1. WHO - PSM Water –part 3 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 Inspection on Water systems

3. WHO - PSM Objectives To understand: 1. The specific requirements for inspecting water systems, including ä the need for a Water Quality Manual ä validation of water treatment systems 2. Water system inspection techniques

4. WHO - PSM Review l What is the water to be used for? ästerile products änon-sterile products äliquid products äsolid dose products äwashing and rinsing l Check specifications and trends

5. WHO - PSM WHO water treatment guidance (1) l All water-treatment systems should be subject to: ä planned maintenance ä validation ä monitoring l Maintenance work should be documented

6. WHO - PSM WHO water treatment guidance (2) For reliable production, water treatment plants should be: 1. Designed 2. Constructed 3. Maintained 4. Operated within design limits 5. Controlled to prevent microbial growth

7. WHO - PSM Prepare a checklist or an aide-memoire and review: 1. Water Quality Manual 2. Water system drawing 3. Validation 4. Sampling procedures, locations and plan 5. Records of testing 6. Sanitation and maintenance 7. Schedules of maintenance

8. WHO - PSM Review water quality manual (1) 1. A water quality manual is advisable but prepare it 2. A brief description of water systems is required 3. Include drawings of the purification, storage distribution system (P&ID)

9. WHO - PSM Review of water quality manual (2) l The water quality manual should show: ä pipelines ä non-return (or check) valves ä breather points ä couplings ä pipe slopes ä velocities  valves  sampling points  drain points  instrumentation  flow rates s

10. WHO - PSM Review water quality manual (3) The manual should contain: 1. Specification for each system element 2. Standard procedures for use 3. System changes 4. Routine and non-routine maintenance 5. Investigations and corrective action 6. Validation studies

11. WHO - PSM Review water quality manual (4) The manual should contain 1. Chemical and microbiological specifications 2. Sampling instructions 3. Test procedures 4. Responsible persons 5. Training requirements

12. WHO - PSM Review validation (1) Validation for water systems consists of three phases l Phase 1: 2 – 4 weeks l Phase 2:4 weeks l Phase 3:1 year

13. WHO - PSM Review validation (2) Phase 1 – Investigational Phase (2 – 4 weeks) l DQ, IQ and OQ l Develop ä operational parameters ä cleaning and sanitization procedures and frequencies l Sample daily at each point of use l End of Phase I, develop SOPs for the water system

14. WHO - PSM Review validation (3) Phase 2 – verifying control (4 - 5 weeks) l Demonstrate the system is in control l Same sampling as in phase 1 Phase 3 – verifying long-term control (1 year) l PQ l Demonstrate the system in control over a long period of time l Weekly sampling once from each point of use/sampling point

15. WHO - PSM Conducting the inspection (1) l Take the drawing and walk around the entire system l Check: ä dead legs ä filter ä pipes and fittings ä DI ä storage tanks ä Maintenance and Calibrations/documents ä Inline measuring/analysis ä Results of analysis  OOS/corrective action  pumps  UV lights  sample points  RO  non return valves ä heat exchangers ä normal use of water/sampling

16. WHO - PSM Conducting the inspection (2) Check: l Stainless steel - PVC and most plastics not recommended l Weld quality l Hygienic couplings l Passivation

17. WHO - PSM Conducting the inspection (3) l Check pipes and pumps ä hygienic couplings ä welded pipes ä hygienic pumps ä hygienic sampling points ä acceptable floor ä no leaks

18. WHO - PSM Staining on water storage tanks Corrosion on plates of heat exchangers indicates possible contamination Conducting the inspection (4) Check condition of equipment

19. WHO - PSM Conducting the inspection (5) l Check maintenance records l Check maintenance of pump seals and O rings

20. WHO - PSM l Check air filters l Check integrity testing, sterilization and replacement frequency Conducting the inspection (6)

21. WHO - PSM Conducting the inspection (8) Further points to check: 1. Activated carbon bed sanitization 2. Temperature-compensated conductivity meters 3. Influence of plastic pipe adhesive on TOC 4. Specifications of the pure steam/Non- condensable gases in pure steam

22. WHO - PSM Conducting the inspection (9) Further points to check: (Contd.) 1. Polypropylene welding inspection ä checking pin holes 2. Retrospective validation of WFI system 3. WFI storage systems 4. Spray ball efficacy

23. WHO - PSM Conducting the inspection (10) Further points to check (Contd.) 1. UV light – monitoring performance and lamp life and intensity 1. Validating ozone dosage 2. Specifications for acids, alkalis for DI and sodium chloride for water softener 3. “Normally open” and “normally closed” valves

24. WHO - PSM Conclusions Water is a very important raw material in pharmaceutical industry Water system should be well maintained There should be a responsible person for the system The function of the system should be well described and well documented Inspectors are very interested and exited about water systems …. Be aware well in advance!

25. WHO - PSM Thank you very much for your attention! hietavam@who.int

26. WHO - PSM Thank you very much for your Kindness and Hospitality