Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices

Inject able Product Manufacturing is booming because of the growth of new Biopharmaceuticals and small molecule anticancer drugs. The requirements for contamination control will become even more stringent than today. Isolators or blow-fill-seal equipment have already replaced the conventional clean rooms and LAF-hoods in many production facilitates. Conventional microbiological monitoring methods, requiring 3 to 5 days of incubation will become inappropriate. Equipment is already available allowing real time, simultaneous viable and non-viable counting.

This Book is a useful reference guide for the SMB (Small and Medium Business) pharmaceutical sector which does not have the resources to have access to such top-quality information in this field. This book therefore represents an unparalleled and unprecedented text in the field of pharmaceutical and Medical device microbiology. Perhaps even more outstanding is the fact that this book not only covers subject matter and technical content which is established as best and expected practice, but also includes content regarded as possible, future and Emerging Technology or processes.

The results of 45 years of scientific and technological development are laid down in these 33 chapters. These chapters, all written by international experts, give a vivid Picture of today’s pharmaceutical microbiology. The high standard of the chapters makes it an essential reference guide that should be on the shelf of everyone who is involved or interested in this field.

Experts from top pharmaceutical Companies like Baxter, Johnson and Johnson, Amgen, Pfizer, Pantheon, Atrocious, Gander, Catalan, British NHS, GE Healthcare and many more top experts from industry and academics have come together to create this collection of Knowledge of Microbiology as related to Pharmaceuticals, Medical Devices and Biotechnology. The list of Authors includes chair and members of USP expert committee on Microbiology and Sterility Assurance, president and senior experts in Potential Drug Association, ISPE and ASTM. Foreword by Hans van Doormen, Chair of EDQM, Committee on Microbiology.

Origins: THE IMPACT OF MICROORGANISMS IN PHARMACEUTICAL AND Medical DEVICE MANUFACTURE :
1. The Essentials of Pharmaceutical Microbiology :
i. Introduction
ii. Overview of Pharmaceutical Microbiology
iii. Manufacturing Environments
iv. Results
v. Microbiology Laboratories
Conclusion
References

2. Relevance of Microorganisms in Pharmaceutical Processing :
i. Introduction
ii. Historical Review of the Involvement of Microbiology with Pharmaceutical Practice
iii. Historical Review of Science-Based Pharmaceutical
iv. Sterilization and Microbiological Quality Control
v. The Broader Picture of Microorganisms and Pharmaceutical Manufacturing: Challenges, Solutions and Pharmacopoeial Guidance
vi. Current Pharmacopoeial Guidance
vii. Batch
viii. The Future
References

3. Microbial Contamination and Spoilage :
i. Introduction
ii. Sources of Microbial Contaminants
iii. Raw Materials
iv. Synthetic Raw Materials
v. Water
vi. Microbial Contamination from the Manufacturing Environment
vii. Factors affecting Microbial Spoilage of Pharmaceutical Products
viii. Consequences of Microbial Growth
ix. Microbiological Control of Raw Materials
Summary
References

4. Microbiological Considerations in Medical Device Industry :
i. Introduction
ii. The Medical Device Microbiology Life Cycle
iii. Inherent and Accumulated Microbial Contamination
iv. Product Design Microbiology
v. Raw Material and Component Microbiology
vi. Shipping and Storage of Raw Materials and Components
vii. Environmental Microbiology
viii. Product Assembly Microbiology
ix. Cleaning of Products
x. Packaging Process Microbiology
xi. Sterilization Process Microbiology
xii. Product Use Microbiology
xiii. Medical Device Microbiological Contamination
xiv. Controlling Product Bioburden
xv. Aseptic Technique
xvi. No Magic Answers for Bioburden Control
xvii. Use of Bioburden Testing to Improve Manufacturing Microbiology
xviii. Use of Sterility Testing to Improve Manufacturing Microbiology
xix. Microorganisms of Concern
xx. Microbiological Challenges for Products with Tissue Components
References

Part II : ASPECTS OF MICROBIOLOGICAL Quality Control :
5. Selection of Microbiological Culture Media and Testing Regimes :
i. Introduction
ii. Types of Culture Media
iii. Media Manufacture
iv. Quality Control of Culture Media
Conclusion
References

6. Microbial Identification :
i. Importance of Microbial Identification
ii. Isolation of Microorganisms
iii. Staining Methods
iv. Microscopy
v. Pre-Differentiation or Confirmation
vi. Taxonomy, Classification, Identification and Nomenclature
vii. Phenotypic Microbial Identification Systems
viii. Automation in Microbial Identification
ix. Genotypic Systems
x. Fungal Identification
Conclusion
References

7. Microbial Examination of Non-sterile Products :
i. Introduction
ii. The Limitations and Values of Microbial Enumeration Tests
iii. Product Sampling for Microbial Examination
iv. Media Growth Promotion Test
v. Method Suitability Test
vi. Enumeration Methods
vii. Media and Incubation
viii. Colony Counting and Interpretation of the Results
ix. Tests for Specified Microorganisms
x. Setting Microbial Limits for Non-Sterile Pharmaceuticals and Raw Materials
Conclusions
References

8. Practical Approaches to Sterility Testing :
i. Introduction
ii. The Sterility Test
iii. Sterility Test Method Validation
iv. Training Programme
v. Validation Documentation
Summary
References

9. Microbial Aspects in Cleaning Validation :
i. Introduction
ii. Regulatory Aspects of Cleaning
iii. Cleaning Agents
iv. Cleaning Procedures
v. Solid Dosage Forms
vi. Semi-solid Dosage Forms
vii. Hold Time Studies
viii. Microbial Testing in Cleaning Validation
ix. Conclusion
References

10. Validation of Microbiological Methods :
i. Introduction
ii. Scope
iii. Strategy for Validation
iv. Protocol Considerations
v. Maintaining Status of Validated Methods
vi. Case Study
Conclusion
References

11. Selection and Validation of Disinfectants :
i. Introduction
ii. Types of Disinfectants
iii. Selection of Disinfectants
iv. Validation of Disinfectants
v. Continued Evaluation of Disinfectant Effectiveness
Conclusion
References

12. Auditing a QC Microbiology Laboratory :
i. Introduction
ii. What is an Audit and Why Should They be Performed
iii. General Principles of the Audit Process
iv. Auditing the QC Microbiology Laboratory, What to Look For
v. Auditing Techniques to Get the Most from your Audit
vi. Reporting the Audit
vii. Final Thoughts
References

13. Quality Assurance in a Microbiology Laboratory :
i. Introduction
ii. Quality Management, QA and QC Principles
iii. Laboratory Quality Manual
iv. Laboratory Staff Qualifications and Training
v. Laboratory Environment
vi. Standard Operating Procedures, Methods and Protocols
vii. Laboratory Notebooks, Log Books and Records
viii. Information Technology and Computer Systems Validation
ix. Archiving Requirements
x. Reference Standards and Samples
xi. Solutions, Reagents and Culture Media
xii. Instruments and Equipment
xiii. Laboratory QA Assessments/Audits & External Quality Assurance
Conclusion
References

Part III : MEASURING AND TESTING FOR MICROORGANISMS :
14. Environmental Monitoring :
i. Introduction
ii. Cleanrooms
iii. Microbiological Environmental Monitoring
iv. Establishing an Environmental Monitoring Programme
v. Personnel
Summary
References

15. Microbial Content Testing of Pharmaceutical and Biotechnologically Derived Products :
i. Introduction
ii. General Methods for the Quantitative Determination of Viable Count
iii. Evaluation of Results by Various Enumeration Methods
iv. Dilutions
v. Replicate Plate Counts
vi. Selection of Method for the Enumeration of Microbial Count
vii. Estimating Number of Micro-Organisms in Suspension for Use in Bioburden
viii. Bioburden Testing
ix. Microbial Limit test (MLT)
x. Spreaders
xi. Suitability of the Enumeration Method in the Presence of Product
xii. Test for Specified Organisms
xiii. Applied Aspects of Bioburden Testing
Conclusions
References

16. Bacterial Endotoxins Test :
i. Introduction
ii. History of Bacterial Endotoxins Test
iii. Endotoxin
iv. Limulus Amebocyte Lysate
v. Bacterial Endotoxins Test in Pharmacopoeias
vi. Validation of Bacterial Endotoxins Test
vii. Practical Suggestions for the Bacterial Endotoxins Test
viii. Curve
References

17. Antimicrobial Effectiveness Testing :
i. Introduction
ii. The Purpose of the AET
iii. Development of the USP Test
iv. Demonstration of Method Suitability
v. Other considerations in preservation
vi. Investigations
References

18. Monitoring of Microbiological Quality Attributes of Water for Pharmaceutical Use :
i. Introduction
ii. Water Types
iii. Regulatory Requirements
iv. Water System Description
v. Water System Validation
vi. Water System Monitoring
vii. Water Data Trending Requirements
Conclusions
References

19. Investigation of Microbiological Data Deviations :
i. Introduction
ii. Microbiological Data Deviations
iii. Objectives of the Investigation
iv. Acceptance Criteria
v. General Process for the Investigation
vi. Laboratory Investigation
vii. Full-Scale Investigation
viii. A Case Study
Conclusion
References

20. Alternative Microbiological Methods and New Pharmaceutical Microbiology Curriculum :
i. Introduction
ii. A “Rapid” History of Microbiology
iii. Today’s Microbiology: The Fundamentals of “Traditional” Microbiology
iv. The New Microbiological Technology Wave for the QC Lab : Alternative and Rapid
v. Metabolic or Growth Based Technologies
vi. Viability Based Technologies
vii. Technologies Based on Cell Component Analysis
viii. ARMMS and the Pharmaceutical Industry
ix. AMM, PAT, and Regulatory Status
x. Microbiology Curricula
xi. The Skill Sets of a Pharmaceutical Quality Control (QC) Microbiologist
xii. Curricula Surveys
xiii. The Disparity between the Tertiary Microbiology Curricula and the Needs of the
xiv. Interesting Step Forward: The United States Professional Science Master
xv. Conclusions and Recommendations
References

21. The Implementation of Rapid Microbiological Methods :
i. Microbiology Trapped In the 19th Century
ii. New Technologies for Pharmaceutical Manufacturing
iii. An Introduction to Rapid Microbiological Methods
iv. RMM Applications
v. Strategy for Implementation
vi. Validating Rapid Microbiological Methods
vii. Implementation and Secondary Site Qualification
viii. RMMS and the Regulatory Environment
ix. FDA Perspectives
x. EMA Perspectives
xi. Changing Acceptance Levels and Specifications
xii. Regulatory Summary
xiii. Developing a Business Case for RMMS
xiv. Chapter Summary
References

22. Risk Management in Pharmaceutical Microbiology :
i. Introduction to Risk Assessment and Risk Management Process
ii. Regulatory Views and Guidelines on Risk Management
iii. The Basics of Risk Assessment
iv. Advantages and Disadvantages of Risk Assessment
v. Risk Assessment and Risk Management Methodologies
References

Part IV : STERILIZATION AND STERILITY ASSURANCE :
23. Sterility :
i. Introduction
ii. Origins of Sterilization
iii. The Microbial Challenge
iv. Consequences of Non-Sterility and Lack of Asepsis
v. What Does Sterile Mean and Can We Test It?
Conclusion
References

24. Process Selection for Sterile Products :
i. Introduction
ii. Terminal Sterilization and Adjunct Processing
iii. Aseptic Processing
Conclusion
References

25. Microbial Contamination Control in Pharmaceutical Manufacturing :
i. Pharmaceutical Cleanrooms and Clean Zones
ii. Cleanroom Cleanliness
iii. Measuring Cleanliness within Pharmaceutical Cleanrooms
iv. Microbiological Contaminants and GMP
v. Pharmaceutical Cleanroom Ventilations Systems
vi. Ventilation Filter for Pharmaceutical Cleanrooms
vii. Cleanrooms and Clean Zones
viii. Pharmaceutical Cleanroom Production Systems
ix. Cleaning and Disinfection of a Pharmaceutical Cleanroom
x. Cleanroom Garments
References

26. Aseptic Process Simulations/Media Fills :
i. Introduction
ii. Documentation
iii. Media Selection
iv. Frequency and Number of Runs
v. Size and Duration of Runs
vi. Line Speed and Container Size
vii. Closure Type
viii. Process/Line Configuration and Set-up
ix. Fill Volume
x. Number of Persons and Activities
xi. Interventions
xii. Line Clearance
xiii. Environmental and Personnel Monitoring
xiv. Other Worst Case Scenarios
xv. Cleaning after Process Simulation
xvi. Incubation and Inspection of Filled Units
xvii. Growth Promotion Test
xviii. Interpretation of Results – Acceptance Criteria
xix. Invalidation and Abortion of Process Simulation Runs
xx. Investigation of Process Simulation Contaminations/Failures
Conclusions
References

27. Biological Indicators for Sterilization :
i. Description
ii. Performance Qualification of Biological Indicators
iii. BI Use in Potential Product Loads
iv. Use of a Process Challenge Device (PCD)
v. Selection of Bus
vi. Contracting for 3rd Party D-Value Testing
vii. Rapid Read-out Biological Indicators
Conclusion
References

28. Moist Heat Sterilization :
i. Introduction
ii. Sterile Products
iii. History of Sterilization with Heat
iv. Mechanisms of Spore Heat Resistance and Inactivation
v. Inactivation of Spores Using Moist Heat Sterilization Processes
vi. Pharmaceutical Products
vii. Selection of a Moist Heat Sterilization Process Type
viii. Product or Item Loading Patterns
ix. Biological Indicators for the Development and Qualification of Moist Heat Sterilization Processes
x. Determination of the Hardest to Sterilize Solution Formulation or Item/Component
xi. The Liquid Products Master Solution Approach
xii. The Process Challenge Device (PCD) Approach for Porous/Hard Goods
xiii. Determination of Hardest To Sterilize Locations or Cold Spots Used For
xiv. Use of Chemical Indicators
xv. Development Moist Heat Sterilization Processes
xvi. Validation of the Moist Heat Sterilization Process
xvii. Routine Monitoring and Control of the Moist Heat Sterilization Process
xviii. Product and Process Change Control
xix. Sterile Product Release Process
Conclusion
References

29. Sterilization and Dehydrogenation by Dry Heat :
i. Introduction
ii. Functions of Dry Heat
iii. Thermodynamically Aspects of Heat Transfer in Dry Heat Processes
iv. Destruction of Microorganisms and end Toxins by Dry Heat
v. Types of Dry Heat Sterilization/Dehydrogenation Processes
vi. Validation and Ongoing Control
Conclusion
References

30. Radiation Sterilization :
i. Introduction
ii. History of Radiation Sterilization
iii. Types of Radiation Sterilization
iv. Microbial Inactivation
v. Validation
vi. Materials Qualification
vii. Process Validation
viii. Routine Monitoring and Control
ix. Maintaining Process Effectiveness
Conclusions
References

31. Sterilization by Filtration :
i. Introduction to Sterilizing Filtration
ii. Filtration Parameters
iii. Filter Types
iv. Filter Materials
v. Filter Construction
vi. Filter Validation
vii. Filter Integrity Testing
viii. Filtration Applications
References

32. Sterilization by Ethylene Oxide :
i. Introduction
ii. Factors Affecting the Lethality of EO Sterilization
iii. The EO Sterilization Process
iv. Product and Process Definition for EO Sterilization
v. EO Sterilization Validation
vi. Routine monitoring of the EO sterilization process
vii. Demonstrating the Ongoing Effectiveness of the EO Sterilization Process
Summary
References

33. Maintaining Sterility :
i. Introduction to Maintaining Sterility
ii. Medical Product Packaging System Development
iii. Microbiological Versus Physical Integrity Test Methods
iv. Test Method Correlation
v. Test Method Sensitivity
vi. Test Method Validation
vii. Sterile Medical Product Classification
viii. Sterile Barrier System Classification
ix. Sterile Barrier Integrity Test Methods
Summary
References