Cleanroom technology : fundamentals of design, testing and operation

Preface .............................................................................................................. xiii Acknowledgements ........................................................................................... xiv 1 Introduction .................................................................................................... 1 1.1 What is a Cleanroom? .................................................................................. 1 1.2 The Need for Cleanrooms .............................................................................. 1.3 Types of Cleanrooms ................................................................................... 5 1.5 What is Cleanroom Technology? ................................................................ 7 2 The History of Cleanrooms .......................................................................... 9 2.1 The Early Years ........................................................................................... 9 2.2 Ventilated Operating Rooms ..................................................................... 12 2.3 Early Industrial Cleanrooms ...................................................................... 15 2.4 Unidirectional Flow Cleanrooms ............................................................... 17 3 Cleanroom Classification Standards ......................................................... 21 3.1 The History ................................................................................................ 21 3.2 The Basis of Cleanroom Standards ............................................................ 22 3.3 Federal Standard 209 ................................................................................. 24 3.3. I The earlier Federal Standards 209 (A to 0) ..................................... 24 3.3.2 Federal Standard 209 E ..................................................................... 24 3.4 IS0 Standard 14644-1 ............................................................................... 26 3.5 Pharmaceutical Cleanroom Classification ................................................. 30 European Union Guide to Good Manufacturing Practice ................ 30 Aseptic Processing ............................................................................. 33 7 3.5. I 3.5.2 Guideline on Sterile Drug Products Produced by 4 Information Sources ................................................................................... 37 4.1 The International Confederation of Contamination Control Societies (ICCCS) ...................................................................................... 37 4.2 International Cleanroom Standards ........................................................... 38 4.2.1 IS0 standards .................................................................................... 38 4.2.2 Federal Standard 209E ...................................................................... 41 4,2.3 Pharmaceutical standards ................................................................. 41 4.3 Cleanroom Books ...................................................................................... 43 vi Cleanroom Technolopy 4.4 Recommended Practices and Guides of the Institute of Environmental Sciences and Technology (IEST) ............................................................... 43 4.4. I IEST Recommended Practices (RPs) .... ......................................... 44 4.4.2 IEST Guides ............... ................................ 4.5 Cleanroom Journals and M zines ..................... 4.5. I Free distribution ...................................................... 4.5.2 Journals and magazines available on subscr 4.6 4.7 lnternational Cleanroom Forum ................................................................. 51 5 5.1 Turbulently Ventilated Cleanrooms ........................................................... 53 Sources of Pharmaceutical Cleanroom Documents ................................... 50 The Design of Turbulently Ventilated and Ancillary Cleanrooms ........ 53 5.1.1 Air supply .............................. 5.1.2 High eficiency air filters ...... 5.1.3 5 . I . 4 Room pressurisation and air movement co 5.1 . 5 5.2.1 Clothing change area ........................................................................ 63 5.2.2 5.3 Containment Rooms .................................................................................. 67 6 Design of Unidirectional Cleanrooms and Clean Air Devices ................ 71 6.1 Unidirectional Cleanrooms ........................................................................ 71 6 . I . 1 ................... 73 6 . 1 . 2 74 6 .I . 3 UnidirectionalJlow rooms used in semiconductor manufacturing ... 76 6.2. I Unidirectional air devices .................................... 6.2.2 Isolators and minienviron ............................................. 83 7 Construction Materials and Surface Finishes .......................................... 91 7.2 Air movement within a turbulently ventilated cleanroom ... Construction materials andfinishes .................................................. 62 5.2 Ancillary Cleanrooms ................................................................................ 63 Materials transfer area ...................................................................... 66 Vertical flow unidirectional cleanrooms ........ Horizontal flow unidirectional flow rooms ....................... 6.2 Clean Air Devices ...................................................................................... 81 7.1 General Requirements ................................................................................ 91 Conventional Building Techniques ........................................................... 93 7.3 Modular Construction ................................................................................ 95 7.3. I Studless wall systems ...................... ........................................... 95 7.3.2 Framed wall systems .............................. ....................... 96 Cleanroom Technology vii 7.4 Doors and Widows ..................................................................................... 98 7.5 Floors .......................................................................................................... 98 7.7 Outgassing and Electrostatic Properties .................................................. 100 8 High Efficiency Air Filtration .................................................................. 103 8.1 Air Filters Used in Cleanrooms ............................................................... 103 8.2 The Construction of High Efficiency Filters ........................................... 104 8.3 Particle Removal Mechanisms ................................................................. 106 8.4 Testing of High Efficiency Filters ........................................................... 109 8.4.1 Military Standard 282 ..................................................................... 109 8.4.2 Sodium Flame Test (Eurovent 4/4) .................................................. 110 8.4.3 Institute of Erwironmental Sciences (ZEST) Recommended Practice ‘Testing ULPA Filters! ...................................................... 110 8.4.4 European Standard (EN 1822) ........................................................ 110 8.5 Probe (Scan) Testing of High Efficiency Filters ..................................... 111 8.6 Filter Housings for High Efficiency Filters ............................................. 112 9 Cleanroom Testing and Monitoring ........................................................ 115 9.1 Principles of Cleanroom Testing ............................................................. 116 9.2 Cleanroom Tests ...................................................................................... 116 9.2.1 Air supply and extract quantities ..................................................... 117 9.2.2 Air movement control between areas .............................................. 117 9.2.3 Filter installation leak test ............................................................... 118 9.2.4 Containment leak testing ................................................................. 118 9.2.5 Air movement control within the room ............................................ 118 9.2.6 Airborne particles and microbial concentrations ............................ 118 9.2.7 Additional tests ................................................................................ 118 9.3 Testing in Relation to Room Type and Occupation State ....................... 119 9.4 Re-testing to Demonstrate Compliance ................................................... 120 9.5 Monitoring of Cleanrooms ................................................................. 121 10 Measurement of Air Quantities and Pressure Differences ................. 123 10.1 Air Quantities ......................................................................................... 123 10.1.1 Measuring air quantities fiom within a cleanroom ....................... 124 10.1.2 Anemometers .................................................................................. 125 10.2 Differential Pressure Tests ..................................................................... 127 7.6 Ceilings ...................................................................................................... 99 ... Vlll Cleanroom Technology 10.2.1 Apparatus for measuringpressure differences ...... 10.2.2 Methods of checking pressure differences.. ........... 11 1 1 . 1 Cleanroom Containment Leak Testing I3 1 11.2 Air Movement Control within a Cleanroom .......................................... .. 134 11.3 Recovery Test Method ............................................................................ 139 12 Filter Installation Leak Testing ............................................................. 141 12.1 12.2 Artificial Smoke and Particle Test Challenges ...................................... 145 Air Movement Control Between and Within Cleanrooms .................. 131 11.1.1 Methods of checking inJltration .......... .............................. 11.2.1 Air movement visualisation ........... ...................... .................................................. The Use of Aerosol Test Challenges ..................................................... 144 12.2. I Cold-generated oils ............................... ............................. 12.2.3 Polystyrene latex spheres ... ............................ 12.3 Apparatus for Measuring Smo .......................... 147 12.3.1 Photometer.. ............................... .......................................... 147 12.3.2 Single particle counters.. ........... ............................... 148 12.4 Methods of Testing Filters and Filter Housings .................................... 149 12.4.1 Scanning methods ................................................................... 12.4.2 TestingJilters in unidirectionalJow rooms .................. 150 12.4.4 Repair of leaks ........................................ 12.2.2 Hot generated smokes ..... 12.4.3 Filter testing in conventionally ventilated room.. ........... 13 Airborne Particle Counts ....................................................................... 153 13.1 13.2 13.3 13.4 Airborne Particle Counters .................................................................... 153 Continuous Monitoring Apparatus for Airborne Particles .................... 156 Particle Counting in Different Occupancy States .................................. 158 Measurement of Particle Concentrations (IS0 14644- 1) ...................... 160 13.4.1 13.4.2 Airborne sampling volume ......... Sample locations and number ..................................... 13.4.3 Acceptance criteria .................... 13.5.1 Number of locations.. ................. ........................... 13.5.3 Sampling results ......................................................... 13.5 Worked Example of IS0 14644- 1 Test Method .................................... 162 Minimum air sampling volume ...................................................... 163 . 162 ....... 163 13.5.2 Cleanroom Technolopy ix 14 Microbial Counts .................................................................................... 167 14.1 Microbial Sampling of the Air ............................................................... 167 14.2 14.1. I Impaction onto agar ...................................................................... i68 Microbial Deposition onto Surfaces ...................................................... 171 Settle plate sampling ...................................................................... 171 Contact surface sampling .............................................................. 173 14.4 Personnel sampling ................................................................................ 175 15 Operating a Cleanroom: Contamination Control ............................... 177 Step 1 : Identification of Sources and Routes of Contamination ............ 178 Sources of contamination .............................................................. 178 15.1.2 Airborne and contact routes of transfer ........................................ 179 Step 2: Assessment ofthe Importance of Hazards ................................ 182 Step 3: Identification of Methods to Control Hazards ........................... 185 14.2. I 14.2.2 Calculation ofthe likely airborne contamination .......................... 172 14.3 Microbial Surface Sampling .................................................................. 173 14.3. I 14.3.2 Swabbing ....................................................................................... 174 15.1 15.1, I I5 . I . 3 Construction of a risk diagram ...................................................... 180 15.2 15.3 15.4 Step 4: Sampling Methods to Monitor Hazards and Control Methods .. 186 15.5 Step 5: Establishing a Monitoring Schedule with Alert and Action Levels ..................................................................................................... 189 15.7 Step 7: Documentation ........................................................................... 190 15.8 16 Cleanroom Disciplines ............................................................................ 193 16.1 16.2 16.3 15.6 Step 6: Verification and Reappraisal of the System .............................. 190 Step 8: Staff Training ............................................................................. 191 People Allowed into Cleanrooms .......................................................... 193 Personal Items Not Allowed into the Cleanroom .................................. 196 Disciplines within the Cleanroom .......................................................... 196 16.3. I Air transfer .................................................................................... 196 16.3.2 Personnel behaviour ...................................................................... 198 16.3.3 Handling materials ........................................................................ 206 Maintenance and Service Personnel ...................................................... 206 17 Entry and Exit of Personnel ................................................................... 209 Prior to Arriving at the Cleanroom ........................................................ 210 17.2 Changing into Cleanroom Garments ..................................................... 210 16.4 17.1 X Cleanroom Technolopy 17.2.1. Approaching the pre-change zone .. .......................................... 211 1 7.2.2 Pre-change zone ....... ............................................................. 213 1 7.2.3. Changing zone ......... ........................... 17.2.4 Cleanroom entrance zone .............................................................. 217 17.3 Exit Changing Procedures ..................................................................... 220 18 Materials, Equipment and Machinery .................................................. 223 18.1 Choice of Materials ................................................................................ 223 18.2 Items Supplied from Outside Manufacturing Sources ........................... 225 18.3 Wrapping Materials ............................................................................... 226 18.4 Transfer of Materials and Small Pieces of Equipment through an Airlock ............................................................................................... 228 18.4. I 18.4.2 Transfer area without a bench .. Transfer area with a bench ................................... 18.5 18.6 Entry of Machinery ................................................................................ 233 Transfer of Materials through Hatches and Sterilisers .......................... 235 19 Cleanroom Clothing ............................................................................... 237 Sources and Routes of Inert Particle Dispersion ................................... 238 Sources ofparticles and mechanisms of release ........................... 239 Routes and Sources ofMicrobia1 Dispersion ........................................ 243 19.2.1 Sources ofmicro-organisms ............ .......................... 241 Types of Cleanroom Clothing ................................................................ 245 19.3.2 Cleanroomfabrics ............................ ................................. 246 19.3.3 Garment construction ................................... .......................... 249 19.3.4 Choice ofgarments ................................................. .............. 249 Processing of Cleanroom Garments and Change Frequency ................. 252 19.4.2 Frequency of change ........................ The Effect of Laundering and Wear ...................................................... 256 Testing of Cleanroom Clothing ............................................................. 256 19.6. I Fabric tests ........................... ................................. 257 19.1 19.1, I 19.1.2 Routes of transfer ofparticles ............................. ..................... 242 19.2 19.2.2 244 19.3.1 Clothing designs ............................................................................ 245 Routes of microbial dispersion .................................. 19.3 19.3.5 Comfort ................................ 19.4.1 Processing ................................................................. 19.4 ............................... 255 19.5 19.6 19.6.2 Dispersal of airborne bacter ......................... 257 Cleanroom Technology XI 19.7 20 Cleanroom Masks and Gloves ............................................................... 263 20.1 Cleanroom Masks .................................................................................. 263 Static Dissipative Properties of Clothing ............................................... 261 20.1. I Dispersion from the mouth ............................................................ 263 20.1.2 Face mas k;s ..................................................................................... 266 20.1.3 Powered exhaust headgear ............................................................ 268 20.2.1 Hand contamination and gloves .................................................... 269 20.2.2 Glove manufacturingprocess ........................................................ 270 20.2.3 Types ofgloves ............................................................................... 270 20.2.4 Testing of Gloves ........................................................................... 272 Why a Cleanroom Must be Cleaned ...................................................... 275 Cleaning Methods and the Physics of Cleaning Surfaces ...................... 276 20.2 Cleanroom Gloves ................................................................................. 269 21 Cleaning a Cleanroom ............................................................................ 275 21.1 2 1.2 21.2.1 Vacuuming ..................................................................................... 277 21.2.2 Wet wiping ..................................................................................... 278 21.2.3 Tacky rollers .................................................................................. 278 21.3 Implements Used to Clean Cleanrooms ................................................. 279 21.3.2 Dry and wet vacuum systems ......................................................... 279 21.3.2 Moping systems .............................................................................. 280 21.3.3 Wipers ............................................................................................ 283 21.3.4 Tacky rollers .................................................................................. 285 21.3.5 Floor scrubbing systems ................................................................ 286 21.4 Liquids Used in Cleaning Cleanrooms .................................................. 286 21.4.1 Cleaning liquids ............................... .......................................... 286 21.4.2 Disinfectants .................................................................................. 288 21.5 How Should a Cleanroom be Cleaned? ................................................. 290 Cleaning methods with respect to area type .................................. 291 21.5.3 Cleaning methods .......................................................................... 293 21.5.1 General points ............................................................................... 290 21.5.2 21.6 Test Methods .......................................................................................... 295 Index ................................................................................................................ 297