CleanroomTestingandCertification_inhouseGHPtraining

Federal Standard 209• First standard was only 9 pages – Covers scope, references, definitions and the actual standard• Remaining 12 pages were a• “Non Mandatory” Appendix – Educational information for suppliers 101

Air Velocity in Appendix• Section 40.2 Laminar Flow Clean Rooms “40.2.7 Airflow velocity. Airflow velocitythrough the cross section of the room ismaintained at 90 feet per minute minimumaverage, with a uniformity within + 20 feetper minute through out the undisturbedroom area. 102

IEST• Institute of Environmental Sciences and Technology – Founded in 1952 for Cold War missile technology – AACC merged in 1973 • Little progress in Contamination control until 1978• Over 40 Recommended Practices currently – IEST RP CC-006 “Testing Cleanrooms” – IEST RP CC-034 “HEPA and ULPA Filter Leak Test”• www.iest.org 103

FDA Aseptic GuidelinesGUIDELINE ON STERILE DRUG PRODUCTS PRODUCED BYASEPTIC PROCESSING, June, 1987 104

Federal Standard 209• Federal Standard 209 1963• Federal Standard 209A 1996• Federal Standard 209B 1973• Federal Standard 209C 1987• Federal Standard 209D 1988• Federal Standard 209E 1992• Cancelled in November 2001 105

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National Environmental Balancing Bureau• NEBB founded in 1971 by Mechanical Contractors Association of America – Originally for Testing, Adjusting and Balancing – 660 firms worldwide with nearly 2,000 certified technicians and professionals• 1987 Cleanroom Performance Testing added – 60+ Certified firms – 90+ Certified Professionals – 30+ Certified Technicians• www.NEBB.org 107

NEBB Cleanroom Standard• “Procedural Standard for the Certified Testing of Cleanrooms” – First Edition 1988 – Second Edition 1996 – Third Edition 2009• Next edition will be an ANSI Standard – Must shorter with less detail• New handbook will have the explanations 108

ISO 14644• 1999 – Used Federal Standard 209E as a template – All metric measurements – Classes based on log of  0.1 um particles/m3 • 209 Classes based on  0.5 um particles/ft3 109

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, Annex1 Manufacture of Sterile Medicinal Products: HistoryDocument History September 2003 November 2005 to December 2007Previous version dated 30 May 2003, 01 March 20091in operation since 110Revision to align classification table ofclean rooms, to include guidance onmedia simulations, bioburdenmonitoring and capping of vialsDate of coming into operation andsupersedingPlease note correction on theimplementation of provisions forcapping of vials1Note: Provisions on capping of vialsshould be implemented by 01 March2010

Grade A Defined The local zone for high risk operations, e.g. fillingzone, stopper bowls, open ampoules and vials, makingaseptic connections. Normally such conditions are providedby a laminar airflow work station. Laminar airflow systems should provide ahomogeneous air speed in a range of 0.36 - 0.54 m/s(guidance value) at the working position in open cleanroomapplication. The maintenance of laminar should bedemonstrated and validated. A uni-directional airflow and lower velocities may beused in closed isolators and glove boxes. 111

Grade B, C and D Defined• Grade B – For aseptic preparation and filling, this is the background environment for the grade A zone• Grade C and D – Clean areas for carrying out less critical stages in the manufacture of sterile products. 112

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Cleanroom Classification• per ISO 14644-1• Classification clearly different from monitoring• Maximum particle concentration per Table• Grade A requires 1 m3 sample per location – 36 minute sample time using a 28.3 lpm counter• Grade A is ISO 4.8 due to only 20 max > 5 um• Note: ISO 14644:2015 only allows ISO 4.5 114

ISO 14644-1: 2015 Class 5 Changes• Does not allow ISO 5 classification at 5 um – Previous limit of 29 was removed• Note: – Sample collection limitations for both particles in low concentrations and sizes greater than 1 m make classification inappropriate, due to potential particle losses in the sampling system 115

ISO 14644-1: 2015 Annex E• Provides Table E.1 for intermediate decimal cleanliness classes• States: Uncertainties associated with particle measurement make increments of less than 0.5 in appropriate• Thus no ISO 4.8 for Grade A• ISO 4.5 allows only 9 paritcles > 5 m/m3• Minimum sample volume = 2.2 m3 or 79 minute sample time of using a 28.3 lpm counter 116

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PIC/S Annex 1• Generally follows EU Guidelines for Annex 1 with minor differences• Does not provide detailed testing methods –Reference EN/ISO standards 118

Cleanroom Performance Testing : Why do we testcleanroom performance periodically 119

Why Test Cleanrooms• Qualification of Initial Installation – Were all components installed correctly – Are all the components operating as specified – Does the facility meet performance requirements• Includes both primary and secondary tests• Provides a baseline data for future monitoring – Facility Monitoring System (FMS) 120

Environmental Monitoring• Environment monitoring department – Routinely sample / measure critical parameters • Airborne particle counts • Viable counts• Data trending to prevent failure – Alarm and action limits• Does NOT replace routine certification 121

Cleanroom Design Stage• Cleanrooms are designed once but tested every six months• Designers have never tested a cleanroom• Certifier should have input early in process – No positive pressure plenums – No huge AHU’s servicing both HEPA filtered and unfiltered areas – Provide aerosol injection and sampling ports – Provide airlocks to maintain room pressures 122

Site Preparation for Initial Certification• Build clean – No Smoking – No Chew – No Gum – No Spitting – No Urinating – No Drinks – Clean Boots – Continuous Clean 123

Site Preparation for Initial Certification• Build clean• Determination aerosol injection / sampling port locations – No debris or metal shaving inside ductwork – May possibly use TAB duct traverse ports• Coordinate with other trades – TAB contractor must have completed work(TAB = Testing, adjusting, and balancing) 124

NEBB Required InstrumentationFunction Min Range Min Accuracy Min ResolutionAirflow Velocity 0.005 m/s (1fpm)Anemometer 0.25 - 12.5 m/s (50  5% of reading  0.50 m/s 0.01” wg < 1” wg (IP) to 2500 fpm) (100 fpm) and  10%  0.50 2.5 Pa  250 Pa (SI)Electronic m/s (100 fpm) 0.1” wg > 1” wg (IP)Manometer 0 - 0.5” w.g. (IP) 25 Pa > 250 Pa (SI) 2% of reading 0.005 m/s (1 fpm)Tube Array 0.13 - 12.5 m/s (25  3% of reading  0.04 m/s (Digital): 1.0 cfm (0.5 L/s) (Analog): 5.0 cfm (2.5 L/s)Airflow Volume to 2500 fpm) from 0.25 to 40 m/s ( 7 fpmFlow MeasuringHood from 50 to 8000 fpm) 100 - 2000 cfm (IP)  5% of reading 50 - 1000 L/s (SI)  5 cfm (US) 2.5 l/s (SI) 125

Aerosol Mixing / Uniforming• Filter integrity testing requires a uniform aerosol challenge across the entire upstream face of the HEPA• No good designs for room side injection• Absolutely never inject through the center port of the filter – For pressure readings and measuring upsteam aerosol concentrations• Fans are not mixing devices 126

Initial Cleanroom Testing• Establish how the aerosol must beintroduced to achieve challenge uniformity• Often PVC pipe used to introduce aerosolinto both sides of the fan at multiplelocations• Manifolds designed into branches of thesupply duct may be required• Clearly record the successful means toachieve challenge uniformity 127

Testing After the Initial Test• Repeat aerosol generation set up that was deemed acceptable in the initial testing• Should remain constant providing no changes to the ductwork or air volume• Always measure challenge concentration (100%) periodically when testing – Detects generator failure and limits starting over if failure should occur 128

Sampling Upstream• Must have sample ports to all filters being challenged• Filters with center ports provide good sample access• Good designs avoid HEPA’s with center ports – Not uncommon for screw driver to damage surrounding media – Not uncommon for plugs to fall out resulting in a very large defect / leak 129

Photometer VS Particle Counter• Aerosol challenge of 10 to • Less than 0.1 ug/l30 ug of oil / liter challenge• Exposure of HEPA filters • Insignificant oil collectionto oil in large systems by filters• Cannot introduce into AHU • Duct leakage in not anif supply duct leaks issue• Coalescence of oil in • No coalescence HVAC• Difficult to introduce into • Aerosol generator ispositive pressure duct positive pressure to duct 130

NEBB Required InstrumentationFilter Integrity Tests – Photometer Option 1Aerosol Photometer The instrument shall have a threshold sensitivity of 10-3 micrograms/liter of challenge aerosol particles and be capable of measuring concentrations over a range of 105 times the threshold sensitivity. Sample flow rate shall be 28.3 L/min (1cfm). Readout shall be either linear with an accuracy of 1% of full scale of the selected range.Pneumatic Aerosol A device that can aerosolize oil medium to Not RequiredGenerator serve as an artificial challenge for filter integrity Not Required testing of systems under 3,000 cfm, typically Laskin nozzle(s) type, thermal generator, atomizer, etc.Thermal Aerosol A device that can aerosolize oil medium toGenerator serve as an artificial challenge for filter integrity testing of systems of 3,000 to 60,000 cfm 131

NEBB Required InstrumentationFilter Integrity Tests – Photometer Option 2Mini Aerosol Generator A device that can aerosolize oil medium to serve as an artificial challenge for filter integrity testing. It must be capable of generating a stable aerosol concentration of < 59 particles / min of  0.3 m in sizeAerosol Diluter A device used with the scanning particle counter to sample the aerosol challenge upstream of a filter under test. The dilution ratio shall be between 300-1,000:1. The resulting counts after dilution should not exceed 100,000 particles.Filter Integrity Tests – Integrated DPC based scanning device Option 3Integrated DPC based scanning device A particle counter based instrument designed forMini Aerosol Generator (same as above) scanning filters. The diluter is integral to the system. The percent penetration displays on the hand probe A device that can aerosolize oil medium to serve as an artificial challenge for filter integrity testing. It must be capable of generating a stable aerosol concentration of < 59 particles / min of  0.3 um in size 132

Conclusion• Accurate testing starts with the facility design• Coordinate with other trades• Have experienced, knowledgeable, personnel – NEBB Professionals must meet high standards• Test results are only as good as the test instrumentation used to collect the data• Verify aerosol injection points and means to measure challenge concentration 133

Filter Integrity : LeakTesting HEPA Filters 134

Filter Tests• Efficiency Testing – Requires a challenge of known particle size • Typically 0.3 m in USA • Typically most penetrating particle size (MPPS) in Europe – Can only be performed in the factory• Total penetration – May be a PAO, DEHS or microsphere challenge • Aerosol size is not reported – Common field test performed in remote filter banks 135

Filter Tests - Continued• Filter Scan Test – Entire face to filter is scanned for leaks • Factory will use a robotic scanning device – Purchase only factory scanned filters if filters are to be scan tested in the field• Resistance – Must report the volume of filter airflow – Pressure reading without airflow volume is meaningless 136

Field Test Methods and Equipment• Photometer total penetration method – Laskin nozzle or thermally generated aerosol• Photometer scan method – Laskin nozzle or thermally generated aerosol• Discrete particle counter scan method – Microsphere challenge – Ultra Low PAO challenge 137

Field Test Aerosols• Poly-dispersed• DOP : Dispersed Oil Particulate• PAO : Polyalphaolefin• DOS (DEHS) – Europe : Dioctylsebacate, di-2-ethyl hexyl sebacate• Microspheres 138

Microspheres 139

Filter Velocity VS Scan Testing• Airflow rate will change the apparent leak size• Leak size increases with the airflow velocity 140

Scanning In Duct Filters• Filter face velocities very high – Typically 1.27 m/s to 2.54 m/s• Leaks appear larger at higher velocities – 0.01% leak @ 0.45 m/s = 0.023% @1.27 m/s – 0.01% leak @ 0.45 m/s = 0.043% @2.54 m/s• Difficult to identify gaskets / seals leaks – High turbulence due to high velocity• Avoid scanning filter banks 141

Photometer or Particle Counter?• PAO may damage gel seals• PAO over challenge of isolators and othersmall systems– One Laskin nozzle = 270 g PAO/liter of air in 1400 l/m• Some applications prefer no oils• EN1822 and ISO29463 factory testsspecify particle counters 142– Leaks of 0.0001% specified

Photometer or Particle Counter?• Oil may not be accepted in all areas or industries• Microspheres may require the technician to obtain a new set of equipment (including a particle counter based integrated system) 143

Microsphere Scan Equipment• Particle counter– 28.3 l/m sample rate or higher– 0.3 um sensitively or smaller– A “beep function” for every particle detected– Isokinetic rectangular scanning probe• Aerosol dilutor• Microsphere generator– Ultrasonic humidifier• Microsphere solution 144

Rectangular Probe 145

Aerosol Dilutor 146

Ultrasonic Humidifier 147

Mini - PAO Generator 148

Laskin Nozzle Output / Challenge• Challenge for aerosol photometer – 10 g PAO/L in 38.2 m3 / min• Challenge for particle counter – 6 million particles > 0.3 um / ft3 in 212 m3 / sec – 20 million particles > 0.3 um / ft3 in 64 m3 / sec – Problem is too much challenge for smaller systems – ¼ Laskin for 1.42 to 14.2 m3 / sec systems• Testing single filters will M generator 149

Microsphere Challenge• Challenge filter with 0.3 m microspheres – Ultrasonic humidifier for microsphere generator• Using 28.3 l/m particle counter verify challenge > 6 million particles 28.3 liters – Requires an aerosol dilutor for concentrations over 80,000 particles per 28.3 liters – 100:1 x 80,000 = 8 million max. Need > 350:1• Record challenge concentration 150