CleanroomTestingandCertification_inhouseGHPtraining

Average Tells Nothing About UniformityData Set 1 Data Set 2Average Velocity Average Velocity 81 65 80 95 79 70 80 90 80 80 201

Normal or Bell Curve 202

Standard Deviation S = standard deviation X = average of data set n = number in sampleUse Excel Function = STDEV() 203

Normal Distribution CurveLess than 1 in 10,000 In a normal distribution, half thepoints is more than 4 points are above and half thestdevs away from the points are below the averagemean In a normal distribution, 68% of the points are within 1 stdev of the mean 95% are within 2 stdevs 204

The Empirical Rule (For a Normal Distribution)•  68 % of the data will be found within +/- one standard deviation of the mean•  95 % of the data will be found within two standard deviations of the mean 205

206

Relative Standard Deviation• Which air volume has a greater relative variation? –720 cfm with a STDEV of 72 cfm or –90 fpm with a STDEV of 9 fpm? 207

Answer1. RSD = (72 / 720) x 100 = 10%2. RSD = (9 / 90) x 100 = 10% Both airflows have the same relative variation! 208

Expressing Uniformity of DataData Set 1 Data Set 2 Velocity Velocity 81 65 80 95 79 70 80 90Average 80 Average 80Standard deviation 1.6 Standard deviation 14.7Rel. Std Dev 2.0% Rel. Std Dev 18.4% 209

Layman’s Terms• For a data set with a relative standard deviation of 10%1 Standard Deviation = 10% of the mean – Thus 68% of all data valves are within +/- 10% of mean – Example: 90 fpm +/- 10% = 81 fpm to 99 fpm2 Standard Deviation = 2 x 10% = 20% – Also 95% of all data valves are within +/- 20% of mean – Example: 90 fpm +/- 20% = 72 fpm to 108 fpm210

AirflowVisualization 211

Testing Airflows in• Pharmaceutical Sterile Manufacturing Facilities –Controlled Area –Critical Area 212

Review of Typical Sterile Manufacturing Suite• ISO Class 5–Unidirectional / Flow control• Filling Areas• Critical Areas• ISO Class 6 to ISO Class 8–Non-unidirectional / Dilution control• Support Areas 213• Controlled Areas

Testing Airflow in Controlled Areas• The controlled area is where unsterilized product, in process materials, and container/closures are prepared. 214

Typical Pharmaceutical Cleanroom LayoutFilling Room Filling RoomISO Class 5 ISO Class 5Critical Area Critical AreaCorridor ISO Class 7 Controlled AreaEquipment Pass- Equipment Pass-Thru ISO Class 8 Thru ISO Class 8 Controlled Area Controlled AreaWarehouse / Ambient / Uncontrolled 215

Controlled Area TestingStrategiesA controlled area per 2004 Aseptic Guideline is:• 20 air changes / hour sufficient for ISO Class8 support rooms• Significantly more for cleaner classifications• Differential pressure of 10-15 Pascal toadjacent less clean areas• Two tests are required:– Airflow volume to determine air exchange rate– Differential pressure across the closed door or asuitable facility monitoring system 216

Air Exchange Rate • Total Airflow to the Room - (m3 / min) x 60 min/hr - Room Volume (m3) “The direct measurement of airflow volume is usually preferable to measurement of airflow velocity and is a more representative test of the final filter air supply for non-unidirectional airflow cleanrooms” (IEST RP-6) 217

Measurement of Total Supply Airflow• The air source contributing to the total room supply must come from outside the room or exit the room & re-enter• Laminar flow hoods recirculating within a room do not contribute to the total airflow 218

Measurement of Room Pressurization• Electronic Micro-manometer or• Mechanical gauge 219

Testing Airflows in Critical Areas ISO Class 5• The critical area is one in which thesterilized dosage form, containers,and closures are exposed to theenvironment.• Reference:– 2004 Guideline on Sterile Drug ProductsProduced by Aseptic Processing– IEST-RP-CC006.X Testing Cleanrooms– ISO 14644-3 220

Critical Area Testing Strategies• 2004 Guideline parameters for critical areas are: “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.”• Justified and appropriate under dynamics conditions – Foot note: 90 fpm +/- 20% has generally been established• Higher velocities may be appropriate in operations generating high levels of particulates 221

Critical Area Testing Strategies, continued• 2004 Guideline parameters for critical areas are: – A pressure differential of 10 to 50 Pascal to adjacent areas of different classification – To adjacent unclassified > 12 Pascal • Ceiling to interstitial space • No positive pressure plenum systems• If deviations occure: – Restore, confirm & document• Suitable facility continuous monitoring system – A pressure differential > 0.02” is generally acceptable between areas. (IEST-RP-CC006.X) EST RP-CC012.2 222

Prove for Critical Areas• Velocity sufficient to sweep particles awayfrom the filling, closing area and maintainunidirectional airflow during operations• Air flows from point of filtration – across product – to returns with no turbulence oreddy currents.• Positive pressure to adjacent areas.• Room maintains performance “as operated”with all processing equipment on and 223personnel in place, as well as at rest.

Velocity Measurement in Critical Areas 224

Velocity Measurement in Critical Areas• Equipment- Hot wire anemometer- Vane anemometer- Multi Point array 225

Velocity Measurement inCritical Areas, continued • 2 Sets of Readings – Entrance plane 150 mm from HEPA filter diffuser • Use 15-30 cm grid – Work surface height – Difficult to get repeatable readings 226

Velocity Measurement in Critical Areas, continued• Acceptance Criteria –Usually 90 fpm +/- 20% @ work height or sufficient to sweep away particles. • Note: Circumstances may dictate higher or lower velocities. –Entrance plane velocities dictated by work height velocities 227

Critical Area Airflow System Validation• Ideally done before media fills areperformed.• Video a visual smoke pattern testacross the entire critical zone–Verify adequate flow to sweep awayprocess generated particulate–Verify proper airflow sequence• Filter – Product – Return 228

Critical Area Airflow System Validation, continued• Video a visual smoke pattern test across the entire critical zone, cont’d. – Smooth, even flow with no refluxing – Positive flow from critical area with no ingress from outside areas – Verify performance maintained with equipment operating – Include personnel interventions 229

Critical Area Airflow System Validation, continued• Ideally a smoke study survey should be performed at a set point and also a certain percentage above and below the set point. – This validates the specification range at which the equipment or zone will perform adequately.• It is not unusual to measure at only one velocity and assume +/- 20% will also be OK• Repeat only when the room configuration is change or filter replacement 230

Considerations for Smoke Pattern TestingVisual Smoke Generator• Glycol vs CO2 vs Liquid N2 vs DI Water – Visibility : Glycol จะเห็นลำของ smoke ไดย้ ำวท่ีสุด จึงเห็น airflow pattern ไดท้ ้งั หมดแมว้ ำงจุดพน่ ต้งั แต่ตน้ ทำงแรกที่พน่ ควนั – Neutral Density – Accuracy – Contamination Potential**ตอ้ งบนั ทึก flow 3 ตำแหน่ง คือ บน-กลำง-ล่ำง เพอื่ ใหเ้ ห็นลำของควนั ตลอดเสน้ ทำงท้งั หมด 231

AirMeasurements 232

Objective• At the end of this session you will be able to: –List methods for quantifying air velocity, air volume and air pressure 233

Testing Procedures for AirflowVelocity, Volume, and Uniformity• Tests are defined in IEST-RP-CC006, ISO14644-3 and NEBB• To determine– Average airflow velocity• Uniformity of velocity– Air supply volume flow rate• Uniformity of flow rate• Calculate air exchange rates per hour• Perform tests after air balancing of thecleanroom or clean air zone 234

Apparatus for Airflow Measurements• Airflow Volume – Electronic micromanometer with airflow hood or equivalent 235

Airflow Velocity• Electronic Manometer • Multipoint Probe• Thermal Anemometer • Vane Type Anemometer with K Factor 236

Air Volume Test• Measurement of airflow volume is preferable to velocity – More representative of final filter air supply• Flow hood measures total flow of filter or diffuser 237

IEST-RP-CC006 6.1.2.a Note• Note 1 – If a flow hood cannot be used, procedures in 6.1.2b or 6.1.2c (calculated airflow volume from velocity) can be applied 238

Airflow Velocity (Unidirectional) Test• Measure velocity in a plane –150 mm from filter or supply source• Measure only unobstructed airflow 239

6.1.2c Airflow Velocity Non- unidirectional Test• Measure each terminal HEPA or diffuser• Support the sensor on a suitable stand• Probe must be iso-axial to flow vector• Measure velocity of each filter or diffuser – 150 mm from filter• Measure on equal grids –  0.37 m2 for every tube array reading –  0.023 m2 for single point 240

Reporting• Record all airflow measurements and grid locations• Calculate and report: –Average airflow velocity / volume –Relative standard deviation 241

6.4 Room Pressurization Test• Verifies from capability to maintain a pressure differential between the cleanroom and its surroundings –Includes spaces above and below the cleanroom 242

Pressurization General Rules• Typically 12 Pa differential is sufficientbetween cleanroom and externalenvironment (อย.ไทย กำหนด 15 Pa)• Positive pressure of at least 5 Pabetween more critical space and anyadjacent space• Note: Negative pressure differentialsmay be required for containment ofmaterials 243

Apparatus for RoomPressurization Test 244

Procedure Room Pressurization TestWith all doors closed or in normal position:• A – Measure the differential pressure between the cleanroom, anteroom (if present) and exterior environment• B – If no anteroom, measure between cleanroom and the external environment• C – If subdivided: – Measure the pressure differentials from innermost rooms outward – Continue until anteroom to exterior is measured245

Reporting RoomPressurization Test• Report measured values tonearest 2.5 Pa• Report the locations wheremeasurements were made• Pressurization acceptanceagreement between buyer andseller 246

Room Pressure Diagram 247

Answer• Add the pressure differences for each room• 13+5+10+14 = 42 Pa 248

Anemometer Principles of Operation• Velocity pressure– Single Point– Multi-point as a Velgrid• Single point thermal resistance– “Hot wire” anemometer• Ultrasonic– Times alternating sound travel between points– Two or three axis average over 5-10 cm distance 249

Velocity Pressure Instruments• Velgrid or Pitot Tube• Velocity pressure (VP) of 0.45 m/s = 0.124 Pa• This is only 13 m wc !! 250