CleanroomTestingandCertification_inhouseGHPtraining

Particle Counts• Oddities and Advice – ISO 14644-1 (2015) allows a “Do Over” – Note Section A Treatment of out-of-specification count A.5.5 If an out-of-specification count is found at a location due to an identified abnormal occurrence, then that count can be discarded and noted as such on the test report and a new sample taken. A.5.6 If an out-of-specification count is found at a location is attributed to a technical failure of the cleanroom or equipment, then the cause should be identified, remedial action taken and retesting performed of the failed sampling location, the immediate surrounding locations and any other locations affected. The choice shall be clearly documented and justified. 301

Particle Counts• Used predominately in ISO 3 and cleaner areas – Semiconductor cleanrooms• It is a statistical process to determine with confidence that a sample location will either pass or fail by analyzing data as it is taken• Due to time constrains, we will not cover it here for a predominately pharmaceutical meeting 302

SecondaryCertification Tests 303

Certification Testing• HEPA Filter Installation Leak Test – using oil aerosol challenge• HEPA Filter Installation Leak Test – using microsphere aerosol challenge• Air Velocity / Uniformity• Airflow Volume & Room Air – Change Rate• HEPA Filter Airflow Resistance (Pressure Drop)• Air Cleanliness Level Survey ISO 14644-1• Air Cleanliness Level Survey Annex 1• Airborne Room Recovery• Light Level Survey• Temperature / Relative Humidity Point in Time Survey• Temperature / Relative Humidity Monitoring 304

Certification Testing, continued• Room Pressurization Test• Sound Level Survey (dBA)• Sound Level Survey (NC Curve)• Directional Airflow Survey Using Visible Vapor• Parallelism Survey using FloViz• Electro-Static Discharge Monitoring• Floor Conductivity Survey• Surface Static Charge Measurement• Electromagnetic Interference (EMI)• Laminar Flow Devices• Bio Safety Cabinets• Exhaust Hoods 305

Temperature / Humidity• To confirm the capability of the facility support systems to control temperature and moisture• To verify uniformity and confirm stability of environmental conditions at control sensing points and throughout the contiguous areas of the Clean Zone.• Temperature and humidity probes utilizing thin film sensors• Monitoring: Temperature and humidity with data collected by and 8 channel data logger – 4 temperature and 4 humidity sensors• Report Temperature / Relative Humidity or Dew Point 306

ComprehensiveTemperature / Humidity• Requires data loggers• Location of the logger can be critical• Requires programming to indicatesample frequency• Requires 24 hour operation of thetemperature control systems• Common test in microelectronic 307 facilities – Not Pharmaceuticals

Temperature / Humidity• Provides valuable information about the performance of the systems• cGMP facilities often requires accuracy eliminating less expensive devices – Not for metrology / calibration – Resolution and response more important• Typical cGMP tolerances would be  0.5F and 2% RH 308

Instrument Accuracy• SpecificationsMeasurement range Temperature: -20 to 70C (-4 to 158F)Accuracy RH: 25% to 95% RHResolution Temperature:  4C from 0 to 40C ( 0.72F from 32 to 104F), see Plot A RH:  3.5% from 25% to 85% RH over 309 the range of 15 to 45C (59 to 113F), see Plot B;  5% from 25% to 95% over the range of 5 to 55C (41 to 131F), see Plot B Temperature: 0.1C at 25C (0.2F at 77F) see Plot A RH: 0.07% @ 25C and 30% RH

Controls Cycling 310

Temperature Stability 311

Light Levels 312• Florescent lighting require a “burn in” – 100 - 300 hours• Testing during construction – Lighting may be spotty or inconsistent• Tooling placement may result in an asymmetrical test grid• Seldom are lighting tests an issue• Generally reported in foot candles or lumens

Light Levels• To verify compliance with specified light intensity levels provided by normal lighting systems in white-light and yellow-light areas• Handed-held light level meter with levels measured in foot candle power 313

UV Light Wave Spectrum Microelectronics Only• To verify that light in the photolithography area has no wavelengths that will cause exposure of the photoresist• Provide scaled X-Y plots showing wavelengths (nanometers) versus radiated power (watts per square centimeter) 314

UV Light Wave Spectrum UV LampThe filtered fluorescent lighting in photolithography cleanrooms contains no 315ultraviolet or blue light in order to avoid exposing photoresists. The spectrum oflight emitted by such fixtures gives virtually all such spaces a bright yellow color.

Sound Level Testing• To verify compliance with specified operating noiselevels• Tools and some measuring equipment is very sensitiveto vibration in microelectronic facilities• Review contract documents– Reporting requirements– NC, NR, RC, dB(a)• Construction must be COMPLETE– Tools like rotoray hammers show up in sound testing• Cleanroom envelop must be complete• Occupancy state of the cleanroom– Tools make noise 316

Noise Rating or NR Curve 317

Noise Criterion or NC Curve 318

Directional Airflow Survey Using Visible Vapor• To determine the direction of the airflow within the cleanroom as it passes through and leaves the work zone• Dry ice, deionized water, or fog generator• Pharmaceutical customers require video 319

Parallelism Microelectronics Only• Used in raised floors – Microelectronics• Support stand that will least affect airflow, Floviz, plump bob, measuring tape, and pointer stand 320

Airflow Parallelism• Microelectronics raised floor cleanroomsonly• Attach a 1.2 m non shedding,monofilament nylon string (FloViz) to amobile stand 2.1 m above the floor• String should deflect < 30 cm from vertical• 30 cm offset in 120 cm = 14 degree angle• Adjust floor dampers to achieve < 14degree offset 321

Parallelism 322

Electrostatic Discharge• To determine the ionization system is operating at the optimal electrical static charge dissipation capability• A Charge Plate Analyzer with an over all capacitance to ground of 20 Pico Farads• The plate should measure 15 cm by 15 cm 323

Floor Conductivity Microelectronics Only• To measure resistance between specified points on the surface of the raised floor panel and from that surface to building ground• A self-contained resistance meter (such as an ohmmeter) or power supplies and current in the appropriate configuration for resistance measurement with  10% accuracy• Two cylindrical 2.27 kg metal electrodes shall have a diameter of 63.5 mm each having contacts of electrically conductive material• Resistance between the electrodes shall be less than 1,000 ohms when measure at 10 volts or less on a metallic surface 324

Floor Conductivity MeasurementWe will definewhere positionson floor to testtemplate are ineach room are. 325

Surface Static ChargeMeasurement• To assure that 1 inch between electrostatic charge is object and field meter kept below levels where product and/or equipment 326 can be adversely affected• Instrument shall be a non- contacting static field meter, capable of reading voltage and polarity on objects up to  20 Kv at a spacing of 12 mm

Electromagnetic Interference Microelectronics only• To determine AC and DC electromagnetic interference emitted by magnetic field sources• Orient the magnetic field sensor so the X-axis is facing east, the Y-Axis is facing north, and the Z-axis is pointing up (vertical)• Record data using a Cartesian coordinate system (X- Y-Z) with the origin (X=0, Y=0) at the southwest corner of the area to be tested. Note the magnitude of the magnetic flux density at those locations. Magnitude is equal to the square root of the X component squared + the Y component squared + the Z component squared at any given measurement location. 327

Electromagnetic Interference 328

Laminar Flow Devices• To assure that the Laminar Flow Device (Unidirectional Flow) meets customers specification• Test shall include: Filter Leak Test, Airflow Velocity/Uniformity, Filter Pressure Drop, Air Cleanliness Level, Light Level, and Sound Level• Laminar flow devices are used in Semiconductore, Pharmaceutical, Food, and Medical Devices industries• Protects the product not the user 329

Bio Safety Cabinets• To assure that the Bio Safety Cabinetsmeet manufacturer or National ScienceFoundation (NSF) specifications• Tests include: Filter Leak test, AirflowVelocity/Uniformity, Filter Pressure Drop,Light Level, Sound Level, and DirectionalAirflow Survey using Visible Vapor• Bio Safety Cabinets are used inPharmaceutical and Food industries• Protects both product and user 330

Exhaust Hoods• To assure that the Exhaust Hood meetsmanufacturer or customer specifications• Test shall include: AirflowVelocity/Uniformity, and Directional AirflowSurvey using Visible Vapor• Exhaust Hoods are used inSemiconductor, Pharmaceutical, Food,and Medical Devices industries• Protects the user 331

TestingDepyrogenation Tunnels 332

Scan Test Critical HEPA Filters• Common to scan HEPA’s every 6 months• No individual leaks > 0.010%• Hot Zone rarely pass this very stringent test – Initially starts at H-14 or 0.025% allowed leak – Eventually may meet H-13 or 0.25% allowed leak 333

Scan or Not to Scan Hot Zone Filters• Two opinion groups• Group One–All HEPA filters must be scanned• Regardless of their location–This often includes remote filterbanks• Note: Dan Milholland is not in thisgroup 334

Scan or Not to Scan Hot Zone Filters• Group 2• Hot zone filters of a depyrogenation tunnel or Batch Oven are an exception 335

2004 Aseptic Guidelines Section D.2 HEPA Filters• “Among the filters that should be leak tested are those installed in dry heat depyrogenation tunnels and ovens commonly used to depyrogenate glass vials. Where justified, alternate methods can be used to test HEPA filters in the hot zones of these tunnels and ovens.” 336

Conventional Testing• Aerosol photometer scan method• Required 10-20 g PAO / liter of airchallenge– 15 g PAO / liter for 30 minutes in 28.3 m3/min = 12.75 gms oil collected• Oil will burn off at temperature• Thermophoresis attracts small elements ofcombustion to colder glassware surfaces• When is all oil burned off the filters? 337

Scanning Limitations• Cannot scan at temperature –Challenge aerosol would ignite• Heat causes filters frames to expand –Conditions at ambient are different than at temperature• Multiple heat cycles result in leaks 338

What is Required• Entire glassware path after cleaning is critical in aseptic processing –Must have ISO 5 or better environment –Less than 1 cfu / 283 l/m or air 339

Alternate Test of HEPA’s• Viable organisms cannot survive the hotzone– Monitoring cfu’s is not necessary in hot zone• Treat entire tunnel as a clean zone(s)• Test for compliance to ISO 5– At temperature or ambient?– Large visible particles are often found frommedia / filter degradation due to heat cycles– Test for > 5 m particles is important 340

Temperature Ramp• Particle events happen during temperature ramp up and down• Different materials expanding and mass difference results in “movement”• Typically ramp at less than 1C/minute• Main concern in batch ovens – No glassware in tunnels when ramping 341

Equipment• Discrete particle counter– 28.3 L / min or greater sample rate• Iso-kinetic probe turned upward• SST tubing of sufficient length to reachzones in tunnel• Thermometer and well to monitor sampletemperature• Possibly a heat exchanger– Coil of tubing in ambient air 342

Caution• Do not use cold water or ice• May cause moisture in sample to form fog – Shows as extremely high counts• Could condense and liquid be drawn into counter• Metal tubing in air is usually adequate as heat exchanger 343

Macro Particles• Visible particles fall out in sample tubing• May require other methods of capture• Microscope slides in petridish – Make multiple passes through tunnel• Counts particles on slides – Report as Particles > x m per y area per pass 344

Air Density Correction• Air at 360C is less dense than at 20C• The counter is drawing in more than 28.3 L of sample in the hot zone• Correct for difference in volume of sample an volume when counted in the counter 345

Temperature Correction• Standard Volumetric Flow Rate =Actual Volume Flow Rate x (Tstd/Tf) x (Pf/Pstd)• For a 350C tunnel: Tstd = TC + 273 = 20 + 273 = 293 293 / (273 + 350) = 0.471/0.47 = 2.12 346

Thank you for your attention 347