Pharmaceutical Manufacturing:

Understanding Your Process Series

Cleaning and Cleanrooms

Paul Lopolito, Jeanne Moldenhauer,

Elizabeth Rivera and Tim Sandle

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CLEANING AND CLEANROOMS

Paul Lopolito, Jeanne Moldenhauer,

Elizabeth Rivera and Tim Sandle

PDA
Bethesda, MD, USA
DHI Publishing, LLC
River Grove, IL, USA

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10 9 8 7 6 5 4 3 2 1

ISBN: 978-1-942911-07-4
Copyright © 2017 Davis Healthcare International Publishing, LLC.
All rights reserved.

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 CONTENTS

1 THE DEVELOPMENT OF CLEANROOMS:

AN HISTORICAL REV1EW
PART 1: FROM CIVIL WAR TO SAFE SURGICAL PRACTICE 1
Tim Sandle
Introduction 1
Early History: Surgical Endeavours 2
Post-war: Industrial Growth 4
1960s: The Space Race and the Cleanroom First Standards 6
Sumary 10
References 10
About the Author 13

2 THE DEVELOPMENT OF CLEANROOMS:

AN HISTORICAL REV1EW
PART 2: THE PATH TOWARDS INTERNATIONAL
HARMONIZATION 15
Tim Sandle
Introduction 15
I970s: Pharmaceuticals 16
1980s: GMP Standards 18
1990s: Towards a Global Standard 18

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iv Cleaning and Cleanrooms

Into the 21st Century 19

Revisions to the ISO 14644 Standard 20
Summary 22
References 22
About the Author 23

3 UNDERSTANDING CLEANROOM CLASSIFICATIONS 25

Jeanne Moldenhauer
Federal Standard 209E 27
Lesser Known Air Cleanliness Standards 29
ISO 14644-1 Classification System 31
FDA’s Aseptic Process Guidance 32
The European Union’s GMP — Annex 1 33
ICA Q7A 35
Aseptic Processes 36
The Problem 36
References 37
About the Author 39

4 CLEANROOM SUPPLIES 41
Jeanne Moldenhauer
Introduction 41
Cleanroom Equipment 41
Cleanroom Garments 43
Sampling Devices 45
Swabs 46
Paper and Labels Used in the Cleanroom 46
Wipes and Wipers 47
Vacuum Cleaners 48
Mops and Buckets 49
Sponges and Sponge Wipes 50
Tacky Mats 51
Tacky Rollers 51
Accessories 51
Bibliography 52
About the Author 53

5 PRACTICAL ASPECTS OF CLEANING, SANITIZING

AND DISINFECTING ROOMS AND SURFACES 55
Jeanne Moldenhauer
Introduction 55
Cleaning Versus Disinfection 56
Aseptic Areas are not Sterile Areas 56
Purposes of Cleaning/Sanitizating/Disinfecting of Rooms and Surfaces 56
Who Will Perform the Cleaning Tasks? 57

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 Contents v

Equipment and Supplies Used for Cleaning 58

Methods Utilized 58
Frequency of Cleaning 59
Preparations of Cleaning/Sanitizng/Disinfecting Solutions 59
Surfactants 60
Residues 61
Cleaning Practices 61
How to Clean 63
The Double Bucket Method 64
Use of Mops and Wipes 65
Rotation of Cleaning Agents 65
How to Verify Cleanliness 66
Conclusion 66
Bibliography 67
About the Author 67

6 CLEANING VALIDATION: PROCESS LIFE

CYCLE APPROACH 69
Paul Lopolito and Elizabeth Rivera
Introduction 69
Stage 1: Cleaning Process Design 72
Selection of cleaning agent and suppliers 73
Defining critical parameters and cleaning methods 74
Design of laboratory and pilot testing 74
Utility design considerations 76
Process equipment design review 76
Product and equipment grouping 77
Analytical detection method 78
Recovery studies 80
Residual limits and acceptance criteria 80
Documentation of the process design stage 81
Stage 2: Process Qualification 82
Cleaning Validation Master Plan 83
Supplier qualification 85
Utility readiness 85
Equipment readiness 86
Analytical method readiness 87
Selection of sampling sites 89
Cleaning validation protocols 90
Standard Operating Procedures 92
Personnel training 93
Validation execution 93
Interim documentation and final package 94
Stage 3: Continued Process Verification 95
Monitoring and process capability 95
Process Analytical Technologies 96
Change control procedures 97

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vi Cleaning and Cleanrooms

Deviations and Out of Specification (OOS) results 98

Procedure review and retraining 98
Corrective and Preventive Action (CAPA) procedures 98
Preventive Maintenance (PM) procedures 98
Quality management review 100
Revalidation versus new validation 100
Conclusions 102
References 102
About the Authors 106

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