A GUIDE FOR NEW FACILITIES VOLUME 3: STERILE MANUFACTURING FACILITIESEXECUTIVE SUMMARYJune 2000A DOCUMENT DEVELOPED IN PARTNERSHIP BY:2ISPE PHARMACEUTICAL ENGINEERING GUIDESTERILE MANUFACTURING FACILITIESFOREWORDAs noted in the Baseline® Guides, Volume 1, the pharmaceutical industry has experienced a ratcheting effect in the cost of new facilities. This increase in cost has been driven in part by uncertainty about the requirements for regulatory compliance. Some significant areas of concern are validation, particularly related to automation systems, and the trend to validate back to source utilities, architectural and HVAC. The absence of a consistent and widely accepted interpretation of regulatory requirements has led to one-upmanship. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing new products to market.In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA). That first discussion allowed for the creation of 12 facility engineering guides, now known as the Baseline® Pharmaceutical Engineering Guides. These guides are intended to assist pharmaceutical manufacturers in the design, construction and commissioning of facilities that comply with the requirements of the FDA. Volume 1, covering Bulk Pharmaceutical Chemicals (BPC), was published in June of 1996. This Guide, for Sterile Manufacturing facilities, is the third volume in the series.As with the BPC Guide, the Sterile Manufacturing Guide, has been sponsored by ISPE’s Pharmaceutical Advisory Council, made up of senior pharmaceutical engineering executives from owner companies, the FDA and ISPE senior management. Overall planning, direction and technical guidance in the preparation of the Sterile Manufacturing Guide was provided by a Steering Committee most of whom were involved in the BPC Guide. The Sterile Manufacturing Guide itself was produced by a task force of around 50 individuals who expended a great deal of their own time in its preparation and development.Editors’ Disclaimer:This guide is meant to assist pharmaceutical manufacturers in the design and construction of newfacilities that comply with the requirements of the Food and Drug Administration (FDA). TheInternational Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant,that a facility built in accordance with this guide will be acceptable to FDA.3ISPE PHARMACEUTICAL ENGINEERING GUIDESTERILE MANUFACTURING FACILITIESACKNOWLEDGMENTSISPE wishes to acknowledge the following for this outstanding effort:Timothy C. Tyson and Robert P. Best, who were responsible for establishing early discussions with FDA and assembling the most senior engineering executives in the industry.From FDA, Sharon Smith Holston (Deputy Commissioner for External Affairs), Jeanne Devers White (Director, Industry Affairs, Office of the Commissioner), Joseph Phillips (Deputy Regional Food and Drug Director, Mid-Atlantic Region) and Paul D’Eramo (Regional Drug Specialist, Mid-Atlantic Region) have been instrumental in establishing a close working relationship with industry during the entire process.The Steering Committee for their input an guidance in the creation of this Sterile Manufacturing Facilities Guide, the previously published Bulk Pharmaceutical Chemical (BPC) Guide, and the Guides which are currently being developed or still in the planning phase.The Membership of the ISPE which provided the critical mass of pharmaceutical industry professionals. Their desire to make a lasting contribution to the industry and to work with the FDA in a unique p artnership is the driving force behind these Guides.The Task Team for the many hours they spent in preparing this document. This effort required innovative thinking, a team approach and a desire to meet deadlines.4The following individuals took lead roles in the preparation of this document:Wesley Wheeler (Steering Committee Chair)Bruce Davis (Sterile Manufacturing Facilities Guide Team Leader)Giorgio de Castiglioni Pharmacia & UpjohnJim Durkin Jacobs EngineeringGordon Farquharson TanvecDennis Fortune Foster WheelerWilliam Huibregste Eli LillyJos Mathot OrganonDavid McLucas / Nick Walker Evans MedicalMichael Mulhall DPS EngineeringGlaxoWellcomeSimon Shelley / Andy Stamford-Smith / ChrisWoodGeert Vandenbossche AlconDimitrios Xilogiannis SandozGrateful thanks to Mel Crichton for his comments on drafts and for his support and encouragement.The Steering Committee and Task Team would like to acknowledge Sion Wyn and Gail Evans of Activa Systems Ltd. for their contribution as technical coordinators and editors.5TABLE OF CONTENTS1. INTRODUCTION.......................................................................................................1.1 BACKGROUND..........................................................................................................1.2 SCOPE OF THIS GUIDE.............................................................................................1.3 KEY FEATURES OF THIS GUIDE................................................................................2. CONCEPTS AND REGULATORY PHILOSOPHY..............................................2.1 PRODUCT REQUIREMENTS.......................................................................................2.2 CRITICAL PROCESS STEPS.......................................................................................2.3 PROTECTION OF THE PRODUCT................................................................................2.4 CROSS CONTAMINATION AND TOXIC PRODUCT ISSUES...........................................2.5 ASEPTIC PROCESSING AREA...................................................................................2.6 INTEGRATED FACILITY DESIGN.................................................................................2.7 TERMINOLOGY FOR MANUFACTURING AREAS AND HVAC.......................................2.8 BARRIER- ISOLATOR TECHNOLOGY..........................................................................2.9 OTHER CONSIDERATIONS.........................................................................................2.10 GOOD ENGINEERING PRACTICE, DIRECT IMPACT SYSTEMS AND INDIRECT IMPACT SYSTEMS.......................................................................................................................................3. PROCESS AND EQUIPMENT CONSIDERATIONS..........................................3.1 INTRODUCTION..........................................................................................................3.2 PROCESS DESCRIPTION...........................................................................................3.3 ALTERNATIVE TECHNOLOGIES.................................................................................3.4 EQUIPMENT INTEGRATION........................................................................................4. ARCHITECTURE AND LAYOUT...........................................................................4.1 INTRODUCTION..........................................................................................................4.2 DESIGN CRITERIA......................................................................................................4.3LAYOUT CONSIDERATIONS.......................................................................................4.4 ROOM FUNCTION......................................................................................................4.5 SURFACE FINISHES & MATERIALS OF CONSTRUCTION............................................4.6 TRANSFER ZONES....................................................................................................4.7 SUPPORT AREAS......................................................................................................5. HVAC...........................................................................................................................5.1 INTRODUCTION..........................................................................................................5.2 COST CONSIDERATIONS...........................................................................................5.3 SOURCES OF PARTICULATE CONTAMINATION..........................................................5.4 ENVIRONMENTAL STANDARDS AND GMP.................................................................5.5 MANUFACTURING LAYOUT AND HVAC PRINCIPLES..................................................5.6 INTEGRATION OF HVAC AND PROCESS EQUIPMENT................................................5.7 HVAC SYSTEM DESIGN.............................................................................................5.8 MONITORING.............................................................................................................65.9 CLEANING & MAINTENANCE OF HVAC SYSTEMS......................................................5.10 QUALIFICATION OF HVAC SYSTEMS........................................................................6. UTILITY SYSTEMS...................................................................................................6.1 INTRODUCTION..........................................................................................................6.2 DESCRIPTIONS..........................................................................................................6.3 SPECIFIC SERVICE CONSIDERATIONS......................................................................7. ELECTRICAL SERVICES.......................................................................................7.1 INTRODUCTION..........................................................................................................7.2 GENERAL REQUIREMENTS.......................................................................................7.3 POWER DISTRIBUTION..............................................................................................7.4 LIGHTING...................................................................................................................7.5 HAZARDOUS ENVIRONMENTS...................................................................................7.6 WIRING......................................................................................................................7.7 DOOR INTERLOCKS...................................................................................................7.8 OUTLETS AND MISCELLANEOUS EQUIPMENT...........................................................8. CONTROL & INSTRUMENTATION.......................................................................8.1 INTRODUCTION..........................................................................................................8.2 GMP CRITICAL ENVIRONMENTAL PARAMETERS.......................................................8.3 PRODUCTION PROCESS PARAMETERS....................................................................8.4 INSTRUMENTATION....................................................................................................8.5 ELECTRICAL INSTALLATION.......................................................................................8.6 GENERAL DESIGN ISSUES........................................................................................8.7 HVAC.........................................................................................................................9. CLEANING : ENGINEERING ISSUES..................................................................9.1 MANUAL CLEANING FOR EQUIPMENT AND FACILITY.................................................9.2 SEMI-AUTOMATIC CLEANING.....................................................................................10. BARRIER-ISOLATOR TECHNOLOGY...............................................................10.1 INTRODUCTION........................................................................................................10.2 BARRIER-ISOLATOR TYPE.......................................................................................10.3 EQUIPMENT DESIGN................................................................................................10.4 STERILIZATION CYCLE DEVELOPMENT....................................................................10.5 VAPOR AND MATERIAL COMPATIBILITY...................................................................10.6 ENVIRONMENTAL MONITORING...............................................................................10.7 BARRIER-ISOLATOR LEAK DETECTION...................................................................10.8 MAINTENANCE.........................................................................................................11. GENERAL CONSIDERATIONS...........................................................................11.1 INTRODUCTION........................................................................................................11.2 ENVIRONMENTAL - AIR............................................................................................11.3 ENVIRONMENTAL - WASTE WATER.........................................................................11.4 ENVIRONMENTAL NOISE.........................................................................................711.5 ENVIRONMENTAL - SOLID AND CONCENTRATED WASTES......................................11.6 HEALTH AND SAFETY..............................................................................................11.7 SITE SELECTION AND LOCATION.............................................................................11.8 ENERGY SOURCES.................................................................................................11.9 AUDITING, MONITORING AND REPORTING...............................................................11.10 SECURITY..............................................................................................................12. COMMISSIONING & QUALIFICATION...............................................................12.1 INTRODUCTION........................................................................................................12.2 QUALIFICATION OF HVAC SYSTEMS.......................................................................13. APPENDIX 1 - REFERENCES.............................................................................13.1 OVERVIEW OF THE STANDARDIZATION PROCESS..................................................13.2 STANDARDS............................................................................................................14. APPENDIX 2 - HVAC EUROPEAN CONSIDERATIONS................................14.1 INTRODUCTION........................................................................................................14.2 KEY DIFFERENCES TO US STANDARDS..................................................................15. APPENDIX 3 - HVAC - ADDITIONAL ENGINEERING INFORMATION.......15.1 INTRODUCTION........................................................................................................15.2 SOURCES OF PARTICULATE CONTAMINATION........................................................15.3 HVAC DESIGN PRINCIPLES.....................................................................................15.4 CALCULATION OF AIR CHANGE RATE......................................................................15.5 PROCESS IMPACT...................................................................................................15.6 HVAC SYSTEM DESIGN...........................................................................................15.7 AIR HANDLING UNIT (AHU) DESIGN CONSIDERATIONS.............................................15.8 HORIZONTAL VS VERTICAL UNIDIRECTIONAL AIR FLOW..........................................16. GLOSSARY (8)1. INTRODUCTION1.1 BACKGROUNDThe design, construction, commissioning and validation of pharmaceutical facilities are significant challenges for manufacturers, engineering professionals and equipment suppliers. In most cases, these facilities are required to meet GMP regulations while remaining in compliance with all other governing codes, laws and regulations.The cost of bringing these facilities on line has been rising, in many cases due to inconsistent interpretation of regulatory requirements. ISPE and engineering representatives from the pharmaceutical industry have entered into a partnership with the US Food and Drug Administration (FDA) to enhance understanding of Baseline cGMP requirements for facilities. This Guide is intended to offer a consistent interpretation, while still allowing a flexible and innovative approach to facility design, construction, commissioning and validation.This Guide was prepared by ISPE, with feedback from industry representatives from all areas and disciplines, and comments provided by FDA (CDER). It reflects current thinking related to engineering of new aseptic manufacturing facilities. Also, it is hoped that this Guide will help meet the standards that will be included in the revision of FDA’s 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing.It is recognized that industry standards evolve and this document reflects the understanding of them as of publication date.1.2 SCOPE OF THIS GUIDEThis is a Guide to be used by industry for the design, construction, commissioning and qualification of new aseptic/sterile manufacturing facilities. It is neither a standard nor a GMP regulation. It is not intended to replace governing laws, codes, guidelines, standards, or regulations that apply to facilities of this type. The use of this document for new or existing facilities is at the discretion of the facility owner or operator.The purpose of this Guide is to focus on engineering issues and how to provide cost effective facilities. Where non-engineering issues are covered (e.g. micro-biological topics, operational issues unrelated to the facility), the information is included to show engineers the importance of such topics, and the impact they have on facility design. Such non-engineering topics, therefore, are not covered comprehensively, and specific advice from QA departments should be sought where additional information is required.This Guide covers facilities for aseptic processing and terminal sterilization of formulated products, generally for parenteral use. It is applicable to formulations that use active ingredients devised from either conventional chemistry or biopharmaceutical processing. It is not applicable to bulk pharmaceutical chemicals, but some parts may be relevant for facilities that produce sterile bulks, for sterile manufacture at development scale, medical devices or other sterile products. It also should be noted that the purpose of the Guide is not to give guidance on production of clinical materials.This Guide is intended primarily for facilities that meet regulatory requirements in order to supply the United States (US) market, and follows US standards and references. The Guide also may be helpful to manufacturers that need to meet European requirements.1.3 KEY FEATURES OF THIS GUIDEThe following key concepts are defined and used as a basis for guidance:9• Product requirements• “GMP Critical Parameters” and “Critical Devices”• Terminal sterilization• Aseptic processing area• Protection of the product• Flow of people and materials• Integrated facility design• Barrier-isolator technology• Consistent HVAC terminology• HVAC principles• In operation condition for HVAC• Selection of materials and finishes• Good Engineering Practice• “Direct Impact Systems”• Enhanced documentation• “Indirect Impact Systems”Some brief explanation of these follow:The product requirement determines the fundamental requirements of the aseptic facility and, from these, the “Critical Parameters” can be determined. For example, terminal sterilization is recommended, but where the product is affected significantly by this particular process step, product requirements may take precedence, and other controlled methods of manufacturing may be used. This Guide seeks to make distinctions, where relevant, between aseptically processed products and those that are terminally sterilized.The aseptic processing area is the area where the product is formulated, filled into containers (usually vials, ampules, or pre-filled syringes) and sealed. Protection of the product and container/closures during these operations is critical, so the flow of people and materials must be controlled. In order to achieve this logical separation of clean and dirty operations, careful consideration of all features must be taken into account, to produce an integrated facility design. Barrier-isolator technology may be the chosen method of operation. This also will affect the design, and should be considered at an early stage.A number of available documents giv e information on aseptic facilities. Many of these use different terminology, particularly for environmental classifications (e.g. Class 100 in US, Grade A in Europe). This Guide references these, and explains the differences between these systems, and uses consistent HVAC terminology. The terms Class 100 etc., are in common use internationally. The FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987, also refers to these classifications. Therefore, it has been decided to use these terms throughout the main part of this Guide. A section on European requirements 10(Appendix 2) also has been included, as there are some differences between these and those used in the US.One of the most fundamental issues, in regard to facilities f or aseptic manufacture, are HVAC principles. In particular, engineers should understand that regulators are particularly interested in the environment during in operation conditions, as this is the time when the product may be exposed. HVAC design and clean area classifications should relate to this situation. Engineers should understand sources of particulate and microbial contamination, and the various ways that air quality can be maintained during manufacturing, for example, by filtration, cleanliness cascades, etc.Furthermore, the importance of avoiding cross-contamination is a key area that can influence HVAC design and engineers should understand its importance.Selection of materials and finishes also is an area where Baseline standards are applicable. Some finishes can be expensive, yet give no better GMP compliance than cheaper alternatives. Similarly, significant sums can be spent on instrumentation and control. From a product point of view, understanding the Critical Parameters and ensuring t h at these are in compliance is important, as they will relate directly to product quality.Finally, Good Engineering Practice should be applied to any facility to ensure that the most economic design solution is found, consistent with meeting manufacturing and quality needs. This Guide uses the term “Direct Impact System” for those engineering systems that have a direct effect on product quality; these should be supported by enhanced documentation. The Guide also uses the term “Indirect Impact Systems” for those engineering systems that do not have a direct impact on product quality. Further explanation of this is given in Chapter 12.An overview of the Chapter structure is given in Figure 1.1.Figure 1.1 Chapter Overview2. CONCEPTS AND REGULATORY PHILOSOPHYThis Chapter describes the regulatory philosophies which have been adopted for the Sterile Manufacturing Facilities Baseline® Guide. It explains terminology used throughout the Guide, and details the concepts including:• Critical Process Steps• Protection of the Product• Cross Contamination and Toxic Product Issues• Aseptic Processing Area• Integrated Facility Design• Terminology for Manufacturing Areas and HVAC• Barrier Isolation Technology• Good Engineering Practice, Direct Impact Systems, and Indirect Impact SystemsSterile products require rigorous control of potential contamination, which may take the form of particulates, microorganisms or endotoxins. The nature of aseptic processing is to minimize or eliminate potential sources of contamination. This Guide considers this and the means by which engineers can design out, or ensure control of, the risk.3. PROCESS AND EQUIPMENT CONSIDERATIONSThis chapter recommends baseline practices intended to apply to sterile processes, and inform facility designers of typical sterile product manufacturing schemes. It provides points for consideration both in selecting sterile processing equipment, and for consideration when integrating sterile processing equipment into the facility design.Each stage encountered in a typical process for both an aseptically processed product and a terminally sterilized product is described. Specific points for consideration in equipment selection and integration, including performance, functionality, construction, and instrumentation are tabulated.A model process flow adopted as the basis of this Chapter is that of a typical vial formulation, either terminally sterilized or aseptically processed. The designer may use this as the basis for design conditions for other presentations, e.g., ampules and syringes.Implications for the design and layout of the manufacturing facility resulting from Blow Fill Seal technology are considered. The final table in the chapter presents facility layout and services information, including air quality, layout, and services information, for each item of the main process equipment.4. ARCHITECTURE AND LAYOUTThe importance of integrated design, facility layout, architectural detailing, and finish requirements are addressed in this chapter. Guidance is given on key layout issues affecting building configuration, equipment layout, general operability and GMP.Layout planning is illustrated using a structured method, with typical drawings demonstrating the key issues of layout, material and personnel flows. Guidance is given on the selection, performance and architectural detailing of construction material and room finishes.Planning layouts to minimize the cost addresses issues such as external building shape, foundations, and internal layout. Additional layout issues, which are required to provide an appropriate working design, are also considered.Comparative costs of the most common types of floor, wall, and ceiling finishes are illustrated with the minimum acceptable standard indicated. Function, layout and impact on building fabric and finishes are discussed for both transfer zones and support areas.5. HVACHVAC systems represent a significant portion of the total cost of a sterile manufacturing facility. This Chapter discusses both capital and operating costs.Sources of particulate contamination, both internal to the sterile manufacturing facility and from external sources are discussed. The FDA Guideline (CDER June 1987), draft USP(1116) (Feb 1997), and EU Annex (1997) expectations for the different environments associated with sterile manufacturing standards are cross-referenced.The following issues are discussed in the context of sterile manufacturing:• Manufacturing Layout and HVAC Principles• Integration of HVAC and Process Equipment• HVAC System Design• Monitoring• Cleaning and Maintenance of HVAC Systems• Qualification (with reference to Chapter 12)6. UTILITY SYSTEMSUtility systems used in sterile manufacturing operations may be categorized as either Process Systems or Process Support Systems. These categories provi de the basis for determining the design, construction, commissioning, and documentation requirements of the system.For the purposes of the Chapter, Process Systems are considered ‘Direct Impact” systems, and Process Support Systems are considered ‘Indirect Impact’ Systems. This Chapter provides general guidance for。
