HEPA and ULPA Filters

[ The Aseptic Core. Coordinated by Ed White HEPA and ULPA Filters Ed White The Aseptic Core discusses scientific and regulatory aspects of aseptic processing, with an emphasis on aseptic formulation and filling. This column provides practical advice to professionals involved in the qualification of aseptic processes and the myriad support processes involved. The primary objective for this column: Useful information. Reader comments, questions, and suggestions are needed to help us meet our objective for this column. Discussion topics and case studies related to aseptic processing submitted by readers are invited. Please e-mail your suggestions to coordinating editor Susan Haigney at shaigney@advanstar.com. KEY POINTS The following key points are discussed in this article: High efficiency particulate air (HEPA) filters and ultralow penetration air (ULPA) filters are used in almost every aseptic process HEPA filters have an efficiency of at least 99.97% for 0.3-micrometer particles. ULPA filters have an efficiency of at least 99.999% HEPA and ULPA filters consist of a filter frame, filter media, separators, bond material, and gasket material HEPA and ULPA filters work by the sieve effect, inertial impaction, interception, and diffusion Use of HEPA and ULPA filters in critical zones is mandated by US and international current good manufacturing practice (CGMP) regulations HEPA and ULPA filter testing generally includes verification of airflow velocity and installed filter leakage testing HEPA and ULPA filter leak tests include the photometer method (most commonly used method) and the discrete particle count method (used for specialized installations) HEPA and ULPA maintenance typically includes periodic replacement of pre-filters, monitoring of pressure drop across the filters, periodic inspection of ductwork upstream of the HEPA and ULPA filters, and periodic inspection of gaskets and gel seals. INTRODUCTION HEPA and ULPA filters are found in every aseptic processing facility. They are necessary for almost every aseptic process, yet few people think much about them. This column provides an overview of HEPA and ULPA filters. WHAT ARE HEPA AND ULPA FILTERS? HEPA and ULPA filters are designations for specialized filters designed to filter dry air with a rated efficiency of 99.97% or greater. They are not absolute filters, but instead provide a rated reduction in particulate burden as verified by a particulate challenge. HEPA and ULPA filters consist of the following components: Filter frame. The filter frame holds the filter media in place, provides a rigid frame to promote uniform air flow, and provides a surface for attachment of a gasket or gel seal. Filter frames can be constructed of many materials, including galvanized steel, stainless steel, plywood, particle board, aluminum, or plastic. Pharmaceutical HEPA filters are typically constructed with an aluminum, stainless steel, or galvanized steel (non-critical application) frame; some biosafety hoods or laminar flow hoods may have plywood or particle board frames. Filter media. The filter media is a fibrous material typically constructed of randomly arranged and tightly packed glass or ceramic fibers. The filter media is typically pleated to provide more filter surface area within [ For more Author information, go to /bios ABOUT THE AUTHOR Ed White is a QA validation specialist at Baxter Healthcare Bioscience, Thousand Oaks, CA. He may be reached at ed_white@baxter.com. 48 Journal of Validation Technology [Summer 2009] ivthome.com

Ed White, Coordinator. a given space. Some ULPA filters are constructed of expanded PTFE fluoropolymer (eptfe). These filters are typically used for specialized applications or in the semiconductor industry, as they are incompatible with polyalphaolefin (PAO). Separators. The separators are used to keep the pleats apart, maximizing the effective filter area of the HEPA. The separators can be constructed of corrugated aluminum or be of the minipleat design. In the minipleat design, shown in Figure 1 and Figure 2, pleated filter media is separated by strips of filter media or adhesive. This design allows the media to be more closely packed than in a HEPA filter with aluminum separators. The majority of HEPA filters used in pharmaceutical facilities is of the minipleat design. Bond material. The bond material is used to attach the filter media to the filter frame. The bond material may be made of several different adhesives, including epoxy, silicone, and polyurethane. Gasket or gel seal. This ensures that air flows through, rather than around, the filter media. Filters may have gasket seals or gel seals, depending on the installation type. Gaskets are either adhesive bonded to the filter frame or are formed in place. Gel seal filters have special channels into which silicone or urethane gel is poured. When installed, the gel channel mates with a knife edge installed in the ceiling grid or filter module. A metal tab typically holds the filter in place, allowing the knife edge to float in the gel. It is important that the knife edge stays above the bottom of the gel channel to ensure a positive seal. Figure 3 illustrates a typical gel seal. HEPA and ULPA filters only differ in their efficiency ratings. HEPA stands for high efficiency particulate air filter. A HEPA filter is capable of filtering out >99.97% of particulate matter averaging 0.3 micrometers in diameter. ULPA stands for ultra-low penetration air filter. An ULPA filter is capable of filtering >99.999% of particulate matter at the most penetrating particle size (MPPS). For most filters, including HEPA filters, the most penetrating particle size is in the range from 0.1 micrometers to 0.2 micrometers. WHY USE HEPA FILTERS? The use of HEPA filtration in critical areas is mandated in the US Food and Drug Administration and international regulations for critical processing areas, including the following: 21 CFR 211.42(c) (1) states, There shall be separate or defined areas or such other control systems for the firm s operations as are necessary to prevent contamination or mix-ups during the course of the following procedures: (10) Aseptic processing, which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or non-laminar 21 CFR 211.46(c) (2) states, Air filtration systems, including pre-filters and particulate matter air filters, shall be used when appropriate on air supplies to production areas The FDA aseptic processing guidance document (3) states, HEPA-filtered air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area. EU GMP Annex 1 (4) states, The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air, which has passed through filters of an appropriate efficiency. The requirement for HEPA filtration of air entering aseptic process areas is critical to maintaining the cleanliness of the aseptic processing environment and in maintaining the sterility of aseptically processed products. Because there is no additional bioburden reduction for aseptically processed products, a single contamination event will compromise the sterility of the product. By supplying HEPA-filtered air to the aseptic processing area, the pharmaceutical manufacturer significantly reduces the probability of a contamination event. The aseptic processing guidance (3) document summarizes this concept in the following statement: To maintain product sterility, it is essential that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be controlled and maintained at an appropriate quality. One aspect of environmental quality is the particle content of the air. Particles are significant because they can enter a product as an extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for microorganisms. Appropriately designed air handling systems minimize particle content of a critical area. Journal of Validation Technology [Summer 2009] 49

The Aseptic Core. Figure 1: Typical minipleat filter construction. Epoxy bond Gasket Pleated filter media Strip of filter media or adhesive used to maintain separation between pleats Frame HOW DO HEPA FILTERS WORK? Because of the filter media used, HEPA filters are more analogous to depth filters than to membrane filters. HEPA filters capture airborne particles through several mechanisms including the sieve effect, impaction, interception, and diffusion, as follows: Sieve effect. This effect occurs for large particles (>5 micrometers in diameter). These particles are just too large to fit through the open areas in the filter media. Removal efficiency for large particles due to the sieve effect is typically >99.9999%. Inertial impaction. Inertial impaction occurs as particles are carried through the filter media by the airstream. As the airstream shifts to flow around fibers, inertia causes the particles carried by the airstream to impact the fibers. This mechanism typically occurs for particles in the 0.5 micrometer to 5 micrometer range. Interception. Smaller particles may be intercepted by the fibers when they come within 1 particle diameter of a fiber when following the gas stream. This mechanism can be effective because of the high fiber density of HEPA and ULPA filter media. This mechanism is effective in the 0.1 micrometer to 1 micrometer range. Brownian diffusion. Brownian diffusion occurs with very fine particles that are small enough to be affected by collision with the gas molecules in the airstream. Brownian motion causes these particles to move randomly within the airstream, increasing the probability of the particles contacting a fiber. HEPA FILTER CLASSIFICATIONS HEPA filters are classified by the Institute for Environmental Sciences and Technology (IEST) in their Recommended Practice IEST-RP-CC001 (5) HEPA and ULPA filter classifications range from Type A to Type K, but not all of these classifications are commonly used in the pharmaceutical industry. HEPA/ULPA filter types C, D, and F are commonly used in the pharmaceutical industry. Type J and type K filters may be used in ultraclean applications such as filling isolators or aseptic compounding. EN1822 types H14 and U15 are commonly used in Europe. The Table lists some common filter types used in the United States and Europe and their ratings. HEPA AND ULPA FILTER TESTING HEPA and ULPA filters are typically tested as part of certification of a cleanroom environment. Tests specific to HEPA and ULPA filters only are discussed. Tests for the larger cleanroom environment will be discussed in an upcoming column. Tests specific to the HEPA and ULPA filters include the following: Airflow velocity is mandatory for unidirectional cleanrooms or clean zones, optional for non-unidirectional cleanrooms or clean zones Airflow volume is mandatory for unidirectional or non-unidirectional cleanrooms or clean zones Installed filter system leakage test (ISO 14644-3, Clause B.6) for all cleanrooms. Airflow Velocity Test For the airflow velocity test, the filter is checked for velocity at several points using an airflow velocity meter or airflow hood. The filter is typically divided into a grid of equal surface areas, not to exceed 4 ft 2 or 0.4 m 2. The average velocity of each filter should be within the range of 0.37 meters/second to 0.54 meters/second (0.45 m/s ±20%). The relative standard deviation (RSD) across the filter bank (or filter for individual filter installations) should be 15% or less. The RSD is calculated by dividing the standard deviation of the readings by the average of the readings, and multiplying the result by 100. The airflow velocity for a particular clean room may differ and should be based on maintaining a proper airflow over critical zones. Higher or lower velocities may be appropriate, especially in specialized installations such as isolators, depyrogenation tunnels, and depyrogenation ovens. Airflow Volume Test This test is typically performed using an electronic micromanometer with an appropriate airflow hood. 50 Journal of Validation Technology [Summer 2009] ivthome.com

Ed White, Coordinator. It can also be performed by multiplying the average airflow velocity of the filter by the effective surface area of the filter. The airflow volume of each filter is measured using the hood (this may require multiple measurements for larger filters), and the total volume of air supplied by all of the filters in a room is divided by the volume of the room to determine the number of air changes per hour in the room. Installed Filter Leakage Test The installed filter leakage test may be performed using one of two methods: the photometer method or the discrete particle count method. In both methods, a challenge aerosol is introduced upstream of the filter, and the filter is scanned to detect leakage >0.01% of the upstream concentration. Installed Filter System Leakage Test Photometer Method The photometer method is the most accepted method in the pharmaceutical and biotech industries. In this method, an aerosol challenge, typically Polydisperse PAO, is introduced upstream of the filter in such a way that the challenge is uniformly distributed across the filter. An upstream concentration is taken, and the aerosol generator is adjusted to achieve a challenge level of approximately 10 µg/l to 90 µg/l. The aerosol photometer is adjusted to read 100% at the upstream concentration, and then it is used to scan the filter. Any measurement >0.01% of the upstream concentration is considered a designated leak, assuming a photometer sampling rate of 1 cubic foot/minute (28.3 L/min). The leak may be repaired using silicone sealant if the repair is less than 1.5 inch (3.8 cm) in any direction and if the repairs cover less than 3% of the filter surface. If either of these criteria is exceeded, the filter should be replaced. Whether the filter is repaired or replaced, the leak test should be repeated. The aseptic processing guidance (3) states, A single probe reading equivalent to 0.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for replacement of the HEPA filter or, when appropriate, repair in a limited area. A subsequent confirmatory retest should be performed in the area of any repair. Figure 2: Typical minipleat HEPA filter with gel seal. Figure 3: Typical gel seal installation. Ceiling grid or filter housing Knife edge Wing nut Silicone or urethane gel Acorn nut Filter frame Adhesive Metal tab Filter media Installed Filter System Leakage Test Discrete Particle Count Method The particle count method is little used in the pharmaceutical and biotech industries because of the somewhat greater complexity of the test, and the greater acceptance of the photometer method by regulatory agencies, especially FDA. This method is widely used in the semiconductor industry because of industry concerns about molecular contamination of silicon wafers with PAO. This method is generally limited to specialized applications such as depyrogenation tunnels and ovens where burn off of PAO after certification procedure is a concern. Large installations of gel-seal filters are also of concern because PAO can interact with gel seals causing hardening or liquifaction of the gel-seal material. This method can use polystyrene microspheres instead of PAO, or may use PAO in much lower concentrations than the photometer method. In this method, a challenge aerosol consisting of polystyrene microspheres or PAO with a count median diameter (CMD) between 0.1 µm and 0.3 µm is introduced upstream Protective screen Journal of Validation Technology [Summer 2009] 51

The Aseptic Core. Table: IEST RP-CC001 and EN1822-1 filter classifications typically used for pharmaceutical and biotech applications. Filter Type Minimum % Efficiency Particle Size μm Integrity Test Method Application B 99.97% 0.3 MMD Two flow leak test HEPA filters for low classification areas C 99.99% 0.3 MMD Photometer-Polydisperse PAO General use HEPA filters D 99.999% 0.3 MMD Photometer-Polydisperse PAO General use HEPA filters; critical zone filters; isolator applications; large installations where hot aerosol generators are needed F >99.999% 0.1-0.2 or 0.2-0.3 Particle count or photometer- Aerosol challenge may be polydisperse PAO or polystyrene microspheres (polystyrene latex beads) Critical zone filters; isolator applications; large installations where hot aerosol are needed J 99.99% 0.1-0.2 or 0.2 to 0.3 Particle count or photometer-polydisperse PAO High airflow installations K 99.995% 0.1-0.2 or 0.2 to 0.3 Particle count or photometerpolydisperse PAO Critical zone filters; isolator applications; large installations where hot aerosol generators are needed H14 (EN1822) 99.995% MPPS Photometer-polydisperse PAO General use HEPA filters U15 (EN1822) 99.9995% MPPS Photometer-polydisperse PAO General use HEPA filters; critical zone filters; isolator applications; large installments where hot aerosol generators are needed *MMD: Mass Median Diameter; MPPS: Most Penetrating Particle Size; PAO: Polyalphaolefin at a concentration of approximately 10 6 particles/ft 3. Challenge concentration is measured using a particle counter with an appropriate measuring range for the particulate challenge. Because the particle counting range is outside the operating range of the particle counter, the sample must be diluted using a special instrument that uses a capillary tube to provide a precise and repeatable dilution factor. The particle count is multiplied by the dilution factor to obtain the concentration of the aerosol in particles/ft 3. The downstream side of the filter is scanned with a particle counter with a specialized probe. Any particle count >0.01% of the upstream concentration is considered a designated leak. In practice, any count >3 particles/ft 3 encountered during scanning should be verified by a stationary scan. IEST Recommended Practice IEST-RP-CC034.2 and ISO 14644-3 give more detailed instructions on how to perform the discrete particle count method and the photometer method. HEPA FILTER MAINTENANCE AND REPLACEMENT Other than periodic recertification, HEPA filters require little maintenance. The types of maintenance required may include the following: Periodic replacement of pre-filters upstream of the HEPA/ULPA filters prevents premature loading of the HEPA/ULPA filters by reducing the particle load reaching the filters. Monitoring of the pressure drop across the filters using a differential pressure sensor. When the differential pressure reaches or exceeds the manufacturer s recommended pressure drop, the filters should be replaced. Periodic inspection of the ductwork upstream of the HEPA filter to ensure that there is no buildup of particulate matter or debris that could damage the HEPA filters. Periodic inspection, where possible, of gaskets or gel seals for evidence of deterioration. 52 Journal of Validation Technology [Summer 2009] ivthome.com

Ed White, Coordinator. VALIDATION IMPLICATIONS It is impossible to validate a critical processing environment without ensuring that the supply air to the environment is properly filtered and that the filters have been installed properly. The validation of HEPA and ULPA filters should provide this assurance. The installation qualification (IQ) should include proper installation of the filters, including inspection of the associated equipment (e.g., prefilters, excessive particulate in ductwork, etc.). Gel seals and gaskets should be inspected. Testing, including pressure drop testing, should be conducted. Requirements for the preventative maintenance program are specified in the IQ. The operational qualification (OQ) would include filter certification testing, including airflow velocity, airflow volume, and system leakage. Filter performance qualification (PQ) testing will be discussed as part of qualifying the cleanroom environment in a future column. HEPA and ULPA filter testing is crucial to any validation program, whether this testing is performed by the validation department, maintenance department, or an external service. Review of the HEPA certification program should be part of the initial qualification or requalification of an aseptic environment. Qualification and requalification of an aseptic processing environment will be covered in the next issue of The Aseptic Core. GLOSSARY Aerosol photometer: Aerosol photometer is an instrument that measures mass concentration of aerosols using the forward light scattering principle. Challenge aerosol: Aerosol generated from a selected aerosol source material to be used as an upstream challenge for HEPA and ULPA filter leak testing. Count median diameter (CMD): CMD is the median diameter of the numeric distribution of the challenge aerosol 50% of the particles in the challenge distribution are larger than the CMD, and 50% of the particles are smaller than the CMD. Designated leak: A designated leak is a leak that should be detectable during scanning of a filter. A leak greater than or equal to 0.01% of the upstream concentration (when using an aerosol photometer) or upstream particle count (when using a discrete particle counter) should be detectable. Discrete particle counter (DPC): Discrete particle counter is an instrument capable of counting and sizing individual airborne particles. This is the familiar cleanroom particle counter. A DPC used for filter leak testing should be able to count particles at 0.3 micrometers or greater. HEPA (high efficiency particulate air) filter: A dry, extended media filter in a rigid frame, having a minimum particle collection efficiency of 99.97% for 0.3 µm mass median diameter particles of PAO. Laskin nozzle aerosol generator: An aerosol generator using a specialized nozzle (Laskin nozzle) to generate a heterogeneous (polydisperse) aerosol from liquid PAO, using compressed air as a source (compressed nitrogen should be used for a hot aerosol generator). For smaller installations, a cold aerosol generator that generates the aerosol directly using a Laskin nozzle may be used. For large installations, a hot generator that superheats the vapor generated by the Laskin nozzles then re-condenses the vapor as a cold polydisperse aerosol is used. Mass median diameter (MMD): Mass median diameter is the 50th percentile of the mass distribution of the aerosol. Monodisperse aerosol: Monodisperse aerosol is one having a relatively narrow distribution of particle sizes. Polystyrene microspheres are an example of a monodisperse aerosol. Most penetrating particle size (MPPS): MPPS is the particle size at which a HEPA or ULPA filter has its lowest efficiency. The MPPS represents the worst-case filter challenge for efficiency testing. PAO: PAO stands for polyalphaolefin, which is a synthetic oil commonly used in the pharmaceutical industry. A Polydisperse aerosol of PAO is commonly used as a challenge material for leak testing of HEPA and ULPA filters. Polydisperse aerosol: Polydisperse aerosol is one having a broad distribution of particle sizes. An example of a Polydisperse aerosol is a PAO aerosol generated by a hot or cold aerosol generator. Polystyrene latex (PSL) beads: PSL beads are a uniform suspension of polystyrene microspheres in water, usually with a small amount of surfactant to ensure stable dispersion of the microspheres. PSL is used as an alternative challenge to PAO when using the particle count method for leak testing ULPA filters. Journal of Validation Technology [Summer 2009] 53

The Aseptic Core. The term polystyrene latex beads is somewhat misleading, as this material does not contain any natural rubber latex. The term latex in this case refers to a stable, uniform suspension of particles in an aqueous medium. Because of the confusion between polystyrene latex and natural rubber or plant-based latex, the term polystyrene microspheres is becoming a common synonym for PSL. Scanning: Method of testing for leaks in HEPA or ULPA filters. During a filter scan, an aerosol photometer or discrete particle counter sampling probe is slowly moved across the filter in a series of parallel overlapping strokes. The sampling probe is typically kept about 1 inch away from the filter surface. When a potential leak is detected, the probe is held stationary for a short period of time to verify the leak. Standard leak penetration: Standard leak penetration is the leak penetration measured by a stationary probe using a particle counter or photometer with a flow rate of 1 cubic foot per minute (28.3 liters per minute). ULPA (ultra-low penetration air) filter: An ULPA filter is a dry extended media filter in a rigid frame, with a minimum particle-collection efficiency of 99.999%. Depending on the filter, the particle-collection efficiency can be measured at 0.3 µm or at MPPS. ULPA filters can be used in most applications where HEPA filters are used. REFERENCES 1. FDA, Code of Federal Regulations, Title 21 Food And Drugs, Chapter I Food And Drug Administration, Department Of Health And Human Services, Subchapter C Drugs: General, Part 211 Current Good Manufacturing Practice For Finished Pharmaceuticals, Subpart C Buildings and Facilities, Sec. 211.42 Design and construction features, Revised as of April 1, 2008. 2. FDA, Code of Federal Regulations, Title 21 Food And Drugs, Chapter I Food And Drug Administration, Department Of Health And Human Services, Subchapter C Drugs: General, Part 211 Current Good Manufacturing Practice For Finished Pharmaceuticals, Subpart C Buildings and Facilities, Sec. 211.46 Ventilation, air filtration, air heating and cooling, Revised as of April 1, 2008. 3. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, 2004. 4. European Commission: Enterprise and Industry Directorate-General, EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products (corrected version), 2008. 5. Institute of Environmental Sciences and Technology, Recommended Practice, IEST-RP-CC001, 2005. JVT GENERAL REFERENCES Institute of Environmental Sciences and Technology, IEST-RP- CC001.4, HEPA and ULPA Filters, 2005. IEST, IEST-RP-CC006.3, Testing Cleanrooms, 2004. IEST, IEST-RP-CC007.2, Testing ULPA Filters, 2007. IEST, IEST-RP-CC021.2, Testing HEPA and ULPA Filter Media, 2005. IEST, IEST-RP-CC034.2, HEPA and ULPA Filter Leak Tests, 2005. International Organization for Standardization (ISO). ISO 14644-1, Cleanrooms and associated controlled environments, Part 1: Classification of Air Cleanliness, 1999. ISO, ISO 14644-2, Cleanrooms and associated controlled environments Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1, 2000. ISO, ISO 14644-3, Cleanrooms and associated controlled environments Part 3: Test Methods, 2005. European Committee for Standardization. EN 1822-1:1998: High efficiency air filters (HEPA and ULPA) Part 1: Classification, performance testing, marking, 1998. ARTICLE ACRONYM LISTING CGMP Current Good Manufacturing Practice CMD Count Median Diameter FDA US Food and Drug Administration HEPA High Efficiency Particulate Air IEST Institute for Environmental Sciences and Technology IQ Installation Qualification ISO International Organization for Standardization MMD Mass Median Diameter MPPS Most Penetrating Particle Size OQ Operations Qualification PAO Polyalphaolefin PQ Performance Qualification RSD Relative Standard Deviation ULPA Ultra-Low Penetration Air 54 Journal of Validation Technology [Summer 2009] ivthome.com