ABSTRACT
Bubble Point Test ............................................. 219 7.3.6 Grow-Through and Endotoxin......................... 222 7.3.7 Adsorption ......................................................... 223 7.3.8 Extractables ...................................................... 225 7.3.9 Thermal and Hydraulic Stress Resistance..... 230 7.3.10 Other Considerations ....................................... 231
7.4 Clarification/Prefiltration Filters ............................... 231 7.4.1 Retention Ratings............................................. 231 7.4.2 Throughput Testing.......................................... 232
7.4.3 Toxicity and Fiber Shedding............................ 232 7.4.4 Bioburden and Endotoxin ................................ 233 7.4.5 Extractables ...................................................... 233 7.4.6 Product Stability............................................... 234 7.4.7 Processing Considerations ............................... 235
7.5 Viral Clearance Filters ............................................... 236 7.5.1 Definitions and Regulatory Requirements ..... 236 7.5.2 Virus Spiking Studies ...................................... 239 7.5.3 Integrity Testing of Viral Clearance Filters ... 244 7.5.4 Other Considerations ....................................... 246
7.6 Validation of Tangential Flow Filters........................ 247 7.6.1 Overview ........................................................... 247 7.6.2 Process Flux...................................................... 249 7.6.3 Pressure Profiles............................................... 249 7.6.4 Retention ........................................................... 250 7.6.5 Yield................................................................... 251 7.6.6 Chemical Compatibility ................................... 251 7.6.7 Bioburden and Endotoxin ................................ 252 7.6.8 Membrane Qualification .................................. 253 7.6.9 Other Considerations ....................................... 253 7.6.10 Bacterial Cell Harvest and Lysate
Clarification ...................................................... 254 7.6.11 Mammalian Cell Clarification ......................... 255 7.6.12 Protein Concentration and Diafiltration ........ 255
7.7 Validation of a TFF System Cleaning Protocol......... 257 7.7.1 Cleaning Considerations .................................. 257 7.7.2 Chemical Compatibility ................................... 259 7.7.3 System Design .................................................. 260 7.7.4 Cleaning Specifications .................................... 261 7.7.5 Membrane Reuse .............................................. 263 7.7.6 Clean-Water Flux ............................................. 264 7.7.7 Integrity Testing ............................................... 265
7.8 Residue Sampling Methods ........................................ 266 7.8.1 Swab Testing..................................................... 266 7.8.2 Solvent Sampling.............................................. 267 7.8.3 Coupon Sampling ............................................. 268 7.8.4 Assays................................................................ 268 7.8.5 Acceptable Residue Limits............................... 269
7.9 Conclusion.................................................................... 270 References............................................................................. 272
7.1 FILTRATION VALIDATION OVERVIEW
Process validation has been defined by the FDA as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes” (FDA, 1987). It is an assurance that a process is robust and reproducible and will consistently produce a product that meets specifications. Validation is born out of Good Manufacturing Practices (GMPs), which require that quality be built into a manufacturing process. The process must exhibit control at each step or unit operation. Sources of variation must be identified, and these variations must be controlled and monitored. Final testing of the product is not sufficient to ensure quality.
