Microbial ContaminationControl in Parenteral

Manufacturingedited by

Kevin L. WilliamsEli Lilly and Company

Indianapolis, Indiana, U.S.A.

M A R C fc Im MARCEL DEKKER, INC. NEW YORK • BASEL

Contents

Preface ///Contributors v.vr

PART I CONCEPTS AND FOUNDATIONS OFPARENTERAL MANUFACTURINGCONTAMINATION CONTROL

1. Historical and Emerging Themes in ParenteralManufacturing Contamination Control JKevin L. Williams

.1 Introduction I

.2 The Birth of Microbiological Theory 2

.3 Historical Development and Regulation of ParenteralDosage Forms 3

.4 From Antibiotics to Biologies 9

.5 Changing Perspectives on Contaminants 16

.6 Emerging Approaches to Finding and IdentifyingContaminants 20

v i i i Contents

2. Microbial Contamination Hazard Analysis in SterileProduct ManufacturingSimon Rusmin

2.1 An Overview of the Evolution and Diversificationof Microorganisms -"2.1.1 The First Billion Years: Earth's Cooling,

Formation of Solid Crust, The FirstAtmosphere and Liquid Water

2.1.2 The Second Billion Years: First Living Organisms,the Bacteria

2.1.3 The Third Billion Years: Age of Prokaryotesand Oxygenic Photosynthesis

2.1.4 The Fourth Billion Years: The Age of Eukaryotesand Sexual Reproduction

2.1.5 The Past Billion Years: Multicellular Organismsand the Grand Parade

2.2 A View of Microbes and Their Relationship to SterileDrug Product Manufacturing 33

2.3 The Microbiological Function in Drug ProductManufacturing -'62.3.1 Why Should There Be a Distinct Microbiological

Function?2.3.2 What Does the Microbiological Function Do

in a Pharmaceutical Company?2.4 Understanding Process Analysis 42

2.4.1 What Is a Process?2.4.2 What Are Process Flows?2.4.3 What Are the Principles of Improving

Quality?2.5 Microbial Contamination Hazard Analysis

Step-by-Step -an Example 482.5.1 Initiation and Team Organization2.5.2 Study of Manufacturing Plan

& Related SOPs2.5.3 Observation of Real Operations2.5.4 Task Analysis for Microbial Contamination

Hazards & Control Point Setup2.5.5 Translation of Control Measures into Operator

Skills Through Training2.6 Hazard Analysis Discussion and Conclusion 52

Contents j x

3. Overview of Modern Parenteral Poducts and Processes 59Arviml K. Bansal

3.1 Parenterals—General Introductionand Product Types 59

3.2 Demands on Parenteral Productsand Manufacturing Processes 60

3.3 Parenteral Manufacturing Processes 623.4 Area Design and Environment Control 633.5 Fabrication of Batch 643.6 Sterility Assurance in Parenteral

Manufacturing 643.6.1 Terminal Sterilization3.6.2 New Techniques of Terminal Sterilization

3.7 Aseptic Processing 683.7.1 Advanced Aseptic Processes and Isolator

Barrier Technology3.7.2 Blow Fill Seal Technology (BFS)3.7.3 Terminal Sterilization of BFS

Containers by Autoclaving3.8 Recent Issues in Sterilization by Filtration 753.9 Sterile Prefilled Syringes (PFS)---Manufacturing

and Terminal Sterilization Perspectives 753.10 Process Validation. Hazard Analysis and Critical

Control Points (HACCP) 763.11 Continuous Processing of Parenteral Products 783.12 Computer-Controlled Automation of Unit

Processes NO3.13 Processing of Biopharmaceut ica l Produc ts 80

3.13.1 Stabilization During Free/e-Dryingof Protein Formulations

3.13.2 Spray-Drying of Protein Formulations3.13.3 Assuring Sterility" of Protein Formulations3.13.4 Sterile Filtration of Protein Formulations3.13.5 Future Trends

3.14 Processing of Packaging Components 833.14.1 Rubber Closures3.14.2 Washing3.14.3 Siliconization3.14.4 Cleaning and Sterilization of Flastomeric

Closures3.15 Future Trends in Parenteral Processim: 86

t Contents

4. The Role of USP in the Microbiological Assessmentof Parenteral Manufacturing 91Roger Dabbah and David Porter

4.1 Introduction " '4.2 The USP Organization 9 2

4.3 USP Legal Recognition and USP Relationshipto FDA 9 3

4.3.1 USP Legal Recognition:4.3.2 USP and Federal Statutes

4.4 Microbiological Assessment Continuum "44.4.1 Step 1 —Assessment of Raw Materials4.4.2 Step 2—Microbiological Assessment Continuum4.4.3 Step 3—Microbiological Assessment Continuum4.4.4 Step 4 -Microbiological Assessment Continuum4.4.5 Step 5- Microbiological Assessment Continuum4.4.6 Step 6—Microbiological Assessment Continuum

5. Sterility and Bioindicators 107Patrick J. McCormick, Catherine J. Finocchario,and James J. Kaiser

5.1 Introduction 1°7

5.2 Sterility Assurance 1 0 8

5.3 Resistance Performance '095.3.1 Population5.3.2 D-Value5.3.3 Survival/Kill Time

5.4 Selection 1125.4.1 Test Organism5.4.2 Format

5.5 Process Challenge Devices 1165.6 Regulatory Status 1175.7 Qualification of Biological Indicators H^5.8 Application 119

5.8.1 Cycle Development5.8.2 Cycle Validation5.8.3 Routine Processing5.8.4 Incubation Times

5.9 Rapid Readout Biological Indicators 1245.10 Conclusion 125

Appendix 5.1 D-Value Calculations 129

Contents xi

PART II CONTROL OF CONTAMINANTS VIAFACILITIES AND UTILITIES

6. Biological Safety Cabinets and Isolators Usedin Pharmaceutical Processing 139Mark Claerbout

6.1 Introduction 1396.2 Design Considerations 140

6.2.1 Partial Barrier Enclosures6.2.2 Full Barrier Enclosures (Isolators)6.2.3 Isolator Materials of Construction6.2.4 Isolator/Operator Interface6.2.5 Isolator Ergonomics6.2.6 Isolator Ventilation6.2.7 Isolator Integrity Testing6.2.8 Rapid Transfer Ports (RTPs)

6.3 Common Lab Isolator Requirements 1506.4 Lab Isolators Used for Sterility Assurance 1516.5 The Sterility Test 1516.6 Isolator Room Requirements 1526.7 Biodecontamination Efficacy 1526.8 Microbiological Monitoring of Sterility Testing

Isolators 1546.9 Isolator Cleaning 154

6.10 Conclusion 154

7. Developing a Process for Aseptic Facility Designand Validation 157Dimitri II irchanskr

7.1 Introduction 1577.2 Defining the Project 15"7.3 Preliminary Project Team 1587.4 Deliverables for the Preconceptual Phase 1587.5 Conceptual Design 1607.6 Developing the Project Core Team 16(1

7.6.1 Architect7.6.2 Process Engineer7.6.3 HVAC Fngmeer7.6.4 Manufacturing Representative7.6.5 QA Representative Validation

XIIContents

7.7 Developing the Basis of Design or "BOD"7.8 Leveraging the Effort

7.8.1 Lining Up Internal Support7.8.2 External Support

7.9 The Design Qualification Process7.9.1 Q7A Guide to cGMP for API7.9.2 Orange Guide, Annex 15

7.10 Example of an Approach to DesignQualification7.10.1 User Requirements7.10.2 System Classification7.10.3 Tying It Together

7.11 Preliminary Engineering

162163

164

165

166

7.7.7.7.7.7.7.7.7

7.17.17.17.17.1

111111111111111

.12.3.4.5

1.61.71.81.910111213

.14

ArchitectureEnvironmental Health and Safety (EHS)ProcessProcess MechanicalCivilStructuralElectricalInstrumentation and Controls (I&C)Building Automation Systems (BAS)HVACProcess PipingPlumbingManufacturing RepresentativeQA Representative—Validation

7.12 The Project Function7.12.1 Detailed Design7.12.2 Construction7.12.3 Startup, Commissioning, and Validation

168

8. Pharmaceutical Water Systems: New Orientationsin System DesignTheodore H. Meltzer and Robert C. Livingston

8.18.28.38.48.5

IntroductionWater Purity StandardsElectronic Rinse WaterEmphasis on PretreatmentsSource Waters8.5.1 Municipal City Water

173

173174175177178

Contents

8.6 Pretreatments 1798.6.1 Chlorination8.6.2 Removal of Trihalomethanes8.6.3 Deep Beds and Multimedia Filtration8.6.4 Softening and Solubility Product8.6.5 Softening or Dechlorination First8.6.6 Fuoss Effect and TOC Adsorption

8.7 Chlorine Removal 1918.7.1 Activated Carbon8.7.2 Reductions with Sodium Sulfite8.7.3 Destruction by Ultraviolet Light8.7.4 Reaction with Ion-Exchange Resins

8.8 Chloramine Removal 1958.8.1 Removal of Chloramines Usually Managed

by Adsorption to Activated Carbon8.9 Organic Entities. TOC 196

8.10 Endotoxins 1978.11 Ultrafiltration 1988.12 Principal Purifications 198

8.12.1 Distillation8.12.2 Ion-Exchange8.12.3 Silica

8.13 Countercurrent Operations 2018.13.1 Hot Water Sanitizations8.13.2 Electrodeionization

8.14 Reverse Osmosis 2078.14.1 RO Membranes8.14.2 Tangential Flow Filtration8.14.3 Reuse of Reject Water8.14.4 Concentration Polarization8.14.5 The Permeate Stream8.14.6 The Extent of Recovery8.14.7 Discontinuous RO Operations8.14.8 Size of RO Unit

8.15 Storage Conditions 2138.16 Conclusion 213

9. Airborne Contamination Control 215Lothar Gail and Dirk Stanischeuski

9.1 Introduction 2159.2 Cleanroom Design and Operation 217

x j v Contents

9.2.1 Processing Concept9.2.2 Zoning Concept9.2.3 Cleanroom Segregation Techniques for Sterile

Processing9.2.4 Airflow Simulation9.2.5 Qualification and Operation

9.3 Metrology and Test Methods 2249.3.1 General9.3.2 Cleanroom Classification9.3.3 Installed Filter Leakage Testing9.3.4 Airflow9.3.5 Pressure Difference9.3.6 Recovery9.3.7 Documentation

10. Disinfection Practices in Parenteral Manufacturing 233Vivian Dennv and Frederic Marsik

10.110.210.3

10.410.510.610.7

IntroductionCurrent Regulatory EnvironmentChemical Disinfectants- -Activity, Mechanismof Action. Mechanism(s) of Resistance

10.2.1 Alcohols10.3.2 Aldehydes10.3.3 Formaldehyde (Methanal)10.3.4 Glutaraldehyde (Pentanedial)10.3.5 Ortho-phthaldehyde (OPA)10.3.6 Halogens10.3.7 Chlorine and Chlorine Containing

Compounds10.3.8 Iodine (I2)10.3.9 Peroxygen Compounds

10.3.10 Hydrogen Peroxide (H2O :)10.3.11 Peracetic Acid (CH^COOOH)10.3.12 Phenolics10.3.13 Quaternary Ammonium Compounds

(Quaes or Quats)Resistance to DisinfectantsSpores and DisinfectantsPrions and DisinfectantsReasons for Using a Disinfectant

233234

236

245246248249

Contents xv

10.8 What to Consider When Choosing a Disinfectant 24910.9 Identifying the Number and Type of Microorganisms

that Need to Be Controlled 25010.10 Determining the Specificity of Microbial Action

of Commercially Available Disinfectants 25010.11 Surface and Disinfectant Compatibility 25010.12 Safety and Precautions 25110.13 Physical and Environmental Factors that Influence

Disinfectant Efficacy 25110.13.1 pH10.13.2 Surface Soils10.13.3 Biofilms10.13.4 Temperature10.13.5 Concentration10.13.6 Compatibility of Disinfectants10.13.7 Economic Considerations

10.14 Preparation of Disinfectant Solutions 25410.14.1 Water10.14.2 Concentration10.14.3 Temperature10.14.4 Sterile Filtration10.14.5 Storage10.14.6 Expiry Date

10.15 Quality Control of Disinfectants 25610.16 Methods for Validation of Disinfectant Efficacy 257

10.16.1 Evaluation of Disinfectant Efficacy Claims10.16.2 Validation Test Development and Efficacy

Parameters10.17 Application of Disinfectants for Contamination

Control 26210.17.1 The Three-Step Disinfection Process10.17.2 Application Techniques10.17.3 Using Sanitizers in Conjunction with

Disinfectants10.17.4 Rotation of Disinfectants10.17.5 Disinfection Program Design Scheduling

Frequency10.18 Developing and Implementing a Disinfection Program 2d6

10.18.1 Steps that Can Be Taken to Developa Program

10.19 Personnel Training and Demonstration of Competency 2~310.19.1 Training and Regulations

XVIContents

10.19.2 Developing a Training Program10.19.3 Documentation-Documentation

10.20 Summary 276

PART III MANUFACTURING PROCESS CONTROLOF CONTAMINANTS

11. Sterile FiltrationMaik W. Jornitz

11.111.2

11.3

11.4

11.5

1.6

11.2.211.2.3

11.2.4

11.7

IntroductionTypes of Filtration11.2.1 Prefiltration

Membrane FiltrationPrefilter and Membrane FilterComparisonCross-Flow Filtration

Modus of Filtration11.3.1 Sieve Retention11.3.2 Adsorptive SequestrationMembrane Filter Materials11.4.1 Manufacturing process11.4.2 Polymer DifferencesFilter Constructions and Design11.5.1 Disc Filters

1.5.2 Cartridge Filters1.5.3 Capsule Filters

Filter Validation.6.1 Guidelines and Documents

Bacteria Challenge TestExtractable TestChemical Compatibility TestOther Tests

Integrity Testing1.7.1 Guidelines and Documents

Bubble Point TestDiffusive Flow TestPressure Hold TestWater Intrusion TestMultipoint Diffusion Test

283

283284

293

297

301

315

1.6.21.6.31.6.41.6.5

1.7.21.7.31.7.4

11.7.511.7.6

324

Contents xvii

12. Process Development of Alternative Sterilization Methods 341Volker Sigwarth

12.1 Introduction 34112.2 Process Development-General 342

12.2.1 Steps of Process Development12.3 Physical Factors and Validation 34512.4 Target Value for Sterilization Effect 354

12.4.1 Biological Indicators (Bis)12.4.2 Survival Time Model of Microbial Reduction12.4.3 D-Value Determination12.4.4 Selection of Biological Indicator12.4.5 Screening Experiment12.4.6 Suitability of BI

12.5 Process-Influencing Factors 37912.5.1 HIOT Surface Decontamination Process12.5.2 Design of Experiment. DoE12.5.3 Main Experiment12.5.4 Interpretation of Process

12.6 Method of Cycle Development and ProcessQuantification 40312.6.1 Experiment 0: Reactive Pattern Recognition12.6.2 Cycle Development12.6.3 Experiment 1-Bacterial Reduction Rate

Achieved. Quantity (ql)12.6.4 Experiment 2: Stability of Decontamination

Effect. Quantity (q2)12.6.5 Estimation of D-Valuehi;M rKllA.12.6.6 Experiment 3: Worst-Case Study.

Duration of Decontamination12.6.7 Experiment 4. Determination of Purge Time12.6.8 Experiment 5. Determination of D-Value12.6.9 Summary of Cycle Development Method

12.7 Additional Studies 41412.8 Conclusion 415

13. Terminal Sterilization and Parametric Release 419Klaus Haherer

13.1 Role and Significance of the Sterility l e s tin the Release of Sterile Pharmaceuticals 419

xviii C o n t e n t s

13.1.1 Role of the Test13.1.2 Statistical Significance of the Test13.1.3 Performance and Correctness of the Test13.1.4 Performance of the Laboratory and the Rate

of False Positives with Implications for theRejection of Compliant Product

13.1.5 Contribution of the Sterility Test to SterilityAssurance for Products Terminally Sterilizedin Their Sealed Container by a ValidatedSterilization Process

13.1.6 Risk Consideration for Failure of TerminalSterilization Processes and Significance of theSterility Test for Failure Detection

13.1.7 Sterility Testing and Release of AsepticallyManufactured Product

13.2 Basic Considerations for Parametric Release 42713.2.1 Principle of Parametric Release13.2.2 Elements Needed for Safe Release of Sterile

Products13.2.3 Elements Considered for Parametric Release13.2.4 Parametric Release and Automated

Manufacture13.2.5 Availability of New Technologies and

Parametric Release13.2.6 Aseptic Processing and Parametric Release

13.3 History of Parametric Release and Present Positionsof the Authorities 43313.3.1 Situation in the United States of America13.3.2 Situation in Europe13.3.3 Situation in Japan13.3.4 The Position of Official Reference Laboratories13.3.5 Positions of Pharmaceutical Manufacturers

13.4 The Future of Parametric Release 44413.4.1 Undecided Manufacturers13.4.2 Criticism of the Positions of the Authorities13.4.3 Need for a Risk-Based Approach

14. Raw Material Contamination Control 449Lisa Gonzales

14.1 Introduction 44914.2 Raw Material Requirements for GMP 450

Contents xix

14.3 Incoming Inspection of Raw Materials Program 45114.4 Qualification of Suppliers 454

15. Endotoxin: Worst-Case Parenteral Pyrogen 461Kevin L. Williams

1515

1515

.1->

.3

.4

IntroductionEndotoxin Nomenclature andas a PyrogenStructure OverviewWhv the Parenteral Focus on

Classification

Endotoxin'?

461

462463466

15.5 Contamination Control Philosophy in ParenteralManufacturing 471

15.6 Developing an Endotoxin Control Strategyfor Drug Substances Excipients 473BET Standardization 477Origin and Importance of LAL 482LAL Discovery 483Hemolymph Coagulation in Limulus and Tachypleus 485Prominent LAL Tests 487Method Development and Validation TheImportance of a Good Test 492Resolving Test Interferences 500Setting Endotoxin Specifications 500Depyrogenation Validation 503Endotoxin Removal in PharmaceuticalManufacturing Processes 512The Future and Endotoxin Testing 513The Whole Blood Pyrogen Test 518

16. Screening Active Pharmaceutical Ingredients and F.xcipientsfor Endotoxin 531James F. Cooper

16.1 Overview16.2 Regulatory Documents for the BET16.3 Endotoxin Alert Levels (EAL) for APIs16.4 Synergistic Effect of Endoloxin with Other Pv logons16.5 Endotoxin Limits for Sterile Pharmacy

Compounding16.6 Endotoxin Limits for Excipients16.7 Interference Testing for APIs and Excipients

15.715.81

151515

15151515

1515

5.9.10.11.12

.13

.14

.15

.16

.17

.18

Contents

17. Viral and Prion Clearance Strategiesfor Biopharmaceutical SafetyHazel Aranha

17.1 Biopharmaceutical Manufacturing: GeneralConsiderations

17.2 Sources of Viral Contaminants 4̂317.3 Virus Detection Methods 545

17.4 Regulatory Considerations: A Risk-Based Approach 54717.5 How Much Viral Clearance is "Enough"? 548

17.6 Virus Clearance Methods 549

17.6.1 General Considerations17.6.2 Viral Clearance Methods Discussion17.6.3 Process Validation for Viral Clearance17.6.4 Process Analysis and Evaluation of Processes

to Validate for Viral Clearance17.6.5 Viral Clearance Studies: Scaling Considerations

and Identification of Critical Parameters17.7 Technical Aspects of Study Design '

17.7.1 Choice of Panel of Test Viruses17.7.2 Virus-Stock-Related Considerations17.7.3 Importance of Adequate Controls in Virus

Study Design17.8 Considerations in Data Interpretation and Estimating

Viral Clearance '17.9 Viral Clearance Validation Studies: Pitfalls

and Cautions " 817.10 Prions 5 5 9

17.11 Etiology of Prion Diseases 56117.12 Mode of Prion Transmission ^17.13 Prion Detection Methods 5 6 4

17.14 Prion Clearance: A Risk-Based Approach 56617.14.1 Risk Minimization17.14.2 Sourcing17.14.3 Risk Management17.14.4 Prion Clearance Methods

17.15 Process Clearance Evaluation: Considerationsand Design Issues 57017.15.1 Spiking Agents17.15.2 Relevance of the Spiking Agent17.15.3 Detection Methods Used in Process Clearance

Evaluation Studies

Contents

17.16 Considerations in Data Interpretation and EstimatingPrion Clearance 572

17.17 Conclusion 572

PART IV SAMPLING, MONITORING, AND IDENTIFYINGCONTAMINANTS

18. Statistical Sampling Concepts 585Hew a Saranadasa

18.1 Introduction 58518.2 Poisson Probability Distribution 586

18.2.1 Example18.3 The Limit of Quantitation 58918.4 Likelihood of Not Detecting an Organism 58918.5 Hypergeometric Distribution 59218.6 Lot-by-Lot Acceptance Sampling Attributes 59418.7 Operating Characteristic Curve 59518.8 Method of Designing a Sampling Plan 596

18.8.1 Computation Strategy18.8.2 Example18.8.3 Inspection Levels18.8.4 Example

18.9 Variable Type Sampling Plans 60218.9.1 Example

18.10 MIL Standard Plans for Variable Type 60318.10.1 Example

18.11 Common Types of Statistics 60518.11.1 Example

19. Environmental Monitoring 609John LDh'ison. Petru Fsswein. Lothar dail.and I Irich Ptlugmachcr

19.1 Introduction 60>)19.2 Microbiological Monitoring 6 |n

19.2.1 Requirements and Procedures19.2.2 Test Procedures. Test Program. Limits,

and Data Evaluation19.2.3 Routine Environmental Monitoring Pro;-1 '"11

ContentsXXII

19.2.4 Water Samples19.2.5 Bioburden Samples19.2.6 Gas Samples19.2.7 Identification of Contaminants

19.3. Paniculate Monitoring and Other Parameters 62119.3.1 Purpose of Paniculate Monitoring19.3.2 Test Methods and Equipment for Paniculate

Monitoring19.3.3 Results and Deviations19.3.4 Other Environmental Parameters

19.4 Overall Performance of EnvironmentalMonitoring 6

19.5 Overall Quality Assessment of EnvironmentalMonitoring Data 6 2

20. Prevention and Troubleshooting of Microbial Excursions 625Elaine Kopis Sartain

20.1 Introduction 6 2 5

20.2 Facilities Design 6 2 6

20.3 Personnel Management "20.4 Cleaning and Sanitization Programs ^20.5 Conclusion 6 3 3

21. Simulation of Aseptic Manufacture **35Nigel A . Halls

21.1 Introduction *>3521.2 Simulation: Its Purpose 63621.3 Placebos 6 3 8

21.4 Process Simulation 6 4 0

21.4.1 Simulation of Aqueous Liquid Aseptic FillingProcesses

21.4.2 Simulation of Lyophilization Processes21.4.3 What Should and What Should Not Be

Simulated?21.4.4 Simulation of Solid Dosage Form Aseptic

Filling Processes21.4.5 Simulation of Processes Involving Aseptic Bulk

Compounding Before Filling

Contents

21.4.6 Simulation of Aseptic Manufacture of SterileSolid Active Pharmaceutical Ingredients

21.5 Microbiological Controls 65521.5.1 Sterility and Growth Support Controls21.5.2 Controls Intended to Expose Incidental

or Laboratory Contamination21.5.3 Environmental Monitoring and Media Fill

Observation21.6 Incubation of Simulation Trials 66021.7 Application 663

21.7.1 Simulation Trials in Validation of Aseptic-Processes

21.7.2 Simulation Trials in Validation of AsepticProcesses for Manufacture of Sterile APIs

21.7.3 Periodic Simulation Trials in RoutineOperation

22. Standard Methods of Microbial Identification 677Myron Sasser

22.1 Introduction 67722.2 Biochemical Test-Based Identification 67«s

22.2.1 Basic Premises22.2.2 Methodology22.2.3 Manual Biochemical-Test Systems22.2.4 Automated Biochemical-Test Systems

22.3 Fatty Acid Based Identification 68022.3.1 Basic Premises22.3.2 Methodology

22.4 Factors to Consider in Choice of Systemfor Identification of Bacteria 681

22.5 Conclusion 683

23. Rapid Methods of Microbial Identification 685Luis Jimenez

23.1 Introduction 68523.2 ATP Bioluminescence 68623.3 Direct Viable Counts (DVC) 692

xxiv Contents

23.4 Flow Cytometry 69323.5 Impedance 69423.6 PCR Technology 69523.7 Immunoassays 69823.8 Criteria for Validating Rapid Methods 70223.9 Conclusion " 704

Index 709