Patent Grant
9266068
The present invention relates generally to air filtration media testing using low concentrations of a challenging aerosol, and is well-suited for use in many different industries and applications, and is particularly well-suited for use in an aseptic pharmaceutical application and air handling system.
In most aseptic pharmaceutical cleanrooms, the final step in removing airborne particles occurs in a high efficiency particulate air (HEPA) or ultra-low penetration air (ULPA) filter that is delivering air into a controlled space. Whether the cleanroom attains and maintains its designed cleanliness class depends largely on the performance of these filters. Hence, it is a common and good practice to test the performance of all filters installed in cleanrooms to ensure that they meet the designed specifications. Filters are typically tested at the time of manufacture for overall efficiency and leaks. However, in some cleanrooms within regulated industries, such as the pharmaceutical industry, these filters are also required to be certified periodically to ensure acceptable performance during their service life. Various organizations issue recommended practices for certification of HEPA and ULPA type filters for filter leak tests and guidelines for testing and classifying such filters.
In current HEPA air filtration micro-glass media, the standard utilized in the pharmaceutical industry in aseptic processing has serious problems due to the media being fragile resulting in damage from handling, pressure, overloading and the like. Such damage can result in leaks of the filtration media thereby compromising functionality. Leakage and damage of microglass filtration media within the pharmaceutical cleanroom environment is significant such that the U.S. Food and Drug Administration has issued guidelines ensuring filtration effectiveness of microglass HEPA filters by testing on a regular basis. Testing of such microglass HEPA filters in such aseptic environment is completed using high concentration oil based aerosols such as DOP (dioctylphthlate), PAO (poly-alpha olefin), DEHS (Di-Ethyl-Hexyl-Sebacat), and other similar compounds measured by traditional photometers capable of measuring such upstream and downstream concentrations. The aerosols used for such filter leak tests and challenging of these filters should meet specifications for critical physicochemical attributes such as viscosity. Leakage threshold rates of 0.01% or greater of upstream concentration from these compounds is typically the testing limit at which the pharmaceutical installation and processing area would either have to replace the filter or repair the same. The upstream concentration typically is measured at the start and end of testing to ensure that the upstream challenge remains consistent over the life of the test. The filter face is scanned to identify defects in the filter media.
Since the 1960's HEPA filters have been tested using high concentrations (e.g., approximately 20 μg/liter) of aerosols such as PAO, DOP, DEHS, and other similar compounds. Traditionally, HEPA filters are tested with photometers which require a high (>10 μg/liter) upstream challenge concentration. Considering a leak size of 0.01% of the upstream concentration, this means that on the downstream side of the filter one must be able to detect a very small amount of PAO. The photometer has a lower limit of being able to measure small concentrations, which is why the larger upstream concentrations are required. A particle counter is another piece of equipment that can be used to leak test filters. Particle counters, unlike photometers, are only able to work with very low concentrations of PAO and are much more sensitive at very or ultra low concentrations of aerosol.
High concentrations of oil have a much greater impact on ePTFE than on glass media HEPA filters. Studies have shown that testing glass media HEPA filters with a photometer at high concentrations (e.g., approximately 20 μg/l) and with a particle counter at low concentrations (e.g., approximately 0.1 μg/l) yield consistent results in regards to sizing leaks. Therefore, there is a desire to develop test apparatus and methods for testing filters (especially, but not limited to, ePTFE HEPA filters) at low concentrations.
In general, however, there has not been a very convenient way to steadily produce a very low concentration of PAO. In the past a Laskin nozzle generator was used and the output was dumped into filters, or other output reduction methods were used. None of these have been ideal, however. The output of typical Laskin nozzle-based aerosol generators is governed by the amount of air flow exiting the nozzle tip. A standard Laskin nozzle requires approximately 2.65 cfm @ 20 psi of compressed air to enter the nozzle, thus resulting in 2.65 cfm of the aerosol mixture that will exit the generator. Air flow through the nozzle equates to flow combined with oil droplets out of the generator. In certain applications, the aerosol output of a generator operating on one Laskin nozzle will result in output concentrations with orders of magnitude higher than desired.
One possible solution to generating lower concentrations is to use a fraction of the Laskin nozzle output under the surface of the oil. Another possibility is to reduce the nozzle pressure. It is common practice to reduce the air pressure to a standard Laskin nozzle or to modify the nozzle by plugging one or more of the holes in the nozzle to reduce the overall aerosol output of the generator. The problem with using a smaller nozzle and/or lower nozzle pressures is that very little air passes through the nozzle and out of the tank. Another problem is that some specialized filter housings may require higher air flow. For example, some filter housings with aerosol injection/dispersion features are typically used with >2 cfm of airflow to inject the aerosol across the filter face. If very low flow were used, the aerosol may be difficult to be injected across the filter face in one of these units. Additionally, the time required for newly generated aerosol to exit the holding tank increases as nozzle flow decreases. This creates a slow response time in generator output at first startup or when attempting to change the nozzle pressure/generation rate of the generator. This increased exit time of the aerosol can also lead to an increase in aerosol particle size with time. A newly generated aerosol that is composed of small particles has a higher probability to grow in size by means of coalescence, ripening, agglomeration, etc., the longer it remains in a high aerosol concentration environment.
The DOP/PAO method for aseptic pharmaceutical room filtration application discussed above is required by regulation at least every 6-12 months by challenging the filtration media with a defined aerosol. The required aerosol challenge is maintained at a high concentration of about 20 μg PAO/L of air. A measurement of 15 μg of PAO/liter corresponds to about 20 grams of PAO/800 cfm filter/hour. For normal or standard microglass filtration media, a one-time oil based challenge compound may not negatively impact filter life of the media but may affect other structures of the filter. However, by testing at such concentrations on a regular basis, standard filter life including regular challenge testing can limit to less than five years the life cycle for microglass HEPA filtration.
In such standard challenging methodology for pharmaceutical applications and installs, a predefined challenging compound such as PAO is provided upstream of the filtration media in place. The PAO is injected into the airstream upstream of the in-situ media by nozzle or other known device at high concentration levels to properly determine filtration effectiveness. Injection devices such as a Laskin Nozzle create a poly-dispersed aerosol composed of particles with light scattering mean droplet diameters in the submicron size range. A challenge concentration, as mentioned, is provided up to about 20 μg/L which is continually introduced upstream of the filter for about three to four hours for a typical certification. An upstream challenging port in the filter housing is utilized for photometric analysis. The filter face is scanned on the downstream side with the photometer probe and leak sizes are calculated as a percent of the upstream challenge. Scanning is conducted on the entire face of the filter to generate proper leakage analysis. Probe readings of about 0.01% as leak criteria would be indicative of a significant leak but requires, as seen, fairly high concentrations of upstream PAO which can have deleterious effects on the filtering media and HEPA performance.
Significant problems also arise in the use of PAO challenge compounds. Significant fouling of the filtration media may occur over a plurality of challenging cycles. Further, such excessive challenging can cause the filter media to become less efficient, exhibiting more of a pressure drop and correspondent higher energy costs. Additionally, the PAO challenge compound has been shown to potentially cause damage to the filtering gel seals and gaskets resulting in potential leakage points. PAO may further cause liquification of silicon based gels or may harden or otherwise reduce the effectiveness of urethane based gel seals.
As a result, improved aerosol generators are required which can effectively produce aerosols of lower concentrations of appropriate challenge compounds to a filtration media, but which can do so consistently for the required amounts of time, and without causing excessive oiling or buildup on the filtration media, and without creating excessive pressure drop across the media.
Filter housings containing PAO dispersion manifolds can be used to provide a uniform aerosol distribution upstream of a filter when performing filter tests. These dispersion manifolds are designed to typically operate properly with a minimum of 2.65 cfm of air. When reducing the pressure below 20 psi for a full Laskin nozzle, or plugging a fraction of the nozzle holes, the output of the generator can fall below the optimal flow to effectively operate the dispersion manifolds. To compensate for the reduction of airflow through the generator outlet, one option is to increase the total output of the generator by adding additional supply air at the generator output. Under this operation, the newly formed aerosol exits the generator before combining with the additional supply air and the transit time for the aerosol to exit out of the holding tank is largely unaffected. However, if supply air is added at the generator output, there can be problems with the supply air not mixing properly with the generated aerosol.
Alternative aseptic pharmaceutical filter designs have included the use of additional pre-filter requirements which work to protect the primary filtration media during normal air handling load and during challenging. Prefilters typically are designed to prevent surface loading due to large particles, such as hair, etc. Such pre-filters, however, can foul earlier in the filter life cycle thereby requiring periodic replacement and increased maintenance costs. Such pre-filtering is undesirable in that additional filtration media is therefore required, doubling of maintenance and handling requirements are expected and a lack of efficiency and increased pressure drop result.
Other problems associated with traditional micro-fiberglass HEPA filters are that they are a relatively fragile filter medium which do not react well to handling, in-place contact, vibration, humidity possibly condensing on the filter media or the particle board frames, or chemical exposure. Such micro-fiberglass media may be readily damaged through normal handling. Damage resulting from these various factors can cause leakage and unfiltered air to pass through the media. Further, the filter can fail normal challenging sequences as a result of such damage to the media. Thus, it is desirable to provide a filtering media that meets full HEPA filtration requirements, may be utilized in the aseptic pharmaceutical industry environment, and is more durable for handling and more reliable in remaining fully functional after required integrity tests or challenging sequences and during normal course of operations.
In addition to filter loading, when considering testing of filters with the conventional use of PAO as a challenge aerosol, under certain conditions, bleed through can also be a potential issue. The issue of bleed through may occur when operating a thermal PAO generator at lower pressures to test ePTFE or glass media filters. This is due to the thermally generated aerosol having a 0.10-0.45 mass mean diameter which is closer to the MPPS of the filter. This creates an issue with a photometer measuring a concentration and looking for leaks at or above 0.01%. The bleed through could erroneously manifest itself as an artificially large leak or in some cases a continuous leak across the filter measuring >0.01%.
It is therefore desirable to provide a fully functional HEPA filtration media which meets all requirements, is relatively durable, may be challenged appropriately to determine filtering effectiveness and leakage and which further meets all required aseptic filtration standards. It is further desirable to provide such filtration media without additional pre-filter requirements and with appropriate methodology to determine full functionality of the media and determine possible leakage points without causing fouling of the in-situ filters.
It is also desirable to provide an aerosol generator capable of producing a steady, consistent output of low concentration challenge compound so as to be compatible with the use of discrete particle counters used for leak testing filter media.
Thus, there is a need in the art to provide a fully functional aseptic pharmaceutical filter media which has associated full testing methodology, is durable, maintains HEPA filtration efficiencies and which has a long in-place filtration life.
It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed. It should also be appreciated that terminology explicitly employed herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the particular concepts disclosed herein.
It is therefore one aspect of the present invention to provide a replacement material and certification testing for leak size and detection of aseptic cleanroom filtering media which utilizes a significantly lower resistant media, thereby substantially reducing energy costs.
It is further desirable to provide a method for certification and testing of media in such conditions using ultra-low concentrations of PAO and a means for detection of the ultra-low concentrations downstream of the filter to determine leak size and filter condition.
It is further desirable to provide an aerosol generation system that supplies an aerosol of challenge material to a filtration media for testing purposes that decreases the likelihood of excessive oiling or occlusion of the filter media.
In another aspect of the present invention, it is desirable to provide a more robust alternative to micro-fiber glass filtering media in such an environment.
It is therefore one aspect of the present invention to integrate ultra-low level PAO testing and challenging of ePTFE HEPA filtration media in an aseptic cleanroom environment. It is a further aspect of the present invention to provide an ePTFE bi-component filtration media which may be appropriately tested and certified on a regular basis for efficiency and leakage with an aerosol without fouling of the ePTFE membrane or filter media.
In some embodiments, the filter system and media of the system described herein includes a dual layer bi-component media of spun-bond material, the bi-component material being a combination of PET (polyethylene terephthalate) and PE (polyethylene) with a total weight of about 80 GSM (grams per square meter) for both layers and a combined stiffness of about at least 400 Gurley.
In various embodiments, the dual layer of bi-component material may include a density of about 8 PPI with an average pleat height of about 25 to about 55 mm. Optimally, in many embodiments, the pleat height will be about 35 mm.
In some filters, the pleat separators can be a clear poly-alpha olefin separator bead applied in between each pleat to assure pleat separation and spacing. In other filters and embodiments, the pleats can be formed by embossing a pattern in the media that assures pleat separation and spacing.
In other aspects, the specially formulated ePTFE membrane thickness may be about 8 to about 15 microns and preferably about 10 microns.
In some aspects, the bi-component filter material may be laminated with the ePTFE membrane at about 160 degrees C.
In various aspects, the resulting material can be rolled and then later pleated as set forth for insertion into air filter assemblies which can include metal gel seal, neoprene or knife edge frame types.
Upon insertion of the ePTFE HEPA filter at an installation, some aspects set forth herein can include regular certification and leakage testing by use of ultra-low PAO challenging aerosol at down to about 0.010 μg PAO/L of air and up to about 1.0 μg/L. More particularly and alternatively, concentrations of about 0.1 μg/L PAO to about 0.5 μg/L with a combination of particle sizes of about 0.3 μm to about 0.5 μm particle count sizing can be used. Correspondingly, a discrete particle counter can be combined with the aerosol generator for challenging and leakage testing, in various embodiments, which can include a counter able to test at 0.5 μm to about 0.3 μm or smaller μm channel size.
In other embodiments, microspheres (polystyrene latex or other materials) may be generated as a challenging material and read on the downstream side of the filtering membrane using a particle counter to similarly determine leakage and filter efficacy. In various examples, microspheres sized from 0.12 and up to 1.00 μm can be utilized. Similar testing and challenging concentrations can as well include challenging measurements of 20×106≧0.3 μm particles of PAO per ft3 to about 7×106>0.5 μm particles of PAO per ft3.
Generally, in the various examples and embodiments provided, a filter and testing methodology is provided wherein a specialized ePTFE HEPA filter may be utilized and appropriately challenged for certification purposes while maintaining the efficiency and efficacy of the filtering media. Usage of the various embodiments described herein provides alternative testing and certification methodology for cleanroom application of ePTFE filtering media without the significant drawbacks of high volume PAO aerosol testing previously seen in the art. Usage of the types of generators described is not limited to any particular filter embodiment.
It is therefore one aspect of the present invention to provide a system for installation and testing of ultra-low concentration challenging PAO or other type of aerosol upstream of an ePTFE HEPA filter for use in aseptic pharmaceutical cleanrooms wherein the challenging concentrations of the PAO or other aerosol is less than about 1.0 μg/L air challenge aerosol with an associated low or ultra-low concentration upstream scanner (such as, but not limited to, a particle counter or photometer), in conjunction with a downstream ultra-low concentration particle detector or other scanner for determination of downstream concentration of the challenging aerosol. To measure a 0.01% leakage rate based on a 1.0 μg/L down to about 0.3 μg/L and further down to about 0.1 μg/L and lower upstream challenge aerosol concentration, a photometer or detector downstream must be sensitive and accurate for measuring a 0.01% leakage rate of the upstream PAO challenge concentrations, or a downstream concentration of less than 0.0001, 0.00003 and further down to about 0.00001 μg/L and lower concentrations, which can be problematic for today's current photometer technology. Such low challenging concentrations thus results in significantly extended challenge life of the filtering media, i.e. total exposure time of the ePTFE media to the PAO, oil based or other type of challenging aerosol. Such low exposure times significantly extend the testing and installation life of an ePTFE filter media filter requiring regular leakage certification.
Various methods of use include installing an ePTFE based filter into an aseptic pharmaceutical installation, introducing an ultra-low challenge concentration of a challenging aerosol, measuring the upstream concentration of the aerosol at the filter face, scanning the downstream side of the filter face, detecting the infinitesimal concentration of aerosol on the downstream face of the ePTFE filter by utilization of a discrete particle counter or photometer and calculating leak sizes based on the ratio of the measured downstream to upstream concentrations.
In other embodiments, the method further incorporates installation and leakage testing of ePTFE filtration media in an aseptic filtration environment including installing a filtration media having an upstream spunbond scrim material or upstream support scrim and a downstream spunbond scrim material or downstream support scrim, interposing an ePTFE membrane between the upstream scrim material and the downstream scrim material, injecting into the upstream air a low or ultra-low concentration of challenging aerosol at or below 1.0 μg aerosol/L air down to about 0.10 μg aerosol/L air or below (approximate equivalent to >6 million particles), measuring the concentration of the challenging aerosol at the upstream spun bond scrim material, allowing the challenging aerosol to penetrate through defects in the ePTFE membrane, measuring the concentration of the challenging aerosol at defect locations by particle detection at the downstream spunbond scrim material to a value as low as from 0.0001 μg aerosol/L air or lower to 0.00001 μg/L, calculating a leakage size within the media to values down to a leakage threshold rate of about 0.01% of the upstream challenging concentration.
Various methods may further include installing a downstream particle scanner for measuring the concentrations at the downstream spunbond scrim material. The scanner may be a discrete particle counter. In other variations, the method may further comprise transmitting the concentration measurements of the upstream scanner to a computer, transmitting the concentration of measurements of the downstream scanner to a computer, calculating a leakage percentage of the challenging aerosol through the ePTFE filtration media over a predetermined period of time.
Alternatively, various methods may further include installing a communication link between an upstream scanner and a downstream scanner, transmitting the concentration measurements of the upstream scanner to a reading device, transmitting the concentration of measurements of the downstream scanner to the reading device, calculating a leakage percentage of the challenging aerosol through the ePTFE media by a processor, and reporting the calculated percentage to a user.
Various systems and methods may also include exemplary solutions which incorporate a divergent or secondary air supply (bypass air) that serves as an aerosol carrier, chamber purge, and/or dilution source. By incorporating a bypass source of air through the holding tank or at the tank outlet, the output flow of the generator can be increased. The addition of bypass air through the holding tank will increase the output while simultaneously reducing the time the newly generated aerosol remains in the holding tank. In addition, the newly generated aerosol is also pre-mixed with the bypass air in the holding tank prior to exiting the generator. Although the bypass air provides benefits with high concentration/flow output generators, the advantages of the bypass air are most significant when assisting low output/flow systems.
A further embodiment may include a system for in situ testing of a filtration media that includes a filtration media for positioning within an air stream of an air stream handling system. An aerosol generator positioned upstream of the filtration media and includes a substantially closed tank configured for containing a liquid there within and a void space above a top surface of the liquid. The aerosol generator includes a generation nozzle located in the holding tank that includes a nozzle outlet located below the liquid top surface. The generation nozzle supplies a first air source or source of pressurized supply air. The aerosol generator includes a bypass nozzle located in the holding tank, with the bypass nozzle supplying a second air source or source of bypass air either above or below the top surface or liquid level. A tank outlet for discharging an aerosol from the substantially closed tank to the air stream handling system. An upstream scanner detects the aerosol produced by the aerosol generator at an upstream side of the filtration media. A downstream scanner detects the aerosol passing through the filtration media. Alternatively, the second air source or source of bypass air may be supplied to the tank outlet of the holding tank.
One embodiment of the aerosol generator may include a substantially closed tank configured for containing a liquid there within and having a void space above a liquid level or top surface of the liquid. At least one generation nozzle located in the holding tank includes a nozzle outlet located below the liquid level. The at least one generation nozzle supplies a first air source or source of pressurized supply air. A bypass nozzle located in the holding tank supplies a second air source or source of bypass air. A tank outlet discharges an aerosol from the substantially closed tank.
Another embodiment of a method of in situ testing of a filtration media may include the steps of providing an air handling system having a filtration media interposed between an upstream environment and a downstream environment. Providing an aerosol generator positioned upstream of the filtration media. The aerosol generator includes a substantially closed tank configured for containing a liquid there within and a void space above a top surface of the liquid. The aerosol generator includes a generation nozzle located in the holding tank having a nozzle outlet located below the top surface. The generation nozzle supplies a first air source or source of pressurized supply air. The aerosol generator includes a bypass nozzle located in the holding tank that supplies a second air source or source of bypass air. A tank outlet for discharging an aerosol from the substantially closed tank to the air stream handling system. Injecting into the upstream environment the aerosol from the aerosol generator. Providing an upstream scanner for detection of the aerosol from the aerosol generator at an upstream side of the filtration media. Providing a downstream scanner at a downstream side of the filtration media for detecting the aerosol passing through the filtration media. Measuring an upstream concentration of the aerosol in the upstream environment. Measuring a downstream concentration of the aerosol having flowed through the filtration media in the downstream environment. Calculating a leakage rate based on a comparison of the upstream concentration to the downstream concentration.
Various embodiments of the present invention provide a particle generator system including a source of compressed air, a secondary source or divergent source of air (bypass air), a liquid holding tank which contains a sufficient void between the liquid surface and tank top, a generation nozzle or plurality of nozzles immersed in the liquid, a nozzle inlet to the liquid holding tank, a secondary inlet to the liquid holding tank that serves as the inlet to a source of clean bypass air, and an outlet on the liquid holding tank for discharging the aerosol.
These and other variations of the system and method for leakage detection in an ePTFE filter media for use in an aseptic pharmaceutical environment are further described herein.
In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.
In the following detailed description, for purposes of explanation and not limitation, representative embodiments disclosing specific details are set forth in order to provide a thorough understanding of the claimed invention. However, it will be apparent to one having ordinary skill in the art having had the benefit of the present disclosure that other embodiments according to the present teachings that depart from the specific details disclosed herein remain within the scope of the appended claims. Moreover, descriptions of well-known apparatuses and methods may be omitted so as to not obscure the description of the representative embodiments. Such methods and apparatuses are clearly within the scope of the claimed invention. For example, the aspects of a fluid filtering system disclosed herein are described in conjunction with a plurality of filter structures that are arranged in a specific fashion and that interface with other structural components of the fluid filtering system in a specific fashion. However, one or more aspects of a fluid filtering system described herein may be implemented with filter structures arranged in alternative configurations and/or with filter structures that interface with other structural components of the fluid filtering system in alternative ways. Also, for example, as described in additional detail herein, filter structures disclosed herein may vary in one or more respects from those specifically depicted herein. Implementation of these and other variations is contemplated without deviating from the scope or spirit of the claimed invention.
In
By low and ultra-low concentrations of challenging aerosol, it is meant that the concentrations are about 1.0 μg aerosol/L air down to about 0.01 μg aerosol/L air and below for ultra-low volumes, as well as detection of concentrations at an ultra-low values by a factor of 0.0001 (0.01%) indicating a detectable concentration of down to about 0.000001 μg aerosol/L. air. Thus, downstream ultra-low particle detection is required to be able to detect such low concentrations of challenging materials using, among other devices, a discrete particle counter.
As set forth herein, a method for use and testing of an ePTFE filtering media is provided. The ePTFE HEPA filter is suitable for use in an aseptic pharmaceutical environment and is combined with a routine testing challenge which ensures filter integrity. As summarized herein, several embodiments of the filter and testing methodology include a HEPA filter having a bi-component scrim wherein an ePTFE membrane is laminated between a top and a bottom bi-component layer. The HEPA ePTFE filtering material may be utilized with a corresponding PAO testing and challenging regimen which includes low concentration PAO exposure to the air stream with the HEPA ePTFE filter in place while utilizing a particle counter to determine corresponding pass through of the PAO challenge material. Detection of even minute particles of PAO by the particle counter may indicate damage to the filter which may then be correspondingly repaired or replaced as needed. By utilizing a pairing of an ePTFE filter with an ultra-low concentration PAO challenge and a particle detector, use of a HEPA ePTFE filter without fouling of the membrane by the PAO is accomplished.
As shown in
The two spunbond layers 10 and 30 may be selected to provide a total weight of about 80 gsm combined such that each individual layer may be more or less than the exemplary 40 gsm layer as needed for the specific application and to provide a good laminating surface for bonding with the ePTFE membrane 20. The bi-component layers may also be selected to provide a combined stiffness of at least about 400 Gurley. These bi-component materials may be selected from many known members but, in various embodiments, polyethylene and PET may be combined to form the spunbond bi-component material. As indicated, an exemplary specification for the scrim may be a PE/PET bi-component spunbond scrim for lamination purposes. In various embodiments, each layer may have a basis weight of 40±3 g/m2 and a thickness of 0.25±0.05 mm. An exemplary air permeability is greater than about 350 cfm with a tensile strength of MD>100 N/5 cm and CD>30.
Returning to
In the present embodiment, the combined filtering media 50 is a HEPA filter mat having fiber diameters of between 0.5 and 2.0 micrometers. As is known, HEPA filters remove at least 99.97% of the airborne particles 0.3 μm (micrometers) in diameter. While the spunbond scrim layers do not provide membrane-like entrapment filtration, they are combined with an actual membrane layer 20 where particles are actually trapped by the tendrils of the ePTFE membrane material. The ePTFE membrane 20 depicted herein provides unique characteristics in combination with the scrim layers as well as the specific testing and challenging methodology using ultra-low PAO concentrations preventing fouling of the membrane by the PAO and maintaining filter efficiency even after multiple certification challenges.
With reference now to
The fine PTFE fine powder is then mixed with an oil at a ratio of about 33% into a doughy billet. The mixing oil may be IP Solvent 2028 with a viscosity of 3.01 m·Pa·s/at 20 degrees C. and a density of 213 to about 262 g/cm3 at about 15 degrees C. This mixture is brought to a boiling point at about 213 to about 262 C with a mixing time of about 10 minutes. Once the material is thoroughly mixed, it can be stretched into a membrane or film through both TDO (transverse direction orientation) and MDO (machine direction orientation) stretching. Initially, an MDO stretch is accomplished at a 5:1 ratio and at a temperature of about 50 degrees C. Three rollers are utilized in MDO stretching, each roller heated to about 250 degrees C. After completion of the MDO stretch, a TDO stretch is accomplished at a ratio of about 30-50 to 1. The membrane is preheated at a temperature (Duct temperature/IR temperature) of about 200/200 degree C., a stretching temperature of 300/300 degree C. and a heat set temperature of about 370/450-560 (adjustable, where higher temperature, lower pressure drop) degrees C. The Duct temperature is the temperature inside the oven and the IR temperature is the temperature towards the membrane. Once the membrane is formed, it can be rolled for later use and combination within a scrim layer for formation of an ePTFE filter material.
An exemplary process for creation of the ePTFE membrane for use in the filter media and method steps discussed herein is shown in
After completion of the TD stretching as depicted in
Referring again to
In some embodiments the ePTFE membrane 20 may include a single or multiple layers with a minimum thickness of about 5 micron and preferably about 10 micron in thickness. However, both porosity and pressure drop may be balanced in the membrane to maintain desired energy efficiency, so various thicknesses may be similarly utilized to create similar energy efficiency. As formed herein, the ePTFE membrane is filled with a number of large nodes and fine fibrils which allow for tolerance of low concentrations of PAO, DOP, DEHS or other test aerosols.
As shown in
Referring now to
Separators 51, depicted in several embodiments of
Bead type separators 56, shown in
In many embodiments, the separator material may be a clear material which does not interact with the PAO or other challenging aerosol used in the certification challenging steps described herein. For example, the separator material may be poly-alpha olefin which is clear and which does not discolor the adjacent ePTFE media when exposed to PAO oil aerosol.
Returning to
As shown in exemplary fashion in
Once the media is properly pleated, it may be cut and prepared for insertion into a frame material 110 as shown in
A single filter unit 100 is shown in
After installation into an aseptic pharmaceutical facility, in place certification must be conducted. As discussed herein, such challenging often includes challenging with an oil based aerosol such as PAO in order to determine leak size and filter structural continuity. In combination with the ePTFE filtering media set forth, a process is provided for ultra-low concentration challenging of filtering media in an aseptic pharmaceutical environment. In general and in various embodiments described herein, one or more ePTFE filter embodiments described herein may be utilized in an ultra-low aerosol concentration challenging step wherein the upstream airflow is entrained with a challenging compound. In general and in various aspects set forth, PAO aerosol may be introduced upstream in order to determine damage to the filter or seal structure. Such normal and periodic leak determination and examination is required in such applications and through use of the ultra-low concentration methodology in combination with the ePTFE filter, filter life can be significantly enhanced up to and including the lifespan of the facility.
In general, and as is depicted by example only in
In some of the embodiments discussed, a challenging material such as PAO aerosol may be utilized. As a result of installing a HEPA ePTFE filtering media in one example, ultra-low concentrations of the PAO may be introduced using an aerosol generator and measured using a particle counter/aerosol diluter combination, as depicted for exemplary purposes in
Downstream concentration measurements by the particle counter 209 may be compared to upstream concentrations calculated by the upstream scanner 208 in order to determine PAO penetration concentrations. As indicated, downstream concentrations of greater than about 0.01% of upstream concentrations would indicate filter integrity issues. And, as a result of embodiments using a HEPA ePTFE media, only ultra-low concentrations of the challenging PAO aerosol can be utilized in order to avoid fouling the media or otherwise resulting in a significant drop in efficiency and filtration capability. As such, specialized ultra-low concentration measuring protocols and equipment must be utilized to determine downstream concentrations and leakage percentage.
As stated herein, an important feature of an aerosol generation system is the ability to provide a source of aerosol challenge applied to a filter media for testing wherein the aerosol comprises droplets that do not agglomerate or coalesce to form larger particles that can create an undesirable pressure drop across the filter media or excessive oiling of the filter media. One method of preventing excessive oiling is to reduce the generator output by decreasing the nozzle pressure or air flow through the nozzle. However, doing so ultimately results in less generator output flow, which may be undesirable, and can also slow down generator response time upon startup or output adjustment.
In one aspect of the present invention, an aerosol generation system is provided which increases output flow of the generator without excessive oiling by adding additional supply air (bypass or secondary air) to the generator. In general, adding bypass air is intended to perform three main functions: (1) to increase the total generator output flow; (2) to prevent newly generated aerosol from remaining in the holding tank for an extended period of time; and (3) to dilute the generated aerosol. Exemplary methods to increase the output flow using bypass air are shown in
Further, although the embodiments illustrate several distinct positions of the inlets of the bypass air supply introducing or supplying bypass air into the generator it should be understood that the bypass air supply may be positioned within the tank, above the liquid level within the tank, below the liquid level within the tank, outside the tank, or any combination thereof. As such, the bypass air supply and inlets may be of a variety of positions, quantities, orientations, sources such as but not limited to the same or different from the generation air supply, and constructions and still introduce bypass air. Further, the duration and amount of pressure of such bypass air may be varied.
The addition of the bypass air to the holding tank above the liquid surface enables the newly generated aerosol to be mixed within the tank and allows the newly formed aerosol to exit the tank rapidly. This has an advantage over adding the bypass air at the generator output as the mixing at the generator output may be less uniform. Adding bypass air to the holding tank below the surface of the liquid (away from the nozzle) achieves a similar result to adding the bypass air above the liquid surface. It should be noted, however, that PAO turbulence in close proximity to the nozzle outlet may increase aerosol output. As such, the amount of agitation may be adjusted by the distance between the generation nozzle and introduction of bypass air beneath the liquid surface.
Referring now to
Compressed air (source not visible in the figures) may pass through a mist separator 730. The mist separator 730 filters particulate matter and some water within the air that enters the generator 700. If “dirty” air enters the system without using a mist separator, particulate matter can potentially clog various elements in the system. Larger filtered compressed air systems may adequately dry the air without a need for a mist separator. If a mist separator is used, water will collect in the mist separator 730 and can be drained off through a drain 731 in the bottom of the collection bowl 732. After passing through the mist separator 730, the compressed air enters a regulator 740. The regulator 740 is preferably a precision regulator that is better able to maintain the downstream pressure than some standard regulators. However, a standard regulator may be used. In order for the generator 700 to produce a stable output, it is important to maintain a stable downstream pressure. The regulator 740 typically supplies a determined pressure of air (in the embodiment shown, approximately 30 psi) to two speed control valves 745, 746. The speed control valves 745, 746 are essentially needle valves that restrict the flow of air. By using two valves 745, 746, the amount of air entering the bypass air inlet 715 and the air entering the generation nozzle 720, and the corresponding pressure at the generation nozzle 720, can be independently controlled. This assumes there is an unlimited supply of air being provided by the compressed air source and that the regulator 740 is able to deliver the air at the determined pressure. The pressure is monitored at the generation nozzle inlet by a pressure gauge 721. The typical operation pressures range from approximately 2 psi to 20 psi. Increasing the pressure on the generation nozzle 720 increases the amount of air flow through the nozzle 720, which increases the amount of particles generated by the nozzle 720.
A check valve 743, 744 is placed after each of the speed control valves 745, 746, respectively. The purpose of the check valves 743, 744 is, in typical fashion, to prevent oil or fluid backflow into the system. The air passing through the generation nozzle 720, the liquid particles being generated by the nozzle 720 and the bypass air will mix within the tank 710 and exit the tank 710 through the single outlet 713. The bypass air will create some air turbulence inside the tank 710 mixing the aerosol with the additional air supplied to the tank. The bypass air will also serve as a carrier, sweeping the newly generated particles out of the tank 710 more rapidly than if there were no bypass air.
There are two standard ways to increase particle generation through the nozzle. One is to provide more pressure to the nozzle and the other is to increase the diameter of the nozzle opening.
Referring again to
Upstream concentrations, even when at ultra-low values as specified herein, may be so large that an upstream discrete particle counter may be overwhelmed. Thus, in some embodiments, a combination of an upstream photometric scanner with a downstream discrete particle counter may be utilized in order to calculate the appropriate downstream penetration percentage concentration of the challenging aerosol. In general, an upstream aerosol photometer with an associated sampling or scanning head 208 may be used to determine ultra-low upstream concentrations. Associated with the upstream aerosol photometer and scanning head 208 may be a modified Laskin nozzle 202 which generates the ultra-low concentrations of the challenge PAO for the filter test and certification. Such Laskin nozzle generator may be used in combination with an aerosol reducer. The modified Laskin aerosol generator may be modified such that finite control and output of the challenge PAO concentrations may be maintained at such low concentrations as to not substantially affect the efficiency and effectiveness of the HEPA ePTFE filtration media 210 depicted. Such concentrations include controllable emissions of from about 1.0 μg/L down to about 0.01 μg PAO/L or lower which may include determination of concentrations down to about 0.1 μm/cubic foot or about 6 million particles per cubic foot or lower. Of course, the upstream detector 208 may be any type of ultra-low concentration detectors capable of accurately measuring the PAO concentrations on the upstream airflow and filter face such that an accurate calculation of the downstream concentration percentage may be made.
Associated with the modified Laskin nozzle 202 and aerosol reducer and upstream detector 208 is a downstream detector which must be capable of measurements as low as 0.01% of the ultra-low upstream concentrations. Thus, an exemplary laser particle counter 209 with a rectangular hand scan probe, as one example embodiment, may be utilized in order to scan the filter corners and having a 0.3 μm particles or smaller minimum detectable size and concentration and a rectangular hand scan probe to fulfill near isokinetic flow conditions.
For example, in some embodiments, a flow-thru system with sheath flow, multi-LED and/or laser diode for excitation may be used. Such associated electronics will utilize scattering for detection and should be capable for detection of particle sizes down to 0.1 μm and mass concentration of about 1 μg/L down to 0.01 μg/L or lower for use of a photodiode or discrete particle detector. Further, for very low concentrations, near particle counter detection may be utilized with mass aerosol at a minimum of 0.1 μm and larger (i.e. particle counter/photometer with the capability to measure the penetration of 0.01% when the upstream concentration is 0.01 μg/L and greater). As indicated, a processor may be integrated into the interfacing for auto-calculating particle counting into penetration of the filtering media to determine leakage.
Once known upstream and downstream concentrations are calculated, a leak rate calculation may be completed wherein the downstream concentration is divided into the upstream concentration to determine the leakage rate. Calculations as low as a value equal to or greater than 0.01% challenge concentrations downstream would indicate a leak within the filter or seal structure. Automated leak calculation may be implemented by electronically connecting the upstream scanner 208 and the downstream scanner 209 such that leakage rates which compare the two scans may be determined. Such electronic connection may be standard communication lines between the devices, electronic communication lines between a centralized computer which reads the data from each device and provides automated leakage calculation, or an integrated scanning device which is capable of interconnected upstream and downstream measurements and which, after a specified exposure time period, calculates the appropriate downstream concentrations and the leakage values.
An exemplary measurement test was conducted on the effects of ultra low (<0.3 mg/m3 (μg/L)) PAO concentration testing of ePTFE filters was performed. The study showed the equivalence and effectiveness of testing ePTFE filters with industry typical concentrations (10 mg/m3 (μg/L) or greater) and ultra low concentrations of PAO to detect leaks and determine their sizes.
The conventional test method of using a photometer and a ≧10 mg/m3 (μg/L) PAO challenge was employed as a means to size defects created in an ePTFE filter. The results were directly compared to an alternative test method that was composed of using a discrete particle counter (DPC) with ultra-low reduced (<0.3 mg/m3 (μg/L)) PAO challenge concentrations. Testing was performed by creating twelve defects in a HEPA filter of a LFH (Laminar Flow Hood). Comparative test data was then taken using the two methods. The testing construction is shown in
An X-Y axis linear bearing sample probe positioning device was placed in front of the LFH as a means to remove sampling variation due to probe positioning. This unit consisted of a base secured on the floor, with movable horizontal and vertical axes for exact probe positioning.
The exemplar was performed using a 610 mm×1220 mm (2 ft×4 ft) horizontal LFH as shown and depicted in
Measurement and test equipment utilized to determine aerosol challenge concentrations upstream of the testing ePTFE HEPA filter was a TSI 2-G photometer and a Lighthouse Solair model 3100 laser particle counter in combination with a Milholland & Associates model 450ADS aerosol diluter as listed in Table 1 below. The particle counter and diluter instrument combination was used to determine the actual number of challenge particles for ultra low level PAO testing (<0.3 mg/m3 (μg/L)) which corresponds to conditions 1 and 2 set forth in Table 1.
Study Conditions
The equipment and materials utilized in this sample test included the following: Discrete Particle Counter; Portable Self-Contained Aerosol Generator; Poly-alpha-olefin (PAO); Photometer; 2′×4′ Horizontal Laminar Flow Hood; Aerosol Dilutor; X-Y Axis Positioning Device; 12″×18′ Flexible Ducting; Air Data Multimeter; Handheld Ultrasonic Aneometer.
Three evaluated conditions were derived from a combination of the particle sizes (0.3 and 0.5 μm), photometer and DPC test equipment, and the selected aerosol challenge concentrations (PAO). The following Table 1 defines the test instruments, concentrations, and particle sizes tested. A PAO aerosol produced by a Laskin nozzle of 38 million particles >0.3 μm is equivalent to approximately 0.2 mg/m3 (μg/L).
Defects consisting of twelve holes were made in the ePTFE media by inserting a 30 gauge hypodermic needle into the media twice at each defect site. The average face velocity of 104 fpm (0.528 msec) was determined using the ultrasonic anemometer. The face area of the filter was 6.52 ft2. The volumetric flow through the filter was calculated to be 675 cfm. Pressure drop across the filter was measured to be 0.158″ wc. It was noted this was approximately 25% of the pressure drop of a comparable wet-laid microglass filter (0.58″ wc @650 cfm) operating at 90% of the airflow volume of ePTFE.
Upstream mixing was verified using a particle counter with ultra low concentrations of PAO as the challenge. Measurements were taken at six locations upstream of the ePTFE filter. The sample locations fell in between the two rows where the defects were created, that being approximately four inches below and above the first and second rows respectively. The PAO sample reading variance for the six locations was less than about 1%.
A quarter-sized Laskin nozzle generator was used in combination with an aerosol reducer (oil mist eliminator with an 18 gauge capillary bypass) to provide the upstream challenge. Thirty-second samples (0.5 ft3) were taken at each of the six locations and the counts per cubic foot are shown above. The differential pressure of the dilutor was measured at 4.89″ wc which corresponded to a dilution factor of 966. The Laskin nozzle generator with the aerosol reducer created a filter challenge of approximately 20 million particles at ≧0.3 μm and approximately 7 million particles at ≧0.5 micron per cubic foot of air. The sizing was repeated 10 times to gain statistical significance.
Ultra Low PAO <0.3 mg/m3 (μg/L) Challenge Using a Discrete Particle Counter (Conditions 1 and 2)
The ePTFE Filter was challenged with an ultra low level of PAO in the range of 0.3 mg/m3 (μg/L), as determined by the photometer. The defect sizes were measured in order starting with defect 1 and continuing sequentially to defect 12. After completing the defect sizing, a new upstream challenge was measured and defect sizing was repeated for a total of 10 runs to give statistically valid numbers.
At the beginning and end of each run the upstream challenge was recorded. At the end of run 8 it was noted that the upstream challenge was increasing at a significant rate. It was theorized that the increase was related to loading of the oil mist eliminator used to reduce the output of the aerosol generator. Runs 9 and 10 were excluded in the analysis due to the abruptly rising challenge concentrations.
Standard PAO 10.0 mg/m3 (μg/L) Challenge Using an Aerosol Photometer (Condition 3)
The third condition consisted of utilizing the traditional PAO aerosol/photometer method to size the defects created in the ePTFE filter. The ePTFE filter was challenged with approximately 10.7 mg/m3 (μg/L) (average upstream of 10 runs) of PAO using a TEC 1.5 Laskin nozzle generator operating at 20 psi. The defect sizes were measured with a photometer in order starting with defect #1 and continuing sequentially to defect #12. After completing sizing for all 12 defects, a new upstream challenge was measured and defect sizing was repeated for a total of 10 runs. The average (over 10 runs) defect size is shown below for each defect 1-12.
The performance of the ePTFE was unaffected during testing. The data showed that the ePTFE filter was unaffected by the testing as it maintained efficiency of at least 99.99% and a pressure drop of 0.1578″ H2O. This is compared to a capture efficiency of 99.99% and a 0.6″ H2O pressure drop across the glass filter at 90% of the airflow.
The average leak sizes for the three test conditions are shown in
Two test methods were employed to size defects in an ePTFE filter.
Ultra low level (˜0.4 μg/l) PAO challenge with a discrete particle counter
Standard level (−10 μg/1) PAO challenge with a photometer.
The results indicate that defects in the ePTFE filter can accurately be sized using ultra low level PAO challenges and a particle counter. Under the aforementioned test methods, both DPC test options (≧0.3 μm and ≧0.5 μm particle count defect sizing) performed adequate in comparison to the photometer.
The variation of sizing leaks with a discrete particle counter as set forth in the method herein falls within the variation of the individual photometer tested. The results provide validity to utilizing low PAO concentrations and DPC's to determine leak size in ePTFE filters. Utilizing this methodology, the loading of the filter will take 150-300 times as long based on previous testing.
Bypass Air Study Conditions
The test generators were operated with and without bypass air in order to compare output characteristics (concentration and particle geometries) of the generator.
While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.
All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This current application is a continuation-in-part of, and claims priority to and benefit from, currently pending U.S. patent application Ser. No. 13/462,017, filed on May 2, 2012, which is a continuation of currently pending PCT International Patent Application Serial Number PCT/US11/59796, filed on Nov. 8, 2011, which claims priority to U.S. Provisional Patent Application Ser. No. 61/411,279, filed on Nov. 8, 2010.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3495440 | Koblin et al. | Feb 1970 | A |
| 4382378 | Wadsworth et al. | May 1983 | A |
| 5076965 | Guelta et al. | Dec 1991 | A |
| 5203201 | Gogins | Apr 1993 | A |
| 5498374 | Sabroske | Mar 1996 | A |
| 5507847 | George et al. | Apr 1996 | A |
| 5876489 | Kunisaki et al. | Mar 1999 | A |
| 6269681 | Hara | Aug 2001 | B1 |
| 6416562 | Shibuya et al. | Jul 2002 | B1 |
| 6435009 | Tilley | Aug 2002 | B1 |
| 6561498 | Tompkins et al. | May 2003 | B2 |
| 6627563 | Huberty | Sep 2003 | B1 |
| 7614280 | Gardner et al. | Nov 2009 | B1 |
| 20030150255 | Hackett, Jr. | Aug 2003 | A1 |
| 20080022642 | Fox et al. | Jan 2008 | A1 |
| 20080236305 | Masset et al. | Oct 2008 | A1 |
| 20080245041 | Choi | Oct 2008 | A1 |
| 20090255325 | Morse et al. | Oct 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 8136437 | May 1996 | JP |
| 8238307 | Sep 1996 | JP |
| 10244116 | Sep 1998 | JP |
| 2002243626 | Aug 2002 | JP |
| 2007178082 | Jul 2007 | JP |
| 2007015803 | Feb 2007 | WO |
| Entry |
|---|
| European Committee for Standardization, “High efficiency air filters (EPA, HEPA and ULPA)”—Parts 1-5, Nov. 2009, pp. 1-151, Brussels. |
| Jornitz, M.W., Meltzer, T.H., “Filtration and Purification in the Biopharmaceutical Industry,” Second Edition, Informa Healthcare, Drugs and the Pharmaceutical Sciences, vol. 174, pp. 627-639. |
| Kahler, C.J., Sammler, B., Kompenhans, J., “Generation and Control of Tracer Particles for Optical Flow Investigations in Air”; Abstract, 420 Session 7, (2002), Exp. Fluids 33, 736-742. |
| Roberts, R., “The Effect of PAO Aerosol Challenge on the Differential Pressure of an ePTFE Media ULPA (Experimental) Filter,” Journal of the IEST 2003 Edition, pp. 74-76. |
| Wikol, M. et al, “Expanded Polytetrafluoroethylene Membranes and Their Applications,” Filtration and Purification in the Biopharmaceutical Industry, Second Edition, Informa Healthcare, pp. 619-640. |
| FDA, “Draft Guidance for Industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice,” Aug. 2003, Pharmaceutical CGMPs, pp. 1-59. |
| FDA, “Draft Guidance for Industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice,” Sep. 2004, Pharmaceutical CGMPs, pp. 1-59. |
| Korean Intellectual Property Office; The International Search Report and the Written Opinion of the International Searching Authority, or the Declaration; International Search Report and Written Opinion for PCT/US/2011/059796; Jun. 27, 2012; pp. 1-10, Korean Intellectual Property Office, Korea. |
| Number | Date | Country | |
|---|---|---|---|
| 20130192344 A1 | Aug 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61411279 | Nov 2010 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2011/059796 | Nov 2011 | US |
| Child | 13462017 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13462017 | May 2012 | US |
| Child | 13804503 | US |
