洁净空调系统验证6.1

1、洁净空调系统验证Validation of HVAC System- - 杜敏杜敏 - -主题 国内外有关法规和指南 Regulation and Guidance HVAC系统的要点 Key points of HVAC system 验证内容 Qualification Content法规和指南 Regulation and Guidance (SFDA) Good Manufacturing Practice, revised in 1998(SFDA) 1998年版GMP European Commission. The Rules Governing Medicinal Produc

2、t in the European Union, Vol. IV, Good Manufacturing Practices. Medicinal products for human and veterinary use. 欧盟药品法规第4卷GMP（人用和兽用药品） Annex 1 to the EU Guide to Good Manufacturing Practice, Manufacture Of Sterile Medicinal Products. 2003 Edition.欧盟GMP的附录1-无菌药品的生产，2003版 Annex 15 to the EU Guide to G

3、ood Manufacturing Practice “Validation and Qualification” 欧盟GMP的附录15-验证和确认法规和指南 Regulation and Guidance(FDA) Title 21, Code of Federal Regulations, Part 210, Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General. (FDA) 联邦法规第21篇第210部分，有关药品生产、加工、包装和贮存的

4、CGMP总则(FDA) Title 21, Code of Federal Regulations, Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals. (FDA) 联邦法规第21篇第211部分，成品药的现行生产质量管理规范(FDA) Title 21, Code of Federal Regulations, Part 11, Electronic Records; Electronic Signature. (FDA）联邦法规第21篇第11部分，电子记录和电子签名(FDA) Guidelin

5、e on Sterile Drug Products Produced by Aseptic Processing, September 2004(FDA）无菌工艺的无菌药品生产的指南，2004年9月法规和指南 Regulation and GuidanceISPE Pharmaceutical Engineering Guides:ISPE制药工程指南：Volume 1: Bulk Pharmaceutical Chemical Facilities卷一：化学原料药厂房Volume 2: Oral Solid Dosage Forms卷二：口服固体制剂Volume 3: Sterile Ma

6、nufacturing Facilities卷三：无菌生产厂房Volume 5: Commissioning and Qualification卷五：调试和确认Volume 6: Biopharmaceutics卷六：生物制药法规和指南 Regulation and GuidanceISO 14644 Clean Room StandardISO 14644洁净室标准Part 1: Classification of air cleanliness第一部份：空气洁净度分类Part 2: Specifications for testing and monitoring第二部分：测试和监视的标准

7、Part 3: Test Methods第三部分：测试方法Part 4: Design, Construction and Start-up第四部分：设计、施工和启动国内外GMP法规和指南的异同点 GMP条款都是原则性的如：FDA cGMP 211.42(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components, drug product containers,

8、 closures, labeling, in-process materials, or drug products, and to prevent contamination. 211.63 Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and

9、 for its cleaning and maintenance. 国内外GMP法规和指南的异同点 欧美有一系列具体GMP实施或检查指南 如：FDA有” Guidance for Industry”和“Guide to Inspection”, 有“水系统”、“口服制剂”、“无菌工艺制剂”、“原料药”、“冻干制剂”、“清洗制剂”、“无菌原料药”等等方面的指南。 欧盟EMEA也有一系列指南作为GMP总则的附件，如Annex1 “无菌制剂”，Annex2 “生物制品”，Annex15 “验证和确认”，Annex18 “原料药GMP”。另外EMEA之下的CHMP也发布了一系列的指南。国内外GMP法

10、规和指南的异同点指南会给出一些具体的标准如：FDA的“Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice , September 2004 ”要求： HEPA过滤器完整性测试：泄漏率0.01% 层流罩空气流速：0.45 +/-20% (距离过滤器表面6 inches（15.2 cm)，并接近操作面） 各个洁净等级的颗粒浓度：100级（3,520个/m3 at 0.5m)10000级（352,000个/m3 at 0.5m）

11、 各个洁净等级的微生物限度（以沉降菌为例）：100级（1cfu, diam.90mm, 4hours)10000级（5cfu, diam.90mm, 4hours)国内外GMP法规和指南的异同点ISPE工程指南最具操作性如厂房布局,墙板和地面材料, 空调系统标准, 换气次数,压差,温湿度, 制水设备, 水系统循环系统要求, 管道材料和抛光要求, 工程文件要求, 验证要求等等.GOOD ENGINEERING PRACTICEHVAC系统的要点法规要求以美国cGMP(21CFR Part 210-211)为例 211.42(a) Any building or buildings used in

12、 the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. 211.42(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent m

13、ixups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall

14、be designed to prevent contamination.HVAC系统的要点 211.46(b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product. 211.46(c) Air filtration systems, inc

15、luding prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, t

16、here shall be adequate exhaust systems or other systems adequate to control contaminants. 211.46(d) Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use. HVAC系统的要点 Key points设计Design施工Constructio

17、n调试Commissioning验证QualificationURS设计标准施工文件变更控制设计文件控制调试报告URS竣工资料URS验证报告验证方案全过程管理Whole Process ManagementHVAC系统要点车间布局和人流物流Layout and FlowsEU GMP 洁净级别 Air Classification Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connecti

18、ons. Grade B : For aseptic preparation and filling, this is the background environment for the grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.EU GMP 洁净级别HVAC系统的要点青霉素类产品车间的要求 中国GMP 第二十条 生产青霉素类等高致敏性药品必须使用独立的厂房与设施，分装室应保持相对负压，排至室外的废气

19、应经净化处理并符合要求，排风口应远离其它空气净化系统的进风口；生产-内酰胺结构类药品必须使用专用设备和独立的空气净化系统，并与其它药品生产区域严格分开。 (欧盟、美国、WHO和ICH的GMP都有类似的规定)HVAC系统的要点避孕药品、激素类、抗肿瘤类化学药品、放射性药品 中国GMP 第二十一条 避孕药品的生产厂房应与其它药品生产厂房分开，并装有独立的专用的空气净化系统。生产激素类、抗肿瘤类化学药品应避免与其它药品使用同一设备和空气净化系统。放射性药品的生产、包装和储存应使用专用的、安全的设备，生产区排出的空气不应循环使用，排气中应避免含有放射性微粒，符合国家关于辐射防护的要求与规定。HVAC系

20、统的要点生物制品 中国GMP第二十二条 生产用菌毒种与非生产用菌毒种、生产用细胞与非生产用细胞、强毒与弱毒、死毒与活毒、脱毒前与脱毒后的制品和活疫苗与灭活疫苗、人血液制品、预防制品等的加工或灌装不得同时在同一生产厂房内进行，其贮存要严格分开。不同种类的活疫苗的处理及灌装应彼此分开。强毒微生物及芽胞菌制品的区域与相邻区域应保持相对负压，并有独立的空气净化系统。HVAC系统的要点 Key points几个主要的设计参数 Design Criteria 洁净度 Air Classification 换气次数 Air Change 压差 Room Differential Pressure 温湿度范围

21、 Temperature and Humidity洁净度Air Classification中国2010版GMP洁净度Air Classification欧盟GMP（2008.11.25 )洁净度Air ClassificationFDA洁净度Air ClassificationISO14644换气次数 Air Change1. 中国GMP没有规定，参考中国洁净室设计标准（GB50073-2013)2. EU GMP Annex1 : the number of air changes should be related to the size of the room and the equi

22、pment and personnel present in the room.3. 参考FDA 指南（Sterile Drug Products produced by Aseptic processing- Current Good Manufacturing Practice)： For Class 100,000 (ISO 8) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. Significantly higher air

23、 change rates are normally needed for Class 10,000 and Class 100 areas. NA: 不适用 ND:未明确 压差 Room Pressure中国GMP: 空气洁净度等级不同的相邻房间之间的静压差应大于5帕，洁净室(区)与室外大气的静压差应大于10 帕FDA:不同洁净等级房间相差12.5Pa欧盟GMP：1015Pa压力分布图温湿度范围 Temperature and HumidityHVAC系统的要点自控系统Control System 控制参数Control Parameters 温度Temperature（主动控制，连续记录）

24、 相对湿度Humidity（主动控制，连续记录） 压差Differential Pressure（主动或被动控制，建议连续记录） 粒子数Particle count（被动控制，建议关键区域连续记录） 控制功能 Control Function 校准 CalibrationHVAC系统的验证V模型FSDSConstructionIQOQPQURSDQ设计确认（DQ)DQ要点设计文件的确认 Design Documents Verification房间布局和HVAC系统图的确认 Room Layout and HVAC P&ID房间参数的确认（风量、温湿度、压差等）Room Parameters

25、Verification (Air volume, temp./hum. Pressure)设备和组件的确认 Components Verification仪器仪表的确认 Instruments Verification系统风管和风口布置图的确认 Ducts and HEPA filters Layout空调控制功能的确认 Control Function Verification偏差报告 DeviationHVAC的设计文件 Design Documents需要有以下文件(Recommended Design documents)：设计说明 Design Specification房间平面图

26、 Room Layout洁净区划分图 Air classification layout人流物流图 Personnel/materials flowsHVAC系统区域划分图 HVAC Zone Layout房间压力分布图Room Pressure LayoutHVAC系统流程图 P&ID of HVAC system风管布置图（送、回、排风）Ducts Layout设备和仪表清单 Components and Instruments list风量平衡计算表 Calculation of air volume balance空气处理计算表（机组冷热负荷计算）Calculation of ther

27、mal /cooling loadIQ要点文件的确认 Documents Verification风管安装的确认 Ducts Installation Verification系统图和布局图的确认 P&ID and Layout Verification设备安装的确认 Components Verification关键仪表和校准的确认 Critical Instruments Verification高效过滤器布置的确认 HEPA filters layout verification公用设施的确认 Utilities Verification偏差报告 Deviation Report运行确认

28、（OQ)OQ要点验证仪器校准的确认 Validation Instruments Verification高效过滤器完整性检查（DOP测试）HEPA Filter Integrity Testing房间风量和换气次数测试 Air Volume and Air Change Testing房间压差测试Room Differential Pressure Testing房间温湿度测试Temperature/Humidity Testing气流流型测试Air Direction Testing自净时间测试 Recovery time Testing洁净度测试（静态）Cleanliness Testing (static)偏差报告 Deviation ReportDOP测试PAO aerosol（10-30g/l)标准：泄漏率小于0.01%DOP测试风量