1. 1 Reminder: Resistivity (ohms) is the reciprocal to conductivity (micro-Siemens)

2. BEWARE of Biofilm Buildup SOURCE: http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm 164

3. Process Water System Design Phase Assemble cross-functional team Determine quality of feed water Determine required specifications Write protocols Pre-validation Calibration of instruments Validation of test methods 3

4. Purified Water System Design Considerations 316LSS material of construction Sanitary electro-polishing and passivation Sanitary clamp fittings or orbital welds Lines sloped to drain 1/8 in/ft Recirculation loop 3-5ft/sec Sanitary pumps, Submicron filters (0.2μm) on tanks and vents Use-point fittings or GMP valves Sanitary diaphragm-type and stem valves only. No ball, gate, plug, butterfly, globe or disc valves. Drains must have air-break to prevent back-siphoning Minimize dead-legs to 6D Control biofilm buildup (recirculation, 85oC, ozonation) No added substances SOURCE: Manfredi, Joe, “Myths, Rumors, Fantasies about Water System Design”, Pharmaceutical Technology CGMP Compliance 2006, pp 28-38 4

5. 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 circulatin g Typical deionizer schematic 1 2 3 4 5 6 1 2 3 4 5 6 Return to deioniczer Cartridge filter 5 µm Cartridge filter 1 µm Water for Pharmaceutical Use

6. Installation Qualification Assure that the system is installed per design criteria Test water before and after each piece of equipment in-line. Not just at point-of-use! Use that data to write your SOPs (backflushing, regeneration, etc.) For example... 6

7. Qualification of Mixed Bed Deionizers Conductivity PSID (scaling) Run length gallonage Amount of regenerate Rinse water gallonage Silica (channeling) Bacterial load Other (eg. Air quality) Monitor feed water and effluent Regeneration In-Use Dilute Base Anion Cation Air Dilute Acid To Waste Purified Process Water Cation & Anion Mixed Bed Mixed bed regeneration requires backwashing for separate treatment with acid and base. They are mixed with air before start-up. 7

8. Operation Qualification Is the system operating correctly? –Pumps at right pressure? –Water flow correct? Continue to test feed water, sample ports and points-of-use Monitor system changes to validate the SOPs 8

9. Water Validation and the Corporate Audit Allow extra time to audit the water system Trained persons are needed to maintain the water system Must check for specifications and acceptance criteria for each sampling point 9

10. 10 Water for Process Use Designed, constructed and validated to prevent microbial proliferation and assure quality SOPs for maintenance, cleaning & sanitization on frequent basis Monitor & test to assure conformance to chemical, physical and microbiological specifications Sanitary sampling ports after each component Check at point-of-use daily Record & document test results Alert & action limits Corrective action plan

11. Performance Qualification Test all sample ports for 30 consecutive days (spring, summer, fall and winter) Validation complete after one full year Trend analysis may help avoid having to revalidate Develop change control procedures Establish acceptance criteria for each piece of equipment Establish alert and action limits Develop corrective action plans Confirm the action had the desired affect 11

12. Establish microbial quality control using trend analysis

13. The Validation Timeline