Table Of ContentCLEANING
VALIDATION
A Practical Approach
•••
Gil Bismuth
Shosh Neumann
informa
healthcare
New York London
CRC Press
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Version Date: 20130325
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Contents
PREFACE ix
PART ONE
DEVELOPING A CLEANING PROCEDURE
1. CONTAMINATION CONTROL 3
Introduction 3
Contamination Types 3
Chemical Contamination 3
Physical Contamination 4
Microbiological Contamination 4
Contamination Control 4
Facilities 4
Equipment 5
Personnel 6
Material and Waste Flows 6
2. REGULATORY REQUIREMENTS 7
3. CLEANING BASIC CONCEPTS 15
Introduction 15
Cleaning Mechanisms 15
Levels of Cleaning 16
Time Limitations 17
iii
iv Cleaning Validation-A Practical Approach
4. CLEANING PROCEDURE 21
Introduction 21
Equipment Design 21
Manufacturing Process 22
Operator 23
Materials and Tools 24
Solvents 24
Cleaning Agents 24
Cleaning Tools 25
Control of Materials and Tools 25
Cleaning Procedure 26
Types 26
Documentation 30
PART TWO
DEVELOPING A CLEANING VALIDATION PROGRAM
5. CLEANING VALIDATION POLICY 35
Introduction 35
Policy 37
Selecting the Worst Case Related to the Product 37
Product Grouping 38
Selecting the Worst Case Related to the Equipment 39
Equipment Grouping 39
Hard-to-Clean Locations 39
Selecting the Scientific Basis for the Contamination Limit 40
Contamination Limit Based on Toxicological Data 44
Dose-Related Contamination Limit 45
Contamination Limit Based on Other Considerations 46
Acceptance Criterion Based on Visual Inspection 47
The Proposed Approach 4 7
Selecting the Sampling Method 48
The Swabbing Method 48
The Rinse Sample Method 51
The Placebo Method 52
Contents v
Selecting the Analytical Method 53
Basic Requirements 53
Analytical Method Survey 54
Analytical Method Validation 55
Analytical Method Implementation 56
6. CONTAMINATION ACCEPTANCE LIMITS 57
Lowest Therapeutic Dose (LTD) 59
Maximal Daily Dose 60
Highest Unit Dose Weight and Smallest Batch Size 60
Calculation of the Sample Contamination Limit
for the Active Ingredient 61
Calculation of the Sample Contamination Limit
for the Cleaning Agent 61
Discussion of the Sample Contamination Limit 61
Averaging of Sample Swab Results 61
Equipment Train 62
7. CLEANING VALIDATION PLANNING AND EXECUTION 65
Introduction 65
Organization 65
Planning 67
Database 68
Equipment Grouping 68
Selection of the Equipment Worst Case 70
Product Grouping 74
Selection of the Product Worst Case 74
Cleaning Agents 78
Calculation of the Contamination Acceptance Limit 78
Active Ingredient 78
Cleaning Agent 78
Cleaning Validation Master Plan 78
Working Plan 80
Execution 80
vi Cleaning Validation-A Practical Approach
Cleaning Validation Protocol 83
Sampling and Testing 84
Cleaning Validation Report 84
8. CLEANING VALIDATION MONITORING AND MAINTENANCE 85
Monitoring 85
Maintenance of Validation 85
9. SPECIAL CLEANING VALIDATION ISSUES 89
Biocontamination 89
Penicillin Contamination 90
Nonpharmaceuticals 91
Contract Manufacturing and Packaging 91
10. CLEANING VALIDATION TRENDS 93
Introduction 93
Contamination Control 93
Personnel 93
Equipment 94
Cleaning Procedure 94
Cleaning Agents and Tools 94
Sampling Technique 95
Analytical Methods 95
Regulatory Issues 95
The Future 96
Contents vii
APPENDICES
CLEANING AND CLEANING VALIDATION PROCEDURES
APPENDIX A-CLEANING 99
Policy-Equipment and Processing Area Cleaning 101
Purpose 103
Responsibility 103
Frequency 103
Procedure 104
Documentation 106
Cleaning Procedure-High Shear Mixer (Diosna) ll1
Equipment 113
Ancillary Equipment 114
Process Area 115
Visual Inspection 116
Reassembly 116
Status Label 116
Storage Conditions 116
Summary 117
Documentation 117
APPENDIX B-CLEANING VALIDATION ll9
Policy-Cleaning Validation 121
Purpose 123
Responsibility 123
Frequency 124
Procedure 124
Standard Operating Procedure-Cleaning Validation 129
Purpose 131
Responsibility 131
Frequency 132
Procedure 132
Documentation 135
viii Cleaning Validation-A Practical Approach
Standard Operating Procedure-Cleaning Validation
Change Control 137
Purpose 139
Responsibility 139
Frequency 139
Procedure 139
Documentation 140
Work Instructions-Swab Sampling for Cleaning Validation 145
Safety 147
Equipment and Materials 147
Procedure 147
Acceptance Criteria 148
Documentation 148
Work Instructions-Swab Characterization for Cleaning
Validation 149
Safety 151
Equipment and Materials 151
Procedure 151
Acceptance Criteria 152
Documentation 152
Work Instructions-Sampling Recovery Test 153
Safety 155
Equipment and Materials 155
Procedure 156
Acceptance Criteria 157
Documentation 157
Cleaning Validation Protocol and Report 159
Purpose 163
Responsibility 163
Frequency 164
Procedure 164
Acceptance Criteria 164
Documentation 164
Conclusion 175
REFERENCES 177
INDEX 183
Preface
Alice: "Would you tell me, please, which way I ought to go from here?"
"That depends a good deal on where you want to get to", said the cat.
"I don't much care where", said Alice.
"Then it doesn't matter which way you go", said the cat.
"So long as I get somewhere", Alice added as an explanation.
"Oh, you're sure to do that", said the cat,
"if you only walk long enough".
Lewis Carroll, Alice in Wonderland
Unless you have gone through the experience yourself, dealing with cleaning validation
appears as an insuperable task. How can one deal with a multitude of products and a
variety of equipment? What resources are needed? Where does one start? The questions
seem as numerous as the products themselves, while the answers are scarce.
Although interest in cleaning validation started at the beginning of this decade,
there are only regulatory recommendations and a relatively small bundle of articles pro
viding some basic principles on selected aspects of this wide field. These are highly
instructive in picturing cleaning validation as a multifaceted undertaking involving a
high degree of understanding and knowledge relating to quite different disciplines, such
as toxicological or clinical studies, pharmaceutics, analytical chemistry, and engineer
ing. Yet the summation of the knowledge acquired is not to give more than a mosaic
of ideas, hints, and triggers. Although very useful, it is not sufficient to build up a com
prehensive cleaning validation program.
Whether or not your company has been recently inspected, or even got an obser
vation on deficiencies of your cleaning validation program, you won't have any diffi
culty in convincing upper management of the need to establish a cleaning validation
program in order to satisfy the regulatory authorities. The U.S. Freedom of Informa
tion Act, through the Food and Drug Administration (FDA) web site of the Internet,
gives real-time access to the citations and the warning letters issued by the FDA to com
panies which did not adequately address this hot topic. Considering that violations cited
ix
x Cleaning Validation-A Practical Approach
in these dreadful letters may result in holding new applications, no company will allow
itself not to enter this relatively new field of the pharmaceutical industry. Cleaning val
idation, however, is not only performed to satisfy authorities. The safety of patients tak
ing your company's medicines is the prime objective, and no company would want to
be involved in a litigation resulting from product contamination.
Now the burden of developing a cleaning validation program is on you, the qual
ity assurance manager or the research and development (R&D) manager or whoever in
your organization is responsible for it. You have gathered all the regulatory requirements,
read all the literature relating to the subject, and participated in one or more of the
many conferences and courses on cleaning validation. Your mind is burgeoning with a
lot of ideas and the everlasting questions What?, When?, and How? are swirling in your
mind like a predator preparing to rush its prey.
Beyond the confusion, and as for any new project, a cleaning validation program
is about understanding the objective, determining the approach, setting a scientifically
sound policy, organizing a program, and allocating adequate resources. The aim of this
book is to provide professionals in charge of the cleaning validation program with a
detailed step-by-step guide to establish a comprehensive, yet manageable cleaning val
idation program, and with practical examples to illustrate the implementation of the
proposed program. The user-friendly database formats and practical data relating to
various aspects of cleaning validation also provided in this book will make it easy for
anyone to rapidly start up the program.
This book shows that what may have started with confusion ends up with a clear
and manageable program which, to the authors' opinion and experience, is deemed to
be acceptable by the various international regulatory authorities.
Gil Bismuth
Shosh Neumann
