Microbial limit and bioburden tests

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In recent years, the field of pharmaceutical microbiology has experienced numerous technological advances, accompanied by the publication of new and harmonized compendial methods. It is therefore imperative for those who are responsible for monitoring the microbial quality of pharmaceutical/biopharmaceutical products to keep abreast of the latest changes. Microbial Limit and Bioburden Tests: Validation Approaches and Global Requirements guides readers through the various microbiological methods listed in the compendia with easy-to-follow diagrams and approaches to validations of such test methodologies.

Includes New and Updated Material

Now in its second edition, this work is the culmination of research and discussions with technical experts, as well as USP and FDA representatives on various topics of interest to the pharmaceutical microbiologist and those responsible for the microbial quality of products, materials, equipment, and manufacturing facilities. New in this edition is an entire chapter dedicated to the topic of biofilms and their impact on pharmaceutical and biopharmaceutical operations. The subject of rapid methods in microbiology has been expanded and includes a discussion on the validation of alternative microbiological methods and a case study on microbial identification in support of a product contamination investigation.

Substantially updated and revised, this book assists readers in understanding the fundamental issues associated with pharmaceutical microbiology and provides them with tools to create effective microbial contamination control and microbial testing programs for the areas under their responsibility.

Preface	p. xiii
The Author	p. xv
Chapter 1 Microbial Life and Ecology	p. 1
An Overview of Microbial Life	p. 1
Microbial Phylogeny	p. 2
Microbial Taxonomy	p. 3
Microbial Growth and Survival	p. 4
Growth Curve	p. 4
Temperature	p. 5
Energy Sources	p. 6
Oxygen	p. 7
Bacteria	p. 7
Cell Shape	p. 8
Mycoplasma	p. 8
Bacterial Growth and Reproduction	p. 9
Cell Structures	p. 10
The Phyla Gram-Positive Bacteria and Proteobacteria	p. 12
Gram-Positive Bacteria	p. 12
Proteobacteria	p. 13
The Gram-Staining Method	p. 14
KOH Test	p. 14
Catalase Test	p. 15
Fungi	p. 15
Cell Structures	p. 16
Fungal Growth and Reproduction	p. 16
Molds	p. 16
Yeasts	p. 16
Microorganisms of Interest	p. 17
Genus Staphylococcus	p. 18
Staphylococcus aureus	p. 19
Genus Pseudomonas	p. 20
Pseudomonas aeruginosa	p. 20
Genus Burkholderia	p. 22
Burkholderia cepacia	p. 22
Genus Ralstonia	p. 23
Ralstonia pickettii	p. 23
Genus Comamonas and Genus Stenotrophomonas	p. 23
Family Enterobacteriaceae	p. 24
Genus Escherichia	p. 24
Escherichia coli	p. 24
Genus Salmonella	p. 26
Genus Shigella	p. 27
Genus Serratia	p. 27
Genus Klebsiella	p. 27
Genus Bacillus	p. 28
Bacillus subtilis	p. 29
Bacillus cereus	p. 29
Genus Clostridium	p. 29
Clostridium perfringens	p. 30
Clostridium sporogenes	p. 30
Candida albicans	p. 31
Zygosaccharomyces rouxii	p. 32
Genus Aspergillus	p. 32
Aspergillus niger	p. 33
Genus Penicillium	p. 33
References	p. 33
Chapter 2 Microbial Contamination and Control	p. 35
Microbiological Contamination	p. 35
Product Recalls	p. 35
Nonsterile Products	p. 38
Microbial Limit Standards	p. 40
The Preservation of Pharmaceutical Products	p. 40
Antimicrobial Activity and Efficacy	p. 41
Types of Preservatives	p. 44
Alcohols	p. 44
Benzalkonium Chloride	p. 44
Benzoic Acid and Salts	p. 45
Boric Acid and Salts	p. 46
Chlorhexidine	p. 46
Cresol	p. 46
Dowicil 200	p. 46
Mercurials	p. 46
Parabens	p. 46
Phenol	p. 47
Sorbic Acid Salts	p. 47
Microbiological Control	p. 47
Risk Assessment	p. 48
Objectionable Organisms	p. 49
Sanitization and Disinfection Practices	p. 51
Definitions and Types of Chemical Products	p. 52
Factors in Choice and Use of Disinfectants	p. 53
Rotation of Disinfectants	p. 54
Qualification of Disinfectants	p. 54
In Situ Testing	p. 55
In Vitro Testing	p. 56
Expiration Date for Disinfectant Solutions	p. 58
Sanitizers Used for Equipment Cleaning	p. 59
Neutralization and Microbial Recovery Studies	p. 59
Requalification and Change Control	p. 60
Conclusion	p. 61
References	p. 61
Chapter 3 The USP Microbial Limit Tests	p. 63
History of the Revision and Harmonization Process	p. 63
USP Chapter Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests	p. 64
Sample Preparation	p. 65
Total Aerobic Microbial Count	p. 66
Total Combined Yeasts and Molds Count	p. 67
Bioburden Tests	p. 67
Two-Media Bioburden Test	p. 67
One-Medium, Dual-Temperature Incubation Bioburden Test	p. 68
TAMC and TYMC Tests via Plate-Count Methods	p. 69
Pour-Plate Method	p. 69
Spread-Plate Method	p. 69
Incubation and Results Calculation	p. 70
Test Controls	p. 72
TAMC and TYMC Tests via Membrane Filtration Method	p. 72
Test Controls	p. 73
TAMC Test by the Multiple Tube Method	p. 74
Procedure	p. 74
Interpretation of the TAMC and TYMC Test Results	p. 77
USP CHAPTER : Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms	p. 77
Sample Preparation for Direct Inoculation Tests	p. 78
Test for Absence of Escherichia coli	p. 79
Test for Absence of Salmonella spp.	p. 79
Test for Absence of Bile-Tolerant Gram-Negative Bacteria	p. 80
Test for Absence of Pseudomonas aeruginosa	p. 81
Test for Absence of Staphylococcus aureus	p. 82
Test for Absence of Candida albicans	p. 83
Test for Absence of Clostridia	p. 84
Quantitative Test for Bile-Tolerant Gram-Negative Bacteria	p. 85
Retesting	p. 86
References	p. 87
Chapter 4 Pharmaceutical Waters	p. 93
Types of Water for Pharmaceutical Purposes	p. 93
Microbial Quality Attributes	p. 96
Testing of Pharmaceutical Waters	p. 98
Sampling Program	p. 99
Sample Collection and Preservation	p. 99
Bioburden Testing	p. 100
Recovery Media	p. 101
Coliform Testing	p. 103
Identification of Waterborne Microorganisms	p. 106
Establishing Alert and Action Levels	p. 107
Validation of Water Systems	p. 108
Microbial Control and Sanitization	p. 111
References	p. 111
Chapter 5 Environmental Monitoring	p. 113
Cleanroom Classification	p. 114
Occupancy State	p. 116
Routine EM Program	p. 116
Testing Frequency and Sampling Sites	p. 122
Setting Alert and Action Levels	p. 122
Test Methods and Equipment	p. 123
Surface Sampling for Viable Particles	p. 124
Active Air Sampling for Viable Particles	p. 126
Active Air Sampling for Nonviable Particles	p. 131
Microbial Identification Program	p. 132
Data Analysis	p. 133
EM During Facility Validation Activities	p. 134
Room Occupancy	p. 135
EM of Isolators	p. 135
Microbial Control in Cleanrooms	p. 136
References	p. 137
Chapter 6 Bioburden Considerations in Equipment-Cleaning Validation	p. 139
Biocontamination Control	p. 141
Disposable and Single-Use Equipment	p. 142
Equipment-Cleaning Methods	p. 142
Validation of Cleaning Methods	p. 144
Sampling Recovery Methods	p. 145
Swabbing of Equipment	p. 145
Rinsing of Equipment	p. 146
Qualification of Sampling Methods	p. 147
Recovery Study Using the Wet Method	p. 148
Recovery Studies Using the Dry Method	p. 150
Effects of Product and/or Cleaning Agent Residue on the Recovery of Microorganisms	p. 151
Establishing Limits	p. 153
Execution of Equipment-Cleaning Validation Protocol	p. 155
Validation of Cleaned Equipment Hold Time	p. 155
Validation of Dirty Equipment Hold Time	p. 156
Ongoing Verification of Cleaning	p. 156
Validation of Holding Time/Shipping Conditions	p. 157
References	p. 158
Chapter 7 Method Validation and Media Suitability Testing	p. 159
Suitability Test Design	p. 160
Representative Challenge Organisms	p. 162
Maintenance and Preparation of Test Organisms	p. 163
Preparation of Working Cultures	p. 165
Validation of Storage Period for Working Cultures	p. 166
Recovery of Injured Organisms	p. 166
Suitability Testing by Direct Inoculation/Plating Methods	p. 167
Validation of Screening for Specified Microorganisms	p. 167
Modifications to the Direct Inoculation Method	p. 174
Validation of the TAMC and TYMC Tests	p. 175
Approach 1	p. 175
Approach 2	p. 176
Modifications to the Plate Method	p. 182
Suitability Testing for Membrane Filtration Methods	p. 182
Validation of Screening for Specified Organisms	p. 183
Validation of TAMC and TYMC	p. 184
Modifications to the Membrane Filtration Method	p. 187
Suitability of Microbiological Media	p. 188
Growth Promotion Testing for Microbial Enumeration Media	p. 190
Growth Promotion Testing for Selective Media	p. 190
Validation of Rapid Microbiological Methods	p. 192
The Validation Package	p. 192
Validation Criteria	p. 193
Validation of Quantitative Methods	p. 194
Accuracy	p. 194
Specificity	p. 194
Precision	p. 195
Limit of Quantitation	p. 195
Linearity	p. 195
Limit of Detection	p. 195
Range	p. 196
Ruggedness	p. 196
Robustness	p. 196
Validation of Qualitative Methods	p. 197
Specificity	p. 197
Limit of Detection	p. 197
Ruggedness	p. 197
Robustness	p. 197
Accuracy and Precision	p. 198
Validation of Automated Microbial Identification Methods	p. 198
Accuracy	p. 198
Precision	p. 198
Robustness	p. 198
Ruggedness	p. 198
Final Thoughts	p. 199
Points to Consider	p. 199
References	p. 201
Chapter 8 Microbiological Quality of Pharmaceutical and Biopharmaceutical Products and Raw Materials	p. 203
Microbiological Testing	p. 203
Raw Materials	p. 203
Biopharmaceutical Products	p. 204
Nonsterile Finished Drug Products	p. 209
USP Chapter	p. 209
Testing Frequency	p. 213
Stability Testing	p. 213
Water Activity	p. 215
Measuring Water Activity	p. 217
The Chilled-Mirror/Dew Point Method	p. 217
Capacity Sensors	p. 217
Pharmaceutical Applications for Water Activity	p. 218
International Harmonization	p. 219
Looking Ahead	p. 220
References	p. 220
Chapter 9 Rapid Testing and Alternative Methods in Microbiology	p. 223
Rapid Method Technology Platforms	p. 224
Impedance/Conductance Technology	p. 225
Gas Consumption or Generation	p. 226
ATP Bioluminescence	p. 227
The Celsis ATP Bioluminescence Systems	p. 230
Automated Biochemical Assays	p. 231
The VITEK System	p. 231
The Biolog Systems	p. 235
Fatty Acid Analysis Using Gas Chromatography	p. 237
The MIDI System	p. 237
Enzyme-Linked Immunosorbent Assay (ELISA)	p. 240
The VIDAS	p. 241
Analysis of Biomolecules Using Mass Spectrometry	p. 242
Polymerase Chain Reaction (PCR)	p. 243
Detection of Microbial Contamination Using PCR Technology	p. 244
Pulse-Field Gel Electrophoresis (PFGE)	p. 245
Riboprinting	p. 246
The Riboprinter	p. 246
Fluorescent Labeling Assays	p. 247
Scan RDI Microbial Detection	p. 247
D-Count	p. 250
Biosensors and Microarrays	p. 251
Laboratory-on-a-Chip Technology	p. 252
Barriers to Implementation	p. 253
Regulatory Climate	p. 254
Future Trends	p. 255
Case Study: Genotypically Similar Staphylococci	p. 256
Contaminant Isolate and Environmental Sampling	p. 256
Ribosomal Gene Sequencing	p. 257
Phenotypic Analysis	p. 257
Genetic Subtyping-PFGE	p. 259
Results and Reporting	p. 259
References	p. 261
Chapter 10 Biofilms	p. 263
Biofilm Definition	p. 263
Biofilm Structure	p. 263
The Biology of Biofilms	p. 265
Biofilm Formation	p. 265
Quorum Sensing	p. 265
Cell Adhesion	p. 266
Smooth versus Rough Surfaces	p. 267
Hydrophobic versus Hydrophilic Surfaces	p. 267
Electrostatic Charge Properties	p. 267
Low-Shear versus High-Shear Environments	p. 267
Biofilm Dispersion	p. 268
Biofilm Resistance and Phenotypes	p. 268
Pharmaceutical Production Equipment and Materials Prone to Biofilm Formation	p. 270
Water Systems	p. 271
Production Equipment	p. 273
Ultrafiltration/Diafiltration (UF/DF) Systems	p. 273
Chromatography Systems	p. 274
Miscellaneous Parts and Materials	p. 276
Biofilm Control and Prevention	p. 277
Heat Treatment	p. 278
Chemical Treatment	p. 278
Prevention of Biofilms	p. 279
Methods for Detection and Recovery of Biofilm Organisms	p. 280
Qualification of Chemical Sanitization Using Biofilm Cells	p. 282
Types of Biofilm Reactors	p. 282
Choosing a Biofilm Reactor	p. 287
Testing Sanitizers Using the CDC Biofilm Reactor	p. 287
Setting up the Biofilm Reactor	p. 287
Exposure of Biofilm to Disinfectant Solution	p. 290
Harvesting Biofilm Cells	p. 290
Sanitizer/Disinfectant Efficacy Evaluation	p. 291
Method Qualification and Test Controls	p. 291
Testing Sanitizers Using a Static Biofilm Reactor	p. 292
Industrial Significance of Biofilms	p. 292
The Future in Biofilm Research	p. 293
References	p. 295
Chapter 11 Handling Aberrant and Out-of-Specification Microbial Data	p. 299
Historical Overview of Investigating OOS Results	p. 299
Out-of-Specification (OOS) Result	p. 300
Laboratory Investigations	p. 301
Conducting the Investigation	p. 304
Retesting and Resampling	p. 305
Testing for Outliers	p. 306
Repeat Testing	p. 307
Concluding the Investigation	p. 308
Product Lot Disposition	p. 309
OOS Investigations and FDA Citations	p. 309
References	p. 310
Index	p. 311

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