Expanded Polytetrafluoroethylene Membranes and Their

Expanded Polytetrafluoroethylene Membranes
and Their Applications
By
Michael Wikol, Bryce Hartmann, Joseph Brendle, Michele Crane,
Uwe Beuscher, Jeff Brake, and Tracy Shickel
W. L. Gore & Associates, Inc.
Newark, Delaware, USA
Extracted from
Filtration and Purification in the Biopharmaceutical Industry, Second Edition
Edited by
Maik W. Jornitz and Theodore H. Meltzer
Brought to you compliments of
W. L. Gore & Associates, Inc.
Wikol_jornitzExtraction.indd 1
2/25/08 10:16:53 AM
23
Expanded Polytetrafluoroethylene
Membranes and Their Applications
Michael Wikol, Bryce Hartmann, Joseph Brendle, Michele Crane,
Uwe Beuscher, Jeff Brake, and Tracy Shickel
W. L. Gore & Associates, Inc., Elkton, Maryland, U.S.A.
INTRODUCTION
The unique properties of expanded polytetrafluoroethylene (ePTFE) membrane make it a
good choice for a number of pharmaceutical applications. Currently, ePTFE constructions
are used for sterile filtration of fermentation feed air, process gases, and tank venting.
They are also used in powder collectors and ultralow penetration air (ULPA) filters. The
unique properties of ePTFE are also being exploited in a number of new innovative
products and technologies. Lyophilization trays, product isolators, and drug delivery
devices are just a few of the new areas of interest to the pharmaceutical industry. This
chapter will:
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discuss some pertinent properties of PTFE
explain how PTFE is made into a microporous membrane
describe the unique characteristics of ePTFE membranes
discuss the benefits of these characteristics in pharmaceutical applications
introduce a selection of emerging technologies based on ePTFE membranes
PROPERTIES OF PTFE
Polytetrafluoroethylene or PTFE (CF2—CF2)n, commonly referred to by the DuPont
trademark Teflon or the ICI trademark Fluon, is well known for its chemical
resistance, thermal stability, and hydrophobicity. PTFE has these desirable characteristics
because of its unique chemical structure, as seen in Figure 1.
PTFE is a simple polymer because it is composed of only two elements: carbon and
fluorine. PTFE has a long, straight carbon backbone to which the fluorine atoms are
bonded. Both the C–C and C–F bonds are extremely strong. In addition, the electron
cloud of the fluorine atoms forms a uniform helical sheath that protects the carbon
backbone. The even distribution of fluorine atoms makes it nonpolar and nonreactive.
The combination of strong bonds, a protective sheath, and nonpolarity make PTFE
extremely inert as well as thermally stable. This explains why PTFE is compatible with
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FIGURE 1 Chemical structure
of polytetrafluoroethylene (PTFE).
TABLE 1
Physical Properties of Polytetrafluoroethylene (PTFE)
Property
Structure
Surface free energy
Melt temperature
Continuous service temperature
— (CF2CF2)—n
18.5 dyn/cm
327˚C
288˚C
nearly all the processing and cleaning fluids that are typically used in the pharmaceutical
industry, including acids, bases, and solvents.
Because of the nonreactivity and nonpolarity of PTFE, it is difficult for anything to
bond to it. This is why PTFE (Teflon) is well-known as a nonsticking and easy-to-clean
product.
Since fluorine is the most electronegative element in the periodic table, it does not
want to share electrons with neighboring fluorine atoms. This results in a low surface free
energy for PTFE. The lower the surface free energy of a material, the less likely it is to
be wetted with higher surface energy fluids such as water. Table 1 summarizes some of
the physical properties of PTFE.
In contrast, other polymeric membrane materials have some or all of the fluorine
atoms replaced with hydrogen or other elements. This results in weaker bonds and a more
polar, reactive molecule. The substitution also increases the surface free energy. Therefore,
these polymers are less hydrophobic, less thermally stable, and more reactive than PTFE.
Figure 2 is a chemical compatibility and temperature map, which is a visual way to
compare the chemical and thermal stability of various polymers.
FIGURE 2 Chemical compatibility &
temperature map.
Expanded Polytetrafluoroethylene Membranes and Their Applications
621
FIGURE 3 ePTFE process flow.
MICROPOROUS PTFE
Since PTFE is chemically inert, thermally stable, and extremely hydrophobic, it is an
ideal polymer for some pharmaceutical applications. As a microporous membrane, PTFE
is a valuable air-filter medium with high flow rates and filtration efficiency.
A schematic of how ePTFE membrane is made is shown in Figure 3. In general, the
process begins with pure PTFE fine powder resin. A lubricating agent is added so that the
powder forms a paste and can then be extruded into sheet form. This sheet is heated and
expanded under the proper conditions to make a microporous sheet. The structure is
stabilized in an amorphous locking step. Though most polymers fracture when subjected to
a high rate of strain, expanding PTFE at extremely high rates actually increases the tensile
strength of the polymer. Since the lubricating agent is extremely volatile, it is completely
removed from the porous structure during processing. The resulting product is 100% PTFE.
Another method used to manufacture porous PTFE is a replication process in which
PTFE particles are mixed with burnable material such as paper fibers, then heated to
remove the fibers. PTFE can also be made porous by removing a fugitive material such as
a carbonate. Because these methods yield products that have lower flow rates and more
contamination, they are of little commercial value to the pharmaceutical industry. The
rest of this chapter focuses on microporous ePTFE membranes.
Figure 4 shows a scanning electron micrograph of an ePTFE structure that is
commonly used in pharmaceutical microfiltration.
FIGURE 4 Scanning electron micrograph (SEM) of ePTFE.
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TABLE 2 Physical Properties of Expanded Polytetrafluoroethylene
(ePTFE)
Property
Range
Porosity
Airflow
Methanol flow rate
Water entry pressure
Isopropanol bubble point
Pore size
1 – 99%
2.0 – 15,000 mL/cm2a
1.0 – 10,000 mL/cm2b
0 – 350 psi
0.1 to > 50 psi
0.02 – 40 mmc
a
Airflow rate measured at 4.88 in. H2O at 21˚C.
Methanol flow rate measured at 27.5 in. Hg at 21˚C.
c
Pore size as correlated to IPA bubble point.
b
The microstructure is characterized by nodes that are interconnected by fibrils.
ePTFE is a single, continuous structure in which all the fibrils and nodes connect. There
are no loose ends or particles to be shed or to contaminate a fluid stream. Even though
there is a high density of thin fibrils, this structure is high flowing because it also has a
high void volume (~85% porous). Table 2 shows that ePTFE has a broad range of
physical properties, including pore sizes, flow rates, and water breakthrough pressures.
Membranes can be engineered and optimized to meet the needs of particular
applications (Figure 5).
Because ePTFE membranes are extremely microporous and hydrophobic, they
retain water droplets, while allowing water vapor to readily pass through as illustrated in
Figure 6.
Moisture vapor flows through an ePTFE membrane by either bulk gas flow or
diffusion. If the pressure differs across the membrane, gas flows from the high pressure
side to the low pressure side. Moisture vapor also diffuses through the microporous
structure if humidity or temperature varies across the membrane.
Expanded PTFE membranes are sometimes laminated to materials for additional
structural reinforcement. They can be laminated to felts, wovens, and nonwovens made
FIGURE 5
Examples of ePTFE structures engineered for specific applications.
Expanded Polytetrafluoroethylene Membranes and Their Applications
623
FIGURE 6 Functional characteristics of ePTFE.
from a variety of materials including polyolefins, polyesters, and fluoropolymers. These
support layers sometimes function as a drainage layer in filters. Support materials
are selected according to the chemical, thermal, and mechanical requirements of the
application.
PORE SIZE MEASUREMENT
As discussed elsewhere in this volume, pore size is a relative term, often depending on the
application and the test method used to measure it. ePTFE is a highly porous material.
Scanning electron micrographs (Figure 4 and Figure 5) make it obvious that ePTFE
resembles a tangled forest more than a neatly perforated plate. Though the fibers are welldefined units, they deviate from an ideal circular pore, like almost all porous materials.
A common method for quantitatively determining the pore size of membranes including
ePTFE is the bubble point method (Figure 7).
In this test, a membrane is wet-out with an appropriate test fluid, such as isopropyl
alcohol. Then gas pressure is applied to one side of the membrane. The pressure at which
FIGURE 7
Bubble point method for measuring relative pore size.
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FIGURE 8 Bubble point equation
assuming cylindrical pore size.
the first steady stream of bubbles (or first measurable bulk gas flow) appears is said to be
the bubble point. The inverse pressure–pore size relationship for a cylindrical pore is
expressed by the equation in Figure 8.
Note that the contact angle for a wetting fluid like isopropyl alcohol is less than 90˚,
which keeps the cosy term positive. For any pore structure other than a cylinder,
modifying shape factors must be added to the equation. Since most membranes, including
ePTFE, do not have a cylindrical pore structure, a complex interaction of the wetting
fluid, membrane, and test gas is actually measured. Therefore, while the general inverse
relationship holds that higher bubble point pressures indicate tighter membrane structures
(smaller pore sizes), an actual pore diameter cannot be precisely determined from a
bubble point measurement.
Water breakthrough or penetration pressure testing of hydrophobic membranes like
ePTFE also gives a relative measure of the pore size of a membrane. Water breakthrough
pressure is the minimum pressure required to force water through the largest pore of a dry
hydrophobic membrane as shown in Figure 9.
The contact angle in this case is larger than 90˚, which leads to a negative pressure
difference (i.e., the liquid pressure has to be higher than the gas pressure). Every
hydrophobic membrane has a unique water breakthrough pressure that depends on the
membrane’s surface free energy, pore size, and shape. The inverse relationship between
pressure and pore size also holds with this test in that tighter structures require higher
pressures to force water through the membrane.
Recently, pore size distribution measurements such as liquid porometry and
mercury porosimetry have become more common as a means to characterize filtration
media. The liquid porometry test is similar to the bubble point test previously described,
but instead of measuring only the largest pore as in the bubble point test, the pressure is
FIGURE 9 Water breakthrough
method.
Expanded Polytetrafluoroethylene Membranes and Their Applications
625
continually increased to open smaller pores. The flow rate through the fraction of open
pores at a given pressure is compared to the flow rate through the dry filtration media to
assess the fraction of open pores at that pressure. This determines the cumulative
volumetric pore size distribution. Mercury porosimetry works similarly to the water
breakthrough test. Mercury, a nonwetting liquid, is forced into the porous structure. The
pressure is continually increased forcing the mercury into smaller and smaller pores
according to the equation in Figure 8. The measured relationship of applied pressure to
the volume occupied by mercury leads to the pore size distribution.
Use and Misuse of Pore Size Measurements
Filtration efficiency testing in both air and liquids provides information about the pore
structure of a membrane. In aerosol filtration, it is difficult to determine the actual pore
size of a membrane because adsorptive effects allow the filter to capture particles that
would otherwise pass easily through the structure. Thus, the efficiency test gives a good
estimate of the pore size only if the dominant filtration mechanism is that of sieving or
size exclusion, which is not necessarily the case for air filtration applications. These tests
can be used, however, to compare the relative effectiveness of different filters in a given
application.
The true pore size distribution of an air filter does not by itself determine the
capture efficiency versus particle size curve, because most particles that can fit through
the pores are still captured by other mechanisms to be discussed later. Moreover, practical
pore-size measurement methods can only infer pore sizes indirectly and imperfectly. For
example, many methods begin by assuming that the pores are cylindrical, but microscopy
shows that this is far from true. Thus, particles that are much smaller than the measured
pore size of a filter are mostly surface-filtered. On the other hand, a filter’s pore-size
rating may be claimed based on the size of the smallest particle that is captured, which,
however, may vary tremendously depending on how the retention is measured (e.g., air
velocity). Air filtration efficiency for an ePTFE membrane having a nominal pore size of
5.0 mm may be better than 99.99% at 0.1 mm. For these reasons, pore size can be a
confusing specification for an air filter, and it is often more useful to specify the retention
efficiency for the particle size and conditions of interest.
AIR FILTRATION THEORY
Modes of Air Filtration
Air filtration occurs in two ways—surface filtration and depth filtration. Simply put,
surface filtration occurs when particles are too large to fit into the pores of a filter and are
trapped on the surface of the filter medium. Depth filtration occurs when particles are
small enough to fit into the pores but are trapped during their journey through the depth of
the filter medium. Therefore, the interaction between the particle size distribution and the
pore size distribution determines whether surface or depth filtration occurs.
The Surface Filtration Mode
Air filters sometimes work by excluding large particles from the smaller pores in the
filter. This mechanism of particle capture is called sieving. Particles that are larger than
the pore diameter do not enter into the depth of the filter. In air filtration, surface filtration
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mode is actually less common than depth filtration. It is only in this relatively uncommon
mode of filtration that pore diameter is important. ePTFE membranes are unusual in that
they often provide good surface filtration due to their small and consistent pores.
In one sense, no element of chance is involved in surface filtration. If a particle is
bigger than the pores, it is collected. But in another sense, chance is still involved,
because the pore sizes all have some statistical distribution. If there is a tiny population of
large pores, then some of the large particles are carried through those pores. If a particle
enters the depth of a filter because it is not surface-filtered, depth filtration remains
available to help capture it.
The Depth Filtration Mode
In depth filtration, particles small enough to enter the filter structure are collected by
chance interactions with the fibers of the filter. If the structure of the filter is the same at
all depths, as it is in most filters, there is an exponential decay in the particle population
as the air passes through the depth of the filter. This filtration mode is consistent with a
constant probability of collection within the next increment of depth for a particle that has
survived the trip so far.
Depth filtration is sometimes incorrectly considered the opposite of absolute
filtration. It is easy to demonstrate that the penetration through some depth filters may be
10 20, 10 50, or less. A penetration of 10 20 cannot be measured, and a penetration of
10 50 has no physical significance at all (being about one atom’s worth of the earth’s
mass). Thus such a depth filter at this efficiency level can be considered absolute.
Depth filtration is a two-step process: transporting the particles to the internal fibers
of the filter and attaching them to the surface of the fiber. Briefly, all depth filtration
mechanisms rely on van der Waals forces, electrostatic adhesion, or both to hold particles
to filter fibers once the particles contact the fibers. However, mechanisms differ in why
particle–fiber contact occurs. Depth filtration works by several particle capture
mechanisms, unlike surface filtration, which works only by sieving. These mechanisms
are discussed in more detail elsewhere in this book and are thoroughly discussed in
Hinds (1982). In the impaction mechanism, large fast-moving particles hit fibers because
their momentum overpowers the airflow deviating around the fibers. In the interception
mechanism, relatively incompressible particles barely touch the fibers, while nearby
airstreams compress together around the particles to slip by the fibers. In the diffusion
mechanism, small particles move vigorously during collisions with individual air
molecules, increasing random contact with fibers. Impaction and interception work better
on larger particles, whereas diffusion favors small particles. Therefore, extremely large or
small particles are collected easily, whereas an intermediate most-penetrating size of
particle is difficult to collect. Filters made of finer fibers have a smaller most-penetrating
particle size than filters made of coarser fibers.
The fibrils in ePTFE membranes designed for filtration are smaller in diameter than
those in any other commonly used filtration medium. Many fibrils in ePTFE are as small as
0.01 or 0.02 mm, with a median diameter of 0.05 or 0.1 mm. In comparison, most fibers in
micro-fiberglass paper are about 1 mm, and fibers in filtration textiles are about 10 mm or
more (other membranes may have fibers for which the diameter is hard to define, though
numbers around 0.1–1 mm are possible). From the viewpoint of the air filtration theorist,
ePTFE is nearly ideal because of its random mesh of fine fibers distributed almost
perpendicularly to the airflow, with a high void fraction. The most penetrating particle
size is around 0.07 mm, depending on air velocity. This makes ePTFE filters very efficient
Expanded Polytetrafluoroethylene Membranes and Their Applications
627
on the basis of total penetrating particle mass, as a 0.07 mm particle contains nearly 80 times
less material than the 0.30 mm particle that is most penetrating for typical filters such as High
efficiency particle air (HEPA) filters. (Remember that the volume of a sphere varies as
diameter cubed). Moreover, very fine fibers offer little resistance to passing air, so good
capture efficiency for ePTFE comes at little expense in air pressure drop.
Pressure Increase and Cleaning in the Two Modes
The most significant implication of using surface versus depth filtration is the location of
captured particles. In surface filtration, the particles accumulate in a thin, dense layer
right at the surface of the filter, whereas in depth filtration they accumulate gradually
throughout some depth. The advantage of depositing the particles right on the surface is
that they can be removed more easily, and the filter can thus be cleaned and recover its
initial airflow. The advantage of depositing the particles throughout the depth is that the
particles are diffused through a discontinuous region, which still has a large fraction of
open space. Airflow is thus more easily maintained without removing the particles in
depth filtration.
It is useful to consider three different cases of loading of a filter. In the lightest
particulate loadings, such as those experienced by high-purity, point-of-use filters or
recirculation filters sealed inside computer disk drives, the effect of particle loading is
unimportant, because hardly any particulates are present. In this case, it is unimportant
whether surface or depth filtration dominates, and filters are chosen based on other
criteria.
When particle loading is very heavy and rapid, it is necessary to clean the filter
frequently, perhaps thousands of times during its lifetime. An example would be bag
house or cartridge collectors for food or pharmaceutical powder collection. In this case,
surface filtration is crucial, making it easy to remove particles thoroughly in each
cleaning cycle. ePTFE membrane filters are very useful in these applications because
they are easy to clean. An additional benefit of ePTFE is the minimal adhesion that exists
specifically between polytetrafluoroethylene and particulates (the same benefit that
favors Teflon frying pans).
In the third case, between these two extremes, the particulate loading is low enough
to make cleaning unnecessary, but high enough to limit usable lifetime. In this case,
surface filtration can be disadvantageous, especially if the particulate is oily and tends to
wick into a continuous sheet. In this case, membrane filters (including ePTFE
membranes) acting as surface filters require a prefiltering layer to perform depth
filtration, especially for larger particles that constitute a great majority of the particulate
mass. Such a prefilter layer with an efficiency of only 95% for all combined mass extends
the life of the membrane 20-fold, making this strategy a successful solution. Interestingly,
the classical dioctylphthalate (DOP) smoke efficiency test falls into this class for ePTFE
membranes if excessively high loadings are used, although the loadings used in the TSI
Model AFT8160 filter tester do not cause a problem.
Improved Efficiency During Cleaning and Lower Pressure Drop
Filters used for extremely high particulate loadings must be cleaned repeatedly. Yet
some filters rely on particles bridging and filter cakes forming over openings in the
nonmembrane filter media to help capture other particles. During cleaning, these
particle bridges are disrupted, and particle retention efficiency is reduced. Relative to
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Wikol et al.
most filters of this type, ePTFE filters have excellent retention efficiencies, even during
the cleaning cycle. The ePTFE membrane on the surface serves as a permanent
size-exclusion layer. However, this permanent layer does not inhibit a pressure drop
like a filter cake.
Summary of Air Filtration Theory
Compared to most other air filtration media, ePTFE membranes are unusual in several
ways:
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Their high density of extremely fine fibrils provides better depth filtration
efficiency.
High porosity and fine fibrils offer little resistance to airflow.
Small and consistent pores often provide surface filtration.
Cleaning of surface-filtered particles is very easy.
Filter efficiency is still high during and immediately after cleaning.
They have high air filtration efficiencies combined with low pressure drop.
STERILIZATION
Materials used in pharmaceutical manufacturing can be sterilized by numerous methods,
including dry heat, steam, ethylene oxide gas (ETO), or ionizing radiation. Because of
PTFE’s thermal stability, ePTFE can be repeatedly thermally sterilized under typical
autoclave, steam-in-place, and dry-heat oven conditions. Also, because PTFE is
chemically inert, it is unaffected by ETO sterilization or cleaning solutions.
Steam and cleaning solutions can wet-out the pores of a hydrophilic or less
hydrophobic polymer. The liquid in the membrane pores can block gas flow as well as
create an environment in which microorganisms can grow. Since PTFE is extremely
hydrophobic, using ePTFE minimizes these risks.
Although PTFE exhibits extraordinary resistance to chemical attack from a wide
range of chemical species, it has only limited resistance to ionizing radiation. Ionizing
radiation causes chain scission of the carbon bonds in the backbone of the helical PTFE
molecule. This not only reduces molecular weight but also reduces the ultimate tensile
strength and ultimate elongation. This decrease in physical properties is observed at
relatively low levels of radiation; significant decreases are observed at less than
0.5 mRad. Because of the decrease in physical properties, ionizing radiation is not a
preferred method of sterilizing PTFE.
In some applications, components containing ePTFE still need to be sterilized with
radiation. Properly designed and supported ePTFE laminates have been radiation
sterilized and successfully used as hydrophobic vents and sterile barriers such as
transducer protectors, intravenous spike vents, and other medical components for a
number of years. In these products, the materials dependably and reliably support the
ePTFE to prevent degradation of physical properties. The microstructure, physical
dimensions, and performance of the laminate are not changed after radiation sterilization.
Physical conditions that cause an ePTFE membrane to fail after radiation sterilization
include excessive elongation, puncture on sharp protrusions, and concentration of stresses
in limited areas.
Expanded Polytetrafluoroethylene Membranes and Their Applications
629
FERMENTATION FEED AIR AND EXHAUST GAS FILTRATION
Large volumes of sterile air and gases are required as a raw material in aerobic
fermentation reactions. These gases require filtering to remove organisms and
particulates. Exhaust gases are filtered to prevent the fermentor from contaminating
the environment as well as to prevent the environment from contaminating the fermentor.
During their service life (typically more than one year), these filters must undergo
repeated steam sterilizations without blinding or losing their integrity. Filter failure is
extremely costly in terms of product yield, product quality, maintenance, and downtime.
Historically, packed towers were used for these types of filtration. While packed
towers are better than no filtration, they have several disadvantages—they are relatively
inefficient, expensive to install and operate, wasteful of space, hydrophilic, and
impossible to integrity test. Cartridges made of glass fiber and borosilicate glass fibers are
more efficient than randomly packed towers, and they also save space. However, users of
membrane filters containing ePTFE are realizing significant improvements in filtration
efficiency, pressure drop, hydrophobicity, and integrity testability (Figure 10).
Because ePTFE membranes have a narrow pore size distribution, they retain
particles and organisms more efficiently than nonwoven depth filtration media. Since
ePTFE is extremely hydrophobic, (i) it remains hydrophobic through repeated
sterilizations, (ii) it resumes its presteam pressure drop with a minimal post-steaming
blowdown, and (iii) it is not susceptible to grow-through.
In addition to the benefits of improved reliability and efficiency, using ePTFE
membrane filters is quite beneficial economically for the following reasons:
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Lower Capital Cost: Capital and replacement costs are further reduced because fewer
filters may be required for a desired flow rate. The installation and capital costs of
heat-tracing filter housings are also reduced.
Lower Energy Cost: The lower pressure drop of ePTFE filters results in significant
energy savings in compressor operation.
Reduced Blow-Down Time: Since ePTFE is extremely hydrophobic, the time it takes
to blow the filter dry is significantly reduced relative to other, less hydrophobic
polymers such as polyvinylidene fluoride.
FIGURE 10 Filter cartridge
containing ePTFE.
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Lower Contamination Cost: Studies have shown that contamination rates are 50%
lower in fermentors with hydrophobic cartridge filters than in a control group of
fermentors with packed towers
The contamination, energy, maintenance, and productivity cost savings realized by
using ePTFE filters can be calculated to determine the total annual cost savings. The
payback period for converting to hydrophobic filters is often less than one year.
PROCESS GAS FILTRATION
Several gases, including nitrogen and oxygen, are used in biopharmaceutical
manufacturing and finishing. These gases must be bacteria- and particulate-free.
ePTFE membranes are ideal for these applications for the same reasons as previously
discussed.
VENT FILTERS
Tanks must be vented to allow gas to exit during filling and enter during emptying. If a
tank is not vented, or if a vent becomes blocked, the tank can either explode or implode.
Even if the filter is only partially blocked, productivity is reduced, because it takes longer
to drain the tank. Therefore, a vent filter must allow gas to flow sufficiently to equalize
pressure while preventing contaminants from entering the tank.
Autoclaves and lyophilizers typically have vent filters to ensure that the air coming
in after sterilization is sterile and particle-free.
Once again, filters made of ePTFE are ideal for these types of applications. The
filters allow for a high flow rate at a low pressure drop. These filters can be regularly
tested to verify their integrity and their installation. Since they are hydrophobic, ePTFE
filters do not “blind” from repeated steam sterilization or incidental contact with aqueous
solutions.
LYOPHILIZATION
Many biopharmaceutical products, such as vaccines and monoclonal antibodies, are
unstable in aqueous solutions over time. Their shelf life can be enhanced by drying, but
many of these substances are also unstable by nature when exposed to heat.
Lyophilization, or freeze-drying, allows these pharmaceutical products to be preserved
with minimum degradation. During lyophilization, the product is first frozen to below its
eutectic or glass transition temperature, usually in the range of 40˚C to 60˚C.
A vacuum is applied and energy is input to create the proper conditions for sublimation.
Removing moisture through sublimation, in which a solid (usually ice) is transferred to
the gaseous phase directly, provides a low-heat input method for preserving and
extending the shelf life of valuable pharmaceutical products that otherwise become
unstable during processing or storage.
Single-dose pharmaceutical products are typically freeze-dried in glass vials. The
conventional method for freeze-drying in vials uses a split-bottom stopper partially
inserted in the top of the vial, leaving an opening throughout the freeze-drying cycle, so
that air and moisture vapor can escape (Figure 11).
Expanded Polytetrafluoroethylene Membranes and Their Applications
631
FIGURE 11 Vapor path during freeze-drying
cycle with conventional split-bottom stopper.
Because most of these products are parenteral (injectable) and heat-sensitive, they
are usually manufactured in aseptic processes and cannot be terminally sterilized. While
environmental controls and other precautions are used to prevent contamination, the vials
are open throughout the process and encounter several inherent risks, including:
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contamination of the product during transport to and loading of the lyophilizer
contamination of the product during the lyophlization cycle
cross-contamination between containers in the lyophilizer
product loss and difficult cleanup due to entrained powder
worker exposure to toxic compounds being lyophilized
Inserting an ePTFE membrane in an overcap minimizes these risks by isolating the
content of the container from the external environment. The product isolator protects and
contains the product during processing using standard glass vials and stoppers
(Figure 12).
Figure 13 shows the following steps for attaching, using, and removing a product
isolator:
1.
2.
3.
4.
5.
6.
7.
Fill the vial in a controlled environment.
Insert the stopper in the down position.
Apply the product isolator in the down position.
Raise the product isolator to the venting position. This automatically raises the
stopper, creating an annular space between the stopper and vial wall. This annular
space provides a path for water and other vapors to escape during sublimation.
Transfer vials to the freeze-dryer, and run the freeze-dry cycle.
At the end of the freeze-dry cycle, the freeze-dryer shelves collapse, which
automatically seat the product isolator and stopper. After lyophilization is complete,
remove the vial from the freeze-dryer.
Remove the product isolator, while keeping the stopper seated.
Crimp the stopper on the vial.
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FIGURE 12 Vapor path during freeze-drying
cycle with product isolator.
The ePTFE membrane allows both diffusion and bulk flow of moisture vapor
through it, ensuring that the sublimate has an exit path from the package throughout the
freeze-dry cycle. At the same time, the ePTFE vent not only contains the dried product
within the package but also prevents foreign particles from entering the package. Also,
since ePTFE is extremely hydrophobic, it retains aqueous solutions during loading and
drying.
The ePTFE membrane is an effective sterile barrier that protects the product from
bacteria, viruses, and other contaminants, allowing manufacturers greater freedom in
facility design. Since the product is in a closed, integral package after liquid filling, it
can be transported between sterile areas or into nonsterile areas without risk of
contamination. The thermal resistance of ePTFE allows it to withstand both freeze-drying
and autoclave conditions. Likewise, ePTFE is chemically inert, so it is not likely to react
with the product.
FIGURE 13
Process for attaching, using, and removing product isolator.
Expanded Polytetrafluoroethylene Membranes and Their Applications
633
In a series of experiments, scientists have found high cross-contamination rates
while using conventional split stoppers in glass vials. Barbaree and Sanchez (1982)
investigated cross-contamination rates from vial to vial in a freeze-dry run. Vials were
filled with either of two bacteria, and the number of times these bacteria traveled from
one vial to another during a standard freeze-dry run was counted. The study found crosscontamination rates to be as high as 80% of vials per run. The Barbaree study was
repeated and expanded upon by Lange et al. (1997). This study found crosscontamination rates for vials with conventional stoppers to be as high as 91% of vials
per run. The Lange et al. study also used two indicator organisms to track the path of
cross-contamination but added a new component to the investigation. It compared the
incidence of bacterial escape and cross-contamination rates for conventional split
stoppers to that for fully seated stoppers with an ePTFE vent.
The Lange et al. study found that in all cases, the indicator organism that
contaminated vials with conventional stoppers came from other vials with conventional
stoppers. On the other hand, no bacteria were ever found to have either escaped from or
entered into the vials with the fully seated ePTFE-vented stoppers. In each run, the
incidence of cross-contamination by indicator organisms in the vials with ePTFE-vented
stoppers was 0%. These results indicate that ePTFE-vented stoppers are an effective
barrier to product contamination.
In recent studies, vials with the isolators and stoppers in the raised position were
subjected to a challenge concentration of 1.9 109 CFU/mL of Bacillus atrophaeus for
60 min followed by a four-hour soak. Following the exposure and soak, the vials were
incubated for seven days at 30–35˚C. None of the samples exhibited growth. These
studies show that even under extreme conditions, the product isolator with ePTFE
membrane is a sterile barrier.
To increase the stability of biopharmaceuticals, bulk intermediates are often freezedried as well. These products have very similar needs and risks as those discussed for vials.
An ePTFE membrane can also be attached to trays and containers to provide the same
product containment and contamination control as discussed for the vials. Figure 14 shows
examples of products currently being used by pharmaceutical companies.
The application of vented freeze-dry packaging takes advantage of several unique
properties of ePTFE, including sterile barrier performance, temperature resistance, and
permeability to moisture vapor. These same principles simplify manufacturing for both
single-dose and bulk pharmaceutical products.
FIGURE 14 R&D and production-scale lyophilization products with ePTFE membrane.
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DRUG DELIVERY DEVICES
The growth of non-invasive drug delivery systems is driving the need for innovative and
multifunctional drug delivery devices and components. These systems enhance patient
compliance and effectively deliver drugs including proteins, peptides, and biologics, as
well as traditional pharmaceuticals.
One of today’s key challenges in drug delivery device technology is providing
accurate dosage while maintaining drug sterility. This has become more of a challenge for
device manufacturers as the industry moves towards alternative drug delivery systems.
Transmucosal delivery—the delivery of drugs via the eyes, ears, nose, and throat—is
expected to grow significantly over the next 10 years.
Many drugs delivered non-orally, such as vaccines, nasal sprays, and eye drops,
contain preservatives to provide sterility and extend shelf life. Unfortunately, since many
preservatives are irritants and cause adverse side effects, significant efforts are being
made to develop unpreserved formulations. Without preservatives, drugs are more
susceptible to contamination and require better protection (Figure 15).
A closed system with no incoming contaminated air is the best approach for
preservative-free drug delivery. This approach is used for single-unit dose devices, but as
the transmucosal drug delivery market grows, the drive for lower-cost, multi-unit dose
devices is increasing. In multi-unit dose containers, pressure must be equalized to deliver
the drug accurately. Thus, air must be allowed to move in and out of the device. Using
0.2 mm ePTFE membrane filters along with a mechanical one-way closure (such as a
check valve) has become a common solution for packaging design of preservative-free
formulations and transmucosal delivery systems (Figure 16).
The ePTFE filter allows for accurate dosage and pressure equalization of the drug
delivery device while filtering the bacteria- and virus-laden aerosols from incoming air.
The ePTFE filter’s hydrophobic properties also repel the liquid drug contained in the
device, allowing air to flow freely in a liquid-tight container.
The use of ePTFE membrane filters for drug delivery offers many benefits. ePTFE
is very low in extractables, is non-particulating, and is chemically inert. It is therefore
unlikely to contaminate the drug or react with it throughout the packaged life of the product.
It is naturally hydrophobic, and its thermal resistance allows for most sterilization methods
to be used.
FIGURE 15 Unfiltered drug
delivery device.
Expanded Polytetrafluoroethylene Membranes and Their Applications
635
FIGURE 16 Drug delivery
device with ePTFE vent and
one-way closure.
ePTFE membrane filtration media easily integrate into drug delivery devices. This
media can be insert-molded, heat-sealed, or ultrasonically sealed into plastic. Various
configurations are offered in which the ePTFE is molded into a separate plastic component
and available for insertion into a drug delivery device. Molded components (Figure 17) can
easily be compression-fit, spun-welded, or snap-fit into the device, making them a useful
and convenient addition to any drug delivery device.
POWDER COLLECTION AND CONTAINMENT
Many pharmaceutical products—whether antibiotics, buffers, antacids, vitamins, or other
specialty products—exist in powder form. Typically, these powders are downstream in
the purification stages or packaging operations. Separation of the powder from the gas
stream requires filtration that must satisfy two requirements:
n
n
prevention of loss of product
prevention of exposure of product to the operators and to the environment
FIGURE 17 Molded components with ePTFE vents.
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Some areas requiring air filtration during processing of pharmaceutical bulk
powders are spray drying, fluid bed drying and granulating, tablet coating, milling and
grinding, mechanical and pneumatic conveying, silo and bin venting, blending,
packaging, and nuisance dust collecting (or local ventilation). The filtration units may
actually be contained in the processing equipment or may be downstream in the form of a
powder collector. The filter elements used in these applications are typically filter bags or
pleated filter cartridges (Figure 18).
Since ePTFE membranes are chemically inert, highly efficient, non-shedding,
hydrophobic, and nonsticking, they are an ideal match for many of these applications.
In a powder collector, the air passes through a filter that retains particles and lets clean
gas pass through. When there is significant powder buildup on the filters, the powder begins
to restrict the flow through the system. The filters then go through a cleaning cycle during
which the filters are pulsed with compressed air or mechanically shaken to release the
powder, which typically falls into a hopper where the solids are collected.
Conventional media for these pharmaceutical applications typically consist of a felt
or woven fabric, such as polyester felt, Nomex felt, or woven nylon, and they rely on
the presence of a primary powder layer or pre-coat to operate efficiently. Media
composed of ePTFE membranes are the most efficient, cleanable media in the fabric
filtration industry. Collection efficiencies may exceed 99.97% at 0.3 mm from the
moment the system starts up. Because all of the product being filtered is captured on the
smooth membrane, product holdup decreases and thus minimizes potential product
degradation and carryover. While fibers from conventional fabric filters sometimes
contaminate the product, this is not possible with ePTFE membrane media, because the
product is collected on the membrane side and does not come into contact with the
material that supports the membrane. With the increase in demand for processing units
with product containment systems, there is an even greater need for an efficient nonlinting, FDA-acceptable material to be used as filters in these units.
FIGURE 18 Filter bags and
pleated filter cartridges.
Expanded Polytetrafluoroethylene Membranes and Their Applications
637
In addition to preventing fibers from contaminating the product, the ePTFE
membrane has nonstick characteristics that allow the powder to release easily and require
less frequent backpulsing. Since particulate matter is not held up within the medium, as
with conventional media, valuable product is not lost when the filter is cleaned or
discarded. Rather, the powder is recovered as useful product.
Laminates composed of ePTFE membrane offer similar benefits in the pleated
cartridge construction. Recently, cartridges have gained popularity because they provide
more filter medium in a given space, which ultimately reduces capital costs, decreases the
amount of time required for change-outs, and thus decreases downtime. A typical
medium for conventional filter cartridges is cellulose paper. The disadvantage of this
media is that cellulose has poor resistance to moisture and poor cake release on sticky
powder, and it is inefficient on very fine particulate unless precoated. Cellulose media
often plug quickly (Figure 19).
Since PTFE is inherently hydrophobic, filters constructed with ePTFE-membrane
laminates recover well from moisture upsets. After the moist cake dries, the backpulsing
releases the cake and operates as it did prior to the moisture upset. This hydrophobic
nature also allows these filters to be rinsed off with water for cleaning. Since PTFE is
extremely inert and thermally stable, ePTFE is well-suited for processing and cleaning
fluids typically used in the pharmaceutical industry, including acids, bases, and solvents.
ULTRALOW PENETRATION AIR AND HIGH EFFICIENCY PARTICLE
AIR FILTERS
High efficiency particle air filters represent a class of air filters that remove greater than
99.97% of airborne particles having a diameter in excess of 0.30 mm. Although the terms
HEPA and ULPA have become standards with specific definitions, they originated as
marketing terms for highly efficient, low resistance air filters. These filters were originally
used in nuclear heating, ventilating, and air conditioning (HVAC) systems but have since
been adopted in the pharmaceutical industry as well as the food, electronics, and other
FIGURE 19 ePTFE (left) and
cellulose (right) cartridges exposed
to the same environment.
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industries. Use in the pharmaceutical industry has primarily been in HVAC and other
air-handling systems, like aseptic processing areas, clean benches, hazardous materials
hoods, and barrier isolation systems. Little has changed in the technology of these types of
filters since their invention. Basically they have been pleated micro-fiberglass paper filters
adhered to a frame. Pleat depths range from less than 1 inch to 12 inches. Frames are
typically rectangular or circular and made of aluminum or stainless steel.
The major problem with traditional micro-fiberglass HEPA filters is that they have a
relatively fragile filter medium. Not only are they easily damaged through normal handling
and have limited shelf life, but the rigors of many pharmaceutical applications can harm
them. The medium consists of many small glass fibers held together with an acrylic binder.
Any breakdown of the binder or fiber causes leaks or shedding. Damaging agents include
handling; in-place contact; vibration; humid environments; exposure to chemicals such as
cleaning agents, sterilizing agents, or process chemicals; elevated temperature; and age.
Disposal of filters that are contaminated with hazardous materials also presents a problem.
To circumvent these problems, zones between the clean space and the HEPA filter are
usually covered and not subjected to full cleaning or sterilization. Also, filters must be
checked for leaks, typically every six months, and are frequently replaced.
The newest innovation in HEPA and ULPA filtration is the use of an ePTFE
membrane as the filter medium (Figure 20).
These filters are inherently chemical-resistant, hydrophobic, easily cleaned, and
very strong. They have filtration efficiencies exceeding 99.99999% at a most-penetrating
particle size of 0.070 mm. The high strength of the medium, combined with the other
properties, makes HEPA filters made of ePTFE an excellent choice for many
applications, including cleanrooms, barrier isolators, aseptic processing areas, sterility
testing areas, and anywhere else where cleanliness, sterility, and contamination control
are needed. The filter medium can be exposed to cleaning and sterilizing agents,
including water and steam, without breaking down. These filters can be subjected to
handling and other physical stresses and still maintain their integrity. In some cases, the
filters may be cleaned and reused.
FIGURE 20 ULPA filters
with ePTFE membrane.
Expanded Polytetrafluoroethylene Membranes and Their Applications
639
HEPA filters are checked for leaks at the factory and in use. This is done by
challenging the filter with particles and using a particle counter or photometer to detect
areas of high penetration. One concern in using ePTFE membrane filters is the use of
DOP, Emery 3004, or other oil-based particle challenges. As previously mentioned in this
chapter, these oil mists can wick into the filter medium and prematurely hinder airflow.
Fortunately, there are many feasible solutions to this problem. As mentioned earlier, a
95% prefilter removes enough mass of oil to prevent dampening of the airflow, leaving
the HEPA filter to accomplish the fine, final filtration. Other particle challenges are
acceptable and commonly used in the electronics industry. Polystyrene latex (PSL)
spheres provide a solid challenge that does not overload the filter. Recent tests have
demonstrated that leak location and sizing can be accomplished equally well using PSLs
or DOP. Because DOP is a suspected carcinogen, its use is diminishing.
FILTERING LIQUIDS
Because ePTFE membrane is chemically inert and has high flow rates, it is well-suited for
various liquid filtration applications. Low surface tension liquids such as alcohols (e.g.,
methanol or isopropanol) or solvents (e.g., methyl ethyl ketone) can readily wet ePTFE
membranes. In these types of applications, no additional prewetting steps are required.
On the other hand, fluids with higher surface tensions such as water do not flow
through hydrophobic membranes like ePTFE at normal operating pressures. If a
hydrophobic membrane is used for an aqueous filtration, it must first be prewetted with a
lower surface tension liquid such as isopropanol. Once properly wetted, aqueous solutions
can be filtered through ePTFE membranes. Depending on the application, the prewetting
solution can be flushed from the filter with water or with the aqueous solution to be
filtered. Prewetting ePTFE membranes is done extensively in the semiconductor industry.
Since prewetting is sometimes inconvenient, a water-wettable or hydrophilic
ePTFE membrane is desirable. The surfaces of ePTFE membranes can be modified to
render the membranes hydrophilic.
CONCLUSION
Expanded polytetrafluoroethylene membranes are valuable in a number of pharmaceutical filtration, venting, and product collection and containment applications. PTFE is
inherently inert, thermally resistant, and extremely hydrophobic, and PTFE can be
engineered into a highly retentive and high-flowing microporous membrane. These
characteristics make ePTFE membranes the filtration media of choice in gas filtration and
venting applications. These desirable characteristics of ePTFE are also being exploited in
many new pharmaceutical applications, such as lyophilization trays, product isolators,
and drug delivery systems. Because of the unique properties of ePTFE membranes, they
are a good choice for these as well as other challenging filtration, separation, venting, and
containment applications.
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