Water for Pharmaceutical Use Part 2 : Water purification and engineering

1. Supplementary Training Modules on Good Manufacturing Practice Water for Pharmaceutical Use Part 2: Water purification and engineering WHO Technical Report Series No 929, 2005. Annex 3

2. Water for Pharmaceutical Use Objectives To examine the basic technology and requirements for: • Water treatment systems • Storage and distribution requirements • Sampling and testing • Sanitization 6.

3. Water for Pharmaceutical Use General • Part 1 – reviewed types of water and water purification systems • Water can be used directly, or stored in a storage vessel for subsequent distribution to points of use • Design appropriately to prevent recontamination after treatment • Combination of on-line and off-line monitoring to ensure compliance with water specification 6.1

4. Water for Pharmaceutical Use WPU system contact materials • Contact materials include: • Pipes • Valves and fittings • Seals • Diaphragms and instruments • Tanks • Pumps, etc. • Proper selection to ensure these are suitable 6.2

5. Water for Pharmaceutical Use WPU system contact materials (2) • Factors to consider (including components) • Compatibility and leaching effect • Corrosion resistance • Smooth internal finishing, ease of jointing • Hygienic / sanitary design • Documentation • Materials of construction (MOC) - (including original/certified copies of material certificates 6.2

6. Water for Pharmaceutical Use WPU system contact materials (3) • Compatibility • With temperature and chemicals used in the system • Leaching effect • Non-leaching at temperature range • Corrosion resistance • PW, HPW, WFI highly corrosive • Stainless steel Grade 316L to be used • System passivated after installation and modification according to SOP 6.2

7. Water for Pharmaceutical Use WPU system contact materials (4) • Smooth internal finish • Biofilms and microbial contamination • Crevices and roughness result in problem areas associated with contamination and corrosion • Internal finish to have arithmetical average surface roughness not greater than 0.8 micrometer arithmetical mean roughness (Ra) • Mechanical and electropolishing needed when stainless steel is used 6.2

8. Water for Pharmaceutical Use WPU system contact materials (5) • Joints • System materials easily jointed, e.g. by welding • Process controlled including requirements such as: • Qualification of operator • documentation of welder set up • work session test pieces • weld logs • visual inspection of defined proportions of welds 6.2

9. Water for Pharmaceutical Use WPU system contact materials (6) • Suitable materials include: • Stainless steel Grade 315 L (low carbon) • Polypropylene (PP) • Polyvinylidenedifluoride (PVDF) • Perfluoroalkoxy (PFA) • Unplasticized polyvinylchloride (uPVC) used for non-hygienic designed water treatment equipment such as ion exchangers and softeners 6.2

10. Water for Pharmaceutical Use System sanitization and bioburden control • Systems in place to control proliferation of microbes • Techniques for sanitizing or sterilization • Consideration already during design stage – then validated • Special precautions if water not kept in the range of 70 to 80 degrees Celsius 6.3

11. Water for Pharmaceutical Use Storage and distribution - Storage vessels • Design and size important • Serves as buffer between generation and use • Avoid inefficiencies and equipment stress during frequent on-off cycles • Short-term reserve in case of failure • Contamination control consideration • Headspace (kept wet with spray ball / distributor device) • Nozzles (no dead zone design) • Vent filters (type, testing, use of heat) • Pressure relief valves and burst discs (sanitary design) 6.4

12. Water for Pharmaceutical Use Storage and distribution – Pipes and heat exchangers • Continuous circulating loop needed • Filtration not recommended in loop and take-off point • Heat exchangers: • Double tube plate or double plate and frame type • Designed to ensure no stasis of water • Where water is cooled before use, done in minimum time, and validated process 6.5, 6.5.1

13. Water for Pharmaceutical Use Storage and distribution – Circulation pumps • Sanitary design with appropriate seals • Standby pumps • Can be used • Configured or managed in a way to avoid trapped dead zones 6.5.2

14. Typical water storage and distribution schematic Hydrophobic air filter & burst disc Feed Water from DI or RO Cartridge filter 1 µm Spray ball Water must be kept circulating Optional in-line filter 0,2 µm UV light Outlets Heat Exchanger Air break to drain Ozone Generator Hygienic pump Water for Pharmaceutical Use

15. Water for Pharmaceutical Use Biocontamination control techniques • Continuous turbulent flow circulation • Specified velocity proven (qualification), and monitored • Avoid dead legs • Hygienic pattern diaphragm valves • Shortest possible length of pipe work • Pipe work of ambient temperature systems, isolated from hot pipes 6.5.3

16. D Flow direction arrows on pipes are important Dead leg section X >1.5D If D=25mm & distance X isgreater than 50mm, we have a dead leg that is too long Sanitary Valve Water scours dead leg Water for Pharmaceutical Use Biocontamination control techniques (2) There should be no dead legs

17. Water for Pharmaceutical Use Biocontamination control techniques (3) 1. Ball valves are unacceptable 2. Bacteria can grow when the valve is closed 3. The water is contaminated as it passes through the valve Stagnant water inside valve

18. Water for Pharmaceutical Use Biocontamination control techniques (4) • Pressure gauges separated from system membranes • Pipe work laid to fall (slope) – allows drainage • Maintain system at high temperature (above 70 degrees Celsius) • Use UV radiation • Flow rate, life-cycle of the lamp • Suitable construction material 6.5.3

19. Water for Pharmaceutical Use Biocontamination control techniques (5) • Periodic sanitization with hot water • Periodic sanitization with super-heated hot water or clean steam • Reliable • Monitoring temperature during cycle • Routine chemical sanitization using, e.g. ozone • Removal of agent before use of water important 6.5.3