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New Regulations Concerning Airborne Particle Counters

New Regulations Concerning Airborne Particle Counters (ISO 21501 and ISO 14644) Bob Latimer, Tony Harrison 2008 Cleanrooms Worldwide eVent. Agenda. cGMP and EU GMP Guidelines ISO 21501 Key Elements What is ISO 21501 Replacing Air Particle Sensors and Calibration – The Basics

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New Regulations Concerning Airborne Particle Counters

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  1. New Regulations Concerning Airborne Particle Counters (ISO 21501 and ISO 14644)Bob Latimer, Tony Harrison2008 Cleanrooms Worldwide eVent

  2. Agenda • cGMP and EU GMP Guidelines • ISO 21501 Key Elements • What is ISO 21501 Replacing • Air Particle Sensors and Calibration – The Basics • Counting Efficiency • Resolution • Signal to Noise Ratio and False Count Rate • Summary

  3. Aseptic Pharmaceutical Manufacturing • The cGMP and EU GMP guidelines specify particle count limits based upon cleanroom classifications such as Grade A, B, etc. • Both EU GMP and cGMP reference ISO 14644-1 for determining cleanroom classification. • The next revision of ISO 14644-1 will refer to ISO21501-4, a calibration standard for air particle counters, ratified February 2007. • ISO 21501 already cross references back to ISO 14644-1 cGMP EU GMP ISO 21501-4 states – “Instruments that conform to this part of ISO 21501 are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 14644-1”

  4. Calibration to ISO 21501 Key Elements • Particle size calibration using PSL particles traceable to an international standard and within a standard uncertainty < =2.5% • The use of a Pulse Height Analyzer (PHA) to determine sensor response for each of the particle counters size channels • The intent is to improve the accuracy of particle count data and improve instrument to instrument correlation

  5. ISO 21501 – Sub Documents • ISO 21501 describes the instruments and calibration requirements. • Part 2: Light scattering liquid-borne particle counter • Part 3: Light extinction liquid-borne particle counter • Part 4: Light scattering airborne particle counter for clean spaces

  6. What Standards/Guidelines ExistedPrior to ISO 21501? 1997 1998 2006 2007 • JIS B 9921:1997 • A Japanese standard which comprehensively deals with OPC design performance, most notably in the area of counting efficiency. • ASTM F 328-98 (updated 2003) • “Standard Practice for Calibration of an Airborne Particle Counter Using Mono-disperse Spherical Particles” (Officially withdrawn 2007). • IEST-RP-CC014.1 • “Calibration and Characterization of Optical Airborne Particle Counters” (Provides actual methods to perform the calibration). • ISO 21501

  7. ISO 21501 Compared to Existing Re-calibration Minimum content on ISO 21501 calibration certificate. A key difference with ISO 21501 is that key calibration attributes are incorporated within the scope of instrument re-calibration.

  8. MET ONE Air Particle Counters and ISO 21501 Calibration MET ONE Air Particle Counter 0.5µm and 5.0µm

  9. Optical Particle Sensor Configuration Collection Optics Detection Zone Light Trap Reflector

  10. Detecting Particles Detector v Collection Optics t Light Trap Laser Diode Particle Oscilloscope Pulse Height Analyser

  11. The Pulse Height Analyzer (PHA) When a particle sensors output is connected to an oscilloscopes input the particles appear as a series of voltage pulses in time. The amplitudes of the pulses relate to the amount of light energy scattered by the particle and are therefore related to the sizes of the particles. When the sensors signal output is connected to Pulse Height Analyzer (PHA) the particles appear as a distribution with the x-axis being pulse height and the y axis being number of particles. The above picture depicts a typical room air sample. The above picture depicts a PHA response to a mono-dispersed challenge such as PSL calibration spheres.

  12. Calibrating Air Particle Counters: NIST-traceable Particles Mean size 498 nm +/- 5 nm Std Deviation 7.9 nm Std Dev x 100 C.V. (RSD) = Mean size 490.1 498 Size (nm) NIST-traceable standard particles have normal size distribution. Nominal size and CV are certified.

  13. Selecting the Correct Calibration Voltage ISO 21501 requires that the PHA response to the PSL spheres is interpreted as the median. This is the point where an equal number of particles fall on each side of the bisected distribution. For normal distributions the mode and the median fall at the same point. This is not always the case in particle counting where skewed or irregular distributions are not uncommon. median mode The calibration voltage for a given PSL introduction

  14. Calibrating Air Particle Counters: Constructing the Calibration Calibration Example 0.3 0.5 1.0 3.5 5.0 Voltage Calibration requires that a variety of different PSL sizes are run and the median voltages are recorded.

  15. Calibration of Air Particle Counters

  16. C Co  = x 100 (%) ISO 21501: Counting Efficiency The particle concentration (C) displayed by particle counter Concentration (Co) of particles drawn into the inlet of an OPC C.E. is the ratio: • Counting efficiency has arguably been the biggest variable impacting the accuracy of airborne counters. • Counting efficiency refers to the ability of the instrument to count particles at a specified size. • ISO 21501 makes use of the specification for counting efficiency that was defined in the JIS B 9921 standard.

  17. Counting Efficiency – ISO 21501 Comparison to 100% Count Standard N UUT ISO 21501 Limits 50% +/- 20% (30% to 70%) Unit Under test Noise Channel 1 size (um) NIST Traceable PSL Challenge N Standard NIST-traceable ‘100% Count standard’ Example: Channel 1. Set to recover 100% of the challenge PLS Noise Channel 1 set to 100% efficiency for UUT channel 1 size

  18. ISO 21501 and Counting Efficiency: A Two Part Test N N At 1.5 x to 2 x the particle counters minimum specified size all particles should be counted in the first channel. ISO 21501 allowed limits are 90% to 110% ISO 21501 Limits 50% +/- 20% (30% to 70%) OPC smallest specified size. Noise Channel 1 size (um) Noise Channel 1 size (um) AND for PLS particles of 1.5 times or over up to and including two times the minimum measurable particle size value, shall be 90% to 110% The counting efficiency for PSL particles of the UUT minimum measurable particle size shall be within the range 30% to 70%

  19. ISO 21501: Resolution N Particle size 0.3µm 0.5µm • Resolution – The ability to differentiate between similarly sized particles • Affected by instrument quality and alignment of the sensor optics

  20. Resolution – Why It Is Important N Particle size 0.3µm 0.5µm A particle sensor with poor resolution, such as the one above, cannot reliably distinguish between different sized particles.

  21. Peak (median) 61% of peak 1 1 D1 D2 D Resolution R% = CV(%) = RSD(%) ISO 21501 requires that resolution be calculated from +/- 1 standard deviation from the median. The higher of the two values for  (SD) is selected. • 2 - P2 XP √ R% = x 100 (%) where R Resolution  Observed SD in µm P PSL SD inmm XP PSL Size in µm

  22. ISO 21501: False Count Rate – Affected by Signal to Noise Ratio Noise Signal Peak to Valley Ratio Channel 1 Channel 1 Note: ISO 21501 does not specify a minimum S:N ratio although False Count Rate is (next slide). Peak to Valley is described although not specified. Hach Ultra maintains an internal Peak to Valley specification of 2:1

  23. ISO 21501 False Count Rate

  24. ISO 21501-4 Summary

  25. Hach Ultra and ISO 21501 • Hach Ultra has completed a full migration to ISO 21501 calibrations. • Hach Ultra offers a complete line of ISO 21501 compliant air particle counters. • Hach Ultra offers full ISO 21501 field and factory calibration offerings designed to ensure accurate and efficient service that goes beyond the instrument • Certified Calibration Service Agreements with your choice of either In-House and\or Service-at-your-Site options. • Prescheduled calibration and preventative maintenance services

  26. Hach Ultra and ISO 21501 Calibrations performed by Hach Ultra ISO 21501 certified technicians • 60 Global Direct Certified field technicians guarantees prompt qualified support • Hach Ultra technicians average over 8 years of Hach Ultra calibration experience per associate • 10 ISO 21501 capable factory service centers • 1 US based ISO 9001:2000 certified factory service center • 3 Strategically located US remote depot service centers to support walk-in and close to customer depot support • 5 European remote factory service centers • 1 Asian remote factory service center

  27. Hach Ultra and ISO 21501 • Customer support available at iso21501@hachultra.com

  28. Thank You

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