AAF Whitepaper HEPA filter leak testing
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This whitepaper discusses the development and current practices of HEPA filter leak testing in cleanroom environments, focusing on two main methods: aerosol photometers (AP) and discrete particle counters (DPC). It outlines the historical context, regulatory requirements, and comparative effectiveness of these methods, highlighting the shift towards DPC technology due to its better resolution and lower toxicity hazards. The paper also references developments in HEPA filters using ePTFE media, which have been adapted for pharmaceutical applications.
![Development and current state of installed HEPA filter leak testing Page 3
HEPA filter leak testing procedures
Installed HEPA filter leak testing on a routine basis was started in most
pharmaceutical companies in the 1970s and 1980s. Traditionally, leak testing
procedures using aerosol photometers (AP) were dominant, and more
recently procedures using discrete particle counters (DPC) were introduced.
Requirements on leak testing using the aerosol photometer method were
published by the U.S. Food and Drug Association (FDA) in their 1987 and
2004 Aseptic Processing Guidance, and the Institute of Environmental
Sciences and Technology (IEST) recommended practices [1,2,3]. Figure 1
shows the measurement method diagrammatically using an aerosol photom-
eter, and figure 2 shows the procedure using a particle counter. Table 1 shows
a comparison of the two test methods, AP and DPC with regard to aerosol
concentration and test method sensitivity.
Figure 1: Aerosol challenge: Photometer
Particle
Generator
Upstream
Concentration
Photometer
% Leak
Downstream
Concentration
HEPA filter
Figure 2: Aerosol challenge: Particle counter
Particle
Generator
Upstream
Concentration
Downstream
Concentration
HEPA filter
Particle Counter
# of Particles
Dilutor
A dilutor is required to keep the particle counter from
over concentrating. Upstream concentration will be
> 6M particles per cubic foot. Most particle counters
have a coincidence error of 10% at 1M p/cf.](https://image.slidesharecdn.com/14-11-2014aafwhitepaperhepafilterleaktestingenglish-141117061605-conversion-gate01/85/AAF-Whitepaper-HEPA-filter-leak-testing-3-320.jpg)
![Development and current state of installed HEPA filter leak testing Page 4
The AP method had to be modified in the late 1980s due to concerns about
potential toxicity hazards with the oil used to generate the test aerosol,
Dioctyl-phthalate (DOP). The use of alternative oils, including poly-alpha
olefins (PAO), and di-ethyl-hexyl-sebacate (DEHS) was developed. Taking into
account the principal disadvantage of the AP method, principally the need
for higher challenge aerosol concentration, and recognizing the potential
hazards concerning the oil used to generate the aerosol, alternative methods
were investigated and introduced. The development of a German VDI
standard on this topic began with an AP procedure, and was finalized in the
1980s with a DPC method [4]. An initial study on the correlation of both test
methods by Kase [5] demonstrated a better resolution for the DPC method.
Some European pharmaceutical companies, particularly those not influenced
by US practice, developed a preference for the method [6]. For the micro-
electronics industry, the advantage of using lower aerosol concentrations,
and the ability to avoid using oil aerosol sources proved crucial to avoid
outgassing airborne molecular contamination. Hence, DPC testing became
the only standard in that industry.
In 1994 Moore et al published a paper comparing the effectiveness of
alternate test challenge aerosols on HEPA filters with controlled defects.
This work demonstrated that less toxic alternatives to DOP are available,
offering safe and reliable leak testing [7]. A further aspect of the Moore
paper was the introduction of the “controlled defect” method, allowing
to clearly identify leaks of the critical size 0.3 mm.
The Moore paper referred to above, ICCCS symposium proceedings,
and subsequent conferences show that using the “controlled defects”
method can demonstrate a satisfactory correlation of data for using different
aerosol substances: DEHS (di-ethyl-hexyl-sebacate), DOP (dioctyl phthalate),
PAO (poly-alpha-olefin), and different procedures (AP & DPC) [8,9].
Since the 1990s, several European pharmaceutical companies reported
presenting their HEPA filter leak detection procedure, using a DPC method
based on the VDI 2083-3 standard to US FDA officials without basic
objections.
Table 1: Comparison of the Aerosol Photometer method (AP) and the Discrete Particle Counting method (DPC)
Critical Parameters Aerosol Photometer (AP) Discrete Particle Counter (DPC)
Aerosol Concentration 20-80 mg/m3 20-80 µg/m3
Sensitivity / Resolution Low High 1)
Particle Size Distribution Broad Narrow
Impact on Ducting and HEPA filters 2) High No
Ease of undertaking the test Relatively simple test method Relatively simple test method
1) Meaning that the test is sensitive to contamination in the environment, suited to determine the performance of ULPA filters.
2) Deposition of oil, loading of filters increasing pressure drop.](https://image.slidesharecdn.com/14-11-2014aafwhitepaperhepafilterleaktestingenglish-141117061605-conversion-gate01/85/AAF-Whitepaper-HEPA-filter-leak-testing-4-320.jpg)
![Development and current state of installed HEPA filter leak testing Page 5
The first international standard dealing with installed HEPA filter leak testing,
ISO 14644-3:2005 presents both methods, clarifying that for ultra low
penetration air filters (ULPA) as well as for large installations only the DPC
method offers suitable resolution [10].
HEPA filters using ePTFE (poly-tetra-fluor-ethylene) media instead of fibreglass
filter media are well established and have been used in microelectronics for
decades. Recently these HEPA filters with ePTFE membrane, featuring reduced
pressure drops and increased mechanical stability, have been introduced in
pharmaceutical industry. For such filters DPC testing is preferred to avoid an
extreme increase of pressure differential that would occur if the filter were
exposed to an oil aerosol [11, 12]. Whereas both procedures, aerosol
photometry and discrete particle counting, are useful for traditional require-
ments of the pharmaceutical industry, the latter seems to offer the greater
opportunity in terms of resolution and precision of installed HEPA filter leak
testing.](https://image.slidesharecdn.com/14-11-2014aafwhitepaperhepafilterleaktestingenglish-141117061605-conversion-gate01/85/AAF-Whitepaper-HEPA-filter-leak-testing-5-320.jpg)
![Development and current state of installed HEPA filter leak testing Page 6
References
[1] Guidance for Industry: Sterile drug products produced by aseptic
processing - Current Good Manufacturing Practice. U.S. Department
of Health and Human Services, Food and Drug Administration FDA,
(September 2004). Rockville, Maryland, USA.
[2] IES-RP-CC006.2 Testing Cleanrooms, Clause 6.2: HEPA and ULPA filter
installation leak tests. IEST Institute of Environmental Sciences and
Technology, Mount Prospect, Illinois.
[3] IES-RP-CC007.1 Testing ULPA Filters, IEST Institute of Environmental
Sciences and Technology, Mount Prospect, Illinois.[4] VDI 2083 Part 3:
Cleanroom technology; Metrology and test methods (1993), Beuth
Verlag, Berlin.
[4] VDI 2083 Part 3: Cleanroom technology; Metrology and test methods
(1993), Beuth Verlag, Berlin.
[5] Kase, T., Y. Suzuki, E. Hitoshi, O. Nobuyoshi, Y. Takeshi, S. Satoki:
A Study on Testing of HEPA Filters. Kuki Seijo to Kontamineshyon
Kontororu Kenkyu Taikai Yokoshu, (1990) vol. 9th, pp. 221 224. Journal
Code Y0789A.
[6] Redeker, F., R. Hünert, M. Rohnen, L. Hänsch: Funktionsprüfung von
Hosch-Filtern in Laminar-flow-Anlagen. Pharm. Ind. 49 (1987) 1.
[7] Moore Jr., D. R., J. G. Marshall, M. A. Kennedy: Comparative testing
of challenge aerosols in HEPA filters with controlled defects. ISPE
Pharmaceutical Engineering March/April 1994.
[8] Gail, L., F.Ripplinger: Correlation of alternative aerosols and test methods
for HEPA filter leak testing, Proc. Int. Symp. on Contamination Control,
IEST Institute of Environmental Sciences and Technology, Phoenix,
Arizona, 1998.
[9] Gail, L. , D. Stanischewski: Installed HEPA Filter Leak Testing by Using
Discrete Particle Counting, Proceedings, International Symposium on
Contamination Control, Institute of Environmental Sciences and
Technology, Anaheim, CA, 2002.
[10] EN ISO 14644-3:2005: Cleanrooms and associated controlled
environments - Part 3: Test Methods, Geneva.
[11] Osborne, M.W., L. Gail, P. Ruiter, and H. Hemel: Applied membrane air
filtration technology for best energy savings and enhanced performance
of critical processes, Proceedings, International Symposium on Contami-
nation Control 2010, Zurich.
[12] Bryan, E., B. Kitch, J. Meek, D. Milholland, N. Nance (2011) “Alternative
Test Methodology for In-Situ Testing of ePTFE HEPA Filters for Pharma-
ceutical Applications“, Pharmaceutical Engineering, vol. 31, no.6.
More information
For more detailed information about HEPA filter leak testing and
HEPA filters featuring ePTFE membrane media, please contact
Dr.-Ing. Marc Schmidt at: marc.schmidt@aafeurope.com
@](https://image.slidesharecdn.com/14-11-2014aafwhitepaperhepafilterleaktestingenglish-141117061605-conversion-gate01/85/AAF-Whitepaper-HEPA-filter-leak-testing-6-320.jpg)
AAF Whitepaper HEPA filter leak testing
- 1. HEPA filter leak testing Development and current state of installed HEPA filter leak testing Whitepaper Dr.-Ing. Marc Schmidt, Dr.-Ing. Lothar Gail, Hugo Hemel MSc.
- 2. Abstract For the leak testing of installed HEPA filters in cleanroom environments, two testing procedures are available being aerosol photo meters (AP) and discrete particle counters (DPC). This paper provides a short outline on the historic development, current state and characteristics of both procedures. Key words: Installed HEPA filter leak testing, ePTFE membrane media, aerosol photometer, discrete particle counter. Development and current state of installed HEPA filter leak testing
- 3. Development and current state of installed HEPA filter leak testing Page 3 HEPA filter leak testing procedures Installed HEPA filter leak testing on a routine basis was started in most pharmaceutical companies in the 1970s and 1980s. Traditionally, leak testing procedures using aerosol photometers (AP) were dominant, and more recently procedures using discrete particle counters (DPC) were introduced. Requirements on leak testing using the aerosol photometer method were published by the U.S. Food and Drug Association (FDA) in their 1987 and 2004 Aseptic Processing Guidance, and the Institute of Environmental Sciences and Technology (IEST) recommended practices [1,2,3]. Figure 1 shows the measurement method diagrammatically using an aerosol photom- eter, and figure 2 shows the procedure using a particle counter. Table 1 shows a comparison of the two test methods, AP and DPC with regard to aerosol concentration and test method sensitivity. Figure 1: Aerosol challenge: Photometer Particle Generator Upstream Concentration Photometer % Leak Downstream Concentration HEPA filter Figure 2: Aerosol challenge: Particle counter Particle Generator Upstream Concentration Downstream Concentration HEPA filter Particle Counter # of Particles Dilutor A dilutor is required to keep the particle counter from over concentrating. Upstream concentration will be > 6M particles per cubic foot. Most particle counters have a coincidence error of 10% at 1M p/cf.
- 4. Development and current state of installed HEPA filter leak testing Page 4 The AP method had to be modified in the late 1980s due to concerns about potential toxicity hazards with the oil used to generate the test aerosol, Dioctyl-phthalate (DOP). The use of alternative oils, including poly-alpha olefins (PAO), and di-ethyl-hexyl-sebacate (DEHS) was developed. Taking into account the principal disadvantage of the AP method, principally the need for higher challenge aerosol concentration, and recognizing the potential hazards concerning the oil used to generate the aerosol, alternative methods were investigated and introduced. The development of a German VDI standard on this topic began with an AP procedure, and was finalized in the 1980s with a DPC method [4]. An initial study on the correlation of both test methods by Kase [5] demonstrated a better resolution for the DPC method. Some European pharmaceutical companies, particularly those not influenced by US practice, developed a preference for the method [6]. For the micro- electronics industry, the advantage of using lower aerosol concentrations, and the ability to avoid using oil aerosol sources proved crucial to avoid outgassing airborne molecular contamination. Hence, DPC testing became the only standard in that industry. In 1994 Moore et al published a paper comparing the effectiveness of alternate test challenge aerosols on HEPA filters with controlled defects. This work demonstrated that less toxic alternatives to DOP are available, offering safe and reliable leak testing [7]. A further aspect of the Moore paper was the introduction of the “controlled defect” method, allowing to clearly identify leaks of the critical size 0.3 mm. The Moore paper referred to above, ICCCS symposium proceedings, and subsequent conferences show that using the “controlled defects” method can demonstrate a satisfactory correlation of data for using different aerosol substances: DEHS (di-ethyl-hexyl-sebacate), DOP (dioctyl phthalate), PAO (poly-alpha-olefin), and different procedures (AP & DPC) [8,9]. Since the 1990s, several European pharmaceutical companies reported presenting their HEPA filter leak detection procedure, using a DPC method based on the VDI 2083-3 standard to US FDA officials without basic objections. Table 1: Comparison of the Aerosol Photometer method (AP) and the Discrete Particle Counting method (DPC) Critical Parameters Aerosol Photometer (AP) Discrete Particle Counter (DPC) Aerosol Concentration 20-80 mg/m3 20-80 µg/m3 Sensitivity / Resolution Low High 1) Particle Size Distribution Broad Narrow Impact on Ducting and HEPA filters 2) High No Ease of undertaking the test Relatively simple test method Relatively simple test method 1) Meaning that the test is sensitive to contamination in the environment, suited to determine the performance of ULPA filters. 2) Deposition of oil, loading of filters increasing pressure drop.
- 5. Development and current state of installed HEPA filter leak testing Page 5 The first international standard dealing with installed HEPA filter leak testing, ISO 14644-3:2005 presents both methods, clarifying that for ultra low penetration air filters (ULPA) as well as for large installations only the DPC method offers suitable resolution [10]. HEPA filters using ePTFE (poly-tetra-fluor-ethylene) media instead of fibreglass filter media are well established and have been used in microelectronics for decades. Recently these HEPA filters with ePTFE membrane, featuring reduced pressure drops and increased mechanical stability, have been introduced in pharmaceutical industry. For such filters DPC testing is preferred to avoid an extreme increase of pressure differential that would occur if the filter were exposed to an oil aerosol [11, 12]. Whereas both procedures, aerosol photometry and discrete particle counting, are useful for traditional require- ments of the pharmaceutical industry, the latter seems to offer the greater opportunity in terms of resolution and precision of installed HEPA filter leak testing.
- 6. Development and current state of installed HEPA filter leak testing Page 6 References [1] Guidance for Industry: Sterile drug products produced by aseptic processing - Current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration FDA, (September 2004). Rockville, Maryland, USA. [2] IES-RP-CC006.2 Testing Cleanrooms, Clause 6.2: HEPA and ULPA filter installation leak tests. IEST Institute of Environmental Sciences and Technology, Mount Prospect, Illinois. [3] IES-RP-CC007.1 Testing ULPA Filters, IEST Institute of Environmental Sciences and Technology, Mount Prospect, Illinois.[4] VDI 2083 Part 3: Cleanroom technology; Metrology and test methods (1993), Beuth Verlag, Berlin. [4] VDI 2083 Part 3: Cleanroom technology; Metrology and test methods (1993), Beuth Verlag, Berlin. [5] Kase, T., Y. Suzuki, E. Hitoshi, O. Nobuyoshi, Y. Takeshi, S. Satoki: A Study on Testing of HEPA Filters. Kuki Seijo to Kontamineshyon Kontororu Kenkyu Taikai Yokoshu, (1990) vol. 9th, pp. 221 224. Journal Code Y0789A. [6] Redeker, F., R. Hünert, M. Rohnen, L. Hänsch: Funktionsprüfung von Hosch-Filtern in Laminar-flow-Anlagen. Pharm. Ind. 49 (1987) 1. [7] Moore Jr., D. R., J. G. Marshall, M. A. Kennedy: Comparative testing of challenge aerosols in HEPA filters with controlled defects. ISPE Pharmaceutical Engineering March/April 1994. [8] Gail, L., F.Ripplinger: Correlation of alternative aerosols and test methods for HEPA filter leak testing, Proc. Int. Symp. on Contamination Control, IEST Institute of Environmental Sciences and Technology, Phoenix, Arizona, 1998. [9] Gail, L. , D. Stanischewski: Installed HEPA Filter Leak Testing by Using Discrete Particle Counting, Proceedings, International Symposium on Contamination Control, Institute of Environmental Sciences and Technology, Anaheim, CA, 2002. [10] EN ISO 14644-3:2005: Cleanrooms and associated controlled environments - Part 3: Test Methods, Geneva. [11] Osborne, M.W., L. Gail, P. Ruiter, and H. Hemel: Applied membrane air filtration technology for best energy savings and enhanced performance of critical processes, Proceedings, International Symposium on Contami- nation Control 2010, Zurich. [12] Bryan, E., B. Kitch, J. Meek, D. Milholland, N. Nance (2011) “Alternative Test Methodology for In-Situ Testing of ePTFE HEPA Filters for Pharma- ceutical Applications“, Pharmaceutical Engineering, vol. 31, no.6. More information For more detailed information about HEPA filter leak testing and HEPA filters featuring ePTFE membrane media, please contact Dr.-Ing. Marc Schmidt at: marc.schmidt@aafeurope.com @
- 7. Development and current state of installed HEPA filter leak testing Page 7 About the authors Dr.-Ing. Marc Schmidt Dr.-Ing. Marc Schmidt is the Business Development Manager Pharma for AAF International, with business responsibility for the Pharmaceutical industry and other Life Science segments in the EMEA (Europe, Middle-East, Africa) region. He is an international air filtration professional, who graduated in Chemical Engineering from today’s KIT - Karlsruhe Institute of Technology (Germany). In his PhD thesis, Schmidt investigated electrostatic effects during particle/droplet collisions. His main professional activities are in the fields of sales and marketing, business development, process development and operations management mainly in the filter industry in Europe and Asia. On behalf of AAF International, Schmidt frequently engages himself in international consulting and training related to high-end air filtration systems in cleanroom environments. He also acts as speaker during various conferences and symposia. He is a member of ISPE (International Society of Pharmaceutical Engineers) as well as EBSA (European Biosafety Association). He can be contacted by e-mail: marc.schmidt@aafeurope.com Dr.-Ing. Lothar Gail Dr.-Ing. Lothar Gail is a senior contamination control consultant, who graduated in Chemical Engineering from Munich Technical University (Germany). In his PhD thesis he developed a model for calculating diffusion in non-homogenous gels. His main professional activities are in the fields of pharmaceutical technology, microcontamination control and cleanroom design, operation and qualification. He is a member of ICCCS (International Confederation of Contamination Control Societies), VDI (German Association for Cleanroom Technology) and a convener of the ISO 14644-4 working group, dealing with cleanroom design, operation and qualification. As chairman of the VDI committee on contamination control he editied the VDI 2083 guideline series on cleanroom technology. He is also an expert of the DIN (German Standard Association) mirror working group and the ISO 14644-1 committee dealing with cleanroom classification. He published numerous scientific papers on sterilization technology, aerosol filtration, personal protection, cleanroom design and cleanroom operation. Further- more he edited a textbook on cleanroom technology and contributed scientific articles to various textbooks. Hugo Hemel MSc. Hugo Hemel MSc. is the Marketing Manager for air filter manufacturer AAF International, with marketing responsibility for the EMEA (Europe, Middle-East, Africa) region. In this role he also led the European market introduction of NELIOR® Filtration Technology, a patented membrane-based HEPA filtration medium. Hugo holds a Bachelor degree in Engineering Management and obtained his MBA from the Rotterdam School of Management (the Netherlands), with a specialization in Management of Technology and Innovation. He obtained subsequent executive degrees at INSEAD Business School and the European Institute for Brand Management (EURIB). Hemel was one of the authors of the technical paper that was present- ed during the ICCCS 2012 symposium about applied membrane air filtration technology, with publications in among others the European Journal of Parenteral Pharmaceutical Sciences. Hemel holds an accreditation by the European Marketing Confederation (EMC) and is a member of various associations in the area of marketing and innovation. He can be contacted by e-mail: hugo.hemel@aafeurope.com
- 8. aafeurope.com | nelior.com This whitepaper is for informational purposes only and the information contained herein is the proprietary and exclusive ownership of AAF International B.V. No part of this document, in whole or in part, may be reproduced, stored, transmitted, or used for any purpose without the prior written permission of AAF International B.V. This whitepaper has been generated with most care for which use has been made of information obtained from selected external sources. AAF cannot be held responsible for the accuracy of this information. Printing and typing errors reserved. WP_102_EN_122014 © AAF International B.V.