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Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices


Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices

Editors: Madhu Raju Saghee, Tim Sandle and Edward C. Tidswell


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.


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.


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

The Essentials of Pharmaceutical Microbiology

by Tim Sandle and Madhu Raju Saghee

History of Microbiology
Fundamental Characteristics of Microorganisms
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
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


Relevance of Microorganisms in Pharmaceutical Processing

by Ossama M. El-Tayeb

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
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

Microbial Contamination and Spoilage

by David G. Allison

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
Types of Water
Disinfection of Water
Microbial Contamination from the Manufacturing Environment
Air supply
Equipment and facilities
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

Microbiological Considerations in Medical Device Industry

by Martell Winters

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

PART: 2 Aspects of Microbiological Quality Control

Selection of Microbiological Culture Media and Testing Regimes

by Tim Sandle

Types of Culture Media
Media Manufacture
Quality Control of Culture Media
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

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
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

Microbial Examination of Non-sterile Products

by Jaymie Tomes and Florence Wu

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
Candida albicans
Bile Tolerant Gram Negative
Setting Microbial Limits for Non-Sterile Pharmaceuticals and Raw Materials

Practical Approaches to Sterility Testing

by Tim Sandle

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
Turbid Samples
Oily Samples
Anti-cancer Treatments
Sterile Aerosols
Cell Lines
Fibrin Sealant
Questions relating to validation that are not directly answered by the
The Stasis Test
Training Programme
Validation Documentation
Validation Protocol
Validation Report

Microbial Aspects in Cleaning Validation

by Andrew Walsh

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

Validation of Microbiological Methods

by Sandy Rubio

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
Review Findings

Selection and Validation of Disinfectants

by Paul Viña, Sandy Rubio and Tim Sandle

Types of Disinfectants
Non-Oxidizing Disinfectants
Acid Anionics
Quaternary Ammonium Compounds (QACs)
Oxidizing Disinfectants
Oxidizing Agents
Selection of Disinfectants
Number, Type, and Location of Microorganisms
Type of Microorganism and Disinfectant Resistance
Location of Microorganisms
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
Further Reading

Auditing a QC Microbiology Laboratory

by Andy Martin

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

Quality Assurance in a Microbiology Laboratory

by Christophe Barcella

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
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
Laboratory QA Assessments/Audits & External Quality Assurance
QA Audit Methodology
External Quality Assessment (EQA)
Internal Quality Assessment (IQA)

Part: 3 Measuring and Testing for Microorganisms

Environmental Monitoring

by Tim Sandle

Cleanroom Classification
Physical Parameters
Air-patterns and Air-Movement
Air Changes
Clean-up Times (Recovery Rate Test)
Positive Pressure
HEPA Filters
Temperature, Humidity, Lighting and Room Design
Microbiological Environmental Monitoring
Viable Monitoring Methods
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
Aseptic Technique
Other Cleanroom Disciplines

Microbial Content Testing of Pharmaceutical and Biotechnologically Derived Products

by Dilip Ashtekar and Tim Sandle

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
Replicate Plate Counts
Consideration of Performing of Replicate Samples in Place of Testing One Large
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
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

Bacterial Endotoxins Test

by Masakazu Tsuchiya

History of Bacterial Endotoxins Test
Structure and Biological Activity of Endotoxin
Stability of Endotoxin
Standard Endotoxin
Variability of Potency of Daily RSE Dilutions
Limulus Amebocyte Lysate
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
Removal of Endotoxin/β-Glucan
Robust LAL Methods Using an Archived Standard Curve
Appendix A (Example of Standard Operating Procedure for Gel-Clot Method)

Antimicrobial Effectiveness Testing

by Scott V. W. Sutton

The Purpose of the AET
What the Test Means
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
In-use Testing
Lab Investigations
Specific Considerations for AET

Monitoring of Microbiological Quality Attributes of Water for Pharmaceutical Use

by Dilip Ashtekar

Water Types
Regulatory Requirements
Water System Description
Activated Carbon
Reverse Osmosis
Ultraviolet Light
Final Filtration
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

Investigation of Microbiological Data Deviations

by Mónica Lagomarsino

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

Alternative Microbiological Methods and New Pharmaceutical Microbiology Curriculum

by Claudio D. Denoya

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
Conclusions and Recommendations

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

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
FMEA - Risk Based Approach in Sterility Testing
Case Study 2
Sterility Testing Isolator: The Case Study
Description of the System
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
Other Available Tools
Ishikawa or Fishbone Diagrams
Risk Ranking
Risk Filtering
Risk Modelling
Contradiction Tables or Matrix
Conclusion: The benefits of Risk management

Part: 4 Sterilization and Sterility Assurance


by Edward C. Tidswell

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

Process Selection for Sterile Products

by James Agalloco

Terminal Sterilization and Adjunct Processing
Aseptic Processing

Microbial Contamination Control in Pharmaceutical Manufacturing

by Matts Ramstorp

Pharmaceutical Cleanrooms and Clean Zones
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
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
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
Potential Risk Factors Associated with Cleanroom Decontamination
Standards and Practices
Cleanroom Garments
What is the Purpose of the Cleanroom Garment?
Garment Systems
Single-use versus Washable Garments
Choice of Material
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
Personal Hygiene and Personal Responsibility
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

Aseptic Process Simulations/Media Fills

by Marco Budini and Francesco Boschi

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
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

Biological Indicators for Sterilization

by Russ Nyberg

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
Test Method Used
Recovery Media
Technique and Lab Utensils/Personnel
Rapid Read-out Biological Indicators

Moist Heat Sterilization

by Michael Sadowski

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
Determination of Minimum Physical Lethality Values for the Product Specific
Determination of Exposure Time to Meet Minimum Physical Lethality
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
Use of Biological Lethality in the Qualification of Moist Heat Sterilization
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

Sterilization and Depyrogenation by Dry Heat

by Madhu Raju Saghee and Gary R. Mitchel

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
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

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
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

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
Solvent (API) Filtration
Ophthalmics Filtration
Cell Culture Media
Buffer Filtration
Fermentor Inlet Air
Fermentor Off-Gas
Vent Filters on Tanks
Autoclave and Lyophilizer Vent Filter
Filtration of Service Gases

Sterilization by Ethylene Oxide

by Gerry A. O'Dell

Factors Affecting the Lethality of EO Sterilization
Gas Concentration
Inherent resistance of microorganisms
Conferred resistance
Combination of factors
The EO Sterilization Process
Sterilization Cycle
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

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
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



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Microbiology & Sterility Assurance
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