1. WHO - PSM Water for Pharmaceutical Use Water –part 2 Workshop on GMP and Quality Assurance of HIV products Shanghai, China 28 Feb - 4 March 2005 Maija Hietava M.Sci.Pharm Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster Tel: +41.22.791.3598 Fax: +41.22.791.4730 World Health Organization E-mail: hietavam@who.int

2. WHO - PSM Water for Pharmaceutical Use Water purification engineering

3. WHO - PSM Water for Pharmaceutical Use 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

4. WHO - PSM Water for Pharmaceutical Use Water system design 1. Pipes 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)

5. WHO - PSM Water for Pharmaceutical Use Further water treatment purification stages downstream of the pre-treatment system 1. Filtration 2. Disinfection 3. Reverse osmosis or de-ionization 4. Distillation or ultra-filtration

6. WHO - PSM Water for Pharmaceutical Use Water system design (1) There should be no dead legs

7. WHO - PSM Water for Pharmaceutical Use 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 Stagnant water inside valve

8. WHO - PSM Water for Pharmaceutical Use 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)

9. WHO - PSM Water for Pharmaceutical Use Cationic column Anionic column Hygienic pump Outlets or storage. Ozone generator UV light HClNaOH Eluates 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 µm Cartridge filter 1 µm

10. WHO - PSM Water for Pharmaceutical Use Use of reverse osmosis (1) l Advantages ä Less chemical handling than ion exchange ä More effective microbial control than ion exchange ä Integrity test possible ä Removes most of organic and non-organic contaminants ä Less energy consumption than distillation

11. WHO - PSM Water for Pharmaceutical Use Use of reverse osmosis (2) l Disadvantages ä Water consumption higher than IE unless waste- water is re-used ä Danger of microbial growth on membrane ä Sterilization/sanitization with steam not possible ä No removal of dissolved gases ä Working at high temperature (>65 °C) only possible with certain types of membrane

12. WHO - PSM Water for Pharmaceutical Use Use of reverse osmosis (3) l Many uses ä purified water /pharmacopoeia specs ä feeding of distillation units or ultra-filtration units ä Water for Final Rinse ä Water for Injections (if permissible)

13. WHO - PSM Water for Pharmaceutical Use Ultra-filtration l Can be used for WFI or for Water For Final Rinsing for parenteral manufacturing (if permitted) l Removes organic contaminants, such as endotoxins l Operation at 80°C, and sterilization at 121 °C

14. WHO - PSM Water for Pharmaceutical Use 1. Single-effect distillation ä simple distillation, single effect ä vapour compression, thermo compression 2. Multi effect distillation ä multiple effect stills 3. Clean steam generators ä used where steam can come into contact with product contact surfaces, e.g. sterilization-in-place (SIP)

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

16. WHO - PSM Water for Pharmaceutical Use Disinfection (1) Heat l One of the most reliable methods of disinfection of water systems Ozone l Produced easily l Leaves no residue

17. WHO - PSM Water for Pharmaceutical Use 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. XO 2 2. Halogen 3. Formaldehyde

18. WHO - PSM Water for Pharmaceutical Use Sampling (1) 1. There must be a sampling procedure/point of use! 2. Sample integrity must be assured 3. Sampler training 4. Sample point 5. Sample size

19. WHO - PSM Water for Pharmaceutical Use Sampling (2) 1. Sample container 2. Sample label 3. Sample storage and transport 4. Arrival at the laboratory 5. Start of test

20. WHO - PSM Water for Pharmaceutical Use Testing - specifications for purified water or WFI in the pharmacopeias

21. WHO - PSM Water for Pharmaceutical Use Testing 1. Method verification 2. Chemical testing 3. Microbiological testing

22. WHO - PSM Water for Pharmaceutical Use Water for Injections 1. International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens 2. Usually prepared by distillation 3. Storage time should be less than 24 hours 4. Microbial limits must be specified

23. WHO - PSM Water for Pharmaceutical Use Water for Final Rinse l Water for final rinse must be of the same quality as the water required for pharmaceutical preparation

24. WHO - PSM Water for Pharmaceutical Use 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