Preface ............................................................... ix Martin C. Easter Fitness for Purpose? Time for a Revolution ......................... i 1. Introduction ........................................................ 1 Martin C. Easter Market Size ........................................................ 2 Issues and Challenges .............................................. 2 Hopes for the Future ............................................... 6 References ......................................................... 6 2. Historical Perspective on Methods Development ....................... 9 Anthony M. Cundell Foundation of the Field of Microbiology ........................... 10 Development of the Classical Microbiological Methods .............. 10 Development of Advanced Microbiological Methods ................... 14 The Search for Rapid Biological Methods ........................... 15 Bibliography ...................................................... 17 3. Microbiological Methods of the Pharmacopoeia: Growth and Recovery of Microorganisms from Pharmaceutical Manufacturing Environments .......................... 19 Klaus Haberer and Marc W. Mittelman Microbial Growth in Pharmaceutical Environments: Starvation-Survival ............................................... 19 Biofilm Formation ................................................. 20 Influence of Environmental Conditions on Microbial Survival ....... 21 Cultivation of Microorganisms on Solid and Liquid Substrates ...... 22 Microbiological Standard Methods of the Pharmacopoeia ............. 31 References ........................................................ 36 4. Overview of Alternative Rapid Microbiological Technologies ......... 41 Paul J. Newby and Bob Johnson Industrial Needs and Requirements ................................. 41 Rapid Methods and the Drug Development Process .................... 43 Available Technologies ............................................ 46 Molecular-Based Technologies ...................................... 54 Identification Systems ............................................ 56 Conclusions ....................................................... 56 References ........................................................ 57 5. Labor-Saving Devices and Automation of Traditional Methods ......... 61 Peter Silley and A.N. Sharpe Blenders, Stomachers, and Pulsifiers .............................. 61 Gravimetric Diluters .............................................. 63 Counting Procedures ............................................... 63 Some Venerable, Inexpensive, and Labor-Saving Methods ............. 73 Methods for Surface Contamination: Agar Contact Methods ........... 74 Spiral Plating Applications ....................................... 75 References ........................................................ 77 6. ATP Bioluminescence and Its Use in Pharmaceutical Microbiology ..... 85 Kirsty Wills The Science ....................................................... 85 The Products Available ............................................ 87 The Future ........................................................ 96 Summary ........................................................... 97 References ........................................................ 97 7. Impedance .......................................................... 99 Peter Silley and Fiona Mortimer History of Development ........................................... 100 Impedance Theory ................................................. 101 Influence of Electrodes .......................................... 104 Principle Factors Affecting Detection Time ....................... 104 Instruments ...................................................... 104 Pharmaceutical Applications of Impedance ......................... 108 Miscellaneous Applications in Drug Development ................... 117 Conclusion ....................................................... 118 References ....................................................... 118 8. Traditional and Automated Rapid Methods for Species Identification and Typing ......................................... 125 Kevin Tyler and Jeffrey M. Farber Genotyping ....................................................... 126 Chemotaxonomy .................................................... 139 Electrophoretic Protein Typing ................................... 149 Conclusion ....................................................... 150 References ....................................................... 150 9. Techniques for Detection of Specific Organisms and Potential for DNA-Based Technologies .......................... 161 Richard Owen Current Established Methods for Specific Organism Detection ...... 161 DNA-Based Technologies ........................................... 162 Why Aren't More Nucleic Acid Assays Being Used? .................. 173 Conclusion ....................................................... 174 References ....................................................... 175 10. Alternative Technologies for Sterility Testing ................... 179 Amy Meszaros Alternate Technologies: Clinical Origins ......................... 180 Alternate Technologies: Nonclinical Origins ...................... 183 Regulatory Acceptance and the Future for Sterility Testing ....... 184 References ....................................................... 185 11. Limulus Endotoxin Test ........................................... 187 Thomas J. Novitsky and H. Donald Hochstein Discovery ........................................................ 187 Early Regulatory Interest in an Alternative to the Rabbit Pyrogen Test .......................................... 188 Commercialization ................................................ 192 Industry Acceptance .............................................. 195 FDA Guidelines ................................................... 197 USP Bacterial Endotoxin Test and Related Monographs .............. 199 European and Japanese Pharmacopoeia Acceptance of the LAL Test .................................................. 202 Methodology ...................................................... 204 Automation ....................................................... 206 Research and Clinical Applications ............................... 206 Future of the Assay .............................................. 206 References ....................................................... 207 12 A Practical Guide to Validation ................................... 211 Kirsty Wills What Is Validation? .............................................. 211 Background ....................................................... 212 Start at the Beginning ........................................... 213 Specification Qualification (SQ) ................................. 213 Validation Plan .................................................. 214 Design Qualification (DQ) ........................................ 215 Installation Qualification (IQ) .................................. 216 Operation Qualification (OQ) ..................................... 216 Performance Qualification (PQ) ................................... 217 Standard Operating Procedures (SOPs) ............................. 217 Validation Summary ............................................... 217 Implementation ................................................... 217 Periodic Review .................................................. 218 Multiple Site Validation ......................................... 218 Amendments to Product Marketing Authorizations ................... 218 Conclusion ....................................................... 219 References ....................................................... 220 13 Regulatory Recognition and Acceptance ............................. 221 Edward A. Fitzgerald Objectives ....................................................... 221 Brief History of Regulation Development .......................... 222 Regulatory Concerns .............................................. 224 Regulatory Acceptance ............................................ 227 Summary and Conclusions .......................................... 230 References ....................................................... 231 14 New Technologies for Microbiological Assays ....................... 233 Larry J. Kricka Immunological Tests .............................................. 234 Cell Components .................................................. 238 Microchips ....................................................... 239 Instrumental Techniques .......................................... 241 Conclusions ...................................................... 242 References ....................................................... 243 Afterword ........................................................ 249 Afterword ............................................................ 249 Martin C. Easter and Anthony M. Cundell Advances in Technology ........................................... 249 Acceptability .................................................... 250 Attitude ......................................................... 250 References ....................................................... 251 Contributors ......................................................... 253 Index ................................................................ 259