1. Water | Slide 1 of 30 January 2006 Water for Pharmaceutical Use Part 3: Inspection of water purification systems Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series No 929, 2005. Annex 3

2. Water | Slide 2 of 30 January 2006 Objectives To understand: lThe specific requirements when inspecting water systems, including associated documentation lWater system inspection techniques and approaches Water for Pharmaceutical Use

3. Water | Slide 3 of 30 January 2006 Prepare an aide-memoire for items to inspect: Schematic drawing review Changes to system since installation Sampling procedure and plan Specifications, results and trends Out-of-specification results Annual system review Deviations Water for Pharmaceutical Use 8.

4. Water | Slide 4 of 30 January 2006 Prepare an aide-memoire for items to inspect (2): Results of system performance monitoring Out of limit results, failure investigations and alarms recorded Sanitization procedures and records Maintenance and repairs logs/records Instrument calibration and standardization Qualification and validation including DQ, IQ, OQ, PQ Requalification when appropriate, etc. Water for Pharmaceutical Use 8.

5. Water | Slide 5 of 30 January 2006 Where to start: What is the water to be used for? –sterile products –non-sterile products, e.g. oral liquid products, external applications –solid dosage forms –washing and rinsing Start: Document review – site verification – followed by additional document review Water for Pharmaceutical Use

6. Water | Slide 6 of 30 January 2006 Verification: Start with document review (e.g. schematic drawing of the system, "water quality manual" if available) Review change control (in case of changes after qualification and validation) On site verification (system in accordance with the drawing) Start source water supply Pre-treatment and treatment systems Water for Pharmaceutical Use

7. Water | Slide 7 of 30 January 2006 Documentation should reflect information on: Pipeline Valves (non-return type) Breather points Couplings Pipe slope Velocities Sampling points Drain points Instrumentation Flow rates Water for Pharmaceutical Use

8. Water | Slide 8 of 30 January 2006 Documentation should reflect information on (2): Specification for each system element Standard procedures for use System changes Routine and non-routine maintenance Investigations and corrective action Validation studies Chemical and microbiological specifications Sampling instructions Test procedures Responsible persons Training requirements Water for Pharmaceutical Use

9. Water | Slide 9 of 30 January 2006 On site review and verification: Walk through the system, verifying the parts of the system as indicated in the drawing Review procedures and "on site" records, logs, results Verify components, sensors, instruments Inspect the finishing, state, calibration status, labels, pipes, tanks etc as discussed in previous parts of this module Start with source water supply – follow whole system "loop" Water for Pharmaceutical Use

10. Water | Slide 10 of 30 January 2006 Well water lInspect exposed parts of the well, depth of well lCheck for nearby septic systems, hazardous materials usage (pesticides, fertilizers, etc.) lWell maintenance Water for Pharmaceutical Use

11. Water | Slide 11 of 30 January 2006 Raw water storage lMay be required prior to pre-treatment lCheck material of construction –Concrete, steel are acceptable but check corrosion –Plastics or plastic linings may leach lCheck cover –To keep out insects, birds and animals lCheck disinfection practices Water for Pharmaceutical Use

12. Water | Slide 12 of 30 January 2006 Water treatment system inspection (1) Checks may include: –dead legs –filters –pipes and fittings –Ionic beds –storage tanks –by-pass lines Water for Pharmaceutical Use

13. Water | Slide 13 of 30 January 2006 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

14. Water | Slide 14 of 30 January 2006 Other checks (1) Stainless steel – PVC and most plastics not recommended Weld quality Hygienic couplings Passivation Air breaks or “Tundish” Water for Pharmaceutical Use

15. Water | Slide 15 of 30 January 2006 Other checks (2) Pipes and pumps –hygienic couplings –welded pipes –hygienic pumps –hygienic sampling points –acceptable floor –no leaks Water for Pharmaceutical Use

16. Water | Slide 16 of 30 January 2006 Staining on water storage tanks Corrosion on plates of heat exchangers indicates possible contamination Other checks (3) Check condition of equipment Water for Pharmaceutical Use

17. Water | Slide 17 of 30 January 2006 Other checks (4) Maintenance records, maintenance of pump seals and O rings Water for Pharmaceutical Use

18. Water | Slide 18 of 30 January 2006 Air filters l Integrity testing, sterilization and replacement frequency l Check burst discs Other checks (5) Water for Pharmaceutical Use

19. Water | Slide 19 of 30 January 2006 l Carefully check by-pass valves and lines l These sometimes leak or are inadvertently left open l A blanking piece is better during operation phase Other checks (6) Zeolite water softener exchanges Ca and Mg for Na Softened water out to deionizer By-pass valve By-pass lines Water for Pharmaceutical Use

20. Water | Slide 20 of 30 January 2006 Other checks (7) lActivated carbon bed sanitization lTemperature-compensated conductivity meters lInfluence of plastic pipe adhesive on TOC lNon-condensable gases in pure steam Water for Pharmaceutical Use

21. Water | Slide 21 of 30 January 2006 Other checks (8) lPolypropylene welding inspection –checking pin holes lRetrospective validation of WFI system lRouging of WFI storage systems lSpray ball efficacy Water for Pharmaceutical Use

22. Water | Slide 22 of 30 January 2006 Other checks (9) lUV light – monitoring performance and lamp life and intensity lValidating ozone dosage lSpecifications for acids, alkalis for DI and sodium chloride for water softener l“Normally open” and “normally closed” valves Water for Pharmaceutical Use

23. Water | Slide 23 of 30 January 2006 Then review additional documentation Qualification protocols and reports Change control request (where applicable) Requalification (where applicable) QC and microbiology laboratory: SOP for sampling Procedures and records Water for Pharmaceutical Use

24. Water | Slide 24 of 30 January 2006 Sampling (1) l There must be a sampling procedure l Sample integrity must be assured l Sampler training l Sample point l Sample size Water for Pharmaceutical Use

25. Water | Slide 25 of 30 January 2006 Sampling (2) l Sample container l Sample label l Sample transport and storage l Arrival at the laboratory l Test method l When is the test started? Water for Pharmaceutical Use

26. Water | Slide 26 of 30 January 2006 Testing lReview method verification lChemical testing lMicrobiological testing –test method –types of media used –incubation time and temperature –objectionable and indicator organisms –manufacturer must set specifications Water for Pharmaceutical Use

27. Water | Slide 27 of 30 January 2006 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 Water for Pharmaceutical Use

28. Water | Slide 28 of 30 January 2006 Pyrogens and endotoxins lAny compound injected into mammals which gives rise to fever is a “Pyrogen” lEndotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments lDetect endotoxins using a test for lipopolysaccharides (LPS) –rabbit test detects pyrogens –LAL test detects endotoxins lUltrafiltration, distillation and RO may remove pyrogens Water for Pharmaceutical Use

29. Water | Slide 29 of 30 January 2006 Group Session You are given a schematic drawing of a water system to discuss. List any problems and their solutions Water for Pharmaceutical Use

30. Water | Slide 30 of 30 January 2006 Group Session Water for Pharmaceutical Use