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Water Part3

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WHO: Supplementary Training Modules on Good Manufacturing Practice

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Water Part3

  1. 1. Supplementary Training Modules on Good Manufacturing Practice Water for Pharmaceutical Use Part 3: Inspection of water purification systems WHO Technical Report Series No 929, 2005. Annex 3Water | Slide 1 of 30 January 2006
  2. 2. Water for Pharmaceutical Use Objectives To understand: The specific requirements when inspecting water systems, including associated documentation Water system inspection techniques and approachesWater | Slide 2 of 30 January 2006
  3. 3. Water for Pharmaceutical Use 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 8.Water | Slide 3 of 30 January 2006
  4. 4. Water for Pharmaceutical Use 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. 8.Water | Slide 4 of 30 January 2006
  5. 5. Water for Pharmaceutical Use 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 reviewWater | Slide 5 of 30 January 2006
  6. 6. Water for Pharmaceutical Use 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 systemsWater | Slide 6 of 30 January 2006
  7. 7. Water for Pharmaceutical Use Documentation should reflect information on:  Pipeline  Valves (non-return type)  Breather points  Couplings  Pipe slope  Velocities  Sampling points  Drain points  Instrumentation  Flow ratesWater | Slide 7 of 30 January 2006
  8. 8. Water for Pharmaceutical Use 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 requirementsWater | Slide 8 of 30 January 2006
  9. 9. Water for Pharmaceutical Use 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 | Slide 9 of 30 January 2006
  10. 10. Water for Pharmaceutical Use Well water Inspect exposed parts of the well, depth of well Check for nearby septic systems, hazardous materials usage (pesticides, fertilizers, etc.) Well maintenanceWater | Slide 10 of 30 January 2006
  11. 11. Water for Pharmaceutical Use Raw water storage May be required prior to pre-treatment Check material of construction – Concrete, steel are acceptable but check corrosion – Plastics or plastic linings may leach Check cover – To keep out insects, birds and animals Check disinfection practicesWater | Slide 11 of 30 January 2006
  12. 12. Water for Pharmaceutical Use Water treatment system inspection (1)  Checks may include: – dead legs – filters – pipes and fittings – Ionic beds – storage tanks – by-pass linesWater | Slide 12 of 30 January 2006
  13. 13. Water for Pharmaceutical Use Water treatment system inspection (2)  Checks may include: – pumps – UV lights – sample points – reverse osmosis – valves – heat exchangers – Instruments, controls, gauges, etc.Water | Slide 13 of 30 January 2006
  14. 14. Water for Pharmaceutical Use Other checks (1)  Stainless steel – PVC and most plastics not recommended  Weld quality  Hygienic couplings  Passivation  Air breaks or “Tundish”Water | Slide 14 of 30 January 2006
  15. 15. Water for Pharmaceutical Use Other checks (2)Pipes and pumps – hygienic couplings – welded pipes – hygienic pumps – hygienic sampling points – acceptable floor – no leaksWater | Slide 15 of 30 January 2006
  16. 16. Water for Pharmaceutical Use Other checks (3) Check condition of equipment Staining on water storage tanks Corrosion on plates of heat exchangers indicates possible contaminationWater | Slide 16 of 30 January 2006
  17. 17. Water for Pharmaceutical Use Other checks (4) Maintenance records, maintenance of pump seals and O ringsWater | Slide 17 of 30 January 2006
  18. 18. Water for Pharmaceutical Use Other checks (5) Air filters Integrity testing, sterilization and replacement frequency Check burst discsWater | Slide 18 of 30 January 2006
  19. 19. Water for Pharmaceutical Use Other checks (6) Softened water out to deionizer By-pass lines By-pass valve Carefully check by-pass valves and lines These sometimes leak or are inadvertently left open A blanking piece is better during operation phase Zeolite water softener exchanges Ca and Mg for NaWater | Slide 19 of 30 January 2006
  20. 20. Water for Pharmaceutical Use Other checks (7) Activated carbon bed sanitization Temperature-compensated conductivity meters Influence of plastic pipe adhesive on TOC Non-condensable gases in pure steamWater | Slide 20 of 30 January 2006
  21. 21. Water for Pharmaceutical Use Other checks (8) Polypropylene welding inspection – checking pin holes Retrospective validation of WFI system Rouging of WFI storage systems Spray ball efficacyWater | Slide 21 of 30 January 2006
  22. 22. Water for Pharmaceutical Use Other checks (9) UV light – monitoring performance and lamp life and intensity Validating ozone dosage Specifications for acids, alkalis for DI and sodium chloride for water softener “Normally open” and “normally closed” valvesWater | Slide 22 of 30 January 2006
  23. 23. Water for Pharmaceutical Use 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 recordsWater | Slide 23 of 30 January 2006
  24. 24. Water for Pharmaceutical Use Sampling (1) There must be a sampling procedure Sample integrity must be assured Sampler training Sample point Sample sizeWater | Slide 24 of 30 January 2006
  25. 25. Water for Pharmaceutical Use Sampling (2) Sample container Sample label Sample transport and storage Arrival at the laboratory Test method When is the test started?Water | Slide 25 of 30 January 2006
  26. 26. Water for Pharmaceutical Use Testing Review method verification Chemical testing Microbiological testing – test method – types of media used – incubation time and temperature – objectionable and indicator organisms – manufacturer must set specificationsWater | Slide 26 of 30 January 2006
  27. 27. Water for Pharmaceutical Use Suggested bacterial limits (CFU /mL) Sampling location Target Alert Action   Raw water 200 300 500 Post multimedia filter 100 300 500 Post softener 100 300 500 Post activated carbon filter 50 300 500 Feed to RO 20 200 500 RO permeate 10 50 100 Points of Use 1 10 100Water | Slide 27 of 30 January 2006
  28. 28. Water for Pharmaceutical Use Pyrogens and endotoxins Any compound injected into mammals which gives rise to fever is a “Pyrogen” Endotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments Detect endotoxins using a test for lipopolysaccharides (LPS) – rabbit test detects pyrogens – LAL test detects endotoxins Ultrafiltration, distillation and RO may remove pyrogensWater | Slide 28 of 30 January 2006
  29. 29. Water for Pharmaceutical Use Group Session You are given a schematic drawing of a water system to discuss. List any problems and their solutions IN C O R R E C T W A T E R T R E A T M E N T PL A N T Water | Slide 29 of 30 January 2006
  30. 30. Water for Pharmaceutical Use Group Session M O D IFIE D W A T E R T R E A T M E N T PL A N TWater | Slide 30 of 30 January 2006

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