filter cake slows the rate of flow; the more so for higher delta Ps. Therefore, for
any suspension characterized by a given total suspended solids (TSS), there
could be a different filterability at each differential pressure level. In practical
terms there is a tradeoff between time and filterability.
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Operation of Filtration Systems

Maintain the lowest possible pressure drop.
Housing
Filter
Cartridge
P1 P2
Pressure Drop = P1 - P2
In its simplest terms, the system required for filtration is a filter contained in
a housing through which the liquid flows in response to a pressure differential.
The achievement of the desired level of particle removal from a liquid
suspension is largely a function of the pore size / particle size distribution and of the
several factors, previously alluded to, that govern adsorptive sequestrations.
The rate of flow is primarily a function of the applied differential pressure as
modified in each particular case by the properties and quantity of the TSS, and of
the filter cake’s amenability to compaction.
The throughput is chiefly a resultant of the TSS level, its quantity and
character, and its susceptibility to compaction at the applied differential pressure.
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Other Operational Parameters to

Optimize
 Temperature  Pressure Available

 Total Throughput – Maximum Available
 Flow Rate – Pulsations
 Retention Rating  Chemical

Compatibility
 Fluid Viscosity
 Fluid Composition
– Adsorption
As stated repeatedly, each of these factors, and particularly the balance

achieved by their interactions will determine the extent to which a filtration can
result in sterile effluent.
Temperature and viscosity stand in an inverse relationship which bears
directly upon flow rate. The applied differential pressure is the prime motivator of
the flow rate; which, in turn, exerts an influence upon the adsorptive sequestration
of particles including organisms. The slower the flow, the longer the dwell time of
the particle within the pore passageways, and the greater the possibility of pore
wall encounter with concomitant adsorptive retention. The exercise of the
adsorptive forces depends, however, upon the physiochemical makeup of the
suspending solution, e.g. ionic strength, pH, osmolarity, etc. The differential
pressure also governs the total throughput by its compaction of the filter cake and
of the polarized particulate layer in front of the filter face, thereby diminishing its
permeation by the liquid.
In a trial setting the membrane should be exposed to the solution whose
filtration is contemplated. The contact time should at least equal the filtration
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processing interval. Subtle incompatibilities that can signal pore changes should
be looked for. They can best be detected by diffusive airflow integrity testing.
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TROUBLE SHOOTING – FILTER FAILURES
This chapter will list some examples of what could go wrong using a filter
and what requires strict attention to avoid damages and flaws. The examples
given are photos of real instances, which happened due to inappropriate
procedures during the filtration process or filter preparation. Most of the examples
resulted due to inappropriate training of the filter user and can be avoided by
regular up-dates of the training. The failures shown are not single incidences, but
most of repeats, not at the same facility, but with different clients. Therefore one
should utilize the photos to train oneself, to become sufficient to analyze a filter
visually, if possible. A first hand analysis in front of the client can tell often, what
happened. It also creates the opportunity to ask the right questions, to have a look
at a specific process or design of a process. These data established are essential
for the laboratories and technical services to determine what went wrong. It is
better to have the answers ready, when the filter in question is send in for further
analysis.
Steam Sterilization
One of the main causes for filter failure or damage is the steam sterilization
procedures used, whether steam-in-place (SIP) or autoclaving. Excessive
temperature/pressure conditions can damage the filter considerably, therefore
performance qualifications (PQ) of the filter within the validation exercise are
required to evaluate whether the filter withstands the individual process conditions
or the process conditions require adjustment. The parameters which are gained
and set during the PQ should be described within a standard operating procedure
(SOP). Additionally the SOP also has to describe in exact forms, what requires to
be done to steam the filter appropriately. Valve handling requires especially a
focus, as any valve which is opened too rapidly can introduce an excessive
pressure pulse towards the filter unit and damages it.
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Excessive Reverse Steam
Within the validation guides of the filter manufacturers, maximum allowable
differential pressure conditions under set temperature levels are described. These
limits should not be exceeded. The filter user has to honor the data established,
otherwise a failure will be inevitable. The robustness of a polymer goes only this
far, i.e. to a certain temperature under a certain differential pressure condition. It
cannot be that this factor is disregarded, even when the process and pipework has
been designed and installed, if the process is hostile to the filter, it has to be
amended.
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Due to the smaller diameter and wall thickness of the inner core of a filter
cartridge, filter units are more stable in forward flow mode than in reverse flow.
Reverse in-line steaming, especially with the common condensate build-up has to
be performed cautiously, otherwise the filters will blow outwards like the above
photos show. Both examples show that the filter was steamed under to rigid
differential pressure conditions. In instances the filter membrane can still be
integral, i.e. a flaw like this may not be detected without visual inspection of the
filter on a routine basis. Such flaw is usually seen in air filtration for example tank
vents, when the tank is steamed and the valve towards the filter opened too
rapidly.
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A very common picture of excessive reverse steam in conjunction with

condensate build-up can be seen in the photo above. Also experienced were air
filters which were installed up-side-down, which would create the opportunity of
condensate build-up within the inner core area. In these instances one will see the
same picture as above. The inner core of a vent filter has to point down to drain
the condensate. The arrows point out that the membrane pleat pack has been
pushed from the inner core towards the outer plastic cage. One sees the pleat
pack of the inner support fleece and the gap towards the membrane pack. This is
a very common sign for reverse steaming, when it is not as obvious as in the two
previous slides.
Certainly, when at a client one has not always the ability to cut the filter
open as shown. There are nevertheless instances, when such action is possible,
i.e. when the client has a multiple failure situation and there are enough filters on
hand for testing within our laboratories. Only then one could perform this exercise.
A better idea would to check the outside pleat pack of the filter, i.e. squeezing the
pack in a bit and one could potentially see outer cage impressions within the pleat
pack.
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When the membrane pleat pack is pushed from the inside towards the outer
support cage, one very commonly finds these outer cage imprintments on the
outside of the pleat pack. These marks are very typical for any reverse excessive
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pressure pulse. Marks as above do not solely result from reverse steaming but
could also be pressure pulses and liquid flows from the inner core to the upstream
side.
Actions:
• Check the steaming process by observing how the filter user steams the
filter system. Best in this instances is the fact that they do not know why the
steaming process will be observed so they do not amend their routine
behavior. Check the pressure conditions and compare these to the set
limits by the filter manufacturer
• Check the Standard Operation Procedure (SOP) for flaws and point these
flaws out
• Check the filter housing positioning and the pipework for obvious design
flaws, for example up-side-down positions or insufficient condensate drains
• Always be a supporter and not a teacher, as you have to win over the user
and not repel him
• Train the user
• If in doubt inform and activate field technical support
Excessive Forward Steam
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Excessive forward or upstream in-line steaming happens mainly when

manual valves, especially butterfly valves, are utilized and are opened too rapidly.
The filter will be hit by high differential pressure and temperatures and if too high
will collapse. In the instances of the photos above the temperature condition has
been elevated to the point of softening or melting the polypropylene support
structure. Additionally, hydrophobic air filters could be compressed due to
excessive condensate build-up in conjunction with pressure and temperature
conditions. Any in-line steaming process requires sufficient condensate drains and
bleed valves to heat up the filter and remove any undesired condensate.
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As with reverse steaming a robust hydrophobic membrane, like PTFE, can

still be integral. The photo above shows that the inner core collapsed, but the
membrane pleat pack stayed bonded to the end cap area. Before the filter was cut
it passed the integrity test. In such instances a visual inspection should be
performed on a routine basis, nevertheless the appropriateness of the steaming
procedure is usually verified during the performance qualification stage. The in-line
steaming or autoclaving procedures used within the production facility will be
evaluated in respect to the thermal and mechanical compatibility of a filter. New
processes will be defined in accordance to the specified limits of filter
manufacturers to avoid any damage or failure of the filters within the processes.
PTFE is highly hydrophobic and it requires a differential pressure of over
3.6 bar (52 psi) to force water at ambient temperatures through a PTFE
membrane. This pressure is lowered at higher temperatures as the water surface
tension drops with elevated temperatures. Nevertheless, higher temperatures also
result in the weakening of the filters construction. In any case before condensate is
forced through a PTFE membrane an excessive pressure differential is needed.
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This excessive pressure can cause the damage, either to the construction or the
membrane pore structure.
Excessive Steaming
Excessive Steaming
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The two example above show very clearly that steaming conditions of filters
have to be tightly controlled. Any excessive temperature conditions can warp the
outer support area or shrink the polymer support fleeces extensively. The later
factor can be seen in the second photo as it shows a minimal pleat height due to
the shrink or melting of the support fleeces. As such temperature conditions have
a major influence on the support cages and fleece layers, also the housings of
disposable filter can be deformed or damaged as the photo below shows.
Inappropriate Autoclaving
In the instance of damages during the autoclaving cycle one has to review
the placement of the filter within the autoclave. Also tightly wrap autoclaving paper
over the inlet and outlet connectors of the filter can cause damage. The filter paper
can become saturated with condensate and creates an air tight barrier. The
autoclaving cycles commonly run with a pre- and post-vacuum cycle. When the
vacuum is pulled and the filter up- and down-stream side is not vented the capsule
housing can warp or deform.
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Actions:
• Check the steaming process by observing the user performing the steaming
process. Always note the sequence of the steaming cycle, especially valve
functions, pressures and temperatures
• Check the valve, condensate drain and pipework design
• Check the position of the filter within the autoclave and the wrapping of the
autoclaving paper
• Check the temperature protocols and diagrams commonly established
during the steaming process for excessive temperatures
• Review the SOP´s and amend such if appropriate
• When in doubt activate field technical services
• Train the personnel performing the steaming cycle
Chemical Compatibility
As the steaming conditions and compatibility requires appropriate

evaluation, the chemical compatibility of the filters membrane and support layers
has to be tested. The examples shown are excessive non-compatibilities and
commonly are found within testing laboratories, which perform compatibility tests
for their clients with the fluid to be filter at process conditions. Such tests are
essential to avoid a membrane break-down as shown, which render the filter non-
functional, moreover will contaminate the downstream process.
Regulatory authorities do not accept anylonger pure compatibility chart
work, but require seeing a proper justification why this particular filter polymer is
used for the application or that the polymer is compatible with the fluid parameters
and process conditions. Charts do not mimic the conditions the filter is actually
used in and therefore render unreliable. The compatibility has to be tested under
the process conditions, as temperature, pH, pressure conditions etc. can enhance
the aggressiveness of the fluid to be filtered. The compatibility test has to be able
to detect even subtle incompatibilities. Such determination is commonly performed
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by utilizing a multitude of tests, e.g. diffusive flow, Bubble Point, burst pressure,
extractable testing or SEM evaluations.
Chemical incompatibilities could not only result into filter damage, but also
create leachables, which could be released into the filtrate. Subtle incompatibilities
may not be detected in a routine process, as the filters does not fail, but the
leachable/extractable level may be excessive. Therefore such possibility requires
to be investigated.
Chemical Incompatibility
The photo above, shows a very typical degradation of the membrane is a

typical oxidative break-down of a polymer membrane. Such break-down can be
seen in long term, hot water applications. The antioxidant within the membrane
polymer is washed out over the filtration period and the membrane starts
degradating. For example such picture can be found utilizing Polyamide
membrane in hot water applications after approximately six months. It therefore is
advisable to exchange the filter on a frequent basis or the use of a different
polymer.
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In the both instances shown (above and below), the incompatibility might
have been triggered by the re-use of the filter without sufficient flush in between. It
can happen that a filter is cleaned by chemicals, flushed or rinsed and afterwards
autoclaved or steam sterilized. Under these circumstances, the chemicals could
be concentrated within the pleat tips. The diluted chemical may not have any effect
on the polymer, but the concentrated chemical could attack the polymer.
Therefore, flush and rinse cycles need to be qualified and observed.
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In addition to the degradation of the membrane polymer, the support fleece

compatibility has to be tested. The polymer of the membrane can be very robust
and chemical inert, for example PTFE membranes, nevertheless the fleeces,
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commonly from Polypropylene could be chemically attacked. In the case shown

above, the fleeces oxidized due to long term use within a hot compressed air
filtration application. Air filters can be used over a multiple months period,
experiencing either hot air or multiple steaming cycles. Especially hot air
applications show a degradation of the support fleeces after around half a year.
Hot compressed air has been used to avoid condensate build-up and blockage of
glass fiber towers, used before membrane filters were available. Since most of the
biopharmaceutical facilities switch from such towers to membrane filters, it is
unnecessary to use hot air, but in instances such environment can be found, even
with membrane filter use. Since hot air requires high energy consumption and
promotes membrane filter support fleece degradation, it would be best to stop the
heating of the air feed. This would prolong the membrane filter life, with the benefit
of energy consumption reduction.
Performance qualification or process validation testing requires to be
performed under process conditions. A main reason for such tests is to find subtle
incompatibilities. Incompatibilities as shown above are very uncommon and are
gross failures. Such failures have to be and will be found in initial filter tests. More
important for compatibility tests is to find the subtle incompatibilities which can be
detected by integrity test methodologies or extractable analysis.
Actions:
• Check the picture of the damage and incompatibility as it will point to a
specific compatibility problem
• Determine the process conditions and the fluid parameters and compare
these to the common compatibility of the utilized filter polymer
• Determine the length of the use of the filter
• Review any historical data, whether such instance occurred before
• When in doubt contact technical services or vendor specialists
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Handling
Aside from validation efforts, training has to be the most important item on
the list of filter users. The validation process and protocols can be as thorough as
possible, but invalid, when insufficiently trained personnel utilize equipment
inappropriately. The outcome can be dramatic damage to the equipment used and
flawed production processes. The following slides show some examples of filter
handling problems. In instances like shown it always is advisable to utilize the filter
manufacturer to review handling, installation and steaming processes to establish
a root cause, respectively a corrective action protocol. Furthermore, the
manufacturers know their products best and have specific training protocols how
to handle such. Therefore the manufacturers are probably the best training source.
Inappropriate Handling
The photos above and below show damaged filter cartridge adapters. Such
damages commonly occur when the o-rings are not wetted before installation and
excessive force is used to install the filter into the filter housing recess. Filter
manufacturers advise in their user leaflets to wet the o-rings with an appropriate
wetting fluid, for example water for injection. Additionally, the filter cartridge
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adapter should not be pushed or turned with excessive force within the recess of
the housing. Once the bayonet locks are properly installed to the endpoint within
the adapter recess it should not be turned further. Filter cartridges of length, for
instance 30” heights should be turned at the bottom, close to the adapter of the
filter cartridge and not at the top of the filter as the leverage would cause a higher
torsion on the adapter.
Scratch marks as shown above are an indication that the cartridge adapter
has not been fully pushed into the housing recess and the cartridge bayonet was
damaged by the housing bayonet recess. The filter cartridge was turned by force
to make the adapter fit, which caused also a break of the adapter body. Commonly
such break cannot be established by normal force, but the filter cartridge in
question has been of higher length and the torsion was enhanced by handling the
filter at the top.
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Both photos above show imprints of the housing adapter recess on the
cartridge adapter base, which show that the filter has been inappropriately aligned
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with the housing recess. When pushed into the recess by force parts of the
adapter can break.
Inappropriate handling does not restrict itself to filter cartridge installations

into filter housings, but also to disposable filter handling. For example, the two
photos above and below show disposable filter capsules, which were accidentally
dropped and cracked. Such accidents can happen, especially when disposable
and gloved hands are wet. For this reason filter manufacturers developed designs
of capsule filters which are better to handle even under described conditions. In
any case, if a filter capsule has been dropped it is recommended to discard and
replace it, as damages do not necessarily need to be as obvious as the shown
examples.
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Another handling problem experienced is the installation of filter into a multi-

round housings and alignment by a retainer plate. If the retainer plate is too much
tightened, the filters do not have any room for expansion. This room has to be
given especially when steam sterilized or flushed with hot water. Commonly such
higher temperature conditions result into an expansion of the filter cartridge length.
If the retainer plate is too tight, the filter will warp or even crack like shown below.
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In other instances a housing bell is used, which is not properly configured

for the filter cartridge design. For example, some housings can only retain filter
cartridges with a flat top adapter instead of the spear adapter shown above. The
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filter cartridge receive excessive pressure and gets pushed. One can see such
vertical force by pleat warps or waves. These are signs that the filter cartridge
experienced excessive longitudal pressures. Pressure marks on the spear adapter
or breaks in the bottom adapter are also signs for such forces.
Excessive Hot Water Contact
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Other handling issues can also be prolonged hot water contact or repeat
flushes with hot water. Hot water is aggressive and will cause oxidation and rinse
out of the stabilizing agent. The polymer starts discoloring, commonly yellow. The
color of the outside support cage can be a visual sign what might happen within
the filter matrix or support material. Therefore routine visual inspection should be
defined with the SOP, when the filter is used over a long-term period. In other
instances, especially with air filters, the filter is used for years. The user should be
aware that during this timeframe the oxidation process will take its toll on the
polymeric structure of the filter. Again visual inspection and routine integrity tests
should be performed to assure appropriate performance. Neglect due to resource
deficiencies will not be accepted by the regulatory authorities. Furthermore, air
filters might be able to last for a long period of time and a cost saving could be
accomplished by changing the filter infrequently, but such savings are commonly
eliminated by just one batch failure. The commercial aspect should play a minority
role in comparison to the safety needs of the biopharmaceutical industry.
Prolonged use of a filter can only be justified when the filter is integrity tested after
or before every batch.
Actions:
• Check the filter installation process by observing how the filter user handles
the filter. Best in this instance is the fact that they do not know why the
installation process will be observed so they do not amend their routine
behavior.
• Check the historical data and the timeframe the filter is used
• Check the Standard Operation Procedure (SOP) for discrepancies to the
user manual and point these out
• Check the hardware used, whether is fits to the filter type
• Always be a supporter and not a teacher, as you have to win over the user
and not repel him
• Train the user
• If in doubt inform and activate field technical support
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Protection
As elaborated previously, membrane filter cartridges are commonly
protected by depth- or pre-filters. Filterability trials are commonly performed to
establish the optimal pre- and final filter combination to achieve the highest
throughput per effective filtration area. In instances, such filter combination
evaluation is not performed, which can have the costly effect of premature
blockage of a final filter and product losses due to the need to exchange the filter
during the production run. Premature blockage has to be avoided and therefore
proper small scale investigation of the filter combination to be used is advisable.
The photos below show just some examples of blocked filters. The fouling of filters
is not restricted to membrane filters only, but also could affect finer pre-filtration
devices. In any circumstance, the entire filter “train” has to be tested before a filter
system is defined.
Inappropriate Protection
Even when filterability trials have been performed and the filter system
worked optimal during these trials and thereafter, seasonality of the raw material,
for example serum, changes in the raw material supplier and any maintenance
38
work can disrupt the fine balance between protection and premature blockage.
Serum qualities are very much depended on the diet of the human or animal and
therefore may vary from season to season. A raw material supplier previously
used had an appropriate pretreatment of the raw material, which may not be so
with another supplier. Any groundwork could potentially cause a lower raw water
supply quality and may block filters prematurely. It is essential to check all these
variations and possibilities of blockage. Therefore an investigation in regard to
premature blockage is commonly more time consuming.
39
The two photos above show iron oxide contamination. Such contaminants
can also be evaluated by the use of 47 mm cellulose nitrate filter discs. 100 ml of
the raw material, commonly water, is filtered through the disc and the coloration of
the disc checked with a reference chart. Iron oxide is a colloidal substance formed
from the oxidation of iron in its dissolved form. A raw material of water can be
perfectly fine, but as soon as air is introduced into the water supply, iron oxide is
created. These colloidal contaminants tend to block 0.45 micron membranes
rapidly. To eliminate iron oxide, adsorptive glass fiber depth filters are used or
active carbon. In any case the contamination requires to be removed to avoid
elevated filter exchanges.
There are a manifold of contaminants, which can cause problems. Other
examples are shown. The one below is a gel particle, which blocked the
membrane. Nevertheless such gel particle can also penetrate depth filter and
taken as a contaminant of the depth filter. In these instances the complaint filed
will be insufficient retention of the depth filter. Again it is essential that all
parameters are evaluated to find the true reason of the problem.
40
The contaminant below is unidentified, but it could also be iron oxide, as it

does not always have to have the typical orange color.
41
Insufficient Protection
All examples given within the trouble shooting section are extremes, but
nonetheless real life cases. It does not mean that failures as described need to be
seen. Commonly, filter failures are by far more subtle. These subtle failures
42
require even more attention as the root cause for the problem does not need to be
very obvious. It is always advisable to utilize a database system, which may record
first time failures or a failure rate, which commonly results in answers. As quoted
beforehand validation of a process is a regulatory and process need, nevertheless
training should never be forgotten. Filters, especially membrane filters are high
tech equipment and therefore require appropriate handling. These filters contain
micron sized pore structures and therefore cannot withstand all conditions
subjected to. When in doubt, one should always contact the filter manufacturer to
receive their support.
Insufficient Protection
Actions:
• Check the entire filter system and the history of every individual filter
blockage. When a final filter blocks faster than a pre-filter, insufficient
protection is the root cause. Additionally, the contaminant may be a result of
raw material changes or variations
43
• Let laboratory services check the individual filter fleeces or membranes of

which is blocked, as it gives you an answer how to optimize the filter
combination
• Check filterability trial data, if available
• Check whether there are product batch to batch variations, and if possible
the quality of the batch the filterability trials was performed with
• Check the SOP´s for wetting procedures, pressure conditions and batch
size specifications and whether these were kept during the filtration process
• Try to evaluate, the contamination source. Check whether the raw material
supply changed
• Water filter blockage, find out whether there has been any ground work in
the area and check seasonality contaminations
• Check whether there were pipework changes or any maintenance work
done recently
• When rust is the contaminant, check the steam supply, water and stainless
steel quality of the pipework
• Some contaminants can be specified by special analytical evaluations in
the laboratory. Try to find out the root cause of the contaminant to eliminate
the root cause. Use technical services, which would utilize such analytical
evaluations
• If needed optimize the filter system and combination by utilizing filterability
trials
44
REGULATIONS
Out-of-Specification (OOS) Situation

Any pharmaceutical process and analytical tests involved in such process
requires to have documented specifications. The process has to work consistently
to deliver the same quality and efficacy. Therefore the entire process and process
controls require to be within a predetermined specification framework.
Any filtration parameter, flow, throughput, differential pressures, and
integrity test limits need to be well documented and again have to stay within a
specified performance band. If a filter failure occurs, whether pre-mature blockage
or integrity test failure, an investigation has to be started to find a) whether or not
the findings were true, if so b) to find the root cause and c) a corrective actions has
to be documented to avoid such failure again. This event is an out-of-specification
(OOS) event and is taken very serious by the regulators. Once such event occurs,
an entire pre-described investigative procedure should be triggered, with the final
outcome of an OOS report. This report has to be available for any auditor and
commonly gets filed within the regulatory annual report.
Regulatory agencies list and describe within guidance documents, when an
OOS is defined as such, what they expect from an OOS procedure and what
requires documentation. One should check such guidances as these are essential
to be CGMP compliant.
OOS procedures have to be logical in respect of the actions taken after an
OOS event. It does not need to be necessary to discard a product, but one has to
create evidence that the product is within the specifications, even when the
equipment used was out-of-specification. If the product is reprocessed the
reprocessing procedure has to be validated and again evidence has to be given
that the drug product is within the specifications set. In respect to filtration, the final
liquid filter will definitely be more critical than an air filter. An air filter which vents
the final product holding tank will be more critical than a WFI tank vent filter.
45
Therefore one has to investigate at what stage in the process an OOS occurred to
active investigations and corrective actions.
Even when the product filtered is discarded the agencies expect an OOS
report, as such event could happen again. The regulatory authorities want to see
the manufacturer in control of the process, therefore when an OOS occurs an
investigation has to be started and documented, under any circumstance. Having
a festering root cause means commonly that this type of problem will happen
again. At this stage the process is out of control.
Within the guidance documents the regulators describe also what
responsibilities different functions within the company have, what is expected of
them in an instance of an OOS and what steps should be taken. Just an example
of an FDA guidance (“Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production”, Draft, September 1998):
The following steps should be taken as part of the supervisor´s assessment:
1. Discuss the test method with the analyst; confirm analyst knowledge of and
performance of the correct procedure
2. Examine the raw data obtained in the analysis, including chromatograms
and spectra, and identify anomalous or suspect information
3. Confirm the performance of the instruments
4. Determine that appropriate reference standards, solvents, reagents, and
other solutions were used and that they meet quality control specifications
5. Evaluate the performance of the testing method to ensure that it is
performing according to the standard expected based on method validation
data
6. Document and preserve evidence of this assessment
The initial investigation commonly focuses on the test results, whether in
the process or laboratory of the client. Once it has been established that the
results are true and verified, the analysis moves into a full-scale investigation
mode using a predefined procedure. Such investigation has to be conducted by
the quality control and should involve all other departments of concern.
IV.A. General Investigational Principles
46
A failure investigation should consist of a timely, thorough, and well-documented

review. The written record should reflect that the following general steps have
been taken.
1. The reason for the investigation has been clearly identified
2. The manufacturing process sequences that may have caused the problems
should be summarized
3. Results of the documentation review should be provided with the
assignment of actual or probable cause
4. A review should be made to determine if the problem has occurred
previously
5. Corrective actions taken should be described
These procedures are also valid for any equipment manufacturer supplying the
industry therefore such investigation can be supported by suppliers.
If one wants to go into the details of OOS guidance documents and investigator
training manuals, the best web site to visit is www.fda.gov.
Validation
The probably most thorough guidance (recommending) document is the

PDA Technical Report No. 26. It thoroughly describes filter structures, usage,
purpose, and integrity testing. Most important, although, is the description of the
filter validation needs within the actual filtration process. The document defines the
needs for viability, product bacteria challenge, extractable, particulate and
adsorption testing. It is not meant as guidance, certainly not as a compliance
document, but one can be rest assured that regulatory authorities also utilize the
report.
Before the PDA Technical Report has been accomplished, FDA’s Guideline
on Sterile Drug Products Produced by Aseptic Processing has been the guidance
document of choice. This document, nevertheless, from 1987 is outdated and a
need for a new guideline is required. Recently, October 2004, the FDA published
the new aseptic guideline. This guideline addresses new requirements as listed in
Technical Report 26. Being a draft or concept paper, it probably will still take a
47
considerable amount of review and one can only speculate, when the final version
will become effective.
Similarly, the ISO 13408 is in a draft format. This guideline leans very much
towards Technical Report 26 and describes appropriate filter validation very much
in the fashion of the mentioned report. Again, it has to been when this document
becomes effective, but utilizing the PDA report will avoid any filter validation
surprises.
The USP (United States Pharmacopeia) 25 as well as any other
pharmacopeia are closely monitored, due to the descriptions of required limits for
particulate, endotoxins, and biocompatibility testing. Within the filter manufacturers
filter qualification tests, pharmacopeial limits are analyzed and need to be met by
the filter products distributed. These tests commonly cover toxicological,
endotoxins, extractable and particulate tests, which are well defined with the
pharmacopeias and any filter utilized within the biopharmaceutical industry
requires being compliant. These tests are the basic requirements to be fulfilled and
should not be misinterpreted as appropriate filter validation studies. Filter
validation requires to be performed with the actual drug product to be filtered
under process conditions. Most of the pharmacopeial tests are performed with
water or other pure solvents.
A guideline of considerable importance, especially in regard to revalidation
or second filter vendor implementation is the FDA Guidance for the Industry -
Changes to an Approved NDA or ANDA, section VII, Manufacturing Process. This
guideline describes distinctively the different needs of prior approvals, if changes
have been made to the actual processes. It defines what is a minor, moderate, or
major change in respect to filtration devices and changes to sterilizing grade filters
and what are the consequences.
Minor change (Annual Report):
filtration not mentioned
Moderate change (Supplement - Changes Being Effected):
CBE 30:
48
- Changes to filtration parameters for aseptic processing (including flow

rate, pressure, time, or volume, but not filter materials or pore size
rating) that require additional validation studies for the new parameters
- Filtration process changes that provide for a change from a single to a
dual product sterilizing filters in series, or for repeated filtration of bulk
CBE:
- For sterile drug products, elimination of in-process filtration performed
as part of the manufacture of a terminally sterilized product
Major change (Prior Approval Supplement):
- Changes in the sterilization method (e.g., gas, dry heat, irradiation).
These include changes from sterile filtered or aseptic processing to
terminal sterilization, or visa versa
- Addition, deletion, or substitution of sterilization steps or procedures for
handling sterile materials in an aseptic processing operation
- Changes in materials or pore size rating of filters used in aseptic
processing
- Changes in the virus or adventitious agent removal or inactivation
methods. This is applicable to any material where such procedures are
necessary, including drug substance, drug product, reagents, and
excipients
- Filtration to centrifugation or vice versa
A guideline, which causes confusion and insecurities in respect to
redundant 0.2 µm filtration, is the EMEA CPMP/QWP/486/95 Guideline. This
guidance document defines a maximum allowable bioburden level of 10 cfu/100 ml
in front of a 0.2 µm sterilizing grade filter. If this level is exceeded, a bioburden
reducing filter has to be used in front of the sterilizing grade filter. Although, the
guidance leaves room for interpretation in respect to what type of filter this could
be, it also states that the use of a second 0.2 µm in front of the final 0.2 µm filter
does not required additional validation. It is now debatable whether the bioburden
limit defined is reasonable, as well as the excessive reliance on pore size.
49
Bacteria Challenge Test

Before performing a product bacteria challenge test, it has to be assured
that the liquid product does not have any detrimental, bactericidal, or
bacteriostatic, effects on the challenge organisms, commonly Brevundimonas
diminuta. This is done utilizing viability tests. The organism is inoculated into the
product to be filtered at a certain bioburden level. At specified times, defined by
the actual filtration process, the log value of this bioburden is tested. If the
bioburden is reduced due to the fluid properties different bacteria challenge test
modes become applicable. There are three bacteria challenge methodologies
described within the PDA Technical Report No. 26; high organisms challenge,
placebo (modified product) challenge and product recirculation with a challenge
after recirculation. If the mortality rate is low the challenge test will be performed
with a higher bioburden, bearing in mind that the challenge level has to reach 107
per square centimeter at the end of the processing time. If the mortality rate is too
high, common definition is > 1 log during processing time, the toxic substance is
either removed or product properties, for example pH, temperature etc., are
modified. This challenge fluid is called a placebo. The third methodology would be
to circulate the fluid product through the filter at the specific process parameters as
long as the actual processing time would be. Afterwards the filter is flushed
extensively with water and the challenge test, as described in ASTM F838-38,
performed. Nevertheless such challenge test procedure would be more or less a
filter compatibility test.
50
Bacteria-Challenge Decision Tree
Sterilizing grade filters are determined by the bacteria challenge tests. This
test is performed under strict parameters and a defined solution (ASTM F 838-83,
not active anylonger). In any case, FDA nowadays requires also evidence that the
sterilizing grade filter will create a sterile filtration, no matter of the process
parameters, fluid properties or bioburden found. This means that bacteria
challenge tests have to be performed with the actual drug product, bioburden, if
different or known to be smaller than Brevundimonas diminuta and the process
parameters. The reason for the requirement of a product bacteria challenge test is
threefold. First of all the influence of the product and process parameters to the
microorganism has to be tested. There may be cases of either shrinkage of
organisms due to a higher osmolarity of the product or prolonged processing times
or starvation due to the extreme low organic properties of the fluid. Secondly the
filters compatibility with the product and the process parameters has to be tested.
The filter should not show any sign of degradation due to the product filtered.
Additionally rest assurance is required that the filter used will withstand the
process parameters, e.g. pressure pulses, if happening, should not influence the
51
filters performance. Thirdly, there are two separation mechanisms involved in

liquid filtration; sieve retention and retention by adsorptive sequestration. In sieve
retention the smallest particle or organism size is retained by the biggest pore
within the membrane structure. The contaminant will be retained, no matter of the
process parameters. This is the ideal. Retention by adsorptive sequestration
depends on the filtration conditions. Contaminants smaller than the actual pore
size penetrate such and may be captured by adsorptive attachment to the pore
wall. This effect is enhanced using highly adsorptive filter materials, for example
glass fiber as a pre-filter or Polyamide as a membrane. Nevertheless certain liquid
properties can minimize the adsorptive effect, which could mean penetration of
organisms. Whether the fluid has such properties, will lower the effect of
adsorptive sequestration, and may eventually cause penetration has to be
evaluated in specific product bacteria challenge tests.
Extractable Test
Besides the product bacteria challenge test, tests of extractable or

leachables substances have to be performed. Previous reliance on non-volatile
residue (NVR) testing as a method of investigating extractable levels have been
dismissed by the regulators in 1994. Since then extractable/leachables analysis
from filters and other components are routinely done by appropriate separation
and detection methodologies. Extractable measurements and the resulting data
are available from filter manufacturers for their individual filters.
52
Extractable Test Method
These tests are performed with a specific solvent, in this case ethanol and
water at “worst case” conditions. Such conditions do not represent true process
realities Therefore, depending on the process conditions and the solvents used,
explicit extractable tests have to be performed. Formerly, these test were done
only with the solvent used with the drug product, but not with the drug ingredients
themselves, because the drug product usually covers any extractable during
measurement. Nevertheless, recently findings have been presented, which
reported the possibility to evaluate extractable utilizing the actual drug product as
the extraction medium. Such tests are conducted by the validation services of the
filter manufacturers using sophisticated separation and detection methodologies,
as GC-MS, FTIR, RP-HPLC, UV-VIS, GPC-RI, HPCE and SFC. These
methodologies are required due to the fact that the individual components possibly
released from the filter have to be identified and quantified. Elaborated studies on
sterilizing grade filters, performed by filter manufacturers showed that there is
neither a release of high quantities of extractable (the range is ppb to max. ppm
per 10” element) nor have been toxic substances been found.
53
Extractable of Different Filter
Authorities and organizations, nowadays seem to change their focus to

other equipment used within the industry, for example disposable media bags,
plastic vials, tubing or stoppers. Pre-filters also become a target. There are
already extractable studies performed on a variety of pleated pre-filter types of
polypropylene and glass-fiber. Nevertheless, lenticular and string wound pre-
filters, widely used within the biopharmaceutical industry still have to undergo such
investigation.
Chemical Compatibility Test
The PDA Technical Report No. 26 describes very specifically “A simple

chemical compatibility chart will often not provide enough information for predicting
filter system compatibility, thereby requiring additional testing.” Chemical
compatibility has been underestimated in the past and reliance has been focused
on chemical chart of pure solutions. The aim of chemical compatibility testing has
54
to be to find subtle incompatibilities, which may happen due to a mix of chemical

components and entities or specific process conditions. Elevated temperatures or
prolonged filtration times may result in a filter incompatibility, which has to be
investigated.
Extractable at Different Temperature
May the filter membrane not be compromised in respect to its retentivity, it

can add to any extractable/leachables problem. Therefore appropriate
compatibility tests have to be performed with the actual drug product at the
process conditions. Commonly, integrity tests before and after the submersion of
the filter in the to be filtered product will show whether or not an incompatibility is
existent. Sole reliance, though, should not be on integrity testing. NVR testing
parallel to integrity testing maybe the procedure of choice, in case the filter is
integral but shows elevated extractable levels. In cases scanning electron
microscopy should be utilized to see any chemical attacks on the membrane
surface. Above mentioned bacteria challenge tests and extractable analysis also
contribute valuable information in respect to the filters compatibility.
55
Incompatibility Example
Other Tests
Particulates are critical in sterile filtration, specifically of injectables. The USP 25

(United States Pharmacopeia) and BP (British Pharmacopeia) quote specific limits
of particulate level contaminations for defined particle sizes. These limits have to
be kept and therefore the particulate release, if, of sterilizing grade filters has to
meet these requirements. Filters are routinely tested, evaluating the filtrate with
laser particle counters. Such tests are also performed with the actual product
under process conditions to proof that the product, but especially process
conditions do not result in an increased level of particulates within the filtrate.
Specific flushing protocol, if necessary, can be established for the filters used.
These tests are also useful for any pre-filter as it reduces the possibility of a
particulate contamination within the process.
56
Flush Protocol Example
Additionally with certain products loss of yield or product ingredients due to

adsorption shall be determined. Specific filter membranes can adsorb for example
preservatives, like benzalkoniumchloride or chlorhexadine. Such membranes need
to be saturated by the preservative to avoid preservative loss within the actual
product. This preservative loss, e.g. in contact lenses solutions, can be detrimental
due to long-term use of such solutions. Similarly problematic would be the
adsorption of required proteins within a biological solution. To optimize the yield of
such proteins within an application, adsorption trials have to be performed to find
the optimal membrane material and filter construction, but also flow conditions and
pre-rinsing procedures. Any yield losses by unspecific adsorption can cost millions
in respect to lost product and its market value. Adsorption studies are helpful to
optimize downstream process in regard to any yield loss and yield losses are also
corresponding to capacity problems, which can be seen within the biotech
industry. Yield losses have a detrimental influence and most commonly such
losses can also be targeted to unspecific adsorption on the wrong choice of
membrane polymers.
57
To summarize, most of the described validation effort have to be performed

and are part of the validation master file of a particular process and drug product.
Interestingly enough, validation receives emphasis and attention, but one also
never should forget training. Without appropriate personnel training any validation
effort is done in vain. Filter users should also test their staff to be able to handle
filtration, the sterilization, and integrity test of such, installation, and sanitization.
Training has to be the focus of all operations to really receive a reliable and
sustainable process.
58
ADDITIONAL READING
1. T.H. Meltzer, M.W. Jornitz, Editors, Filtration in the Biopharmaceutical Industry.
Marcel Dekker, New York, 1998
2. FDA, Center for Drugs and Biologics and Office of Regulatory Affairs, Guideline
on Sterile Drug Products Produced by Aseptic Processing. 1987
3. American Society for Testing and Materials (ASTM), Standard F838-83,
Standard Test Method for Determining Bacterial Retention of Membrane Filters
Utilized for Liquid Filtration. 1983, Revised 1988
4. Technical Report No. 26, Sterilizing Filtration of Liquids. PDA Journal of
Pharmaceutical Science and Technology, Vol. 52 No. S1, 1998
5. M.W. Mittleman, M.W. Jornitz, and T.H. Meltzer, Bacterial Cell Size and Surface
Charge Characteristics Relevant to Filter Validation Studies, PDA J. Pharm. Sci.
Tech. 52 (1): 37-42., 1998
6. M.W. Mittlemann, K. Kawamura, M.W. Jornitz and T.H. Meltzer, Filter
Validation: Bacterial Hydrophobicity, Adsorptive Sequestration and Cell Size
Alteration, PDA J. of Science and Technology: 422 – 429, 2001
7. FDA, Center of Drug Evaluation and Research (CDER), Guidance for the
Industry – Changes to an Approved NDA or ANDA, November 1999
8. EMEA, CPMP/QWP/486/95, Note for Guidance on Manufacture of the Finished
Dosage Form, London, April 1996
9. O.W. Reif, P. Sölkner, J. Rupp, Analysis and Evaluation of Filter Cartridge
Extractables for Validation in Pharmaceutical Downstream Processing. PDA
Journal of Pharmaceutical Science and Technology, 50, 399-410, 1996
10. M.W. Jornitz and T.H. Meltzer, Sterile Filtration – A Practical Approach, Marcel
Decker, New York, 2000
11. ISO/DIS 13408-2 Draft, Aseptic processing of health care products – Part 2.:
Filtration, 2002
12. M.W. Jornitz, J.P. Agalloco, J.E. Akers, R.E. Madsen and T.H. Meltzer (2001),
Filter Integrity Testing in Liquid Applications, Revisited ; Parts I & 2, Pharm. Tech.
Part I, 25 (10):34-50; Part II, 25 (11):24-35
59
13. T.H. Meltzer, R.E. Madsen and M.W. Jornitz (1999), Considerations for
Diffusive Airflow Integrity Testing, PDA J. Pharm. Sci. Tech. 53(2):L 56-59.
14. R.E. Madsen, Jr. and T. H. Meltzer; An Interpretation of the Pharmaceutical
Industry Survey of Current Sterile Filtration Practices, PDA Journal of
Pharmaceutical Science and Technology, 1998, Vol. 52, No. 6: 337-339
15. M.W. Jornitz, P.J. Waibel, T.H. Meltzer, The Filter Integrity Correlations,
Ultrapure Water, Oct. 1994, pp. 59 - 63
16. T.H. Meltzer, M.W. Jornitz, P.J. Waibel, The hydrophobic air filter and the
water intrusion test, Pharm. Tech., 18(9):76-87, 1994
17. S.W. Tarry, J. Henricksen, M. Prashad, H. Troeger, Integrity testing of ePTFE
membrane filter vents, Ultrapure Water 10(8):23-30, 1993
18. S. Tingley, S. Emory, S. Walker, S. Yamada, Water-flow integrity testing: a
viable and validatable alternative to alcohol testing, Pharm. Tech., 19(10):138-146,
1995
19. P.J. Waibel, M.W. Jornitz, T.H. Meltzer, Diffusive airflow integrity testing, PDA
J. Pharm. Sci. Tech., 50(5):311-316, 1996
20. M.W. Jornitz, D.J. Brose, T.H. Meltzer, Experimental Evaluations of Diffusive
Airflow Integrity Testing, PDA J. Parenter. Sci. Technol., 1998
21. FDA, Center for Drug Evaluation and Research (CDER), Draft - Guidance for
Industry – Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production, FDA CDER, Rockville, MD, September 1998
22. FDA, Draft - Guidance for Industry Sterile Drug Products Produced by Aseptic
Processing — Current Good Manufacturing Practice, FDA, Rockville, MD, 2003
60
Authors Information
JOACHIM WEISSE-BLANKE
Weender Landstrasse 94-108
37075 Goettingen. GERMANY
Tel. +49.551.3082494 Fax +49.551.308.2801
E-mail: [email protected]
Joachim Weisse-Blanke works for the Quality Assurance Department at the

Sartorius Headquarters in Göttingen, Germany. With over 20 years of experience
in static filtration and filter systems, he has the local QA responsibility for complaint
management, failure analysis, production and R & D projects. He additionally
supports the Bacterial Challenge Test-laboratory of Sartorius, Goettingen,
Germany.
Weisse-Blanke receives his final examination as a Technical Assistant at the
Institute for Agricultural Science at the Georg-August-University in Goettingen,
Germany.
MAIK W. JORNITZ
131 Heartland Boulevard
Edgewood, NY 11717, USA
Tel. +1 631 254 4249 Fax +1 631 253 5409
E-mail: [email protected]
Maik W. Jornitz is Vice President Product Management at the Sartorius Stedim

Headquarters North America. With close to 25 years of experience in separation
technologies and regulations, Jornitz supports the biopharmaceutical industry on a
world-wide basis. As a member of the PDA Board of Directors, Jornitz has been
part of multiple PDA task forces, for example the Technical Report # 26 task force,
and program committee member. He is also member of the ISPE, ASTM, DIA and
BFS group. He is the author and co-author of numerous professional papers and
book chapters on membrane filtration, integrity testing, and validation studies. He
is co-editor and -author of the books Filtration in the Biopharmaceutical Industry,
Sterile Filtration – A Practical Approach, Filtration Handbook – Integrity Testing
and Filtration Handbook – Liquid Filtration. He has contributed the chapter Filters
and Filtration to the Encyclopedia of Pharmaceutical Technology, Membrane
Filtration in the book Development and Manufacture of Protein Pharmaceuticals
and Sterile Filtration in the book Microbial Contamination Control in Parenteral
Manufacturing. He holds several patents related to biopharmaceutical process
equipment. Mr. Jornitz received his Diploma in Process Engineering at the College
for Advanced Technology in Hamburg, Germany and accomplished the PED
program at IMD Business School in Lausanne, Switzerland. He is also founder of
BioProcess Resources LLC (www.go-bpr.com).

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Sterile Filter Handling & Troubleshooting

Maik W. Jornitz and Joachim Weisse-Blanke

Sterile Filter Handling & Troubleshooting

Maik W. Jornitz and Joachim Weisse-Blanke

TROUBLE SHOOTING – FILTER FAILURES

• Out-of-Specification (OOS) Situations

We wish to acknowledge our colleagues and friends within all filter

Handling Filtration Systems

 Note part number, lot number, and description

Filter Cartridge Installation

Water (sterile) or alcohol, if not inappropriate, should be used as a lubricant

Handling Filtration Systems

 Wet any filter cartridge o-rings with water

Operation of Filtration Systems

Other Operational Parameters to

 Temperature  Pressure Available

 Flow Rate – Pulsations

 Retention Rating  Chemical

As stated repeatedly, each of these factors, and particularly the balance

TROUBLE SHOOTING – FILTER FAILURES

Excessive Reverse Steam

Within the validation guides of the filter manufacturers, maximum allowable

far, i.e. to a certain temperature under a certain differential pressure condition. It

Excessive Reverse Steam

Excessive Reverse Steam

A very common picture of excessive reverse steam in conjunction with

Excessive Reverse Steam

Excessive Reverse Steam

Excessive Forward Steam

Excessive Forward Steam

Excessive forward or upstream in-line steaming happens mainly when

Excessive Forward Steam

As with reverse steaming a robust hydrophobic membrane, like PTFE, can

As the steaming conditions and compatibility requires appropriate

The photo above, shows a very typical degradation of the membrane is a

In addition to the degradation of the membrane polymer, the support fleece

commonly from Polypropylene could be chemically attacked. In the case shown

Inappropriate handling does not restrict itself to filter cartridge installations

Another handling problem experienced is the installation of filter into a multi-

In other instances a housing bell is used, which is not properly configured

Excessive Hot Water Contact

The contaminant below is unidentified, but it could also be iron oxide, as it

• Let laboratory services check the individual filter fleeces or membranes of

Out-of-Specification (OOS) Situation

A failure investigation should consist of a timely, thorough, and well-documented

The probably most thorough guidance (recommending) document is the

- Changes to filtration parameters for aseptic processing (including flow

Bacteria Challenge Test

Bacteria-Challenge Decision Tree

filters performance. Thirdly, there are two separation mechanisms involved in

Besides the product bacteria challenge test, tests of extractable or

Extractable Test Method

Extractable of Different Filter

Authorities and organizations, nowadays seem to change their focus to

Chemical Compatibility Test

The PDA Technical Report No. 26 describes very specifically “A simple

to be to find subtle incompatibilities, which may happen due to a mix of chemical