洁净空调系统验证 HVAC validation

法规和指南 Regulation and Guidance
ISO 14644 Clean Room Standard ISO 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 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
HVAC系统的要点
211.46(b) Equipment for adequate control over air pressure, microorganisms, 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, including 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, there 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.
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 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) Guideline 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
HVAC系统的要点 Key points
全过程管理Whole Process Management
设计Design
施工 Construction
调试 Commissioning
验证 Qualification
URS
设计标准
变更控制
施工文件
URS
调试报告 竣工资料
URS
验证报告
设计文件控制
验证方案
HVAC系统要点
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 Product 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 Good Manufacturing Practice “Validation and Qualification” 欧盟GMP的附录15-验证和确认
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。
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 ＞0.5μm) 10000级（352,000个/m3 at ＞0.5μm） 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)
车间布局和人流物流Layout and Flows
211.42(a) Any building or buildings used in 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 mixups between different components, drug product containers, closures, labeling, inprocess materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, inprocess materials, and drug products through the building or buildings shall be designed to prevent contamination.
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, 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 for its cleaning and maintenance.
国内外GMP法规和指南的异同点
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：
洁净空调系统验证
Validation of HVAC System - Macroprocess -
来自百度文库题
• 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
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 PRACTICE
HVAC系统的要点
法规要求 以美国cGMP(21CFR Part 210-211)为例
法规和指南 Regulation and Guidance
ISPE 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 Manufacturing 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