practical aseptic processing: fill and finish volume 1

PRACTICAL ASEPTIC PROCESSING: FILL AND FINISH VOLUME 1

CONTENTS

Preface xiIrving J. Pflug

Introduction xvJack Lysfjord

Acknowledgements vvxii

Dedication xix

Glossary xxi

Part One: Current Global Influences on AsepticProcessing

1 Regulatory Background to Aseptic Processing 3Richard Johnson and Gordon Farquharson

Introduction 3Global Regulatory Guidance 5

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www.pda.org/bookstore

US FDA 5EU Annex 1 11Canadian Regulation 14Japanese Guidance 15Other Useful References 16Conclusion 17About the Authors 17

2 Development Requirements of BiopharmaceuticalParenteral Dosage Forms 19

John A. BontempoKey Requirements to Consider Before Preformulations

and Formulations of Biopharmaceuticals Begin 20Summary 32References 32About the Author 34

3 BiopharmaceuticalTherapeutics Dosage FormsDelivery Systems and Current Status ofExtractables and Leachables in RespectiveParenteral Dosage Forms 35

John A. BontempoPre-filled Syringes 38Auto-injectors 43Pen Injector 45Needle-free Injectors 46Summary 46Current Status of Extractables and Leachables in

Respective Dosage Forms 46What are Extractables and Leachables 47Rigid Needle Shield 51References 52About the Author 53

4 Vaccines: Moving into the Future 55John Finkbohner

Introduction 55Vaccines in the United States 56Use of Vaccines in the U.S. 63Overview of Immune Responses 63

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Type of Vaccines 64Challenges Facing the Modern Vaccine Business 66Challenges of Vaccine Manufacturing 67Formulation of Vaccines 71Future Growth of Vaccines 74Summary 76References 77About the Author 80

PartTwo: Current Aseptic ProcessingTechniques

5 Container Preparation —Washing, Sterilizationand Deyprogenation 85

Johannes Rauschnabel, Patrizia Dittmer and Thomas KosianContainer Cleaning 86Sterilization and Depyrogenation with Dry Heat 93References 103About the Authors 103

6 Vial Processing —Accumulating, Conveying, Fillingand Stoppering the Most Common ParenteralContainer 105

Alan PetersonIntroduction 105Vial Infeed 107Vial Transport — Intermittent Versus Continuous Motion 110Overall Vial Transport Design 115Vial Handling — Neck Vs. Bottom 117Dosing Systems — Introduction 119Product Contact 120Filling Needles (Nozzles) 120Product Considerations 122Product Supply and Special Handling 123CIP/SIP 125Stoppering 125Quality Control 131Summary 133About the Author 133

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7 Checkweighing Fill Weight of Parenteral Productis the Heart of Process Quality 135

Alan PetersonIntroduction 135Precision and Accuracy of Fill Volumes — Definitions

and Statistical Analysis 136Checkweighing Methods 138Summary 144About the Author 144

8 Filling Methods as they Apply to ParenteralProduct Quality and Biopharmaceutical Microdosing 145

Alan PetersonIntroduction 145Time Pressure Filling 146Fill by Weight 149Mass Flow Filling 150Gravimetric Filling 153Peristaltic Pump Filling 156Piston Pumps 157Rolling Diaphragm Pump 161Microdosing 162Summary 165About the Author 165

9 Disposables — Single-Use Systems for Aseptic Processingand Filling Operations 167

Eric IsbergBackground 167Use in Dosing Systems 170Materials of Construction 176Usage Considerations 177Materials Testing 178Sterility 179About the Author 180

10 Parenteral Non-Vial Container Formats —Ampoules,Syringes, Cartridges, Opthalmics and IV Bags 181

Alan PetersonIntroduction 181

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Ampoules 182Syringes 183Bulk Glass Syringes 183Syringe Filling and Stoppering 187Cartridges 189Nested Syringe Processing 189Plastic Syringes 191Ophthalmics — Plastic Bottles Dominate 193IV Bags 195Summary 195About the Author 197

11 Application and Insights for Lyophilization ofParenteral Products 199

Edward H.TrapplerIntroduction 199Applications of Lyophilization in Sterile Product Processing 201Unique Requirements of Lyophilized Products 202Characteristics of Lyophilized Psarenterals 204Processing Steps 205Lyophilization Process Overview 205Freezing 207Primary Drying 209Secondary Drying 209Applications of Basic Principles 210Methods of Analysis 211Importance of the Phase Transition Temperature 211Examples of Freeze Drying Cycles 213Influences of Aseptic Process in Manufacturing 214Process Control Parameters 215Lyophilization Equipment 216References 228About the Author 229

12 Today’s Integration of the Lyophilizer —AutomatedLoading and Unloading 231

Ernesto RenziIntroduction 231History 233Modern Loading/Unloading Systems 238Flexible Loading Systems 239

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Fixed Loading System 243Freeze Dryers Designed for Loading Systems 250Shelves 250Freeze Dryer Chamber 252Hydraulic Stoppering System 253Equipment Layout 255Conclusion 258About the Author 259

13 Crimp Sealing ParenteralVials 261F.William Bogle, Roger P. Asselta and Lawrence Pepper

Determining Percent Compression of Rubber Stoppersand Correlation to RSF in Parenteral Vials 263

Jaw Type Sealing 265Spinning Roller Designs 267Sealing Rail Cappers 269Monitoring of Sealing Forces 269Capping Environments 270Alternatives 271References 272About the Authors 273

14 Inspection of Parenteral Products inVials,Ampoules,Syringes and Cartridges 275

Mike de la Montainge, Pedro J. Méndez and Ryosaku TagayaIntroduction 275Manual, Semi-Automated, and Automated Inspection Methods 276Comparing the Quality, Economy and Efficiency of

Inspection Methods 277Visual (Human) Inspection Systems 278Manual Inspection Systems 281Semi-automated Visual Inspection Systems 281Automated Inspection Systems 283Reflected Light (Camera-Based) Automated Inspection

Systems 283Transmitted Light (Static Division) Automated

Inspection Systems 284Static Division System Operation 287Static Divison Sensor 287Sensing Capabilities 288Conveyance of Containers 289

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Fill Level Check 290Camera-based Systems for Particulate and

Cosmetic Inspection 290Typical Areas of Inspection by Container Type 294Validation of Automated Inspection Systems 296Visual Observation Tool 300Summary 301References 302About the Authors 304

15 New Inspection Developments 305James Veale

Introduction 305Nondestructive Headspace Analysis 207Regulatory Issues and Perspective 309Laser Technology for Rapid and Nondestructive

Headspace Analysis 313Headspace Inspection Systems 321Aseptic Processing Applications 336Conclusion 369References 370About the Author 372

16 PracticalThings to Improve Aseptic ProcessEquipment System Operation, Reduce Interventionsand Reduce Product Risk 373

Jack LysfjordAbout the Author 386

17 Dealing with the Complexities of Control Systemsand Systems Integration 387

Terrance G. PetroIntroduction 387Description of the Isolated Fill Line 387Boundaries of the System 389Overall Scope Definition 390Requirements of the System 392Control Room Selection 392Synchronization of Equipment 393SCADA Communication 394

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Machine Specific Control Issues 395General Control Issues 396Conclusion 398About the Author 398

Index 401

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PREFACE

Irving J. Pflug

The manufacturing isolator, as it is used in 2009, is the culmination of perhaps, 60years of developments in the microbial control of the sterile productsmanufacturing environment.

Equipment developers Al Larson and Jack Lysfjord of TL Systems Corp.were forward-looking innovators, who in 1985 had a vision that they could installa manufacturing line in the already proven glove-box containment system.Working with Hans Melgaard of Despatch Industries Inc., an expert in HVAC andparticulate control in air systems, they developed a system where containers werefed from a washer and continuous sterilization–depyrogenation tunnel directlyinto a fill finish isolator system where high efficiency particulate air (HEPA)-filtered air was used to pressurize the system.

The microbiology quality of injectible pharmaceutical products produced inthe 1950s clean room was of continuous concern.

Knowledgeable operators recognized that the microbiological quality of theproducts produced in the 1950s clean room system was related to the humanoperators in the clean room — the human in the clean room was the source of thecontamination. Control measures were taken, starting with gowns, hair coveringsand masks, then a full bunny suit; however, the human was still in the clean room.

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The leap forward in control was moving the barrier from the operator to theproduction line. Instead of putting coverings (bunny suit) on the individual andtrying to contain the microorganisms within a bunny suit (to keep them fromescaping to contaminate the manufacturing area), the barrier was placed aroundthe production line with the human operator outside the enclosure or isolator. Thiswas a positive, controllable approach to solving the problem of the microorganismshed by the human operators from contaminating the product being packaged.

The availability of air, essentially free of microbial contamination, is acritical component of the isolator system. Today the development of the HEPAfilter, laminar/unidirectional flow clean room system is often taken for grantedand assumed by the young to have always existed. This system was developed withthe support of the National Aeronautical and Space Administration (NASA) forproducing higher levels of quality in intricate space vehicles (basis for theimportant original U.S. Federal Standard 209 which has recently been supersededby ISO 14644), and is one of the more import and recent technological advancesthat has helped the pharmaceutical industry in many ways. The HEPA filteredclean air is a critical part of the manufacturing isolator system.

The isolator itself will prevent microbial ingress, however, a method ofdecontaminating the isolator is a basic requirement of the manufacturing isolatorsystem. We have been able to sterilize biological material, media and hardware,primarily using saturated steam under pressure for 100 years. We have been usingethylene oxide (EO) for sterilization for 50 years. Neither of these agents is suitedfor the isolator. The isolator is a large enclosure, not readily suited for oneatmosphere of over pressure, and it requires human operators to work intimatelywith the system. Hydrogen peroxide (H2O2), an old chemical with many importantattributes, has become the sterilant of choice for the manufacturing isolatorsystem. We are surprised that, in recent years, it has not received very muchattention in the microbial-control area. The oxidizing capacity of H2O2 is so strongthat the chemical is considered a highly reactive oxygen species. It is usedextensively in the pulp and paper industry. The FDA has classified H2O2 a lowregulatory priority (LRP) drug. A 3% solution is sold as an over-the-counter drugand is used for cleaning wounds and as an oral debriding agent.

Hydrogen peroxide is used to decontaminate the manufacturing isolator in anair–H2O2 system or in an atmospheric steam–H2O2 system. In the atmosphericsteam–H2O2 system at 100.0°C, the kill of Geobacillus stearothermophilis sporesis faster than in saturated steam at 15 psi pressure and 121.1°C.

The pharmaceutical manufacturing isolator is an engineering system whichis capable of high production rates of products with both high quality level and ata unit cost not heretofore possible. As pharmaceutical products become more

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potent and more hazardous to healthy individuals, operators must be protectedfrom harmful agents. Isolators are one of the best engineering solutions forprotecting both the product and operator. This represents a giant leap forward fromthe manufacturing systems in use only 20 years ago.

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INTRODUCTION

Jack Lysfjord

The seed for this book was planted in September 2005 at the PDA/FDA meetingin Washington D.C. Amy Davis, publisher of this book, and I were discussing howaseptic processing had changed since the mid 1990s.

Regulations have certainly changed with ISO 14644 cleanroom standards,2004 FDA Aseptic Processing Guidelines, revision of Annex 1 of EU GMPs andInternational Council on Harmonization (ICH) working toward better globalalignment of regulatory issues between countries.

Aseptic processing technology had changed with the use of AdvancedAseptic Processing techniques, such as blow/fill/seal (BFS), isolators andRestricted Access Barrier Systems (RABS). I believe that the productcontamination rate can be improved from 1 contaminated unit out of 1,000 withconventional cleanroom processing to 1 out of 1,000,000 or even 1 out of10,000,000 with the proper use of these advanced aseptic processing techniques.Conventional cleanroom processing has an inherent risk of human operatorsshedding of particles with viable micro-organisms into the containers.

Validation philosophy has evolved with the 5th edition of Good AutomatedManufacturing Practices (GAMP 5). It is truly better understood today by industryas well as regulators. Process Analytical Technology (PAT), Quality by Design(QbD) with ICH Q8 (pharmaceutical development), Q9 (risk assessment) and Q10(quality systems) tying things together for a better controlled process.

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Products are changing with the increasing dominance of biologicals andbiotech products including vaccines. Several large, well establishedpharmaceutical companies (over 100 years old) have now declared themselves tobe “Biotech Companies”.

Today, more products are being produced that have a containmentrequirement, such as cytotoxics, to protect operators of process equipment andnurses who administer drugs to the patient.

Manufacturing of clinical trial material is a growing critical phase of asepticprocessing as is the compounding of sterile preparations.

The rate of change is increasing rapidly. I felt as a contribution to newcomersto the industry, the seasoned person in operations, engineering or quality,pharmacists and regulators, that this book would draw a line in the sand for 2009as to what is being done at this point in time. Current Good ManufacturingPractices (cGMP) are the current “state of the art”. We all need to stay on top of“what is current?”.

To limit the scope of this book, it will deal with manufacturing asepticproducts until the container is closed, inspected and can be placed into “in processinventory” under quarantine. It will not deal with the downstream operations thatinvolve “paper products” such as labeling, cartoning, casepacking etc.

I have worked hard to assemble a global group of authors for chapters thatare experts in their particular topic to share their knowledge with you. I hope thisinformation will be valuable for years to come.

Jack LysfjordLysfjord Consulting LLC

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ACKNOWLEDGEMENTS

I want to thank my bride of 41 years, Pat, for sharing our life’s journey togetherand putting up with my numerous travels and idiosyncrasies in corporate life andnow as an independent consultant officing at home.

I also want to thank these people who come to mind. Who were and arementors for life:

• Larry McGrath, with business, strategic vision, motivation, planning andweaving fun into work strengths

• Jerry Potter, with a “business nose”, sales skills and having fun whileworking philosophy

• Some of the TL Systems “Old Timers” from the good old days

– Alan Peterson, Terry Petro, Dale Enwiller, Steve Braunschweig, SteveSwanson, Mike Beel, Ted Jagger, Carl Larson and Fred Nungesser

• The godfather of microbiology, Irving J. Pflug, for his wisdom and knowledge

• The drivers for what became the BUGS and LUMs groups

– Irving J. Pflug, University of Minnesota, Allan Larson, president, TLSystems and Hans Melgaard, VP Technology, Despatch Industries

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• Bob Best, president, ISPE who took on the idea of barriers and isolators

• Two pharmacists who help me see through their eyes:

– Berthold Duethorn and Tom Jeatran

• Some of the regulators who helped advance the technology of asepticprocessing:

– Terry Munson, Ken Muhvich, Peter Cooney, Bob Sausville and RickFriedman

Life is a journey. Enjoy it! Live your Bliss!

Jack LysfjordMinnetonka, Minnesota, March 10, 2009

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DEDICATION

I dedicate this book to the patients of the world! Everyone has been, is or will bea patient. I hope the contents of the book will positively influence thegovernments, regulators and the pharmaceutical and related industries to producemore, better, safer and more cost effective products to help patients lead a fullproductive life.

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practical aseptic processing: fill and finish volume 1

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