Pharmaceutical Microbiological Quality Assurance and Control: Practical Guide for Non-Sterile Manufacturing

Cover......Page 1
Title Page......Page 5
Copyright Page......Page 6
Contents......Page 7
Editors......Page 21
List of Contributors......Page 23
Preface......Page 29
Foreword......Page 35
Acknowledgments......Page 37
 1.1 Introduction......Page 39
 1.2 Overview of a Microbial Control Strategy Program......Page 40
  1.3.1 Controlled Facilities......Page 42
  1.3.3 Controlled Product Ingredients......Page 48
  1.3.4 Controlled Utilities......Page 50
  1.3.5 Controlled Equipment......Page 51
  1.3.6 Controlled Formulation......Page 53
 Bibliography......Page 56
2 Microbial Contamination Risk Assessment in Non‐sterile Drug Product Manufacturing and Risk Mitigation......Page 61
 2.2 Regulatory, Compendia, and Industry Guidance......Page 62
 2.3 Putting into Perspective the Microbiological Risk Associated with Non‐sterile Products......Page 63
  2.3.1 75 000 Deaths Annually Caused by Infectious Diseases!......Page 64
  2.3.2 Susceptibility of Different Patient Populations......Page 66
 2.4 Risk Assessment Tools......Page 67
  2.4.1 Impact Matrix......Page 68
  2.4.3 Hazard Analysis and Critical Control Points (HACCP)......Page 69
  2.6.1 Hierarchy of Risk by Pharmaceutical Ingredient......Page 73
  2.6.2 Hierarchy of Risk by Dosage Form and Processing Steps......Page 80
  2.6.3 Hierarchy of Risk by Utility System......Page 83
  2.7.3 Hurdle Technology Concept......Page 84
  2.8.1 Jet Milling Micronization......Page 86
  2.8.2 Hot Melt Extrusion......Page 88
  2.8.3 Continuous Tablet Manufacturing......Page 89
 2.9 A Case History......Page 90
 Bibliography......Page 91
 3.1 Introduction......Page 95
  3.2.1 Qualification and Re‐Qualification of Laboratory Personnel......Page 96
  3.2.2 Equipment Qualification: Which Equipment Needs to Be Qualified in a Microbiological Laboratory?......Page 98
  3.2.3 Equipment Qualification: How to Qualify Laboratory Equipment......Page 103
 3.3 Critical Aspects of Microbiological Methods......Page 106
  3.3.1 Antibiotic Susceptibility Testing (AST)......Page 107
  3.4.1 Titrations......Page 110
  3.4.3 Recovery Rate of Microbiological Swab Sampling......Page 111
 Bibliography......Page 114
4 Introduction to Culture Media in Pharmaceutical Microbiology for Non‐sterile Products......Page 117
 4.1 Introduction......Page 118
 4.4 Culture Media Are all Different......Page 121
  4.4.1 Importance of Raw Materials......Page 122
  4.4.3 Development of Culture Media......Page 125
  4.4.4 Stability Studies......Page 126
  4.5.1 Objectionable Organisms Recall......Page 129
  4.6.1 Quality Release Test Performed by the Culture Media Manufacturer (External Provider or In‐house Media Manufacturer)......Page 130
  4.6.2 Quality Control Test Performed on Ready‐to‐Use Culture Media Purchased from External Manufacturers......Page 133
  4.6.3 Importance of the Quality Control Strains......Page 134
  4.6.4 Outsourcing Strategy and How to Perform an Audit at a Growth Media Partner......Page 135
 4.7 Culture Media Troubleshooting......Page 136
  4.7.1 Temperature Storage Issues......Page 137
  4.7.3 Fertility Issues......Page 138
  4.7.4 Crystals in Xylose Lysine Deoxycholate (XLD) Culture Medium......Page 140
 Bibliography......Page 141
5 Microbiological Examination of Non‐sterile Final Dosage Forms and Raw Material Including Acceptance Criteria and Testing Frequency......Page 143
  5.1.1 Final Dosage Forms......Page 144
  5.1.2 Raw Materials......Page 148
  5.1.3 Internal Out of Expectation (OOE) Limits......Page 149
  5.2.1 Final Dosage Forms......Page 150
  5.2.2 Drug Substances and Excipients......Page 154
 5.4 Sampling......Page 155
 5.5 Nutrient Medium Controls......Page 158
  5.5.3 Growth Promotion Tests......Page 159
 5.6 Test Method Overview......Page 163
  5.7.1 Sample Preparation......Page 165
  5.7.2 Method Suitability for Microbial Enumeration Tests......Page 167
  5.7.3 Suitability of the Test Method for Absence of Specified Microorganisms......Page 177
  5.7.4 Examples of Procedures in Case the Method Suitability Fails......Page 178
  5.8.1 Microbial Enumeration Tests: Membrane Filtration and Plate Count Methods......Page 180
  5.8.3 Test for Specified Microorganisms Procedure......Page 183
 5.9 Elements to Consider for Raw Data Sheets......Page 186
 Bibliography......Page 187
6 Microbial Requirements and Testing of Primary Packaging......Page 191
  6.1.1 Definition of Primary Packaging......Page 192
  6.1.2 Microflora in Packaging Materials......Page 194
  6.1.3 Antimicrobial Packaging......Page 196
 6.2 Guidelines and Literature......Page 199
  6.3.1 Examples of Acceptance Criteria......Page 202
  6.3.2 Calculation Approach to Define Acceptance Criteria......Page 205
  6.3.4 Testing Frequency......Page 207
 6.4 Test Methods......Page 208
  6.4.1 Membrane Filtration......Page 210
  6.4.3 Contact Plates and Swabs......Page 211
 6.5 Suitability Test......Page 212
  6.5.1 Suitability Test Approach for the Membrane Filtration Method......Page 213
  6.5.3 Pour‐Plate Method and Specified Microorganisms......Page 214
 6.6 OOS Procedure......Page 215
 6.7 Examples of OOS or OOE Cases......Page 216
  6.7.1 Example 1: OOE of a Metal Container (1 l) Used for API Storage......Page 217
  6.7.2 Example 2: Possible OOS for a Foil Used for Inhalation Products......Page 219
  6.7.3 Example 3: Contaminated Inhaler......Page 221
 6.8 Conclusion......Page 222
 Bibliography......Page 223
7 Utilities Design and Testing......Page 227
 7.1 Introduction......Page 228
  7.2.1 What Are Utilities?......Page 229
  7.2.2 Good Design Principles......Page 230
  7.2.4 Qualification of Utilities......Page 233
  7.2.5 Upgrading, Reconstructing, and Renovating Utilities......Page 234
  7.2.6 Outsourcing......Page 235
  7.3.1 Compressed Air and Gases......Page 236
  7.3.2 Cleanrooms and Controlled Environments......Page 246
  7.3.3 Water Systems......Page 250
  7.3.5 Clean Steam......Page 259
  7.3.6 Clean Equipment, Sanitization, and Cleaning Validation......Page 260
 7.4 Conclusion......Page 264
 Bibliography......Page 265
8 Microbiological Environmental Monitoring......Page 269
 8.1 Introduction......Page 270
 8.3 Cleanliness Zoning Concept for Non‐sterile Products......Page 271
 8.4 Microbiological Environmental Monitoring Strategy......Page 272
  8.5.1 Microbiological Monitoring of Air......Page 273
  8.5.2 Microbiological Monitoring of Surfaces......Page 274
  8.5.3 Microbiological Monitoring of Detergents and Disinfectants......Page 275
  8.6.1 Choice and Validation of Nutrient Media......Page 276
  8.6.2 Incubation Temperature and Incubation Period......Page 278
  8.6.3 Experimental Studies to Evaluate the Impact of the Applied Testing Method Toward Microbial Recovery......Page 279
  8.6.4 Recovery Rate......Page 280
  8.6.5 Sample Hold Time......Page 281
  8.7.1 Initial Validation of Cleanrooms......Page 282
  8.7.2 Initial Validation of Production Equipment......Page 283
  8.8.1 Definition of Microbiological Control Levels......Page 284
  8.8.2 Definition of Monitoring Frequencies......Page 286
  8.8.3 Definition of Sampling Locations......Page 287
  8.8.4 Measures if Microbiological Control Levels Are Exceeded......Page 288
  8.8.5 Trending of Results......Page 289
  8.9.1 Example for the Definition of Sampling Locations for a Production Area......Page 291
  8.9.2 Examples for Deviation Handling......Page 293
 8.10 Conclusion......Page 299
 Bibliography......Page 300
9 Identification of Microorganisms......Page 303
 9.1 Introduction......Page 304
 9.2 History and Challenges of Bacterial Taxonomy and Classification......Page 306
  9.2.1 Definition of Strains......Page 307
  9.2.2 Evolution of a Phylogenetic Marker......Page 308
  9.2.3 Setting a New Starting Point......Page 310
  9.2.4 The Contemporary View of Microbial Taxonomy......Page 311
  9.2.5 Limits of Resolution......Page 312
 9.3 History and Challenges of Fungal Taxonomy and Classification......Page 314
  9.3.1 Identification of Fungi Using the rRNA Region......Page 316
 9.4 Current Identification Technologies......Page 317
  9.4.1 Considerations of the Different Systems......Page 318
  9.4.2 Challenges with Nomenclature and Reference Data......Page 320
  9.4.3 Considerations for Using an In‐house System or a Contract Testing Lab......Page 321
  9.4.4 Phenotypic Systems......Page 322
  9.4.5 Proteotypic Systems......Page 325
  9.4.6 Genotypic Systems......Page 329
  9.4.7 Next‐Generation Sequencing Systems......Page 335
  9.4.8 Other Spectroscopy or Spectrometry Methods for Identification and/or Strain Typing......Page 337
  9.4.9 Strain‐Level Differentiation......Page 340
 9.5 Strengths and Weaknesses with Each Categorical Method......Page 344
  9.6.1 A Caveat to Identifying QC Strains......Page 347
  9.6.2 Odoribacter Are Not Bacillus: The Importance of Accurate Reference Data......Page 348
  9.6.3 Synonyms of Fungal Strains: Taxonomic Investigations......Page 349
  9.6.4 Synonyms of Bacterial Strains: Taxonomic Investigations......Page 350
 9.7 Conclusion......Page 351
 Bibliography......Page 352
10 Calculating Alert Levels and Trending of Microbiological Data......Page 367
 10.1 Introduction......Page 368
  10.3.1 Introduction......Page 370
  10.3.2 Distribution of Microbiological Data......Page 373
  10.3.3 Data to Be Included in the Calculations......Page 376
  10.3.4 Calculating Alert Levels Using Control Charts......Page 377
  10.3.5 Calculating Alert Levels Using Percentile Ranking......Page 384
  10.3.6 Conclusion Calculation of Alert Levels......Page 390
  10.4.2 Defining and Investigating Adverse Trends......Page 393
  10.4.3 Examples of Trending Methods ......Page 396
 Acknowledgments......Page 405
11 Exclusion of Objectionable Microorganisms from Non‐sterile Pharmaceutical Drug Products......Page 409
 11.1 Introduction......Page 410
 11.2 What Is an Objectionable Microorganism?......Page 412
  11.3.1 Microbial Characterization, Identification, and Strain Typing......Page 421
  11.3.2 Screening of Objectionable Microorganisms......Page 422
  11.3.4 Selectivity of the USP Absence of Specified Microorganism Tests with Regards to B. cepacia Complex......Page 423
  11.4.1 Low‐Risk Products......Page 426
  11.5.1 Pharmaceutical Ingredients......Page 427
  11.5.5 Manufacturing Environment......Page 429
 11.6 Risk Assessment to Determine if a Microorganism Is Objectionable in a Non‐sterile Drug Product......Page 430
  11.6.2 Potential Microbial Proliferation in the Drug Product......Page 431
  11.6.3 Risk Level in Targeted Patient Populations......Page 432
  11.7.1 Allopurinol Tablets for Cancer Patients......Page 433
  11.7.4 Non‐sterile Alcohol Wipes in an Intensive Care Unit......Page 434
  11.7.6 Comforts for Baby Water with Fluoride......Page 435
 11.8 Conclusions......Page 436
 Bibliography......Page 437
 12.1 Data Integrity......Page 439
 12.2 General Concept for Microbiological Excursion......Page 448
  12.2.1 Level 1 Investigation......Page 449
  12.2.2 Level 2 Investigation......Page 451
  12.3.1 Excursion with Environmental Monitoring......Page 458
  12.3.2 Excursion with Water Testing......Page 460
  12.3.3 Excursion in the Growth Promotion Test......Page 462
  12.3.4 Excursion with Microbiological Examination of Non‐sterile Products......Page 464
 Bibliography......Page 465
 13.1 Introduction......Page 467
 13.2 The Current State of Microbiology Testing......Page 469
 13.3 Rapid Microbiological Methods......Page 470
 13.4 Applications for Non‐sterile Pharmaceutical Drug Products......Page 471
 13.5 Technology Review......Page 473
  13.5.1 Growth‐Based RMMs......Page 474
  13.5.2 Cellular Component‐Based Technologies......Page 476
  13.5.3 Viability‐Based Technologies......Page 478
  13.5.4 Spectroscopy‐Based Technologies......Page 479
  13.5.5 Nucleic Acid Amplification‐Based Technologies......Page 482
 13.6 Validating Rapid Microbiological Methods......Page 485
 13.7 Developing a Business Case for Rapid Methods......Page 492
 13.8 Summary......Page 493
 Bibliography......Page 494
14 Validation of a Rapid Microbiological Method for the Microbiological Examination of Non‐sterile and Nonfilterable Drug Products, APIs, and Excipients......Page 497
 14.1 Introduction......Page 498
  14.1.1 Workflow Rapid MET......Page 499
  14.2.1 General Validation Strategy......Page 500
  14.2.2 Statistical Data Evaluation......Page 501
  14.2.3 Experimental Conditions for Validation Experiments......Page 506
  14.2.4 Method Validation Results......Page 507
  14.3.1 Sample Effects Study......Page 517
  14.3.2 Suitability of the Test Method......Page 519
 14.4 Discussion......Page 521
 Acknowledgments......Page 524
 Bibliography......Page 525
 15.1 Foods, Drugs, and Quality......Page 527
 15.2 Why Microbes Confound a Census......Page 530
 15.3 Microbiological QA Decisions......Page 532
 15.4 Who Has Responsibility for Quality?......Page 533
 15.5 Product and Process Planning......Page 534
 15.6 Quality and Documentation in Drug Manufacturing......Page 537
 15.7 Summary......Page 538
 Bibliography......Page 539
 16.1 Introduction......Page 543
 16.2 General Requirements......Page 544
  16.3.1 General Overview......Page 546
  16.3.2 Organization and Personnel......Page 547
  16.3.4 Culture Media......Page 548
  16.3.5 Trends......Page 549
  16.3.7 Facilities......Page 550
  16.3.8 Equipment......Page 551
 16.4 Regulatory Audits in the Microbiology Department......Page 552
 16.5 Conclusions......Page 554
 Bibliography......Page 555
 17.1 Introduction......Page 557
  17.2.1 Specialization and Know‐How in Analytical Testing......Page 560
  17.2.2 Challenges for Outsourcing......Page 561
  17.3.1 The New Challenges in Pharmaceutical Environment......Page 562
  17.3.2 Outsourcing to Strengthen the Core Business......Page 563
  17.3.3 Which Testing May Be Outsourced......Page 564
  17.3.4 Sample Hold Time and Transport......Page 565
 17.4 Hidden Costs......Page 566
  17.5.2 Regulatory Aspects and Contents of a Modern Quality Agreement......Page 567
  17.7.1 Example 1: Implementation of a New Technology – Qualification and Validation......Page 570
  17.7.2 Example 2: System Suitability Test, Setup of Test for Microbiological Quality......Page 571
  17.7.3 Example 3: Setup Environmental Monitoring for Microbial Contamination......Page 572
 17.8 Conclusions......Page 573
 Bibliography......Page 574
Index......Page 577
EULA......Page 585