Supplementary Training Modules on Good Manufacturing Practice

1. Water for Pharmaceutical UsePart 2: Water purification engineeringPresented byDr. Errol Allcoc 30 June 2005, Pretoria, South AfricaErrol.Allcock@microsep.co.za083-459 6267 Supplementary Training Modules on Good Manufacturing Practice

2. Objectives To examine the basic technology and requirements for: • Water treatment systems • Storage requirements • Sampling and testing • Different types of water used in pharmaceuticals • Microbial limits, disinfection

3. Water system design • Pipes sloped so water does not pool and can drain easily • Sanitary fittings & connections • Constructed of suitable materials such as stainless steel • Circulate the water • Incorporate non-return valves (NRV)

4. Further water treatment purification stages downstream of the pre-treatment system • Filtration • Disinfection • Reverse osmosis or de-ionization • Distillation or ultra-filtration

5. D Flow direction arrows on pipes are important Deadleg section X <2D If D=25mm & distance X isgreater than 50mm, we have a dead leg that is too long. Sanitary Valve Water scours deadleg Water system design (1) There should be no dead legs

6. Water system design (2) 1. Ball valves are unacceptable 2. Bacteria can grow when the valve is closed 3. The water is contaminated as it passes through the valve Stagnant water inside valve

7. Water system design (3) • Sanitary pumps • Clamps and O rings versus threaded fittings • Heat exchangers • Side arm level measuring devices are unacceptable

8. Typical de-ionizer schematic from water softener HCl NaOH 6 6 5 5 4 4 3 3 2 2 1 1 Water must be kept circulating Anionic column Cartridge filter 5 µm Cartridge filter 1 µm Cationic column UV light Eluates to neutralization plant Ozone generator Hygienic pump Return to de-ioniser Outlets or storage. Drain line Air break to sewer

9. Up and Down Flow DOWNFLOW : No channeling and better ion capture, but higher risk of UPFLOW : clogging Channeling Used in but lower Polishing risk of clogging Used in Pretreatment

10. SEM of Ion-Exchange Resin Bead Bead diameter: 300 to 1200 µm (0.3 to 1.2 mm) Beads pores: 1 to 100 nm (0.001 to 0.1 µm) Bead dry weight 40 to 60%

11. Ion-Exchange Resin Bead model Fixed Anion Counter Cation Styrene Cross linking Agent (DVB) Hydrating Water

12. 1 2 1 2 Reverse Osmosis Reverse Osmosis Osmosis P Osmotic pressure 1 2 Reverse osmosis membrane (RO) Feed water Purified water

13. Low pressure High pressure Feed water under pressure Semi-permeable membrane Purified water raw water Reject water Permeate water drain or recycle Reverse osmosis (RO) theory

14. Reverse Osmosis Membrane Permeate Feed Water Reject

15. Typical 2-stage RO schematic Water from softener or de-ioniser Second stage reject water goes back to first stage buffer tank 1st stage buffer tank First stage RO cartridge Branch Branch 1st stage reject concentrate First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank . Air break to sewer Second stage RO cartridge 2nd stage buffer tank High pressure pump Cartridge filter 1 µm Hygienic pump Second stage RO water meets Pharmacopoeia standards Water returns to 1st stage buffer tank Outlets or storage

16. Use of reverse osmosis • Advantages • Disadvantages • Many uses • purified water • feeding of distillation units or ultra-filtration units • Water for Final Rinse • Water for Injections (if permissible)

17. Ultra-filtration • Can be used for WFI or for Water For Final Rinsing for parenteral manufacturing (if permitted) • Removes organic contaminants, such asendotoxins • Operation at 80°C, and sterilization at 121 °C

18. Ultrafiltration • Ultrafilters are asymetric membranes, sometimes composite • Under pressure,small size molecules go through the membrane,whereas molecules larger then the NMWL are retained

19. Single-effect distillation • simple distillation, single effect • vapour compression, thermo compression • Multi effect distillation • multiple effect stills • Clean steam generators • used where steam can come into contact with product contact surfaces, e.g. sterilization-in-place (SIP)

20. Typical water storage and distribution schematic Hydrophobic air filter & burst disc Feed Water from DI or RO Cartridge filter 1 µm Spray ball Water must be kept circulating Optional in-line filter 0,2 µm UV light Outlets Heat Exchanger Air break to drain Ozone Generator Hygienic pump

21. Disinfection (1) Heat • One of the most reliable methods of disinfection of water systems Ozone • Produced easily • Leaves no residue

22. Disinfection (2) UV • UV does not “sterilize” • Flow rate critical • Post-irradiation recontamination may be an issue • Lamps have finite life Other chemicals • XO2 • Halogen • Formaldehyde

23. UV Technology :Electromagnetic Spectrum Gamma rays X Rays U.V. Visible Infrared 10-10 10-7 10-6 10-4 10-3 Wavelength(m) Ultraviolet radiation Ultra short Short Medium Long wave UV-C UV-B UV-A 315 100 400 200 280 Wavelength (nm)

24. U. V. Technology Relative intensity Wavelength (nm) 185 254 313 Emission of a low pressure mercury lamp.

25. Germicidal Action 100% 80% 254nm 60% 40% 20% 0% 300 320 240 260 280

26. Conversion of traces of organic contaminants to charged species and ultimately CO2 (185 + 254) Limited destruction of micro-organisms and viruses (254) Limited energy use Easy to operate Polishing technique only: may be overwhelmed if organics concentration in feed water is too high. Organics are converted, not removed. Limited effect on other contaminants Good design required for optimum performance. UV Technology (185 + 254 nm)

27. Contaminants Removal CONTAMINANT STILL MF DI RO UF AC IONS ORGANICS PARTICLES COLLOIDS BACTERIA VIRUSES GASES UV : converts organic molecules to CO2 or charged molecules

28. Sampling (1) • There must be a sampling procedure • Sample integrity must be assured • Sampler training • Sample point • Sample size

29. Sampling (2) • Sample container • Sample label • Sample storage and transport • Arrival at the laboratory • Start of test

30. Testing - setting specifications for purified water or WFI - (1) Ph. Eur. JP USP Int. Ph. pH 5.0-7.0 5.0-7.0 5.0-7.0 pass test Cl< 0.5 pass test - pass test SO4pass test pass test - pass test NH4< 0.2 < 0.05 - pass test Ca/Mgpass test - - pass test Nitrates < 0,2 pass test - pass test Nitrites - pass test - -

31. Testing - setting specifications for purified water or WFI (2) Ph. Eur. JP USP Int. Ph Conductivity (µS/cm)- - < 1.3 - Oxidizable subs. pass test pass test - pass test Solids (ppm) < 10< 10 - nmt(*) 10 TOC (ppm) - < 0.5 < 0.5 - Heavy metals - - - pass test CO2 - - - pass test

32. Testing • Method verification • Chemical testing • Microbiological testing • test method • types of media used • incubation time and temperature • objectionable and indicator organisms • manufacturer must set specifications

33. Water for Injections • International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens • Usually prepared by distillation • Storage time should be less than 24 hours • Microbial limits must be specified

34. Water for Final Rinse • Water for final rinse must be of the same quality as the water required for pharmaceutical preparation

35. 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 • Detectendotoxins using a test for lipopolysaccharides (LPS) • rabbit test detects pyrogens • LAL test detects endotoxins • Ultrafiltration, distillation, &ROmay remove pyrogens

36. 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 10 100 Suggested bacterial limits (CFU/mL)