1、Designation: E2500 07 (Reapproved 2012)Standard 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 of
2、original adoption 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
3、 and biopharmaceutical 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 thr
4、oughout the rest ofthis 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 exist
5、ing systems, and theircontinuous 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
6、purport to address 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:2E
7、2363 Terminology Relating to Process Analytical Technol-ogy in the Pharmaceutical Industry2.2 Other Publications:ICH Q8 Pharmaceutical Development Handbook3ICH Q9 Quality Risk Handbook3Pharmaceutical cGMPs for the 21st Century A Risk-Based Approach43. Terminology3.1 DefinitionsFor definitions of ter
8、ms 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 orother authorized entity.3.1.2 design reviewsplanned and systematic reviews ofspecifications, design, and design development and continuous
9、improvement changes performed as appropriate throughout thelife-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 biopharmaceu
10、tical 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 experts (SMEs
11、)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, are fitfor in
12、tended 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 as1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products and is the direct r
13、esponsibility of Subcommittee E55.03on General Pharmaceutical Standards.Current edition approved Oct. 15, 2012. Published November 2012. Originallyapproved in 2007. Last previous edition approved in 2007 as E2500 07. DOI:10.1520/E2500-07R12.2For referenced ASTM standards, visit the ASTM website, www
14、.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 International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals f
15、or Human Use (ICH), ICHSecretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.4Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,Rockville, MD 20857, http:/www.fda.gov.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700
16、, West Conshohocken, PA 19428-2959. United States1qualification, commissioning and qualification, verification,system validation, or other.4. Summary of Guide4.1 This guide describes a risk-based and science-basedapproach to the specification, design, and verification ofmanufacturing systems and equ
17、ipment that have the potentialto affect product quality and patient safety.4.2 This guide describes a systematic, efficient, and effec-tive way of ensuring that manufacturing systems and equip-ment are fit for intended use, and that risk to product quality,and consequently to patient safety, are eff
18、ectively 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 support defined and controlled processes that canconsistently produce product meeting defined quality require-ments.4.4 The approach described wit
19、hin this guide also supportscontinuous process capability improvements and enables inno-vation such as the implementation of Process AnalyticalTechnology (PAT).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, d
20、esign, and verifi-cation process, and4.5.3 A description of the required supporting processes.5. Significance and Use5.1 Application of the approach described within this guideis intended to satisfy international regulatory expectations inensuring that manufacturing systems and equipment are fit for
21、intended use, and to satisfy requirements for design,installation, operation, and performance.5.2 The approach described in this guide applies conceptsand principles introduced in the FDA initiative, Pharmaceuti-cal cGMPs for the 21st CenturyA Risk-Based Approach.5.3 This guide supports, and is cons
22、istent with, the frame-work described in ICH Q8 and ICH Q9.5.4 This guide may be used independently or in conjunctionwith other proposed E55 standards to be published by ASTMInternational.6. Key Concepts6.1 This guide applies the following key concepts:Risk-based ApproachScience-based ApproachCritic
23、al Aspects of Manufacturing SystemsQuality by DesignGood Engineering PracticeSubject Matter ExpertUse of Vendor DocumentationContinuous Process Improvement6.2 Risk-based Approach:6.2.1 Risk management should underpin the specification,design, and verification process, and be applied appropriatelyat
24、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 basedon scientific knowledge and ultimately link to the protection ofthe patient.6.2.2.2 The level of effort, formality and documentation ofthe quality r
25、isk management process should be commensuratewith the level of risk.6.2.3 These principles should be applied to specification,design, and verification of manufacturing systems.6.2.4 The scope and extent of quality risk management forspecification, design, and verification activities and documen-tati
26、on 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 toproduct quality and patient safety, should be used as the basisfor making science- and risk-based decisions that ensure thatthe manufacturing systems
27、are designed and verified to be fitfor their intended use.6.3.2 Examples of product and process information toconsider include: critical quality attributes (CQAs), criticalprocess parameters (CPPs), process control strategyinformation, and prior production experience.6.4 Critical Aspects of Manufact
28、uring Systems:6.4.1 Critical aspects of manufacturing systems are typi-cally functions, features, abilities, and performance or charac-teristics necessary for the manufacturing process and systemsto ensure consistent product quality and patient safety. Theyshould be identified and documented based o
29、n scientificproduct and process understanding.6.4.2 For brevity, these are referred to throughout the rest ofthis guide as critical aspects.6.4.3 Verification activities should focus on these aspects ofmanufacturing systems and should be documented. The veri-fication process is defined in 7.4.6.5 Qu
30、ality by Design:6.5.1 Quality by design concepts should be applied toensure that critical aspects are designed into systems during thespecification and design process. The critical aspects of thedesign and associated acceptance criteria should be docu-mented.6.5.2 Assurance that manufacturing system
31、s are fit forintended use should not rely solely upon verification afterinstallation, but be achieved by a planned and structuredverification approach applied throughout the system life cycle.6.6 Good Engineering Practice:6.6.1 Good Engineering Practice (GEP) should underpinand support the specifica
32、tion, design, and verification activi-ties.6.6.2 Good Engineering Practice is defined as those estab-lished engineering methods and standards that are appliedthroughout the life cycle to deliver appropriate and effectivesolutions.6.6.3 Examples of Good Engineering Practices include:E2500 07 (2012)26
33、.6.3.1 Specification, design, and installation activitiesshould take full account of all applicable requirements, includ-ing GxP, safety, health, environmental, ergonomic, operational,maintenance, recognized industry standards, and other statu-tory requirements.6.6.3.2 Adequate provisions related to
34、 quality should beincluded in specification, design, procurement, and other con-tractual documents.6.6.3.3 Life-cycle documentation covering planning,specification, design, verification, installation, acceptance, andmaintenance should be produced.6.6.3.4 An appropriate degree of oversight and contro
35、lshould be achieved by suitable verification of execution,construction and installation activities.6.7 Subject Matter Experts:6.7.1 Subject matter experts are defined as those individualswith specific expertise and responsibility in a particular area orfield (for example, quality unit, engineering,
36、automation,development, operations, and so forth).6.7.2 Subject matter experts should take the lead role in theverification of manufacturing systems as appropriate withintheir area of expertise and responsibility.6.7.3 Subject matter expert responsibilities include planningand defining verification
37、strategies, defining acceptancecriteria, selection of appropriate test methods, execution ofverification tests, and reviewing results.6.8 Use of Vendor Documentation:6.8.1 Vendor documentation, including test documents maybe used as part of the verification documentation, providing theregulated comp
38、any 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 of GEP such that informationobtained from the vendor will be accurate and suitable to meetthe purpose of verification.6.8.2 If inadequacies a
39、re found in the vendor quality system,technical capability, or application of GEP, then the regulatedcompany may choose to mitigate potential risks by applyingspecific, targeted, additional verification checks or other con-trols rather than repeating vendor activities and replicatingvendor documenta
40、tion.6.8.3 The decision and justification to use vendordocumentation, to support the verification of critical aspects ofthe manufacturing element, should be based on the intendeduse of the manufacturing system, and should be documentedand approved by subject matter experts including the qualityunit.
41、6.9 Continuous Improvement:6.9.1 As experience is gained in commercial production,opportunities for improvements should be sought based onperiodic review and evaluation, operational and performancedata, and root-cause analysis of failures.6.9.2 Change management should provide a dependablemechanism
42、for prompt implementation of technically soundimprovements following the approach to specification, design,and verification described in this guide.7. Process7.1 OverviewThe process of specification, design, andverification of manufacturing systems should include thefollowing activities:Requirements
43、 definitionSpecification and designVerificationAcceptance and release7.1.1 Good Engineering Practice should be applied through-out the process.7.1.2 Risk management should be performed as appropriateto evaluate the risks to product quality and patient safetyrelated to the manufacturing system and co
44、rresponding designsolution. Risk management is a supporting process and isdefined in 8.2.7.1.3 Design reviews should be performed as appropriatethroughout the life-cycle of the manufacturing system. Thedesign review process is a supporting process and is defined in8.3.7.1.4 Change management should
45、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 requirements should be identified and shouldprovide the basis of further specification, design, and verifica-tion of the manufacturing system.7.2.2
46、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 knowledge and understanding,7.2.2.3 Regulatory requirements, and7.2.2.4 Company quality requirements.7.2.3 Product and process knowledge and unde
47、rstanding,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
48、processknowledge forms the basis of scientific understanding asdescribed in ICH Q8 and process control strategy.7.3 Specification and Design:7.3.1 Firms should develop appropriate mechanisms tocommunicate requirement inputs, including product qualityconsiderations, to those responsible for design, s
49、o that themanufacturing system may be properly designed based uponrelevant knowledge of product, process, and other require-ments.7.3.2 Specification and design activities should include afocus on those aspects that have been identified as beingcritical to product quality and patient safety. These criticalaspects of the manufacturing system should be identified anddocumented by subject matter experts.7.4 VerificationA systematic approach should be definedto verify that manufacturing systems, acting singly or incombination, are fit for intended use, have been properlyinst
