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Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices
Editors: Madhu Raju Saghee, Tim Sandle and Edward C. Tidswell

Book Code: PHMSP50040
Availability Status: IN STOCK
Edition: 1st, 2011
ISBN: 9788190646741
Presentation: Hardbound 996 Pages
Book Price in US $
Book Price in EURO
USD 245.00
EURO 195.00
Contents of the Book:
MSPPH50050

THE GOLD STANDARD FOR STERILE MANUFACTURING

Injectable 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 facilitities. 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, Patheon, Sartorious, Gador, Catalent, 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 Parenteral Drug Association, ISPE and ASTM. Foreword by Hans van Doorne, Chair of EDQM, Committee on Microbiology.

Editors

Madhu Raju Saghee, M.Sc - Madhu Raju Saghee is working in corporate quality and sterility assurance department at Gland Pharma Limited, India.

Tim Sandle, Ph.D, CBiol, MSBiol. - Dr. Sandle is the Head of Microbiology at the UK NHS Bio Products Laboratory. His role involves overseeing a range of microbiological tests, batch review, microbiological investigation and policy development.

Edward C. Tidswell, PhD - Dr. Tidswell is the Senior Director of Sterility Assurance for Baxter Healthcare; located north of Chicago, IL (USA). Responsibilities include: leading Baxter’s research, development and implementation of new (or optimized) sterilization and aseptic technologies, qualification and validation of sterile and aseptic manufacture for parenterals and medical devices.


Contents

PART: 1     The Impact of Microorganisms in Pharmaceutical and Medical                       Device Manufacture

 

The Essentials of Pharmaceutical Microbiology

by Tim Sandle and Madhu Raju Saghee

Introduction
  History of Microbiology
  Fundamental Characteristics of Microorganisms
    Bacteria
    Fungi
    Protozoa
    Algae
    Viruses
    Microbial Taxonomy
    Microbial Growth
    Microbiological Culture Media
    Identification and Characterization of Microorganisms
    Types of Bacteria
Overview of Pharmaceutical Microbiology
  The Scope of Pharmaceutical Microbiology
    Product Related Testing Regimes
    Starting Materials
    In-Process Samples / Intermediate Product
    Final Product Formulations
    Finished Product
    Testing of Utilities
    Environmental Monitoring
  The Application of Pharmaceutical Microbiology
    Counting
    Sampling
    Microorganisms Detected From Pharmaceutical Manufacturing Environments
    Contamination Control
    Other Microbiology Laboratory Tests
        Microbial Identification
        Water Activity
        Disinfectant Efficacy Testing
        Antimicrobial Susceptibility Testing
        Microbial Immersion Studies
        Cleaning Validation Studies
        Investigation of Out of Limits and Out of Trend Results
        Microorganisms Used In Pharmaceutical Microbiology Laboratories
        Other Activities

Conclusion
References

 

Relevance of Microorganisms in Pharmaceutical Processing

by Ossama M. El-Tayeb

Introduction
Historical Review of the Involvement of Microbiology with Pharmaceutical Practice
   Implications of aseptic surgery, personal and public hygiene
   Implications of Food Microbiology
   Implications of the introduction of parenteral therapy: {earliest procedures for        
      sterilization and preservation}
   Early tests for sterility: influence of diagnostic medical microbiology
   Early pharmacopoeial guidance on sterilization and sterility testing
Historical Review of Science-Based Pharmaceutical Sterilization and Microbiological   Quality Control
   Re-definition of the pathogenicity of microorganisms
   Contributions of the study of microbial injury and death
   Contributions of the food processing technologies: the over-kill approach to                  sterilization
   Contributions of the aerospace and electronics industries.
   Hospital sterilization and Central Sterile Supply vs. on site sterilization
   Impacts of material sciences and development of cold sterilization methods
   Filtration as a breakthrough and the bio-burden approach to sterilization.
   Impact of statistical fallacies in sterility testing and population death kinetics.
The Broader Picture of Microorganisms and Pharmaceutical Manufacturing: Challenges, Solutions and Pharmacopoeial Guidance
   Microorganisms and Ophthalmic Dosage Forms
   Microorganisms and Oral Dosage Forms
   Microorganisms and Topical Dosage Forms
   Microbiological Challenges, Solutions and Pharmacopoeial Requirements
Current Pharmacopoeial Guidance
   The Fundamental Concepts
   Sampling for Microbial Quality Control and the Microbiologically Homogenous 
      Batch
   Quality Assurance as an Essential Element in Microbial Quality
   The Roles of the Microbial Quality Control Laboratory
   Current Pharmacopoeial Guidance {on sterilization, sterility testing and microbial 
      quality of non-sterile dosage forms}
The Future
   Will all Pharmaceuticals be Aseptically Processed?
   The future of the Microbiological Quality Control Tests
References

 

Microbial Contamination and Spoilage

by David G. Allison

Introduction
Sources of Microbial Contaminants
Raw Materials
Materials of Natural Origin
   Microorganisms from Plant Material
   Microorganisms from Animal Sources
   Microorganisms from Mineral-Derived Materials
Synthetic Raw Materials
Water
   Types of Water
   Disinfection of Water
Microbial Contamination from the Manufacturing Environment
   Air supply
   Equipment and facilities
   Personnel
   Users / consumers
Factors affecting Microbial Spoilage of Pharmaceutical Products
   Preparation and Storage
   Nature of the Contaminant Inoculum
   Moisture Content
   Nutritional Factors
   pH and Redox
Consequences of Microbial Growth
Microbiological Control of Raw Materials
Summary
References

 

Microbiological Considerations in Medical Device Industry

by Martell Winters

Introduction
The Medical Device Microbiology Life Cycle
Inherent and Accumulated Microbial Contamination
Product Design Microbiology
Raw Material and Component Microbiology
Shipping and Storage of Raw Materials and Components
Environmental Microbiology
Product Assembly Microbiology
Cleaning of Products
Packaging Process Microbiology
Sterilization Process Microbiology
Product Use Microbiology
Medical Device Microbiological Contamination
Controlling Product Bioburden
Aseptic Technique
No Magic Answers for Bioburden Control
Use of Bioburden Testing to Improve Manufacturing Microbiology
Use of Sterility Testing to Improve Manufacturing Microbiology
Microorganisms of Concern
Microbiological Challenges for Products with Tissue Components
References

 

PART: 2     Aspects of Microbiological Quality Control

 

 

Selection of Microbiological Culture Media and Testing Regimes

by Tim Sandle

Introduction
Types of Culture Media
Media Manufacture
Quality Control of Culture Media
  Supplier
  When to Perform Quality Control?
  Establishing a Nutritive Properties Testing System
    Micro-organisms: Typed Cultures
    Micro-organisms: Environmental Isolates or ‘Wildtypes’
    Micro-organisms: The Microbial Challenge
    Micro-organisms for the Testing of Selective Media or Differential Media
    Test Method
    Test Regime
    Sterility Test of Media
    Expiry Time Assessment of Culture Media
    New Lots of Media
  Media Release and Quarantine
Conclusion
References

 

Microbial Identification

by Ziva Abraham

Importance of Microbial Identification
Isolation of Microorganisms
Staining Methods
  Gram Staining
  Spore Stain
  Fluorescent Stains
  India Ink (Colloidal Carbon) Stain
  Acid-Fast (Ziehl Neelsen) Stain
  Lactophenol Cotton Blue Stain
Microscopy
  Stereo Microscope
  Bright Field Microscopy
  Dark Field Viewing
  Phase Contrast Microscopy
  Differential Interference Contrast (DIC) Microscopy
  Florescent Microscopy
Pre-Differentiation or Confirmation
Taxonomy, Classification, Identification and Nomenclature
Phenotypic Microbial Identification Systems
  API Panels
Automation in Microbial Identification
   Vitek® Microbial Identification Systems
   BiologTM System
   MIDI Sherlock® Microbial Identification System using Fatty Acid Methyl Ester  
       (FAME) Analysis
Genotypic Systems
  Polymerase Chain Reaction (PCR)
  DiversiLab® Strain Typing
  Microarrays in Microbial Identification
Fungal Identification
Conclusion
Acknowledgements
References

 

Microbial Examination of Non-sterile Products

by Jaymie Tomes and Florence Wu

Introduction
The Limitations and Values of Microbial Enumeration Tests
Product Sampling for Microbial Examination
    Sampling Schemes   
    Sample Sizes
    Sample Preparation
Media Growth Promotion Test
Method Suitability Test
Enumeration Methods
Media and Incubation
Colony Counting and Interpretation of the Results
Tests for Specified Microorganisms
    Staphylococcus aureus
    Pseudomonas aeruginosa
    Escherichia coli
    Salmonella
    Clostridium
    Candida albicans
    Bile Tolerant Gram Negative
Setting Microbial Limits for Non-Sterile Pharmaceuticals and Raw Materials
Conclusions
References

 

Practical Approaches to Sterility Testing

by Tim Sandle

Introduction
The Sterility Test
Sterility Test Method Validation
   Validation of Culture Media
   Sterility Test Validation
     Dealing with ‘Difficult’ Products
     Membrane Filtration
         Type of Membrane Filter
         Type and Number of Rinse Solutions
    Direct Inoculation
         Type of Neutralising Agent
         Dilution
    Turbid Samples
    Antibiotics
    Oily Samples
    Anti-cancer Treatments
    Implants
    Sterile Aerosols
    Cell Lines
    Fibrin Sealant
    Questions relating to validation that are not directly answered by the 
         Pharmacopoeias
  The Stasis Test
Training Programme
Validation Documentation
   Validation Protocol
   Validation Report
Summary
References

 

Microbial Aspects in Cleaning Validation

by Andrew Walsh

Introduction
Regulatory Aspects of Cleaning
   API Manufacturing
   Finished Pharmaceuticals
   Cleaning Processes
Cleaning Agents
Cleaning Procedures
   Manual Cleaning
   Clean-Out of-Place (COP)
   Clean-in-Place (CIP)
Solid Dosage Forms
   Setting Microbial Acceptance Criteria for Solid Dosage Forms
Semi-solid Dosage Forms
   Setting Microbial Acceptance Criteria for Semi-solid Dosage Forms
Hold Time Studies
Microbial Testing in Cleaning Validation
Conclusion
Acknowledgements
References

 

Validation of Microbiological Methods

by Sandy Rubio

Introduction
Scope
   Why is Bioburden Testing Important?
Strategy for Validation
Protocol Considerations
   Description of Product
   Manufacturing Process
   Challenge Microorganisms
   Current Validation Status
   Regulatory and Guidance Documents
   General Protocol Considerations
   Bacteriostasis/Fungistasis Evaluation
   Acceptance Criteria
   Method Development
   Sample Hold Time Determination
Maintaining Status of Validated Methods
Case Study
   Background
   Review Findings
Conclusion
References

 

Selection and Validation of Disinfectants

by Paul Viña, Sandy Rubio and Tim Sandle

Introduction
Types of Disinfectants
   Non-Oxidizing Disinfectants
     Alcohols
     Aldehydes
     Amphoterics
     Acid Anionics
     Biguanides
     Phenolics
     Quaternary Ammonium Compounds (QACs)
   Oxidizing Disinfectants
     Halogens
     Oxidizing Agents
Selection of Disinfectants
   Number, Type, and Location of Microorganisms
     Number
     Type of Microorganism and Disinfectant Resistance
     Location of Microorganisms
   Concentration
   Time
   Temperature and pH
   Interfering Substances
Validation of Disinfectants
   Test Methods
     Basic Suspension Test
     Bactericidal Suspension Test and Fungicidal Suspension Test
     Surface Test
   Test Variables
     Challenge Microorganism Selection and Inoculation of Surface Materials
     Selection of Test Surfaces
     Disinfectant Test Concentration and Preparation
     Establishing the Disinfectant Expiration Date
     Evaluating Interference from Organic Material
     Application of Disinfectant to Surface Coupons
     Contact Time
     Selection of Neutralizing Agents
Continued Evaluation of Disinfectant Effectiveness
Conclusion
References
Further Reading

 

Auditing a QC Microbiology Laboratory

by Andy Martin

Introduction
What is an Audit and Why Should They be Performed
General Principles of the Audit Process
Auditing the QC Microbiology Laboratory, What to Look For
   Strategy for Microbiological Control
   Sample Receipt
   Product Sample Testing
   Bacterial Endotoxin Testing
   Media Control and Testing
   Incubator, Refrigerator and Freezer Control and Monitoring
   Culture Collections
   Water Testing and Water System Monitoring
   Environmental Monitoring
   Isolate Identification, Gram stain techniques and ID system validation
   Autoclave control
   Antibiotic assays and Preservative testing
   Sterilization, Cleaning and disinfection validation efficacy
   Microbiological Training of Laboratory and Production Staff
   Validation of Holding Times
   Atypical Results and Out Of Specification Procedures
Auditing Techniques to Get the Most from your Audit
Reporting the Audit
Final Thoughts
References

 

Quality Assurance in a Microbiology Laboratory

by Christophe Barcella

Introduction
Quality Management, QA and QC Principles
    Quality Management
    Quality System
    Quality Assurance
    Quality Control
Laboratory Quality Manual
Laboratory Staff Qualifications and Training
        Training Policy
        Job Description
        Curriculum Vitae
        Staff Training Records
Laboratory Environment
        General
        Air Ventilation
        Lab Sanitation and Environment Monitoring
        Environmental Hygiene and Health
        Protective Equipment
Standard Operating Procedures, Methods and Protocols
        Development, Review and Approval of SOPs
        New Method Development, Validation and Amendment
        Quality Attributes for a New Method
Laboratory Notebooks, Log Books and Records
        Minimum Acceptable Procedures for Laboratory Notebooks
        Review of Test Results
        Electronic Records
Information Technology and Computer Systems Validation
        Definition of Hardware and Software
        Computer Security and Backups
        Computer Systems Validation (CSV)
Archiving Requirements
        Archiving Physical Facilities
        Archiving Personnel
        Archiving Electronic Records
        Format of Archived Materials
        Laboratory Test Samples and Preserved Wet Materials
        Duration of the Archive
Reference Standards and Samples
        Reference Standards for Microbiological Testing
            Reference Standards Storage, Handling and Labeling
            Standard References Records
        Microbiological Reference Strains
        Management of Samples
Solutions, Reagents and Culture Media
        Reagent General Specifications
        Reagent Tracking
        Reagent Solutions
        Quality Control of Culture Media
Instruments and Equipment
        Equipment Installation and Qualification
        Equipment Operations
        Equipment Calibration and Maintenance
        Glassware and Volumetric Micropipettes
            Glassware Grades
            Micropipettors
Laboratory QA Assessments/Audits & External Quality Assurance
        QA Audit Methodology
        External Quality Assessment (EQA)
        Internal Quality Assessment (IQA)
Conclusion
References

 

 

Part: 3     Measuring and Testing for Microorganisms

 

 

Environmental Monitoring

by Tim Sandle

Introduction
Cleanrooms
   Isolators
   Cleanroom Classification
   Physical Parameters
   Air-patterns and Air-Movement
   Airflows
   Air Changes
   Clean-up Times (Recovery Rate Test)
   Positive Pressure
   HEPA Filters
   Temperature, Humidity, Lighting and Room Design
Microbiological Environmental Monitoring
   Viable Monitoring Methods
     Swabs
     Contact Plates
     Active Air Monitoring
     Types of Active Air-Sampler
     Settle Plates
   Non-viable Monitoring Methods
Establishing an Environmental Monitoring Programme
   Sampling Plans
   Sample Frequencies
   Sample Limits
Personnel
   Aseptic Technique
   Other Cleanroom Disciplines
   Clothing
   Cleaning
Summary
References

 

Microbial Content Testing of Pharmaceutical and Biotechnologically Derived Products

by Dilip Ashtekar and Tim Sandle

Introduction
General Methods for the Quantitative Determination of Viable Count
   Membrane Filtration
   Pour Plate
   Surface Spread plate
   Most Probable Number
Evaluation of Results by Various Enumeration Methods
   Points to Consider for Counting CFU
   Rounding and Averaging
   Significant Figures
   Countable Range
   Statistical Errors from Low Counts
Dilutions
Replicate Plate Counts
   Consideration of Performing of Replicate Samples in Place of Testing One Large 
        Sample
Selection of Method for the Enumeration of Microbial Count
Estimating Number of Micro-Organisms in Suspension for Use in Bioburden    
     Validation or Suitability Test for MLT
Bioburden Testing
   Bioburden Test Method Validation
   Validation Requirements
Microbial Limit test (MLT)
   A1: The TAMC Test
   Reporting of Enumeration Test Results
Spreaders
Suitability of the Enumeration Method in the Presence of Product
Test for Specified Organisms
Applied Aspects of Bioburden Testing
   Method Limitations
   Sample Expiry
     Incubation Parameters
     Influencing Factors
   Staff Proficiency Training
     Plate Counting
     Pour Plates
Conclusions
References

 

Bacterial Endotoxins Test

by Masakazu Tsuchiya

Introduction
History of Bacterial Endotoxins Test
Endotoxin
   Structure and Biological Activity of Endotoxin
   Stability of Endotoxin
   Standard Endotoxin
   Variability of Potency of Daily RSE Dilutions
Limulus Amebocyte Lysate
   Principle
   Methods
   Reactivity of LAL
   Pyrogenicity and LAL Test
Bacterial Endotoxins Test in Pharmacopoeias
Validation of Bacterial Endotoxins Test
Practical Suggestions for the Bacterial Endotoxins Test
   Uncertainty of Bacterial Endotoxins Test
   Interfering Factors
   Contamination
   Removal of Endotoxin/β-Glucan
   Robust LAL Methods Using an Archived Standard Curve
Conclusion
References
Acknowledgment
Appendix A (Example of Standard Operating Procedure for Gel-Clot Method)

 

Antimicrobial Effectiveness Testing

by Scott V. W. Sutton

Introduction
The Purpose of the AET
   What the Test Means
   USP
   Pharm Eur
Development of the USP Test
   USPXVIII - The Original Test
   USP XIX - Refinements
   USP XX, XXI and XXII – Little Activity
   USP 23, 24 and 25 - Reducing Variability
   USP 23, 24 and 25 - Harmonization?
Demonstration of Method Suitability
   Importance of Preservative Neutralization
   Development of USP <1227>
   Method Suitability for Quantitative Studies
Other considerations in preservation
   Container/Closure
   In-use Testing
Investigations
   Lab Investigations
   Specific Considerations for AET
Summary/Conclusions
References

 

Monitoring of Microbiological Quality Attributes of Water for Pharmaceutical Use

by Dilip Ashtekar

Introduction
Water Types
Regulatory Requirements
Water System Description
   Prefiltration
   Activated Carbon
   Softeners
   Deionization
   Reverse Osmosis
   Ultrafiltration
   Ultraviolet Light
   Ozone
   Final Filtration
   Distillation
   Storage Tanks
   Distribution Systems
Water System Validation
   Installation Qualification
   System Characterization Studies and Testing
   Operational Qualification
   Performance Qualification
     Phase I PQ Testing
     Phase II PQ Testing
   Post-Validation Monitoring
Water System Monitoring
   Sampling and Frequency of Monitoring
   Sample Collection and Testing
    Alert and Action Levels
   Response to Confirmed Alert and Action Level Excursions
Water Data Trending Requirements
Conclusions
References

 

Investigation of Microbiological Data Deviations

by Mónica Lagomarsino

Introduction
Microbiological Data Deviations
Objectives of the Investigation
Acceptance Criteria
General Process for the Investigation
Laboratory Investigation
Full-Scale Investigation
A Case Study
Conclusion
References
Recommended Bibliography

 

Alternative Microbiological Methods and New Pharmaceutical Microbiology Curriculum

by Claudio D. Denoya

Introduction
A “Rapid” History of Microbiology
Today’s Microbiology: The Fundamentals of “Traditional” Microbiology
The New Microbiological Technology Wave for the QC Lab: Alternative and Rapid    
       Microbiological Method (ARMMs)
Metabolic or Growth Based Technologies
Viability Based Technologies
Technologies Based on Cell Component Analysis
ARMMs and the Pharmaceutical Industry
AMM, PAT, and Regulatory Status
Microbiology Curricula
The Skill Sets of a Pharmaceutical Quality Control (QC) Microbiologist
Curricula Surveys
The Disparity between the Tertiary Microbiology Curricula and the Needs of the 
         Pharmaceutical Industry QC Microbiologist
An Interesting Step Forward: The United States Professional Science Master''''''''s 
        Programs
Conclusions and Recommendations
Acknowledgments
References

 

The Implementation of Rapid Microbiological Methods

by Michael J. Miller

Microbiology Trapped In the 19th Century
New Technologies for Pharmaceutical Manufacturing
An Introduction to Rapid Microbiological Methods
RMM Applications
Strategy for Implementation
Validating Rapid Microbiological Methods
   Initial Activities
   The Validation Strategy
     Risk Assessment
     Validation Master Plan (VMP)
     User Requirements Specifications (URS)
     Design Qualification (DQ)
     Supplier Assessment/Audit
     Functional Design Specifications (FDS)
     Requirements Traceability Matrix (RTM)
   Training and SOPs
   The Test Plan
   Installation Qualification (IQ)
   Operational Qualification (OQ)
     Validation Criteria for Quantitative Tests
     Validation Criteria for Qualitative Tests
     Validation Criteria for Microbial Identification Tests
   Performance Qualification (PQ)
   Validation Summary Report
Implementation and Secondary Site Qualification
RMMS and the Regulatory Environment
FDA Perspectives
   Pharmaceutical cGMP’s for the 21st Century: A Risk-Based Approach
   Process Analytical Technology (PAT)
   Sterile Drug Products Produced by Aseptic Processing – cGMP
   RMM’s for Sterility Testing of Cellular and Gene Therapy Products
   Encouragement from FDA’s Microbiology Review and Compliance Staff
   Strategies for Implementing RMMs with the FDA
EMA Perspectives
   EMA Revised Variations Regulation
   PDA Forum on Implementing RMMs in Europe
   Type Variations
   Scientific Advice
   RMM Validation
   The EMA PAT Team
Changing Acceptance Levels and Specifications
Regulatory Summary
Developing a Business Case for RMMS
   Where Can Savings Come From?
   Creating an Economic Analysis
     Operating Costs Associated with the Conventional Method
     Operating and Investment Costs Associated with the RMM
     Cost Savings/Cost Avoidances Associated with the RMM
   Return on Investment (ROI)
   Payback Period (PP)
   Net Present Value (NPV)
Chapter Summary
Acknowledgement
References

 

Risk Management in Pharmaceutical Microbiology

by Tim Sandle

Introduction to Risk Assessment and Risk Management Process
Regulatory Views and Guidelines on Risk Management
The Basics of Risk Assessment
Advantages and Disadvantages of Risk Assessment
Risk Assessment and Risk Management Methodologies
   HACCP: Risk Based Approach in Environmental Monitoring
     Case Study 1
     Deconstructing the Process
          Route Map
          Identification of Hazards
          Process Flow
          Environmental Monitoring
     Risk Assessment
          Perform a Simulation
     Evaluation
   FMEA - Risk Based Approach in Sterility Testing
     Case Study 2
     Sterility Testing Isolator: The Case Study
     Description of the System
     Application
     The FMEA Study on the Sterility Testing Isolator System
     Designing the FMEA Scheme
     The FMEA Exercise
           Examination 1: The Isolator Room
           Examination 2: Potential of Sanitisation Cycle Failure
           Examination 3: Frequency of Isolator Sanitisations
           Examination 4: Compromise of Isolator Integrity
           Examination 5: Connection of Transfer Isolator to Main Isolator and 
                   Transfer-in / out of Material
           Examination 6: Incomplete Transfer Isolator Sanitisation
           Examination 7: Failure of a Daily, Weekly or Six-monthly Physical 
                  Parameter - HEPA filters / Pressure Leaks to Canopy
           Examination 8: Pressure Leaks to Gloves
           Summary
    Other Available Tools
     Ishikawa or Fishbone Diagrams
     Risk Ranking
     Risk Filtering
     Risk Modelling
     Contradiction Tables or Matrix
Conclusion: The benefits of Risk management
References

 

Part: 4     Sterilization and Sterility Assurance

 

Sterility

by Edward C. Tidswell

Introduction
Origins of Sterilization
The Microbial Challenge
Consequences of Non-Sterility and Lack of Asepsis
What Does Sterile Mean and Can We Test It?
Conclusion
References

 

Process Selection for Sterile Products

by James Agalloco

Introduction
Terminal Sterilization and Adjunct Processing
Aseptic Processing
Conclusion
References

 

Microbial Contamination Control in Pharmaceutical Manufacturing

by Matts Ramstorp

Pharmaceutical Cleanrooms and Clean Zones
   Introduction
    The Use of Proper Hygiene
    The Historic Development of Microbiology
    Aseptic Techniques
   Production of Medicinal Products
   Why is Pharmaceutical Production Different from Microelectronics?
   Classification of Pharmaceutical Cleanrooms
   Good Manufacturing Practice (GMP)
   Design of Pharmaceutical Cleanrooms
     How to Proceed with the Design of a Pharmaceutical Cleanroom
   Cleanroom Cleanliness
     Pharmaceutical Cleanroom Classification
   Measuring Cleanliness within Pharmaceutical Cleanrooms
     Particle Counting
     Microbial Monitoring
     Analysis of Microbiological Contaminants in the Air
   Sampling of Microorganisms
     Sampling of Microorganisms in the Air of a Cleanroom
        The Andersen Sampler
        Slit-to-Agar-Sampler
        The RCS-Sampler
         Liquid Impinger
     Surface Sampling
   Microbiological Contaminants and GMP
   Pharmaceutical Cleanroom Ventilations Systems
     Conventional Ventilated Cleanrooms
     Unidirectional Flow Cleanrooms
   Ventilation Filter for Pharmaceutical Cleanrooms
   Cleanrooms and Clean Zones
     Working in Clean Zones
   Pharmaceutical Cleanroom Production Systems
     Production using Terminal Sterilization
     Aseptic Production
Cleaning and Disinfection of a Pharmaceutical Cleanroom
   Introduction
   What is the Purpose of Cleaning?
   What is Cleaning?
         How to Work with Preventive Cleaning
         Active Cleaning
   Classification of Surfaces in a Cleanroom
   Cleaning Program for Cleanrooms
         Example of a Cleaning Program
   How to Analyse and Control Cleaning
   Cleaning Techniques
         Cleaning Methods
            Dry Cleaning Methods
            Wet Cleaning Methods
   Cleaning Solution
   The Zinner Circle
    Disinfection
   Potential Risk Factors Associated with Cleanroom Decontamination
   Standards and Practices
Cleanroom Garments
   Introduction
   What is the Purpose of the Cleanroom Garment?
   Garment Systems
   Single-use versus Washable Garments
   Choice of Material
   Comfort
   Construction of Garment Systems
   The EU GMP and Cleanroom Garment Systems
   Using Cleanroom Garments
   Clothing, Personal Items and Underwear
   Processing of Clothing and Change Frequency
   Risk Factors Associated With Cleanroom Clothing
    Conclusions
Personal Hygiene and Personal Responsibility
   Introduction
   Humans as Particle Generators
         Particles and Fibres
         The Normal Flora of Man
   Good Manufacturing Practice in Relation to Personnel
   Personal Hygiene
   The Interconnection between Personnel and the Process
   Contamination Hazards Connected to Personnel
   General Rules when Working in Cleanrooms and other Controlled Environments
Acknowledgement
References

 

Aseptic Process Simulations/Media Fills

by Marco Budini and Francesco Boschi

Introduction
Documentation
Media Selection
Frequency and Number of Runs
Size and Duration of Runs
Line Speed and Container Size
Closure Type
Process/Line Configuration and Set-up
Fill Volume
Number of Persons and Activities
Interventions
Line Clearance
Environmental and Personnel Monitoring
Other Worst Case Scenarios
Cleaning after Process Simulation
Incubation and Inspection of Filled Units
Growth Promotion Test
Interpretation of Results – Acceptance Criteria
Invalidation and Abortion of Process Simulation Runs
Investigation of Process Simulation Contaminations/Failures
Conclusions
References

 

Biological Indicators for Sterilization

by Russ Nyberg

Description
Performance Qualification of Biological Indicators
BI Use in Parenteral Product Loads
Use of a Process Challenge Device (PCD)
Selection of BIs
Contracting for 3rd Party D-Value Testing
   Equipment
   Test Method Used
   Recovery Media
   Technique and Lab Utensils/Personnel
Rapid Read-out Biological Indicators
Conclusion
References

 

Moist Heat Sterilization

by Michael Sadowski

Introduction
Sterile Products
History of Sterilization with Heat
Mechanisms of Spore Heat Resistance And Inactivation
Inactivation of Spores Using Moist Heat Sterilization Processes
   Use of Semilogarithmic Survivor Curve Model for Characterizing and Predicting 
          Microbiological Inactivation
Pharmaceutical Products
Selection of a Moist Heat Sterilization Process Type
   Saturated Steam Sterilization Processes
   Gravity Displacement Processes
    Pre-vacuum Processes
   Air Overpressure Processes
   Steam/Air Mixture Processes (SAM)
   Superheated Water Air Overpressure Processes
Product or Item Loading Patterns
 Biological Indicators for the Development and Qualification of Moist Heat Sterilization Processes
Determination of The Hardest to Sterilize Solution Formulation or Item/Component
The Liquid Products Master Solution Approach
The Process Challenge Device (PCD) Approach for Porous/Hard Goods
Determination of Hardest To Sterilize Locations or Cold Spots Used For            
      Penetration Probes
Use of Chemical Indicators
Development Moist Heat Sterilization Processes
   Development of the Sterilization Process Heat Up/Conditioning Phase
   Development of the Sterilization Process Cooling/Drying Phase
   Development of the Exposure Phase
   Determination of the Minimum Physical Lethality Value
   Minimum Physical Lethality Values Prescribed in Regulatory Standards
   Minimum Physical Lethality Values Required for the Overkill Cycle Design 
        Approach
    Determination of Minimum Physical Lethality Values for the Product Specific 
        Approach
    Determination of Exposure Time to Meet Minimum Physical Lethality 
         Requirements
   Use of Biological Lethality in the Determination of Exposure Time
   Use of the Fractional Exposure Approach in the Determination of Exposure Time
Validation of The Moist Heat Sterilization Process
   Installation Qualification
   Operational Qualification
     Pre-vacuum Sterilizer Vacuum Leak Rate Test
     Steam Penetration or Bowie Dick Type Test
     Steam Quality Tests
   Performance Qualification
    Use of Physical Lethality in the Qualification of Moist Heat Sterilization 
           Processes
    Use of Biological Lethality in the Qualification of Moist Heat Sterilization 
           Processes
Routine Monitoring and Control of the Moist Heat Sterilization Process
   Preventive and Unplanned Maintenance
    Calibration Program
   Ongoing Sterilizer and Utility System Functionality Tests
Product and Process Change Control
Sterile Product Release Process
   Bioburden Testing
   Sterilizer Functionality
   Sterilization Cycle Parameters
   Chemical Indicator and Biological Indicator Results
   The Sterility Test
   Parametric Release
Conclusion
Acknowledgement
References

 

Sterilization and Depyrogenation by Dry Heat

by Madhu Raju Saghee and Gary R. Mitchel

Introduction
Functions of Dry Heat
Thermodynamical Aspects of Heat Transfer in Dry Heat Processes
Destruction of Microorganisms and Endotoxins by Dry Heat
   Spectrum of Activity on Microbial Populations
      Effect of Microbial Water Content in Dry Heat Sterilization Processes
      Effect of Temperature and Time
   Destruction of Endotoxins
Types of Dry Heat Sterilization/Depyrogenation Processes
   Batch Process
   Continuous Process
Validation and Ongoing  Control
   Temperature Measurement Errors
   Validation Approach
   Installation Qualification
   Operational Qualification
   Performance Qualification
   Routine Monitoring and Control
Conclusion
References
Acknowledgements
Appendix A (Example of an outline for an Installation Qualification protocol)
Appendix B (Example of an outline for Operational and Performance Qualification protocols)

 

Radiation Sterilization

by Mark A. Seybold and John A. Williams

Introduction
History of Radiation Sterilization
Types of Radiation Sterilization
   Gamma Sterilization
   Electron Beam Sterilization
   X-Ray Sterilization
   Radiation Sterilization Applications
Microbial Inactivation
   Mode of Action
   Microbial Resistance to Ionizing Radiation
   Radiation Resistance Factors
      Environmental Factors
      Organism Characteristics
   Inactivation Kinetics
Validation
   Installation Qualification
   Operational Qualification
    Performance Qualification
   Microbiological Validation of Radiation Sterilization Processes
     Dose Setting
     Method 1
     Method 2
     Method VDmax
   Materials Qualification
   Process Validation
Routine Monitoring And Control
Maintaining Process Effectiveness
   Biorburden Monitoring Program
   Dose Audits
   Radiation Equipment
Conclusions
References

 

Sterilization by Filtration

by Maik W. Jornitz and Theodore H. Meltzer

Introduction to Sterilizing Filtration
Filtration Parameters
    Contamination Removal
    Rate of Flow
    Total Throughput
    Unspecific Adsorption
Filter Types
Filter Materials
Filter Construction
Filter Validation
Filter Integrity Testing
    Bubble Point Test
    Diffusion Test
    Pressure Hold Test
    Water Intrusion Test
    Product Wet Integrity Testing
Filtration Applications
    Liquids
         Solvent (API) Filtration
         Ophthalmics Filtration
         Cell Culture Media
         Buffer Filtration
      Gases
         Fermentor Inlet Air
         Fermentor Off-Gas
         Vent Filters on Tanks
         Autoclave and Lyophilizer Vent Filter
         Filtration of Service Gases
References

 

Sterilization by Ethylene Oxide

by Gerry A. O’Dell

Introduction
Factors Affecting the Lethality of EO Sterilization
   Gas Concentration
   Humidity/Moisture
   Temperature
   Inherent resistance of microorganisms
   Conferred resistance
    Combination of factors
The EO Sterilization Process
   Preconditioning
   Sterilization Cycle
   Aeration
Product and Process Definition for EO Sterilization
   Product definition
   Process definition
EO Sterilization Validation
   Installation Qualification
   Operational Qualification
   Performance Qualification
       Microbiological PQ
       Physical PQ   
Routine monitoring of the EO sterilization process
   Conventional Release
   Parametric Release
   Use of tests for sterility
Demonstrating the Ongoing Effectiveness of the EO Sterilization Process
    Addressing changes (change control)
    Process equivalence
    Product adoption
    Periodic requalification
Summary
References

 

Maintaining Sterility

by Michelle A. Luebke & Bonnie J. Heredia

Introduction to Maintaining Sterility
Medical Product Packaging System Development
   Packaging Development Phase
   Routine Manufacturing/In-Process Control Phase
   Stability/Product Testing Phase
Microbiological Versus Physical Integrity Test Methods
Test Method Correlation
   Direct Approach
   Indirect Approach
Test Method Sensitivity
Test Method Validation
   Method and Vendor Requirements
   Validation Plan
   Installation Qualification
   Operational Qualification
   Performance Qualification
Sterile Medical Product Classification
   Medical Devices
     Medical Devices - Sterile Designation
     Medical Devices - Sterile Fluid Path Device Designation
   Needleless Medical Devices
   Drugs and Biologics
Sterile Barrier System Classification
   Seals
   Closures
Sterile Barrier Integrity Test Methods
   Physical Methods
     Visual Inspection
     Bubble Test
     Pressure/Vacuum Decay
     Dye Test
     Tracer Gas Leak Detection
   Microbiological Methods
     Microbial Challenge - Liquid Immersion
     Microbial Challenge - Aerosolization
     Static Aerosol Challenge
     Dynamic Aerosol Challenge
     Simulated Clinical Use Test Method
   Miscellaneous Methods
Summary
References

Index


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