Disclaimer: This Guide is meant to assist pharmaceutical manufacturers in the design and construction of new and renovated

facilities that are required to comply with the requirements of the US Food and Drug Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this Guide will be acceptable to the FDA.

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ofthem,beliableforanydamagesofanykind,includingwithoutlimitationanyspecial,incidental,indirect,orconsequentialdamages,whetherornotadvisedofthepossibilityofsuchdamages,andonanytheoryofliabilitywhatsoever,arisingoutoforinconnectionwiththeuseofthisinformation.

© Copyright ISPE 2011. All rights reserved.

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ISBN 978-1-936379-15-5

Volume 3

Sterile ProductManufacturing

FacilitiesSecond Edition / September 2011

Page 2 ISPE Baseline® Guide: Sterile Product Manufacturing Facilities

Foreword Theglobalpharmaceuticalindustryandregulatorsarerespondingtothechallengeofsignificantlyimprovingtheway

drug development and manufacturing is managed. New concepts are being developed and applied including science-based risk management approaches, a focus on product and process understanding, and modern Quality Systems.

Uncertainty about the requirements for regulatory compliance may discourage innovation and technological advancement, and can drive up costs. ISPE Guides aim to describe current good practices that can help a company todevelopanapproachthatiseffective,cost-efficient,andincompliancewithexistingregulationsandrelatedguidance. We thank the FDA for their review and comments to this Guide.

ISPE seeks close involvement of international regulators, including the US FDA, in the development of the ISPE Guides, which cover many important aspects of pharmaceutical development and manufacturing. These Guides are excellentexamplesofhowtheISPE,regulators,andindustrycanworkco-operativelyforpublicbenefit.

The Guides are solely created and owned by ISPE. They are not regulations, standards, or regulatory guideline documents, and facilities built in conformance with the Guides may or may not meet FDA or other regulatory requirements.

A continued working relationship between ISPE and international regulators will be fruitful for regulators, industry, and most importantly for public health.

ISPE Baseline® Guide: Page 3Sterile Product Manufacturing Facilities

Acknowledgements This Guide was developed by an integrated US-European team under the leadership of Bruce Davis of Bruce Davis

Global Consulting.

Chapter Writers and Reviewers

The following individuals took lead roles in the preparation of this document and the co-leaders of this Guide recognizetheseparticipants,whowentaboveandbeyondexpectationstomeetdeadlinesandkeeptheeffortontrack.ThecompanyaffiliationsareasofthefinaldraftoftheGuide.

Jeff Biskup CRB Consulting Engineers, Inc. USA Mel Crichton Eli Lilly & Company (retired) USA Bruce Davis Bruce Davis Global Consulting United Kingdom Gordon Farquharson Critical Systems Ltd. United Kingdom Russell Madsen The Williamsburg Group, LLC USA Mark Von Stwolinski CRB Consulting Engineers, Inc. USA

SpecialthankstoIanSymonds,GlaxoSmithKline,andrepresentativesofAstraZeneca,Sweden,whocontributedtothis document. Thanks also to Jim Agalloco, Agalloco and Associates, for his contributions to Table 9.1 and to many other individuals, including those from the ISPE Community of Practice, who provided topics and comments prior to, and during, the writing of this Guide; although they are too numerous to list here, their input is greatly appreciated.

FDA Reviewers

We would like to thank the following FDA representatives for providing comments on this Guide:

KristenEvans,FDAInvestigator/CDERComplianceOfficer,retiredandnowemployedbyAmgen,USA Richard Friedman, Director, CDER/OC/DMPQ/FDA, USA Diane Raccasi, Microbiologist, CDER/OC/DMPQ/FDA, USA BrendaUratani,ConsumerSafetyOfficer,CDER/OC/DMPQ/FDA,USA

The Sterile Task Team would like to thank ISPE for technical writing and editing support by Gail Evans (ISPE Guidance Documents Writer/Editor) and Sion Wyn (ISPE Technical Consultant). Thanks are also given for support provided by Russell Madsen (ISPE Senior Guidance Documents Advisor) in reviewing the Guide, and as a member of the Task Team.

Coverphoto:CourtesyofCentocorR&D,www.janssenbiotech.com.

ISPE Headquarters600 N. Westshore Blvd., Suite 900, Tampa, Florida 33609 USA

Tel:+1-813-960-2105,Fax:+1-813-264-2816

ISPE Asia Pacific Office20 Bendemeer Road, #04-02 Cyberhub, Singapore 339914

Tel:+65-6496-5502,Fax:+65-6496-5599

ISPE China OfficeSuite 2302, Wise Logic International Center

No. 66 North Shan Xi Road, Shanghai, China 200041 Tel+86-21-5108-1512,Fax+86-21-5116-0260

ISPE European OfficeAvenue de Tervueren, 300, B-1150 Brussels, Belgium

Tel:+32-2-743-4422,Fax:+32-2-743-1550

www.ISPE.org

ISPE Baseline® Guide: Page 5Sterile Product Manufacturing Facilities

Table of Contents 1 Introduction ......................................................................................................................... 9 1.1 Background .................................................................................................................................................. 9 1.2 Scope of this Guide...................................................................................................................................... 9 1.3 Key Features of this Guide ........................................................................................................................ 11 1.4 Terminology Used in this Guide ................................................................................................................. 14

2 Concepts, Regulatory and Manufacturing Philosophy ................................................. 15 2.1 Updated Guidance ..................................................................................................................................... 15 2.2 Product Requirements and Risk Assessment ............................................................................................ 16 2.3 Critical Process Steps ................................................................................................................................ 18 2.4 Protection of the Product and Avoidance of Contamination ....................................................................... 19 2.5 Hazard/Risk and Operator Protection ........................................................................................................ 22 2.6 Environmental Contamination Control Approaches ................................................................................... 22 2.7 Categories of Sterile Product Processing .................................................................................................. 22 2.8 Open and Closed Processing .................................................................................................................... 24 2.9 Integrated Facility Design .......................................................................................................................... 26 2.10 Terminology for Manufacturing Areas and HVAC ....................................................................................... 27 2.11 Other Considerations ................................................................................................................................. 32 2.12 Terminology Used in this Guide ................................................................................................................. 32

3 Process Equipment Considerations ............................................................................... 35 3.1 Introduction ................................................................................................................................................ 35 3.2 Process Description ................................................................................................................................... 36 3.3 Equipment Integration ................................................................................................................................ 58

4 Architecture and Layout................................................................................................... 67 4.1 Introduction ................................................................................................................................................ 67 4.2 General Design Criteria ............................................................................................................................. 71 4.3 Layout Considerations ............................................................................................................................... 73 4.4 Room Function ........................................................................................................................................... 78 4.5 Surface Finishes and Materials of Construction ........................................................................................ 78 4.6 TransferZones ........................................................................................................................................... 84 4.7 Support Areas ............................................................................................................................................ 84 4.8 Concept Diagrams ..................................................................................................................................... 85

5 Heating, Ventilation, and Air Conditioning (HVAC) ........................................................ 89 5.1 Introduction ................................................................................................................................................ 89 5.2 Cost Considerations................................................................................................................................... 91 5.3 Sources of Particle Contamination............................................................................................................. 92 5.4 Environmental Requirements..................................................................................................................... 94 5.5 Environmental Critical Parameters ............................................................................................................ 95 5.6 Risk Assessment ........................................................................................................................................ 97 5.7 Facility Layout and HVAC Design .............................................................................................................. 97 5.8 Process Knowledge and HVAC Design ................................................................................................... 102 5.9 Monitoring ................................................................................................................................................ 105 5.10 QualificationsofHVACSystems .............................................................................................................. 109 5.11 Cleaning and Maintenance of HVAC Systems ......................................................................................... 110

Page 6 ISPE Baseline® Guide: Sterile Product Manufacturing Facilities

6 Utility Systems .................................................................................................................113 6.1 Introduction .............................................................................................................................................. 113 6.2 Descriptions ............................................................................................................................................. 113 6.3 SpecificServiceConsiderations .............................................................................................................. 115

7 Electrical Services ...........................................................................................................119 7.1 Introduction .............................................................................................................................................. 119 7.2 General Requirements ............................................................................................................................. 119 7.3 Power Distribution .................................................................................................................................... 120 7.4 Lighting .................................................................................................................................................... 120 7.5 Hazardous Environments......................................................................................................................... 121 7.6 Wiring ....................................................................................................................................................... 121 7.7 Door Interlocks ......................................................................................................................................... 121 7.8 Outlets and Miscellaneous Equipment..................................................................................................... 121

8 Control and Instrumentation.......................................................................................... 123 8.1 Introduction .............................................................................................................................................. 123 8.2 Critical Process Parameters – Environmental ......................................................................................... 123 8.3 Production Process Parameters .............................................................................................................. 126 8.4 Instrumentation ........................................................................................................................................ 127 8.5 Electrical Installation ................................................................................................................................ 129 8.6 General Design Issues............................................................................................................................. 129 8.7 HVAC ....................................................................................................................................................... 129

9 Barrier and Isolator Technology .................................................................................... 133 9.1 Introduction .............................................................................................................................................. 133 9.2 SystemDefinitions ................................................................................................................................... 133 9.3 Equipment Design.................................................................................................................................... 143 9.4 Decontamination Cycle Development (Isolators) ..................................................................................... 146 9.5 High-Level Disinfection (RABS and other Barrier Designs) ..................................................................... 148 9.6 Environmental Monitoring ........................................................................................................................ 148 9.7 Leak Detection (Isolators) ........................................................................................................................ 149 9.8 Air System Testing ................................................................................................................................... 150 9.9 Maintenance ............................................................................................................................................ 151

10 General Considerations ................................................................................................. 153 10.1 Introduction .............................................................................................................................................. 153 10.2 Environmental – General ......................................................................................................................... 153 10.3 Environmental – Waste Water ................................................................................................................. 154 10.4 Environmental Noise ................................................................................................................................ 155 10.5 Environmental – Solid and Concentrated Wastes ................................................................................... 155 10.6 Health and Safety .................................................................................................................................... 156 10.7 Site Selection and Location ..................................................................................................................... 158 10.8 Energy Sources ....................................................................................................................................... 158 10.9 Auditing, Monitoring, and Reporting......................................................................................................... 159 10.10 Security .................................................................................................................................................... 160

ISPE Baseline® Guide: Page 7Sterile Product Manufacturing Facilities

11 Appendix 1 – HVAC: Additional Engineering Information .......................................... 163 11.1 Introduction .............................................................................................................................................. 163 11.2 Sources of Particulate Contamination...................................................................................................... 163 11.3 HVAC Design Principles .......................................................................................................................... 165 11.4 Calculation of Air Change Rate ................................................................................................................ 167 11.5 Process Knowledge ................................................................................................................................. 168 11.6 HVAC System Design .............................................................................................................................. 171 11.7 Air Handling Unit (AHU) Design Considerations ...................................................................................... 176 11.8 HorizontalversusVerticalUnidirectionalAirflow(UAF) ........................................................................... 177 11.9 HVAC Risk Assessment ........................................................................................................................... 179 11.10 Other HVAC Considerations .................................................................................................................... 181

12 Appendix 2 – Science-Based Quality Risk Management ............................................ 183 12.1 ICH Q9 Quality Risk Management Approach........................................................................................... 183 12.2 Overview of the Quality Risk Management Process ................................................................................ 184 12.3 Initiating Quality Risk Management ......................................................................................................... 185 12.4 Risk Assessment ...................................................................................................................................... 185 12.5 Risk Control ............................................................................................................................................. 186 12.6 Risk Communication ................................................................................................................................ 187 12.7 Risk Review ............................................................................................................................................. 187 12.8 Quality Risk Management Tools .............................................................................................................. 187

13 Appendix 3 – References ............................................................................................... 189

14 Appendix 4 – Glossary ................................................................................................... 191 14.1 Acronyms and Abbreviations ................................................................................................................... 191 14.2 Definitions ................................................................................................................................................ 192

1 Introduction

ISPE Baseline® Guide: Page 9Sterile Product Manufacturing Facilities Introduction

1 Introduction1.1 Background

Thedesign,construction,commissioning,andqualificationofpharmaceuticalfacilitiespresentsignificantchallengestomanufacturers,engineeringprofessionals,andequipmentsuppliers.ThesefacilitiesarerequiredtomeetGMPregulationswhileremainingincompliancewithothergoverningcodes,laws,andregulations.

Lackofunderstandingofregulatoryrequirementsmaycauseinvestmentandoperationalcoststoescalate.ThisGuideisintendedtoofferaconsistentinterpretation,whileallowingaflexibleandinnovativeapproachtofacilitydesign,construction,commissioning,andqualification.

ThisGuidewaspreparedbyISPEanditreflectsISPE’scurrentthinkingrelatedtoengineeringofnewsterileproductmanufacturingfacilities.IttakesintoaccounttheFDA’s“GMPsforthe21stCentury”andtheFDASeptember2004“GuidanceforIndustry:SterileDrugProductsProducedbyAsepticProcessing–CurrentGoodManufacturingPractice”(whichsupersedesthe1987GuidelineonSterileDrugProductsProducedbyAsepticProcessing).ItalsoreferstoAnnex1oftheEuropeanUnionGMPs,whichwaslastupdatedinFebruary2008.AnothersignificantchangesincetheoriginalISPESterileGuidewaspublished,isthatISO14644-1:1999“ClassificationofAirCleanliness”hasreplacedUSFederalStandard209E:1992“AirborneParticulateCleanlinessClassesinCleanroomsandCleanZones.”Thereaderalsoshouldbeawarethatthereareotherstandardsandguidanceavailableinthissubjectarea,suchasISO13408-1:11998“AsepticProcessingofHealthcareProducts”(References5,7,9,and11,Appendix3).

ThisGuideisbasedfundamentallyontheUSrequirements,butmuchofitappliesinternationally.

Itisrecognizedthatindustrystandardsevolveandthisdocumentreflectsanunderstandingofthemasofpublicationdate.

1.2 Scope of this Guide

ThisGuidemaybeusedbyindustryforthedesign,construction,commissioning,andqualificationofsterileproductsmanufacturingfacilities.ItisneitherastandardnoraGMPregulation.Itisnotintendedtoreplacegoverninglaws,codes,guidelines,standards,orregulationsthatapplytofacilitiesofthistype.Theuseofthisdocumentforneworexistingfacilitiesisatthediscretionofthefacilityowneroroperator.

ThepurposeofthisGuideistofocusonfacilityengineeringissuesandhowtoprovidecosteffectivefacilitieswhichmakebestuseofavailablemoderntechnologiestoensurethatproductsofthehighestqualityareconsistentlymanufactured.Wherenon-engineeringissuesarecovered(e.g.,microbiologicaltopics,operationalissuesunrelatedtothefacility),theinformationisincludedtoshowengineerstheimportanceofsuchtopics,andtheimpacttheyhaveonfacilitydesign.Suchnon-engineeringtopics,therefore,arenotcoveredcomprehensively,andspecificadvicefromQAdepartmentsshouldbesoughtwhereadditionalinformationisrequired.

ThisGuidecoversfacilitiesforasepticprocessingandterminalsterilizationofAPIsandformulatedproducts,generallyforparenteraluse.ItisapplicabletoformulationsthatuseAPIsdevisedfromeitherconventionalchemistryorbiopharmaceuticalprocessing.

ThisGuideisfocusedoncommercialscalemedicinalsterileproduction.Itdoesnotcovermedicaldevices.ItdoescoverthefacilityaspectsofsterileAPIsbutitdoesnotcovertheprocessandequipmentaspectsofsterileAPIs,detailsofwhicharecoveredintheupdatedISPEBaseline®GuideonActivePharmaceuticalIngredients(BulkPharmaceuticalChemicals)(Reference12,Appendix3).Notethatmanyaspectsoftheguidancecontainedinthisdocument(e.g.,environmentalandengineeringmatters)maybeapplicabletothemanufactureofclinicalsuppliesorInvestigationalMedicinalProducts(IMPs)andtosterilemedicaldevicesandsteriledrug/devicecombinations.