ABSTRACT
License Applications and New Drug Applications.... 332 9.3.1 Chemistry Manufacturing and Controls......... 332 9.3.2 Establishment Description .............................. 334 9.3.3 CBER/CDER Reorganization........................... 335
9.4 Facility Design............................................................. 335 9.4.1 General Considerations.................................... 335
9.4.1.1 Cell Inoculum Suites .......................... 336 9.4.1.2 Fermentation/Harvest Areas.............. 337 9.4.1.3 Purification Areas ............................... 338 9.4.1.4 Bulk Filtration Areas ......................... 338 9.4.1.5 Support Areas ..................................... 339
9.4.2 Specific Considerations .................................... 341
9.4.2.1 Closed Systems ................................... 341 9.4.2.2 Gray Space .......................................... 342 9.4.2.3 Good Large-Scale Practice ................. 342
9.5 Utilities: Design and Operation ................................. 343 9.5.1 Water Systems .................................................. 344
9.5.1.1 Incoming Potable Water ..................... 344 9.5.1.2 Water Purification Systems ............... 344 9.5.1.3 Distillation........................................... 346 9.5.1.4 Storage and Distribution Systems .... 346 9.5.1.5 Materials of Construction .................. 347 9.5.1.6 Passivation .......................................... 348 9.5.1.7 Water System Qualification ............... 348
9.5.2 Heating Ventilation and Air-Conditioning (HVAC) Systems ............................................... 348 9.5.2.1 HVAC Components ............................. 350 9.5.2.2 Recirculated versus Once-Through
Systems................................................ 350 9.5.2.3 HVAC Requirements for Aseptic
Processing............................................ 351 9.5.2.4 HVAC System Qualification and
Monitoring ........................................... 351 9.6 Facility Cleaning ......................................................... 352
9.6.1 Cleaning Procedures......................................... 352 9.6.2 Cleaning Agents and Equipment .................... 353 9.6.3 Monitoring Cleaning Effectiveness ................. 354 9.6.4 Recommissioning Activities ............................. 354
9.7 Environmental Monitoring ......................................... 355 9.7.1 Nonviable Particulate Monitoring................... 355 9.7.2 Airborne Viable Microbial Monitoring ............ 356 9.7.3 Contact Plates and Swabs ............................... 357 9.7.4 Temperature and Humidity Monitoring ......... 358 9.7.5 Gowning Qualification...................................... 359 9.7.6 Water Monitoring ............................................. 359 9.7.7 Data Management and Trending .................... 361
9.8 Multiproduct Considerations...................................... 363 9.8.1 Types of Multiproduct Facilities...................... 363 9.8.2 Design Considerations ..................................... 365 9.8.3 Product Changeover Procedures ..................... 367
9.8.4 Cleaning Validation .......................................... 368 9.8.4.1 Goals of a Cleaning Validation .......... 369 9.8.4.2 Common Inspectional Pitfalls............ 373
9.8.5 Introduction of New Products into a Multiproduct Facility........................................ 374
9.9 Contract Manufacturing ............................................. 376 9.9.1 Regulatory Issues ............................................. 377
9.9.1.1 Compliance Issues .............................. 377 9.9.1.2 Confidentiality Issues......................... 381
9.10 Facility Inspections ..................................................... 381 9.10.1 History and Statutory Requirements for
Facility Inspections........................................... 381 9.10.2 Current Focus of Inspections........................... 383
9.10.2.1 Process Validation............................... 384 9.10.2.2 Contamination and
Cross-Contamination .......................... 385 9.10.2.3 Quality Assurance Functions............. 386
9.11 Summary...................................................................... 387 References............................................................................. 388
9.1 INTRODUCTION
Properly designed manufacturing facilities are critical to the successful approval of biotechnology-derived (biotech) products. The Food and Drug Administration (FDA) has established regulations that govern establishments used to manufacture biological products. These include the Code of Federal Regulations (CFR), Title 21, Part 600, Subpart B Establishment Standards [1] and Parts 210 and 211 of current Good Manufacturing Practice (cGMP) regulations [2]. These regulations were established prior to the advent of biotech products. The intent of the regulations, however, is applicable to facilities designed to produce biotech products.
