William V. Collentro ULTRAPURE WATER Pharma 2010 New Brunswick, New Jersey May 20-21, 2010

Compendial Water System – Feed Water Analysis Official Monograph United States EPA National Primary Drinking Water Regulations (NPDWR) Equivalent European Regulations Equivalent Japanese Regulations World Health Organization Reference

Compendial Water System – Raw Water Analysis United States EPA – NPDWR Regulated Items Total Viable Bacteria “Private” Water Supplies

Microorganisms Cryptosporidium Giardia lamblia Heterotrophic Plate Count Legionella Total Coliform (including fecal coliform and E. coli) Turbidity Viruses (enteric) Compendial Water System – Raw Water – Regulated Items

Raw Water Microorganisms – Health Effects ParameterHealth Effects CryptosporidiumGastrointestinal Illness Giardia lambliaGastrointestinal Illness Heterotrophic Plate CountNo direct health effects but employed to indicate the general bacteria contamination level of water LegionellaLegionnaire’s Disease Total ColiformIndicator of the presence of pathogens TurbidityAssociated with disease causing organisms VirusesGastrointestinal Illness

Raw Water Microorganisms – Health Effects ParameterSource CryptosporidiumHuman and Animal Fecal Waste Giardia lambliaHuman and Animal Fecal Waste Heterotrophic Plate CountEnvironmental Bacteria LegionellaEnvironment – Cooling/Heating Systems Total ColiformNatural, Human Fecal Waste, Animal Fecal Waste TurbiditySoil Runoff, Construction VirusesHuman and Animal Fecal Waste

Raw Water Microorganisms – Health Effects ParameterMaximum Contaminant Level/Treatment Technique CryptosporidiumSWTR – Monitored and Controlled Giardia lamblia99.9% Removal/Inactivation Heterotrophic Plate Count ≤500 cfu/ml LegionellaNo Limit but Requires Control of Giardia and Viruses Total ColiformNMT 5% positive/month (≥40 samples/month), NMT 2 consecutive confirmation for E.coli or Fecal Coliform Turbidity≤1 NTU (≤0.3 NTU at least 95% of tests) Viruses99.99% Removal/Deactivation

Disinfection Byproducts Bromate Chlorite Haloacetic Acids (HAA5) Total Trihalomethanes (TTHMs) Compendial Water System – Raw Water – Regulated Items

Disinfection Byproduct – Bromate MCL = mg/l Ozone Primary Disinfecting Agent Increased Risk of Cancer Disinfection Byproduct – Chlorite MCL = 1.0 mg/l Chlorine Dioxide Primary Disinfecting Agent Anemia, Nervous System Compendial Water System – Raw Water – Regulated Items

Haloacetic Acids (HAA5) – (0.060 mg/l) Dichloroacetic Acid Trichloroacidic Acid Monochloroacidic Acid Bromoacetic Acid Dibromoacetic Acid Increased Risk of Cancer Compendial Water System – Raw Water – Regulated Items

Total Trihalomethanes (0.80 mg/l) Chloroform Dibromochloromethane Bromodichloromethane Bromoform Increased Risk of Cancer, Liver, Kidney, or Central Nervous System Compendial Water System – Raw Water – Regulated Items

Regulated Item – Disinfectants (Distribution) Chlorine Chloramines Chlorine Dioxide Compendial Water System – Raw Water

Regulated Items – Inorganic Chemicals Antimony Arsenic Asbestos Barium Beryllium Cadmium Total Chromium Copper

Compendial Water System – Raw Water Regulated Items – Inorganic Chemicals Cyanide Fluoride Lead Mercury Nitrate Nitrite Selenium Thallium

Compendial Water System – Raw Water Regulated Items – Organic Chemicals (53 Total) Sewage/Wastewater Treatment Herbicides Landfill Leachates Chemical/Industrial Facility Waste Fumigants Petroleum /Refinery Waste Insecticides

Compendial Water System – Raw Water Regulated Item – Radionuclides Alpha Particles Beta Particles and Photon Emitters Radium 226 Uranium

Compendial Water System – Feed Water Analysis Total Viable Bacteria No “enforceable” limit in NPDWR Total Coliform (Confirmed as Fecal Coliform or E. coli, used as indicator) “Action Limit” of 500 cfu/ml in non enforceable General Information Section of USP TVB only indicates a fraction of viable organisms present

Compendial Water System – Feed Water Analysis Regulated Items - Testing Municipality? Pharmaceutical Facility? Compliance? Obligation? Consequences?

USP Purified Water System – “Classical” Periodic Monitoring General Monitoring – Storage and Distribution System Point-of-Use TVB Online Conductivity Online TOC

USP Purified Water System – “Classical” Periodic Monitoring General Monitoring – Water Purification System Final TVB Inline RO Feed Water and Product Water Conductivity – RO Unit % Rejection of Ions Inline Post RO Polishing Conductivity

USP Purified Water System – “Classical” Periodic Monitoring Frequent Monitoring – Water Purification System Silt Density Index (Test Kit) Total Hardness (Test Kit) Chlorine (Test Kit)

USP Purified Water System – “Classical” Periodic Monitoring Less Frequent Monitoring – Water Purification System Inline ORP for Reducing Agent Injection Inline Total Hardness Monitor Inline Chlorine Monitor

USP Purified Water System – Suggested Periodic Monitoring Raw WaterPost Multimedia Post Activated Carbon Post UVPost Lead Water Softener Post Polish Water Softener Post Cartridge Filter NPDWR Tests X TVB XXXXXXX BET X-X---X Chlorine XXX---- TOC XXX---- TSS XXX-XX- Total Hardness X-X-XX- Total Iron XXX-XX- Turbidity XX----- SDI X

USP Purified Water System – Suggested Periodic Monitoring Post RO Break Tank Post ROPost CEDIPost UVPost Final Filter TVB XXXXX BET XX--- pH XX--- TOC XXXXX Carbon Dioxide XX---

Compendial Water System – Periodic Monitoring Monitoring of Pretreatment and Ion Removal steps identifies a problem before it effects point-of-use values. Frequency of the monitoring program established for each application Regulatory concerns

Raw Water Impurities – Current Issues Trihalomethanes (Chloroform) Removal Process? Volatile Presence in USP/EP Water for Injection? Ozonated USP Purified Water Systems Chloride Pitting Corrosion of Austenitic Stainless

Raw Water Impurities – Current Issues Mononchloramine Disinfection Properties in Raw Feed Water pH of Feed Water Type of Activated Carbon “EBCT” Critical!!! Detection TOC Interference During Removal Effect on Microbial Results Careful Selection of Polishing Components

Raw Water Impurities – Current Issues Catalytic Activated Carbon Volume Required = (EBCT) x Flow Rate/7.48 Where, EBCT is the “Empty Bed Contact Time” expressed in minutes, Flow Rate is expressed in gallons per minute and the Catalytic Activated Carbon volume is expressed in cubic feet. AT pH = 8.0, Monochloramine = 3.0 mg/l, and TOC < 3.0 mg/l, EBCT = 8.0.

Raw Water Impurities – Current Issues Use of 185 Nanometer UV Downstream of RO TOC Reduction to Meet 0.50 mg/l? TOC Reduction to Control Bacteria? Generation of Hydroxyl Radical Very Strong Oxidant Violation of USP General Notices Section Fragmentation of Organic Material Chloride and Nitrate Ions - Generation Degradation in Conductivity

Raw Water Impurities – Current Issues Use of 185 Nanometer UV Downstream of RO Non Representative TVB Data “Delivered” Water – With Hydroxyl Radical “Delivered” Water – Without Hydroxyl Radical Effect on Other Product Ingredients Effect on Research “Duplication” of Data Based on Use

Conclusions There is an increasing regulatory focus on the quality of water (chemical and microbial) throughout a compendial water system. Knowledge of impurities in raw water and their removal by water purification unit operations is critical. There is no “magic” bullet. A technical sound pretreatment system remains a critical part of any compendial water system.

Questions?