Water2 0506

Water for Pharmaceutical Use Part 2: Water purification engineering Presented by Dr. Errol Allcoc 30 June 2005, Pretoria, South AfricaErrol.Allcock@microsep.co.za083-459 6267: 

Water for Pharmaceutical Use Part 2: Water purification engineering Presented by Dr. Errol Allcoc 30 June 2005, Pretoria, South Africa Errol.Allcock@microsep.co.za 083-459 6267 Supplementary Training Modules on Good Manufacturing Practice

Slide2: 

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

Slide3: 

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)

Slide4: 

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

Slide5: 

Water system design (1) There should be no dead legs

Slide6: 

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

Slide7: 

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

Up and Down Flow: 

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

SEM of Ion-Exchange Resin Bead: 

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%

Ion-Exchange Resin Bead model: 

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

Slide12: 

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

Slide13: 

Reverse osmosis (RO) theory

Slide14: 

Feed Water Membrane Permeate Reject Reverse Osmosis

Slide16: 

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)

Slide17: 

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

Slide18: 

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

Slide19: 

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)

Slide21: 

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

Slide22: 

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

Slide23: 

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

Slide24: 

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

Slide25: 

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

Slide26: 

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)

Slide27: 

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

Slide28: 

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

Slide29: 

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

Testing - setting specifications for purified water or WFI - (1): 

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 SO4 pass test pass test - pass test NH4 < 0.2 < 0.05 - pass test Ca/Mg pass test - - pass test Nitrates < 0,2 pass test - pass test Nitrites - pass test - -

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 Testing - setting specifications for purified water or WFI (2)

Slide32: 

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

Slide33: 

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

Slide34: 

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

Slide35: 

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, & RO may remove pyrogens

Slide36: 

Suggested bacterial limits (CFU /mL)