1、Designation: E 2500 07Standard Guide forSpecification, Design, and Verification of Pharmaceuticaland Biopharmaceutical Manufacturing Systems andEquipment1This standard is issued under the fixed designation E 2500; the number immediately following the designation indicates the year oforiginal adoptio
2、n or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide is applicable to all elements of pharmaceu-tical and biopharmac
3、eutical 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 res
4、t ofthis guide as manufacturing systems.1.3 This guide may also be applied to laboratory, informa-tion, 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,
5、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 purport to ad
6、dress 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 2363 Termino
7、logy Relating to Process Analytical Tech-nology 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 terms used in t
8、his guide,refer to Terminology E 2363.3.1.1 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 continuousimprovement
9、 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 biopharmaceutical manuf
10、acturing 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)individual
11、s with spe-cific expertise and responsibility in a particular area or field(for example, quality unit, engineering, automation, develop-ment, operations, and so forth).3.1.5 verificationa systematic approach to verify thatmanufacturing systems, acting singly or in combination, are fitfor intended us
12、e, have been properly installed, and are operat-ing correctly. This is an umbrella term that encompasses all1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products and is the direct responsibility of Subcommittee E55.03on General Pharmaceutical Standards.
13、Current edition approved June 1, 2007. Published August 2007.2For referenced ASTM standards, visit 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.
14、3Available 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.4Available from Food and Drug Administration (FDA),
15、5600 Fishers Ln.,Rockville, MD 20857, http:/www.fda.gov.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.types of approaches to assuring systems are fit for use such asqualification, commissioning and qualification, verification,syste
16、m 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 equipment that have the potentialto affect product quality and patient safety.4.2 This guide describes a systematic, ef
17、ficient, 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 effectively managed tothe extent that these are affected by such systems and equip-ment.4.3 The overall objective is to
18、 provide manufacturing capa-bility to support 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 implement
19、ation 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, design, and verifi-cation process, and4.5.3 A description of the required supporting processes.5. Significance and Us
20、e5.1 Application of the approach described 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, installa-tion, operation, and performance.5.2 The approach des
21、cribed 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 consistent with, the frame-work described in ICH Q8 and ICH Q9.5.4 This guide may be used independently or in conjunct
22、ionwith other proposed E55 standards to be published by ASTMInternational.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 Do
23、cumentationContinuous Process Improvement6.2 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
24、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 risk management process should be commensuratewith the level of risk.6.2.3 These principles should be applied to sp
25、ecification,design, and verification of 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 p
26、rocess 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 are designed and verified to be fitfor their intended use.6.3.2 Examples of product and process information tocons
27、ider include: critical quality attributes (CQAs), criticalprocess parameters (CPPs), process control strategy informa-tion, 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
28、 performance or charac-teristics necessary 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 ofthi
29、s 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 Quality by Design:6.5.1 Quality by design concepts should be applied toensure that critical aspects are designed i
30、nto 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 systems are fit forintended use should not rely solely upon verification afterinstallation, but be achieved by a plann
31、ed 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 specification, design, and verification activi-ties.6.6.2 Good Engineering Practice is defined as those estab-lished engi
32、neering methods and standards that 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
33、, safety, health, environmental, ergonomic, operational,maintenance, recognized industry standards, and other statu-tory requirements.E25000726.6.3.2 Adequate provisions related to quality should beincluded in specification, design, procurement, and other con-tractual documents.6.6.3.3 Life-cycle do
34、cumentation covering planning, speci-fication, 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
35、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, automation,development, operations, and so forth).6.7.2 Subject matter experts should take the lead role in theverific
36、ation of manufacturing systems as appropriate withintheir area of expertise and responsibility.6.7.3 Subject matter expert responsibilities include planningand defining verification strategies, defining acceptance crite-ria, selection of appropriate test methods, execution of verifi-cation tests, an
37、d 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 company has assessed the vendor, and has evidenceof:6.8.1.1 An acceptable vendor quality system,6.8.1.2 Vendor technic
38、al 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 are found in the vendor quality system,technical capability, or application of GEP, then the regulatedcompany may c
39、hoose to mitigate potential risks by applyingspecific, 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 vendor documen-tation, to support the verification of critical as
40、pects of themanufacturing element, should be based on the intended use ofthe manufacturing system, and should be documented andapproved by subject matter experts including the quality unit.6.9 Continuous Improvement:6.9.1 As experience is gained in commercial production,opportunities for improvement
41、s 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 for prompt implementation of technically soundimprovements following the approach to specification, design,and
42、verification described in this guide.7. Process7.1 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
43、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 corresponding designsolution. Risk management is a supporting process and isdefined in 8.2.7.1.3 Design reviews s
44、hould 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 be applied throughout theprocess. The change management process is a supportingprocess and is defined in 8.4.7.
45、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.FIG. 1 The Specification, Design, and Verification ProcessE25000737.2.2 These specific requirements relative to produ
46、ct 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 understanding,including knowledge of sources of v
47、ariability 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 scientifi
48、c 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, so that themanufacturing system may be properl
49、y 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 properlyinstalled, and are operating correctly. This verific
