GMP Water System(cGMP培训系列1).

1、GMP Water System GMP水系统 GMP Training Module 12 1 Disclaimer The following slides are copied from WHO presentation on water system in Shanghai on Feb 28 March 4, 2005. 声明 根据世界卫生组织的有关培训材料改写而成 2 Part I Water Pre-treatment 3 水的预处理 Water Introduction and treatment 水的引入和处理 4 Objectives目标 1. Introduction t

2、o Water for Pharmaceutical Use 2. Review WHO GMP guidance 3. Sources and types of water for pharmaceutical use 4. Storage of bulk, untreated raw water 5. Pre-treatment of water 5 Principles (1) Like any starting material, water must conform to Good Manufacturing Practice norms It must be “potable” a

3、nd comply with WHO Guidelines for drinking-water quality 原则 1 必须符合GMP对原料的基本要求 必须至少是饮用水标准 6 Principles (2) 1.Potential for microbial growth 2. Systems must be properly validated 3. Water for parenteral use could be contaminated with pyrogens or endotoxins 4. Specifications and periodic testing is req

4、uired 原则2 微生物生长可能 系统必须被论证 注射用水可能被污染 定期测试 7 Types of water used in pharmaceutical processes 1. Purified water 2. Water for Injections PFW & WFI 3. Softened Water 4. Water for Final Rinse 5. Pure, or clean Steam 6. Water for cooling Autoclaves 原则2 微生物生长可能 系统必须被论证 注射用水可能被污染 定期测试 8 Why purify raw water?

5、水为什么要净化？ 1. Although reasonably pure, it is always variable 2. Seasonal variations may occur in water 3. Some regions have very poor quality water 4. Must remove impurities to prevent product contamination. 5. Control microbes to avoid contaminating products 9 Contaminants of water (1)水的可能污染源 There

6、is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants Contaminant groups: 1. Inorganic compounds 2. Organic compounds 3. Solids 4. Gases 5. Micro-organisms 无机，有机，固体，液体，微生物 10 Contaminants of water (2)水的污染源2 Treatment depends on waters chemistry and contaminants, i

7、nfluenced by: 1. Rainfall 2. Erosion 3. Pollution 4. Dissolution 5. Evaporation 6. Sedimentation 7. Decomposition 雨水，腐蚀，污染，水溶物，蒸发物，沉淀物及 分解物 11 Contaminants of water (3) Problem minerals 水的污染物 3 矿物质 1. Calcium and magnesium 2. Iron and manganese 3. Silicates 4. Carbon dioxide 5. Hydrogen sulfide 6. P

8、hosphates 12 Contaminants of water (4) Further problem minerals 水的污染物4 重金属 1. Copper 2. Aluminium 3. Heavy metals Arsenic, lead, cadmium 4. Nitrates 13 Contaminants of water (5) Micro-organisms Biofilm 水的污染物5 生物膜 水草，原生动物，细菌 1.Algae 2. Protozoa Cryptosporidium Giardia 3. Bacteria Pseudomonas Gram neg

9、ative, non-fermenting bacteria Escherichia coli and coliforms 14 Water hardness classification mg/L or ppm as CaCO3 Soft0-60 Moderate61-120 Hard121-180 Very Hard 180 Water hardness水的硬度 15 Source of raw water -水源 1. Rain water 2. Surface or ground water 3. Well or borehole 4. Municipal or civil “tap

10、water” 5. Purchased in bulk 16 Water treatment guidance 水处理指导 The following should be monitored Sources of water Treatment procedures Water treatment equipment Treated water tests Monitoring records required 17 水源 处理程序 处理设备 水测试 记录监督 Pre-treatment steps 1.Primary filtration and multi-media filter 2.

11、Coagulation or flocculation 3. Desalination 4. Softening 预处理程序 预过滤，多媒质过滤 凝结 去盐 软化 18 raw water in S” trap to sewer Water is kept circulating To water softener & DI plant Pretreatment schematic drawing cartridge filter 5 micrometers activated carbon filter spray ball break tank air break to drain cen

12、trifugal pump air filter float operated valve sand filter excess water recycled from deioniser 19 图表 brine and salt tank brine hard water in zeolite water softener -exchanges -Ca and Mg for Na drain soft water to deioniser by pass valve Water Softener schematic drawing 软化剂图表 20 Part II Water Purific

13、ation 水净化 21 Objectives To examine the basic technology and requirements for: 1. Water treatment systems 2. Storage requirements 3. Sampling and testing 4. Different types of water used in pharmaceuticals 5. Microbial limits, disinfection 22 目标 水处理系统 存储要求 取样，测试 水的种类 微生物，消毒 Water system design 1. Pip

14、es sloped so water does not pool and can drain easily 2. Sanitary fittings & connections 3. Constructed of suitable materials such as stainless steel 4. Circulate the water 5. Incorporate non-return valves (NRV) 23 水系统测试 管子呈一定坡度，以避免回流和方便排放 卫生要求 不锈钢材料 保持循环 不回复阀门 Further water treatment purification s

15、tages downstream of the pre-treatment system 1. Filtration 2. Disinfection 3. Reverse osmosis or de-ionization 4. Distillation or ultra-filtration 24 预处理后的净化步骤 过滤 消毒 反渗透/去离子 蒸馏或超净化 Water system design (1) There should be no dead legs Water scours deadleg If D=25mm & distance X is greater than 50mm,

16、we have a dead leg that is too long. Deadleg section 2D Flow direction arrows on pipes are important Sanitary Valve D X 25 绝对要避免盲管的发生! 3. The water is contaminated as it passes through the valve 2. Bacteria can grow when the valve is closed Water system design (2) 1. Ball valves are unacceptable Sta

17、gnant water inside valve 26 球阀不可用 1. Sanitary pumps 2. Clamps and O rings versus threaded fittings 3. Heat exchangers 4. Side arm level measuring devices are unacceptable Water system design (3) 27 Cationic columnAnionic column Hygienic pump Outlets or storage. Ozone generator UV light HClNaOH Eluat

18、es to neutralization plant Air break to sewer Drain line from water softener Water must be kept circulating Typical de-ionizer schematic 1 2 3 4 5 6 1 2 3 4 5 6 Return to de-ioniser Cartridge filter 5 m Cartridge filter 1 m 28 水必须保持循环 raw water High pressure Feed water under pressure Reject water Se

19、mi-permeable membrane Permeate water drain or recycle Low pressure Purified water Reverse osmosis (RO) theory 29 反渗透 Branch Branch 2nd stage buffer tank Cartridge filter 1 m Second stage RO cartridge First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank . 1st stage rej

20、ect concentrate Air break to sewer Second stage reject water goes back to first stage buffer tank Second stage RO water meets Pharmacopoeia standardsOutlets or storage 1st stage buffer tank Water from softener or de-ioniser Water returns to 1st stage buffer tank Typical 2-stage RO schematic Hygienic

21、 pump First stage RO cartridge High pressure pump 30 Use of reverse osmosis Advantages No harmful by-products Energy efficient Disadvantages Slow speed Possible contamination Waste water Many uses purified water feeding of distillation units or ultra-filtration units Water for Final Rinse Water for

22、Injections (if permissible) 31 RO优点和缺点 Ultra-filtration超过滤 Can be used for WFI or for Water For Final Rinsing for parenteral manufacturing (if permitted) Removes organic contaminants, such as endotoxins Operation at 80C, and sterilization at 121 C 32 1. Single-effect distillation simple distillation

23、, single effect vapour compression, thermo compression 2. Multi effect distillation multiple effect stills 3. Clean steam generators used where steam can come into contact with product contact surfaces, e.g. sterilization- in-place (SIP) 33 Typical water storage and distribution schematic Water must

24、 be kept circulatin g Spray ball Cartridge filter 1 m Air break to drain Outlets Hygienic pump Optional in-line filter 0,2 m UV light Feed Water from DI or RO Heat Exchanger Ozone Generator Hydrophobic air filter & burst disc 34 典型水储存和流向图 Disinfection (1)杀菌 Heat One of the most reliable methods of d

25、isinfection of water systems Ozone Produced easily Leaves no residue 35 Disinfection (2) UV 1. UV does not “sterilize” 2. Flow rate critical 3. Post-irradiation recontamination may be an issue 4. Lamps have finite life Other chemicals 1. XO2 2. Halogen 3. Formaldehyde 36 Sampling (1)取样 1. There must

26、 be a sampling procedure 2. Sample integrity must be assured 3. Sampler training 4. Sample point 5. Sample size 37 Sampling (2) 1. Sample container 2. Sample label 3. Sample storage and transport 4. Arrival at the laboratory 5. Start of test 38 Testing - setting specifications for purified water or

27、WFI - (1) Ph. Eur. JP USPInt. Ph. pH 5.0-7.05.0-7.0 5.0-7.0 pass test Cl 0.5 pass test - pass test SO4 pass test pass test - pass test NH4 0.2 0.05 - pass test Ca/Mg pass test - - pass test Nitrates 0,2 pass test - pass test Nitrites - pass test - - 39 水的指标 Ph. Eur. JP USPInt. Ph Conductivity (S/cm)

28、 - 1.3 - Oxidizable subs.pass test pass test -pass test Solids (ppm) 10 10 - nmt(*) 10 TOC (ppm) - 0.5 0.5 - Heavy metals - -pass test CO2 - -pass test Testing - setting specifications for purified water or WFI (2) 40 Testing测试 1. Method verification方法验证 2. Chemical testing化学测试 3. Microbiological te

29、sting微生物测试 test method types of media used incubation time and temperature objectionable and indicator organisms manufacturer must set specifications 41 Suggested bacterial limits 细菌含量 (CFU /mL) Sampling locationTarget AlertAction Raw water200300500 Post multimedia filter100300500 Post softener10030

30、0500 Post activated carbon filter50300500 Feed to RO20200500 RO permeate1050100 Points of Use110100 42 Part III Water System Inspection 水系统的检验 43 Raw water storage水的储存 l May be required prior to pre-treatment l Check material of construction Concrete, steel are acceptable but check corrosion Plastic

31、s or plastic linings may leach l Check cover To keep out insects, birds and animals l Check disinfection practices Water for Pharmaceutical Use 44 Water treatment system inspection (1) Checks may include: dead legs filters pipes and fittings Ionic beds storage tanks by-pass lines Water for Pharmaceu

32、tical Use 45 盲管 过滤器 管道 离子床 储存罐 支管 Water treatment system inspection (2) Checks may include: pumps UV lights sample points reverse osmosis valves heat exchangers Instruments, controls, gauges, etc. Water for Pharmaceutical Use 46 泵 紫外灯 取样点 反向渗透 阀 热交换器 设备，仪表等 Other checks (1) Stainless steel PVC and m

33、ost plastics not recommended Weld quality Water for Pharmaceutical Use 47 材料 焊接点 Other checks (2) Pipes and pumps hygienic couplings welded pipes hygienic pumps hygienic sampling points acceptable floor no leaks Water for Pharmaceutical Use 48 Staining on water storage tanks Corrosion on plates of h

34、eat exchangers indicates possible contamination Other checks (3) Check condition of equipment Water for Pharmaceutical Use 49 Other checks (4) Maintenance records, maintenance of pump seals and O rings Water for Pharmaceutical Use 50 维修记录 Air filters l Integrity testing, sterilization and replacemen

35、t frequency l Check burst discs Other checks (5) Water for Pharmaceutical Use 51 Other checks (7) l Activated carbon bed sanitization l Temperature-compensated conductivity meters l Influence of plastic pipe adhesive on TOC l Non-condensable gases in pure steam Water for Pharmaceutical Use 52 Other

36、checks (8) l Polypropylene welding inspection checking pin holes l Retrospective validation of WFI system l Rouging of WFI storage systems l Spray ball efficacy Water for Pharmaceutical Use 53 Other checks (9) l UV light monitoring performance and lamp life and intensity l Validating ozone dosage l

37、Specifications for acids, alkalis for DI and sodium chloride for water softener l “Normally open” and “normally closed” valves Water for Pharmaceutical Use 54 Then review additional documentation Qualification protocols and reports Change control request (where applicable) Requalification (where app

38、licable) QC and microbiology laboratory: SOP for sampling Procedures and records 55 Sampling (1)取样 l There must be a sampling procedure l Sample integrity must be assured l Sampler training l Sample point l Sample size 56 Sampling (2)取样 l Sample container l Sample label l Sample transport and storag

39、e l Arrival at the laboratory l Test method l When is the test started? 57 Testing测试 l Review method verification l Chemical testing l Microbiological testing test method types of media used incubation time and temperature objectionable and indicator organisms manufacturer must set specifications 58

40、 Suggested bacterial limits (CFU /mL) Sampling locationTarget AlertAction Raw water200300500 Post multimedia filter100300500 Post softener100300500 Post activated carbon filter50300500 Feed to RO20200500 RO permeate1050100 Points of Use110100 59 Does Yinjing have two separated parts in the water system purification and distribution? Where is the “dead lake” at the beginning? Before which stage of purification system? For the RO column/system, how often do they get changed? Does Yinjing have stainless stee