2009 Co-packer GMP Standard

国外药品检查资料汇编GUOW AI Y AOPIN JIANCHA ZILAO HUIBIAN欧盟药品GMP指南OUMENG YAOPINGMP ZHINAN国家食品药品监督管理局药品认证管理中心中国医药科技出版社目录第一部分欧盟药品管理概述 (1)第二部分欧盟GMP基本要求 (33)引言 (35)基本要求I：人用药品及兽药制剂生产质量管理规范 (37)基本要求Ⅱ：原料药生产质量管理规范 (64)第三部分欧盟GMP附录 (103)欧盟GMP附录l无菌药品的生产 (105)欧盟GMP附录2人用生物制品的生产 (119)欧盟GMP附录3放射性药品生产 (126)欧盟GMP附录4兽用非免疫药品的生产 (130)欧盟GMP附录5免疫类兽药制品的生产 (134)欧盟GMP附录6医用气体生产 (143)欧盟GMP附录7草药制剂的生产 (152)欧盟GMP附录8原辅包装材料的取样 (156)欧盟GMP附录9液剂、霜剂和油膏的生产 (160)欧盟GMP附录10定量吸人式气雾剂的生产 (163)欧盟GMP附录ll计算机系统 (166)欧盟GMP附录12药品生产中电离辐射的应用 (170)欧盟GMP附录13临床试验用药的生产 (177)欧盟GMP附录14人血液或血浆制品的生产 (191)欧盟GMP附录15确认和验证...............................................................(19r7) 欧盟GMP附录16药品放行责任人签发证书和放行批产品 (206)欧盟GMP附录17参数放行 (215)欧盟GMP附录19对照样品和留样 (219)欧盟GMP附录20质量风险管理 (224)欧盟GMP术语 (241)第一部分欧盟药品管理概述目录一、欧盟概况 (4)1．欧盟简史 (4)2．体制 (4)3．机构名称 (5)二、欧盟制药业及其产业政策 (6)1．欧洲企业理事总会目标及产业政策 (6)2．制药行业分管机构的目标和使命 (8)三、药品的审评及检查 (9)1．欧洲药品管理局的机构及廉政措施 (9)2．欧洲药品管理局的职能 (11)3．欧盟药事法规 (12)4．产品放行责任人 (15)5．药品审评程序 (17)(1)集中审评程序 (17)(2)互认程序 (20)(3)分散审评程序 (22)6．GXP检查 (22)7．GXP检查问答 (26)四、《欧洲药典》及欧洲药品质量理事会 (27)1．《欧洲药典》 (27)2．欧洲药品质量理事会 (28)3．《欧洲药典》适用性认证 (29)五、药品信息一药品说明书、标签和广告 (29)六、药品安全的持续监控 (30)附录 (32)一、欧盟概况1．欧盟简史二次大战以后，欧洲国家实现团结一致的强烈愿望，以及使欧洲子孙后代有一个和平和稳定的经济发展环境的共同目标，最终导致了欧洲经济共同体机构的产生和演变。

2.2. The increased number of the defects of medicinal products occurred dueto deficiencies in the process of labelling and packaging has drawninspectors’ attention towards the need for identi fying and clarifying thecritical aspects of this specific stage of inspection, in order to have auniform interpretation of the provisions of the current GMP guideconcerning packaging of medicinal products and prevention of mix-up.越来越多的发生在标签和包装工艺中的缺陷导致的的药品缺陷已经引起来检查官的注意，他们认为需要对这个特定的步骤的检查的关键点进行识别和说明，从而对现行GMP指南关于药品包装的条款进行统一解释，并防止药品混淆。

2.3. In the light of technological progress, considering the wide variety ofmedicinal products developed, the 2005 PIC/S Seminar (Bucharest,Romania) was dedicated to the GMP inspection of the final stage ofmanufacturing process (primary and secondary packaging, labelling.)由于科技进步，考虑到现在已有各种不同新研发的药品，PIC/S的2005年研讨会（布加勒斯特，罗马尼亚）专题讨论了生产工艺的最后步骤（内包装、外包装和标签）的GMP检查问题。

2009年沃尔玛给各供应商的验厂（ES、FCCA、GSV）新标准尊敬各合作伙伴:沃尔玛人权标准在2009年有以下变化,请做好倡导及对策工作一.自2009年1月1日起所有WM验厂结果期限及补救措施时限延长1绿灯:2年后跟进评估(不变)2黄灯:每12个月跟进评估(由6个月改为12个月)3橙灯:每6个月跟进评估(由4个月改为6个月)二.所有由第三方进行评估的初审与追踪审核的费用由工厂负责---2009.4.1生效2.1以上适用于2009.4.1或之后按排/指定的所有审核2.2所有确认由Wal-Mart合作人完成的审核,工厂不用承担费用---2009.4.1生效三.. 追踪审核将是不通知的--2009.4.1生效3.1以上适用于2009.4.1或之后按排/指定的所有审核3.2第三方审核公司的审核可以提供4-6周的窗口给供货商/工厂,但具体的未宣布的审核日期将不会告知.四..对于A型GP供货商的资格预审----实时生效4.1如果工厂收到年龄违规(1~2个童工)的评估,工厂将不会通过资格预审的人权部分.4.2 如果追踪审核30天内确定补救发现的童工(1~2个童工),工厂可以通过Wal-mart验厂最新标准修正红灯－冻结的政策：从2009年5月1日起，从上次的审核日期算，两年内得到3个橙灯评估=红色－冻结一年。

今年2009年1月，橙灯的后续审计期间从120天改为180天，以便留出更多的时间给工厂改善和补救．让供应商发展的努力更加有效。

鉴于这种延长，红灯－拒绝进程GP 和非ＧＰ采购供应商的工厂也已修订。

此前是，２年内累计４个橙灯=红色－冻结一年。

•有2个橙灯的工厂：在过去两年内已经有２个橙灯，如果再增加一个橙灯，那么就等于等到一个红灯将导致他们被冻结。

•在第二个橙灯跟进审计，工厂将有6个月时间来替换工厂，在这6个月内，该工厂能继续生产和出货。

过了６个月的有效期后，工厂将会被变为“冻结”状态。

•第二个橙灯工厂的重新使用，必须获得相应的采购的批准．方可改为“正常”的状态•当一家工厂收到的第2次橙色评估的结果，今后的订单是无法保证的．取决与wal-mart，•在过去２年间有收到３个橙灯的工厂，最近一次审核的日期是2009年5月1日的工厂将仍然可以接收订单。

EU GMP requirements q and inspections p of API manufacturers organized by EDQMShanghai, Shanghai , 29 June 2012Florence BenoitFl Benoit B it-Guyod, G d EDQM Inspector I t Certification of Substances Division, EDQMOverview O e e• • • • • The EU GMP for APIs International API inspection programme What’s new ? Main deficiencies Statistics: activity review, compliance trends dDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 2Responsibility p y of the marketing g authorisation holder (MAH) of the medicine• APIs must be produced according to EU GMP(Directives 2001/83/EC and 2001/82/EC)• It is the responsibility of the manufacturer to ensure EU GMP compliance of the active substance manufacturer • Declaration D l ti of f th the Q Qualified lifi d P Person (QP) of f the th manufacturer in the marketing application (andsubsequent b t variation) i ti )Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 3Role of the National Competent Authority in EU• The Competent Authority may inspect an API manufacturer in order to ensure that the manufacturing authorisation holder of a product has fulfilled its obligations g medicinal punder Article 46 (f) and/or Article 50 (f) of the below mentioned Directives (Article 111 of Directive2001/83/EC and Article 80 of Directive 2001/82/EC)• NB NB: in i contrast t t to t medicines, di i i inspections ti are not t carried out systematicallyDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 4Responsibility of the manufacturer•I In the th CEP procedure d th the API manufacturer has to declare: - Compliance to Good Manufacturing Practices (GMP) - Willingness to be inspectedDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 5Conditions for an inspection• Wh When requested t d by b a member b St State, t EMA (European medicines agency), European Commission or EDQM (if thereare g grounds for suspicion of non-compliance, need to verify data submitted)• When requested by the manufacturer itselfDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 6European AuthoritiesEUROPEAN UNION, EUROPEAN COMMISSION, DG EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES (EDQM) EUROPEAN MEDICINES AGENCY (EMA)GMP INSPECTORATESNATIONAL LICENSING AUTHORITIESDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 7GMP / GDP I Inspectors t Working W ki Group G• Takes place at EMA, London • Gathers EEA member states representatives • Provides input and recommendations on all matters relating to a u ac u g Practice ac ce (G (GMP) ) - Good Manufacturing - Good Distribution Practice (GDP)Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 8GMP / GDP Inspectors Working Group: main i activities ti iti relating l ti to t GMP– – – – – – – – – Discussions of EU Legislation EudraGMP database GMP for Medicinal Products ( (Part I, , Annexures) ) GMP for Active Substances (Part II, Annexures) GDP Product defects & inspections under centralised procedure Management of MRA in the field of GMP ICH Q8, Q9 and Q10 implementation Management of the Community ProceduresDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 9Role of EMA: Compilation of Procedures• EMA is i responsible ibl f for maintaining i t i i and d publishing bli hi on behalf of EC Commission • Collection of GMP inspection-related procedures and forms (Quality System for GMP Inspectorates) agreed by all member states • To facilitate:– Collaboration – Harmonisation – Exchange of InformationDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 10Role of EMA: Compilation of procedures EMA/INS/459921/2010Sharing of information-API program Sharing of information-API programSharing of information API program Sharing of information-API programSharing of information-API programEDQM Inspection programme EDQM Inspection programmeAim: to verify the compliance withAim:EDQM Inspection Program EDQM Inspection ProgramEDQM Inspection Program EDQM Inspection Programof the sites Selection of the sitesRisk Based Selection of the Sites s ased Se ect o o t e S tes Request from the assessors: inconsistencies Reinspection: dependingAPI related criteria: physico-chemicalCompany related criteria: information fromRequests from Assessors Requests from AssessorsSterile Grade Suspicion Potential weak points: Potential weak •Inspection isroutinely performedfor any sterileb tp regarding the dossier •Inconsistencies p process-related or specification-related •Starting material close points: site-related •Suspicion of low substance •Preferably priorgranting the CEPDraw attention to ain the data •Suspicion of fake data to the final step is not prepared by the manufacturer itself + lack of information Suspicion of low awareness and knowledge of the GMP principles S i i f i k f •Draw attention to a specific point; e.g.tray lyophilisation lack of information •Complex or badly explained process steps•Subcontracting some•Suspicion of risk of cross-contaminationsteps of manufacturingprocessHow the System Works How the System WorksimmediatelyRole of inspectors, observers,pinterpretersParticipation of Inspectorates Participation of Inspectorates EEA:MRA partners:Other partners:Inspection Outcome Inspection OutcomeInspection follow-up Inspection follow-upPositive Outcome Positive OutcomeNegative Outcome gNegative Outcome Negative OutcomeSuspension of the CEPs Suspension of the CEPsSuspension vs withdrawal: what’s the difference?h t’th diff?What’s What s new ? SMF• Th The « EDQM questionnaire ti i » is i now replaced by a Site Master File (SMF) based on the PIC/S template • EU has also a similar SMF • Rationale: having a document potentially recognised by numerous inspectorates in the worldDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 31What’s What s new ? GPS/DUNS• GPS coordinates and DUNS number requested q for any CEP application (as well as prior to an inspection) • EDQM specific requirements:• GPS is mandatory, DUNS is optional • System: WGS 84 (World Geodetic System 1984) g minutes seconds • Unit: degree DDD,DDDDD or DDD MM,MMM or DDD MM SS • Recorded at the entrance of the site– Also requested in the EU and PIC/S SMFDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 32New requirement for GPS/DUNS: how the forms look like–T To be b recorded d d with ith a GPS device d i or by b using i appropriate softwares (eg Google Earth or other equivalent application)Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 33GPS/DUNS: why ?• Experience p with CEP applications pp showed that the addresses may be incomplete or inconstant:– Addresses with a street or road name without a number – Street/road name or number has changed for urban b or administrative d i i t ti reason – Reorganization by the local authorities• Need to better identify the location of the manufacturing sitesDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 342011 main GMP deficienciesCompliance C li  to  CEP dossier & EP        29 4%Quality related  matters  (1,3,6, 12 12, ,13 13, ,1 5,16); 16); 278 278; ;  36% 36 %Laboratory  controls (11) ;  120; 16%Production &  IPC  Rejection &  IPC, reuse of  materials (8, 14) 57 7% Buildings &  facilities (4) ; 77;  10% Quality related matters: Qualitymanagement, Personnel, Documentation, Validation, Change control, Complaints and recalls, Contract manufacturersProcess  equipment ( (5 5) 92 12% 12 %Materials  management,  Storage, distri bution, Packag ing i   (7,10, 10, 9, 17 17); );  113; 113 ; 15 15% %Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 35Main GMP deficiencies• Quality related matters– Quality review: not a quality tool for companies – Change control / Deviation management: not a deep-rooted practice, deviations are underreported – Validation of p processes: CPP not based on scientific rationale, micronisation not addressed – Cleaning validation poor – Qualification of equipment: lack of appropriate user requirement specification, weakness of water y systemsDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 36Main GMP deficiencies• Process equipment / Buildings and facilities– Design – CleanlinessCleanliness Maintenance• Laboratory controls– Qualification of equipment – Chemical reference standards• Materials management– Traceability – Key y starting g material vendor approval pp – StorageDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 372011 QC deficienciesValidation/Qualifi Monitoring, 5% cation, 4% OOS, 2% Documentation (general aspects), 15 15% % Inconsequency to EP, 13% Stability, 6% Reference standards, 8% Tests & Results, 9%Chemicals, Solve nts, Media etc 13 etc, 13% % Sampling & Retained Samples, 13 13% %Equipment & Premises, 13%Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 38Statistics 2004-2011: Locations100% 80%0 3 01 2 00 1 00 5 31 2 30 2 11 1 5460%9 13 13 16 142 2 1101040%920%106139101370%IndiaChinaAsia otherEEAElsewhereDr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 39Inspection figures in 2011• 22 sites covered by EDQM inspections • 25 sites covered by exchange of information (i (inspections ti by b EEA inspectorates) i t t )– 3 sites refused to be inspected (suspension of CEPs)• CEPs suspended: 16 • CEPs withdrawn : 8Dr Florence Benoit-Guyod © 2012 EDQM, Council of Europe, All rights reserved 40General Compliance General Compliance TrendsPerspectivespConclusions from the companies’ sideConclusions from the Conclusions from the inspectorates’ sideWebsite: www.edqm.eu: www.edqm.eu WebsiteWebsite::www edqm eu。

EUROPEAN COMMISSIONENTERPRISE AND INDUSTRY DIRECTORATE-GENERALConsumer goodsPharmaceuticalsBrussels, 14 February 2008EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines toGood Manufacturing PracticeMedicinal Products for Human and Veterinary UseAnnex 1Manufacture of Sterile Medicinal ProductsDocument HistoryPrevious version dated 30 May 2003, in operation since September 2003Revision to align classification table of clean rooms, to include guidance on media simultations, bioburden monitoring and capping of freeze-dried vials November 2005 to December 2007Date for coming into operation and superseding 01 March 200911Note: Provisions on capping of freeze-dried vials should be implemented by 01 March 2010.Commission Européenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel – Belgium. Telephone: (32-2) 299 11 11ANNEX 1MANUFACTURE OF STERILE MEDICINAL PRODUCTSPrincipleThe manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.Note:This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.General1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.For the manufacture of sterile medicinal products 4 grades can be distinguished.Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated.A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.Grade B: For aseptic preparation and filling, this is the background environment for the gradeA zone.Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.Clean room and clean air device classification4. Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table.Maximum permitted number of particles per m 3 equal to or greater than the tabulated sizeAt rest In operation Grade0.5 µm 5.0µm 0.5 µm 5.0µm A3 520 20 3 520 20 B3 520 29 352 000 2 900 C352 000 2 900 3 520 000 29 000 D3 520 000 29 000 Not defined Not defined 5. For classification purposes in Grade A zones, a minimum sample volume of 1m 3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. . For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.6. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0µm in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be used in unidirectional airflow systems.7. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.Clean room and clean air device monitoring8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in theprocess that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 µm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals.12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.13. In Grade A and B zones, the monitoring of the ≥5.0 µm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of ≥5.0 µm particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor practices during machine set-up and routine operation.14. The particle limits given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations.15. The monitoring of Grade C and D areas in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period” should be attained.16. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard.17. Examples of operations to be carried out in the various grades are given in the table below (see also paragraphs 28 to 35):Grade Examples of operations for terminally sterilised products. (see paragraphs 28-30)A Filling of products, when unusually at riskC Preparation of solutions, when unusually at risk. Filling of productsD Preparation of solutions and components for subsequent fillingGrade Examples of operations for aseptic preparations. (see paragraphs. 31-35)A Aseptic preparation and filling.C Preparationofsolutions to be filtered.D Handling of components after washing.18. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.19. Recommended limits for microbiological monitoring of clean areas during operation:Recommended limits for microbial contamination (a)Grade air samplecfu/m3settle plates(diameter 90 mm)cfu/4 hours (b)contact plates(diameter 55 mm)cfu/plateglove print5 fingerscfu/gloveA < 1 < 1 < 1 < 1B 10 5 5 5C 100 50 25 -D 200 100 50 -Notes(a) These are average values.(b) Individual settle plates may be exposed for less than 4 hours.20. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.Isolator technology21. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechanisms.22. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devices.23. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D.24. Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.25. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.Blow/fill/seal technology26. Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment.27. Because of this special technology particular attention should be paid to, at least the following:•equipment design and qualification•validation and reproducibility of cleaning-in-place and sterilisation-in-place•background clean room environment in which the equipment is located•operator training and clothing•interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.Terminally sterilised products28. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination, (for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels), then preparation should be carried out in a grade C environment.29. Filling of products for terminal sterilisation should be carried out in at least a grade C environment.30. Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams,suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation.Aseptic preparation31. Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background.32. Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background.33. Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background.34. Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment.35. Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered.Personnel36. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible.37. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision.38. Staff who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed.39. High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person.40. Wristwatches, make-up and jewellery should not be worn in clean areas.41. Changing and washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas.42. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. 43. The description of clothing required for each grade is given below:•Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area.•Grade C: Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter.•Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.44. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session.45. Clean area clothing should be cleaned and handled in such a way that it does not gather additional contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of shedding of particles. Premises46. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used.47. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason.48. False ceilings should be sealed to prevent contamination from the space above them.49. Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.50. Sinks and drains should be prohibited in grade A/B areas used for aseptic manufacture. In other areas air breaks should be fitted between the machine or sink and the drains. Floordrains in lower grade clean rooms should be fitted with traps or water seals to prevent back-flow.51. Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimize microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should, in the at-rest state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms.52. Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time.53. A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of 10 - 15 pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The various recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations.54. It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or machine to a zone of higher product risk.55. A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be recorded regularly or otherwise documented. Equipment56. A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).57. As far as practicable equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. If sterilisation is required, it should be carried out, wherever possible, after complete reassembly.58. When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work.59. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced,stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C.60. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved.Sanitation61. The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.62. Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.63. Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places.Processing64. Precautions to minimize contamination should be taken during all processing stages including the stages before sterilisation.65. Preparations of microbiological origin should not be made or filled in areas used for the processing of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be filled, after inactivation, in the same premises as other sterile medicinal products.66. Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill).Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium.67. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst-case situations.68. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process.69. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:。

美国药典简介1. 标题和修订（Title and Revision）. 92. 药典地位和法律认可（Official status and legal recognition）92.10 药典正文(Official Text) 92.20 药典物品（Official Articles）. 92.30 法律认可（Legal Recognition）. 103. 与标准的符合性（Conformance to standard）. 103.10 标准的适用性 (Applicability of standard) 103.10.10 制剂、原料药、辅料的标准的适用性（Applicability of Standards to Drug Products, Drug Substances, and Excipients）. 103.10.20 医疗器械、营养补充剂、以及其组成成分的标准的适用性（Applicability of Standards to Medical Devices, Dietary Supplements, and Their Components and Ingredients）113.20 一致性的标示（Indicating Conformance）. 114. 药典各论和通则（Monographs and general chapters）124.10 各论(Monographs) 124.10.10 检测程序的适用性(Applicability of Test Procedures) 124.10.20 接受标准(Acceptance Criteria) 124.20 附录（General Chapter）. 125. 各论组成（Monograph Components）. 135.10 分子式（Molecular formula）. 135.20 附加物质、赋形剂、组分(Added Substances, Excipients, and Ingredients) 135.20.10官方原料药中附加的物质、赋形剂、组分（Added Substances, Excipients, and Ingredien ts in Official Substances）. 135.20.20官方制剂中的附加物质、赋形剂、组分（Added Substances, Excipients, and Ingredients in Official Products）. 135.30 性状和溶解性（Description and Solubility）. 145.40 鉴定试验（Identification Test）. 145.50 含量分析（Assay）. 155.50.10 效价单位（生物效价）(Units of Potency (Biological)) 155.60 杂质和外来物质（Impurities and Foreign Substances）. 155.60.10 USP和NF物品的其它杂质（Other Impurities in USP and NF Articles）155.60.20 USP和NF物品中的残留溶剂（Residual Solvents in USP and NF Articles）165.70性能检测（Performance Tests）. 165.80 USP标准品（Residual Solvents in USP and NF Articles）. 166. 检验规范和分析方法（Testing practices and procedures）166.10 安全的实验室规范（Safe Laboratory Practices）. 166.20 自动化程序（Automated Procedures）. 166.30 可选择的和谐的方法与程序（Alternative and Harmonized Methods and Procedures）166.40 干燥的、无水的、灼烧的、无溶剂的（Dried, Anhydrous, Ignited, or Solvent-Free Basis）176.40.10 灼烧至恒重（Ignite To Constant Weight）. 176.40.20 干燥至恒重（Dried T o Constant Weight）. 176.50 溶液的制备（Preparation of Solutions）. 186.50.10 过滤（Filtration）. 186.50.20 溶液（Solutions）. 186.60 完成一个实验所需多少单位（Units Necessary to Complete a Test）. 186.60.10 片剂（Tablets）. 186.60.20 胶囊（Capsules）. 196.70 试剂（Reagents）. 196.80 设备（Equipment）. 196.80.10 测量仪器（Apparatus for Measurement）. 196.80.20 仪器设备（Instrumental Apparatus）. 197. 测试结果（Test Results）. 207.10 质量要求的解释 (Interpretation of Requirements) 207.10.10 滴定程序中的等效表述 (Equivalence Statements in Titrimetric Procedures) 207.20 修约原则 (Rounding Rules) 208. 术语和定义 (Terms and Definitions) 218.10 缩写 (Abbreviations) 218.20 大约 (About) 218.30 乙醇含量 (Alcohol Content) 218.40 原子量(Atomic Weights) 228.50 空白试验(Blank Determinations) 228.60伴随(Concomitantly) 228.70 干燥器(Desiccator) 228.80 对数（Logarithms）. 228.90 微生物菌株(Microbial Strain) 228.100 可忽略的（Negligible）. 228.110 NLT/NMT 228.120 气味(Odor) 228.130 百分比(Percent) 228.140 百分比浓度(Percentage Concentrations) 238.150 压力(Pressure) 238.160 反应时间(Reaction Time) 238.170 比重(Specific Gravity) 238.180 温度(Temperatures) 238.190 时间(Time) 238.200 转移（Transfer）. 238.210 真空（Vacuum）. 238.220 真空干燥器（Vacuum Desiccator）. 238.230 水（Water）. 248.230.10 水作为官方制剂中的组分（Water as an Ingredient in an Official Product）24 8.230.20 水用于官方原料药的生产（Water in the Manufacture of Official Substances）24 8.230.30 药典实验操作用水（Water in a Compendial Procedure）. 248.240 称量和测量（Weights and Measures）. 249. 开处方和配药（Prescribing and Dispending）. 259.10 公制单位的使用（Use of Metric Units）. 259.20 体积的改变（Changes in Volume）. 2510. 保存、包装、储存、贴签（preservation，packaging，storage and labeling）2510.10 在非特定条件下储存（Storage Under Nonspecific Conditions）. 2510.20 包装容器（Containers）. 2510.20.10显窃启包装（Tamper-Evident Packaging）. 2610.20.20 避光容器（Light-Resistant Container）. 2610.20.30密闭良好的容器（Well-Closed Container）. 2610.20.40密封的容器（Tight Container）. 2610.20.50严封的容器（Hermetic Container）. 2710.20.60单元包装（Single-Unit Container）. 2710.20.70单剂量包装（Single-Dose Container）. 2710.20.80单元剂量容器（Unit-Dose Container）. 2710.20.90单元使用的容器（Unit-of-Use Container）. 2710.20.100多单元容器（Multiple-Unit Container）. 2710.20.110多剂量容器（Multiple-Dose Container）. 2710.20.120毒物保护包装法案（Requirements under the Poison Prevention Packaging Act (PPPA)） 2710.30 储存温度和湿度（Storage Temperature and Humidity）. 2810.30.10 冷冻（Freezer）. 2810.30.20冷处（Cold）. 2810.30.30 凉处（Cool）. 2810.30.40 可控的凉爽温度（controlled cold temperature）. 2810.30.50 室温（room temperature）. 2910.30.60 可控的室温（Controlled Room Temperature）. 2910.30.70 温暖（warm）. 2910.30.80 过热（Excessive Heat）. 2910.30.90 防冻（Protection From Freezing）. 2910.30.100 干燥处（Dry Place）. 2910.40 标签（Labeling）. 2910.40.10每个剂量单元中组分的量（Amount of Ingredient Per Dosage Unit）3010.40.20 首位和末位零的使用（Use of Leading and Terminal Zeros）. 3010.40.30药品中盐的标示（Labeling of Salts of Drugs）. 3010.40.40含维生素产品的标示（Labeling Vitamin-Containing Products）. 3010.40.50含植物药材的产品的标示（Labeling Botanical-Containing Products）3110.40.60非肠道和局部制剂的标示（Labeling Parenteral And Topical Preparations）3110.40.70电解液的标示（Labeling Electrolytes）. 3110.40.80乙醇的标示（Labeling Alcohol）. 3110.40.90特殊的胶囊和片剂（Special Capsules and Tablets）. 3110.40.100有效期和失效期（expiration date and beyond-use date）. 3110.50 USP-NF药典正文中关于包装和储存的指南（Guidelines for Packaging and Storage State ments in USP–NF Monographs）. 32General Notices and Requirements(凡例和要求)Change to read:凡例部分为药典的解释和应用提出了基本的假定、定义、默认条件。

欧洲共同体：European Communities (EC)。

欧洲联盟：European Union (EU)，简称欧盟。

人用药品注册技术标准国际协调会：ICH欧盟GMP附录1无菌药品的生产注：冻干瓶轧盖的条款自2010年3月1日开始实施。

原则为降低微生物、微粒和热原污染的风险，无菌药品的生产应有各种特殊要求。

这在很大程度上取决于生产人员的技能、所接受的培训及其工作态度。

质量保证极为重要，无菌药品的生产必须严格按照精心制订并经验证的方法和规程进行。

产品的无菌或其它质量特性绝不能仅依赖于任何形式的最终操作或成品检验。

注：本指南没有对微粒、浮游菌和表面微生物等测试方法详细进行阐述，可参阅欧洲标准或国际标准（CEN/ISO）及药典资料。

总则1.无菌药品的生产必须在洁净区内进行，人员和（或）设备以及物料必须通过缓冲进入洁净区。

洁净区应当保持适当的洁净度，洁净区的送风须经具有一定过滤效率过滤器的过滤。

2.原料配制、产品加工和灌装等不同操作必须在洁净去内彼此分开的单独区域内进行。

生产工艺可分为两类：一类是最终灭菌工艺；第二类是部分或全部工序为无菌操作的工艺。

3.应按所需环境的特点确定无菌产品的洁净级别。

每一步生产操作都应达到适当的动态洁净度，以尽可能降低产品（或原料）被微粒或微生物污染。

洁净区的设计必须符合相应的“静态”标准，以达到“动态”的洁净要求。

“静态”是指安装已经完成并已运行，但没有操作人员在场的状态。

“动态”是指生产设施按预定的工艺模式运行并有规定数量的操作人员进行现场操作的状态。

应确定每一洁净室或每组洁净间的“动态”及“静态”标准。

无菌药品生产所需的洁净区一般可分为4个级别：A级：高风险操作区，如：灌装区，放置胶塞桶、敞口安瓿瓶、敞口西林瓶的区域及无菌装配/连接操作的区域。

通常用单向流操作台/罩来维护该区的环境状态。

单向流系统在其工作区域必须均匀送风，风速为0.36-0.54m/s（指导值）。

欧盟和美国一次性使用卫生用品法规要求概览及安全要求徐昌芬通标标准技术服务有限公司厦门分公司一 中、欧、美一次性使用卫生用品法规体系概述●中国在中国，GB15979-2002标准中对一次性使用卫生用品的定义如下：使用一次后即丢弃的，与人体直接或间接接触的，并为达到人体生理卫生、抗菌或抑菌目的而使用的日常生活用品。

中国对一次性使用卫生用品的管理策略是：生产企业需持有“卫生许可证”方可生产，可向所在省份申请该资质。

必须遵守国家强制标准GB15979-2002，且有一系列国家推荐性标准，不同的一次性使用卫生用品一般都有与其对应的产品标准。

如GB/T 8939-2018 卫生巾（护垫）、GB/T 28004-2011纸尿裤（片、垫）、GB/T 20810-2018卫生纸（含卫生纸原纸）、GB/T 27728-2011湿巾等。

此外，一个变化趋势是，在GB/T 36420-2018 生活用纸和纸制品化学品及原料安全评价管理体系中，对生产使用的原料提出要求，如禁止添加的化学品、限用物质清单及限制含量的化学物质等；GB/T 35613-2017 绿色产品评价纸和纸制品则对生活用纸（纸巾纸、卫生纸）和生活用纸制品（卫生巾、纸尿裤、人体用湿巾）做出规定，涵盖资源、能源、环境、品质属性，较为全面的对化学风险物质进行了管控。

中国对于一次性使用卫生用品的管理，主要从“卫生”的角度出发制定相关要求和准则，缺乏必要的“安全”要求。

尽管当前我国已经颁布GB/T 35613-2017绿色产品评价纸和纸制品等标准，补充了对很多风险物质的管控要求，但对产品的“安全”要求管理仍显不够。

市场上层出不穷的创新型产品，如液体卫生巾、卫生棉条等产品至今在国内尚无相应的产品标准，而产品标准的制修订，往往需要几年的时间，以至部分产品处于无标准可依的局面。

●欧盟欧盟法规体系较为完备，对于不同类型的一次性使用卫生用品都有适用的法规要求，且主要以“化学安全”为主，对卫生无强制要求。

GMP2009征求意见稿（1-8章）工作相关 2009-10-13 17:06 阅读113 评论0第一章总则第一条根据《中华人民共和国药品管理法》和《中华人民共和国药品管理法实施条例》的有关规定, 制定本规范。

第二条本规范是对药品生产质量进行控制和管理的基本要求，以确保持续稳定地生产出适用于预定用途、符合注册批准或规定要求和质量标准的药品，并最大限度减少药品生产过程中污染、交叉污染以及混淆、差错的风险。

第三条药品生产质量管理的特殊要求，以附录的形式发布并根据情况随时修订。

第四条企业可以采用经过验证的创新或改进的方法，达到不低于本规范的要求。

第五条执行本规范的基础是诚实守信，任何虚假、欺骗行为都是对本规范的严重背离。

第六条本规范不包括有关环境保护、劳动安全方面的管理要求。

第七条本规范的英文名称是Good Manufacturin g Practice for Pharmaceuticals，简称药品GMP。

第二章质量管理第八条企业必须建立涵盖本规范的全面的质量保证系统，应以完整的文件形式明确规定质量保证系统，并监控其有效性。

药品生产的质量保证系统包括了影响药品质量的所有因素，是为确保药品质量符合预定用途所需的有组织、有计划的全部活动总和，包括了药品的设计与研发，明确规定了药品的生产和质量控制活动。

第九条企业应建立并实施质量目标，将药品注册中有关安全、有效和质量可控的所有要求，系统地贯彻到药品生产、控制及产品放行、发放的全过程中，确保所生产的药品适用于预定的用途，符合药品注册批准或规定的要求和质量标准。

第十条企业高层管理人员应确保实现既定的质量目标，各部门不同层次的人员以及供应商、经销商应共同参与其中并承担各自的责任。

第十一条企业必须配备足够的、符合要求的人员、厂房、设施和设备，为实现质量目标提供必要的条件。

第十二条企业应建立质量风险管理体系，运用前瞻或回顾的方式对药品整个生命周期进行质量风险的评估、控制与审核。