1. Pharmaceutical Water Systems Alain Kupferman Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009

2. 2 |2 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 FACTORS CONTRIBUTING TO QUALITY PRODUCTS Raw Materials Personnel Procedures Validated processes Equipment Premises Environment Packing Materials Water for Pharmaceutical Use PW HPW WFI CS

3. 3 |3 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 PREREQUISITES FOR OPERATION AND (RE)QUALIFICATION As usual…… Good design Good engineering Good execution Good operation Good documentation and Good maintenance

4. 4 |4 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 DEFINING THE NEEDS Regulatory (Pharmacopeia) PW HPW WFI EU ? PICS ? FDA ? User requirements Data on raw water

5. 5 |5 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 DEFINING THE NEEDS: WHICH TYPE OF WATER WHERE ? Regulatory (Pharmacopeia) PW HPW WFI EU ? PICS ? FDA ? Regulatory (EMEA)

6. 6 |6 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 DEFINING THE NEEDS: WHICH TYPE OF WATER WHERE ?

7. 7 |7 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 GMP + GEP Drainability : slopes Flow speed In-process controls, sampling points Valves and accessories Size of generator(s) and storage tanks Critical parameters handling Etc.

8. 8 |8 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 USER REQUIREMENTS Quantitative data: how much when ? Installation type: IE, RO, double RO, EDI Multi-effect, thermocompression,.. Loop type and storage: hot, cold, mixed, multiple fixed or variable speed pump deadlegs, valve types, … Sanitisation: heat, chemical, ozone Materials: stainless steel ? + treatment Heat exchangers: type

9. 9 |9 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 Critical parameters handling I C R A I=Indicate C=Control R=Record A=Alarm Base for instrumentation qualification QUALIFICATION ITEMS

10. 10 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 QUALIFICATION ITEMS IQ Inspection of mechanical installation and documentation (manuals, data sheets, components certificates) System installed in accordance with P&I diagram Check of components (agree with description in components list) Gap between waste water and drain Dead legs in distribution system (6D, 3D, 1,5 D ???) FDA not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use WHO Deadlegs in the pipework installation greater than 1,5 times the branch diameter should be avoided

11. 11 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 GMP + GEP CALCULATION Size of generator(s) and storage tanks

12. 12 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 QUALIFICATION ITEMS IQ Welding documentation (material certificates for pipes and fittings, FDA certificates for gaskets) Isometric drawings with weld numbers Welded seam documentation (machine protocols) Welder approval test certificate Pickling and passivation protocol Endoscopic photos Analytical certificate of inert gas

13. 13 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 QUALIFICATION ITEMS OQ Calibration of measuring equipment (Pressure, temperature, conductivity) Leak test Operation of softener (residual hardness, regeneration) Operation of RO plant (flow rates, conductivity) Operation of bisulphite dosing (if required) Function of regulating circuits in RO plant Operation of ozone generator and ozone meter (ozone concentration) Operation of UV unit (Ozone concentration, intensity of light) System parameters and limit-value settings Flow rate (Reynolds value) Water quality (conductivity, microbiological situation, TOC)

14. 14 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 QUALIFICATION ITEMS OQ Gradients in distribution system Drainability of distribution system Inspection of electrical hardware Emergency-off switch Analogue inputs and outputs Program steps disinfection softener, RO Program steps sanitisation softener, RO, EDI, loop Alarms Access rights, passwords

15. 15 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 PERFORMANCE QUALIFICATION 3-phased approach Phase I (2-4 weeks) Water is not used for production purposes

16. 16 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 PERFORMANCE QUALIFICATION 3-phased approach Phase II (2-4 weeks) Same sampling scheme as phase I Water can be used for production purposes

17. 17 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 PERFORMANCE QUALIFICATION 3-phased approach Phase III (50 weeks) Water can be used for production purposes

18. 18 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 SUBSEQUENT PERIODS Continuous system monitoring Maintenance (preventative) System reviews trending, performance, changes failures, investigations, OOS, etc.

19. 19 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009 Questions, please…. ?