1、Designation: E2500 13Standard Guide forSpecification, Design, and Verification of Pharmaceuticaland Biopharmaceutical Manufacturing Systems andEquipment1This standard is issued under the fixed designation E2500; the number immediately following the designation indicates the year oforiginal adoption
2、or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide is applicable to all elements of pharmaceu-tical and biopharmaceut
3、ical manufacturing systems including:facility equipment, process equipment, supporting utilities,associated process monitoring and control systems, and auto-mation systems that have the potential to affect product qualityand patient safety.1.2 For brevity, these are referred to throughout the rest o
4、fthis guide as manufacturing systems.1.3 This guide may also be applied to laboratory,information, and medical device manufacturing systems.1.4 This guide is applicable to both new and existingmanufacturing systems. The approach may be used for theimplementation of changes to existing systems, and t
5、heircontinuous improvement during operation.1.5 This guide is applicable throughout the life-cycle of themanufacturing system from concept to retirement.1.6 This standard does not address employee health andsafety, environmental, or other non-GxP regulations. Thisstandard does not purport to address
6、 all of the safety concerns,if any, associated with its use. It is the responsibility of the userof this standard to establish appropriate safety and healthpractices and determine the applicability of regulatory limita-tions prior to use.2. Referenced Documents2.1 ASTM Standards:2E2363 Terminology R
7、elating to Process Analytical Technol-ogy in the Pharmaceutical IndustryE2474 Practice for Pharmaceutical Process Design UtilizingProcess Analytical TechnologyE2475 Guide for Process Understanding Related to Pharma-ceutical Manufacture and ControlE2476 Guide for Risk Assessment and Risk Control as i
8、tImpacts the Design, Development, and Operation of PATProcesses for Pharmaceutical ManufactureE2537 Guide for Application of Continuous Quality Verifi-cation to Pharmaceutical and Biopharmaceutical Manu-facturingE2629 Guide for Verification of Process Analytical Technol-ogy (PAT) Enabled Control Sys
9、tems2.2 Other Publications:FDA Guidance for Industry Process Validation: GeneralPrinciples and Practices3ICH Q8 Pharmaceutical Development4ICH Q9 Quality Risk Management4ICH Q10 Pharmaceutical Quality System4ICH Q11 Development and Manufacture of Drug Substances(Chemical Entities and Biotechnologica
10、l/Biological Enti-ties)4Pharmaceutical cGMPs for the 21st Century A Risk-Based Approach33. Terminology3.1 DefinitionsFor definitions of terms used in this guide,refer to Terminology E2363.3.1.1 acceptance criteriathe criteria that a system orcomponent must satisfy in order to be accepted by a user o
11、rother authorized entity.3.1.2 design reviewsplanned and systematic reviews ofspecifications, design, and design development and continuousimprovement changes performed as appropriate throughout the1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products a
12、nd is the direct responsibility of Subcommittee E55.03on General Pharmaceutical Standards.Current edition approved Nov. 1, 2013. Published November 2013. Originallyapproved in 2007. Last previous edition approved in 2012 as E2500 07 (2012).DOI: 10.1520/E2500-13.2For referenced ASTM standards, visit
13、the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,Rockville, MD 20857, http:/www
14、.fda.gov.4Available from International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH), ICHSecretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.Copyright ASTM International, 100 Barr Harb
15、or Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1life-cycle of the manufacturing system. Design reviews evalu-ate deliverables against standards and requirements, identifyproblems, and propose required corrective actions.3.1.3 manufacturing systemselements of pharmaceuticaland
16、biopharmaceutical manufacturing capability, includingmanufacturing systems, facility equipment, process equipment,supporting utilities, associated process monitoring and controlsystems, and automation systems, that have the potential toaffect product quality and patient safety.3.1.4 subject matter e
17、xperts (SMEs)individuals with spe-cific expertise and responsibility in a particular area or field(for example, quality unit, engineering, automation,development, operations, and so forth).3.1.5 verificationa systematic approach to verify thatmanufacturing systems, acting singly or in combination, a
18、re fitfor intended use, have been properly installed, and are operat-ing correctly. This is an umbrella term that encompasses alltypes of approaches to assuring systems are fit for use such asqualification, commissioning and qualification, verification,system validation, or other.4. Summary of Guide
19、4.1 This guide describes a risk-based and science-basedapproach to the specification, design, and verification ofmanufacturing systems and equipment that have the potentialto affect product quality and patient safety.4.2 This guide describes a systematic, efficient, and effec-tive way of ensuring th
20、at manufacturing systems and equip-ment are fit for intended use, and that risk to product quality,and consequently to patient safety, are effectively managed tothe extent that these are affected by such systems and equip-ment.4.3 The overall objective is to provide manufacturing capa-bility to supp
21、ort defined and controlled processes that canconsistently produce product meeting defined quality require-ments.4.4 The approach described within this guide also supportscontinuous process capability improvements and enables inno-vation such as the implementation of Process AnalyticalTechnology (PAT
22、).4.5 The main elements of this guide are:4.5.1 The underlying key concepts that should be applied,4.5.2 A description of the specification, design, and verifi-cation process, and4.5.3 A description of the required supporting processes.5. Significance and Use5.1 Application of the approach described
23、 within this guideis intended to satisfy international regulatory expectations inensuring that manufacturing systems and equipment are fit forintended use, and to satisfy requirements for design,installation, operation, and performance.5.2 The approach described in this guide applies conceptsand pri
24、nciples introduced in the FDA initiative, Pharmaceuti-cal cGMPs for the 21st CenturyA Risk-Based Approach.5.3 This guide supports, and is consistent with, the frame-work described in ICH Q8, ICH Q9, ICH Q10, and ICH Q11.5.4 This guide may be used independently or in conjunctionwith other E55 standar
25、ds published by ASTM International.6. Key Concepts6.1 This guide applies the following key concepts:Risk-based ApproachScience-based ApproachCritical Aspects of Manufacturing SystemsQuality by DesignGood Engineering PracticeSubject Matter ExpertUse of Vendor DocumentationContinuous Process Improveme
26、nt6.2 Risk-based Approach:6.2.1 Risk management should underpin the specification,design, and verification process, and be applied appropriatelyat each stage.6.2.2 Two primary principles of quality risk managementare identified in ICH Q9:6.2.2.1 The evaluation of the risk to quality should be basedo
27、n scientific knowledge and ultimately link to the protection ofthe patient.6.2.2.2 The level of effort, formality and documentation ofthe quality risk management process should be commensuratewith the level of risk.6.2.3 These principles should be applied to specification,design, and verification of
28、 manufacturing systems.6.2.4 The scope and extent of quality risk management forspecification, design, and verification activities and documen-tation should be based on the risk to product quality and patientsafety.6.3 Science-based Approach:6.3.1 Product and process information, as it relates topro
29、duct quality and patient safety, should be used as the basisfor making science- and risk-based decisions that ensure thatthe manufacturing systems are designed and verified to be fitfor their intended use.6.3.2 Examples of product and process information toconsider include: critical quality attribut
30、es (CQAs), criticalprocess parameters (CPPs), process control strategyinformation, and prior production experience.6.4 Critical Aspects of Manufacturing Systems:6.4.1 Critical aspects of manufacturing systems are typi-cally functions, features, abilities, and performance or charac-teristics necessar
31、y for the manufacturing process and systemsto ensure consistent product quality and patient safety. Theyshould be identified and documented based on scientificproduct and process understanding.6.4.2 For brevity, these are referred to throughout the rest ofthis guide as critical aspects.6.4.3 Verific
32、ation activities should focus on these aspects ofmanufacturing systems and should be documented. The veri-fication process is defined in 7.4.6.5 Quality by Design:6.5.1 Quality by design concepts should be applied toensure that critical aspects are designed into systems during theE2500 132specificat
33、ion and design process. The critical aspects of thedesign and associated acceptance criteria should be docu-mented.6.5.2 Assurance that manufacturing systems are fit forintended use should not rely solely upon verification afterinstallation, but be achieved by a planned and structuredverification ap
34、proach applied throughout the system life cycle.6.6 Good Engineering Practice:6.6.1 Good Engineering Practice (GEP) should underpinand support the specification, design, and verification activi-ties.6.6.2 Good Engineering Practice is defined as those estab-lished engineering methods and standards th
35、at are appliedthroughout the life cycle to deliver appropriate and effectivesolutions.6.6.3 Examples of Good Engineering Practices include:6.6.3.1 Specification, design, and installation activitiesshould take full account of all applicable requirements, includ-ing GxP, safety, health, environmental,
36、 ergonomic, operational,maintenance, recognized industry standards, and other statu-tory requirements.6.6.3.2 Adequate provisions related to quality should beincluded in specification, design, procurement, and other con-tractual documents.6.6.3.3 Life-cycle documentation covering planning,specificat
37、ion, design, verification, installation, acceptance, andmaintenance should be produced.6.6.3.4 An appropriate degree of oversight and controlshould be achieved by suitable verification of execution,construction and installation activities.6.7 Subject Matter Experts:6.7.1 Subject matter experts are d
38、efined as those individualswith specific expertise and responsibility in a particular area orfield (for example, quality unit, engineering, automation,development, operations, and so forth).6.7.2 Subject matter experts should take the lead role in theverification of manufacturing systems as appropri
39、ate withintheir area of expertise and responsibility.6.7.3 Subject matter expert responsibilities include planningand defining verification strategies, defining acceptancecriteria, selection of appropriate test methods, execution ofverification tests, and reviewing results.6.8 Use of Vendor Document
40、ation:6.8.1 Vendor documentation, including test documents maybe used as part of the verification documentation, providing theregulated company has assessed the vendor, and has evidenceof:6.8.1.1 An acceptable vendor quality system,6.8.1.2 Vendor technical capability, and6.8.1.3 Vendor application o
41、f GEP such that informationobtained from the vendor will be accurate and suitable to meetthe purpose of verification.6.8.2 If inadequacies are found in the vendor quality system,technical capability, or application of GEP, then the regulatedcompany may choose to mitigate potential risks by applyings
42、pecific, targeted, additional verification checks or other con-trols rather than repeating vendor activities and replicatingvendor documentation.6.8.3 The decision and justification to use vendordocumentation, to support the verification of critical aspects ofthe manufacturing element, should be bas
43、ed on the intendeduse of the manufacturing system, and should be documentedand approved by subject matter experts including the qualityunit.6.9 Continuous Improvement:6.9.1 As experience is gained in commercial production,opportunities for improvements should be sought based onperiodic review and ev
44、aluation, operational and performancedata, and root-cause analysis of failures.6.9.2 Change management should provide a dependablemechanism for prompt implementation of technically soundimprovements following the approach to specification, design,and verification described in this guide.7. Process7.
45、1 OverviewThe process of specification, design, andverification of manufacturing systems should include thefollowing activities:Requirements definitionSpecification and designVerificationAcceptance and release7.1.1 Good Engineering Practice should be applied through-out the process.7.1.2 Risk manage
46、ment should be performed as appropriateto evaluate the risks to product quality and patient safetyrelated to the manufacturing system and corresponding designsolution. Risk management is a supporting process and isdefined in 8.2.7.1.3 Design reviews should be performed as appropriatethroughout the l
47、ife-cycle of the manufacturing system. Thedesign review process is a supporting process and is defined in8.3.7.1.4 Change management should be applied throughout theprocess. The change management process is a supportingprocess and is defined in 8.4.7.2 Requirements Definition:7.2.1 Specific requirem
48、ents should be identified and shouldprovide the basis of further specification, design, and verifica-tion of the manufacturing system.7.2.2 These specific requirements relative to product qualityand patient safety should be based upon:7.2.2.1 Product knowledge and understanding,7.2.2.2 Process knowl
49、edge and understanding,7.2.2.3 Regulatory requirements, and7.2.2.4 Company quality requirements.7.2.3 Product and process knowledge and understanding,including knowledge of sources of variability in the productand process, the identification of critical quality attributes, andprocess control strategy information, should be based onscientific data gathered during experimental and developmentwork and manufacturing experience. Product and processknowledge forms the basis of scientific understanding asdescribed in ICH Q8, ICH Q11, and Guide E2475.E2500 1337.3 Specification
