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Storage Tank UV O 3 Ozone Generator Heat Exchanger Treated Water Supply Points of Use 1. Determine O 3 concentration in storage tank. 2. Determine O 3 concentration is “zero” after ozone destruct loop during production. 3. During loop sanitization, determine O 3 concentration at loop return. No production during this time. O 3 O 3 TOC TOC C O 3 C 3. Storage and Distribution Measurement Points Conductivity C O 3 Dissolved Ozone TOC TOC TOC 2 Water Purification Technologies Global Pharmaceutical Water Compliance Conductivity and TOC Requirements Pharmaceutical Water Preparation Unit Process Parameters Cond/Res Temp TOC pH/ORP O 3 Press Level Flow Media Filters, Depth & Sand Filters • • • • Softeners • • • • Carbon (GAC) Filters • • • • pH Adjust (Acid/Caustic Inj.) *PID Control • * Reverse Osmosis • • • • • • Ion-Exchange (Mixed-Bed) • • • • Electrodeionization • • • • Distillation • • • Ozone (injection, destruction, sanitization) • Storage Tank • • • • Distribution Loop • • • • • • Pharmacopeia Requirements for TOC Calibration and Test Requirements for Conductivity CONDUCTIVITY ELECTRONICS (ResIsTAnCe MeAsuReMenT) • Calibration required, frequency not specified, determined by owner, annual calibration accepted. • Temperature measurement circuit to be verified. • Instrument reports uncompensated conductivity or resistivity. • Display resolution of 0.1 μs/cm minimum. 1.0 μs/cm resolution is unacceptable. • Verify performance to ±0.1 μs/cm by replacing sensor with traceable precision (0.1%) resistor. For example: 50 kΩ resistor with 0.1 cm -1 cell constant should display 2.0 ± 0.1 μs/cm. CONDUCTIVITY SENSOR • Cell constant known to ± 2%. • Calibrate sensor in a solution with a stated conductivity (from nIsT or certified solution). • Calibrate sensor in a solution prepared to a specific conductivity (AsTM D1125 standard or ultrapure water). • Calibrate sensor vs. another calibrated traceable sensor – performed in-line or in-lab or return to manufacturer. • Temperature accurate to ± 2°C. Pharmacopeia Requirements for Conductivity Pharmaceutical Water Distribution Attribute USP EP JP ChP IP Source Water for PW and WFI us, eu, Japan, WHO drinking water Human consumption JP water specification Potable water or Purified Water Potable water or Purified Water PURIFIED WATER Production Method suitable process suitable process Distillation, ion-exchange, uF, or combination Distillation, ion-exchange, or suitable process Distillation, ion-exchange, or suitable process Total Aerobic (cfu/mL) 100 100 100 100 100 Conductivity (μs/cm at 25°C) 1.3 (3 stage) 5.1 (1 stage) 1.3 on-line or 2.1 off-line 5.1 (1 stage) 1.3 (3 stage) TOC (mg/L) 0.5 0.5 (optional) 0.5 (0.3 for control) 0.5 0.5 Nitrates (ppm) 0.2 0.2 Required Acidity/Alkalinity Required Ammonium (ppm) 0.2 Required Oxidizable Substances Required WATER FOR INJECTION Production Method Distillation or suitable process Distillation Distillation or RO with uF, from Purified Water Distillation Distillation Total Aerobic (cfu/100 mL) 10 10 10 10 10 Conductivity (μs/cm at 25°C) 1.3 (3 stage) 1.3 (3 stage) 1.3 on-line or 2.1 off-line 1.3 (3 stage) 1.3 (3 stage) TOC (mg/L) 0.5 0.5 0.5 (0.3 for control) 0.5 0.5 Bacterial Endotoxins (eu/mL) 0.25 0.25 0.25 0.25 0.25 Nitrates (ppm) 0.2 0.2 Required Heavy Metals Required Acidity/Alkalinity Required Ammonium (ppm) 0.2 Bulk Purified Water and Water for Injection www.mt.com/ism-pharma 5000TOCi with IsM • Complete process control and precise data trending • Plug and Measure functionality • Instant notification of excursion • simplified record keeping for ssT and CAL • Trouble-free maintenance • Robust, reliable design virtually free from moving parts • Compliant with all pharmacopeias Delivering the power of an analyzer with the convenience of a sensor. M800 • Multi-channel (2 or 4) transmitter with multi-parameter measurement flexibility • Intelligent sensor Management (IsM) • Plug and Measure simplicity • iMonitor – predictive maintenance • Dynamic Lifetime Indicator • Trending graphics for all sensors • Assured compliance with pharmacopeia regulations simple menu operation with unparalleled performance and accuracy. M300 • Multi-channel (2) transmitter with multi-parameter measurement flexibility • Intelligent sensor Management (IsM) • Plug and Measure simplicity • Measurements are available within seconds of connection • Meets all pharmacopeias’ requirements for calibration Quick and easy installation thanks to Plug and Measure sensor capabilities. uniCond ® with IsM • Conductivity Factory Calibration data stored internally in sensor • Plug and Measure functionality • Integral high-performance measuring circuit • Robust digital output signal • Complete calibration for pharmaceutical compliance Calibration tracked by iMonitor (M800) to ensure compliance. Ozone with IsM • Rapid, accurate response • easy maintenance with drop-in membrane • Plug and Measure functionality • Positive zero detection • Assured compliance with “no added substance” rule Confidently monitor complete sanitization and confirm ozone destruction. Compliance comes easy with METTLER TOLEDO Thornton‘s Intelligent Sensor Management (ISM ® ) Points of Use 1. Pre-treatment 2. Purification 3. Storage and Distribution Multi-media Filter RO Unit Ultra Filtration Unit Electrodeionization (EDI) UV Softener GAC UV Cartridge Filter (1-5μ) Break Tank Distillation for WFI PW or HPW Storage Tank Feed Water Water treatment can be divided into three stages: 1. Pre-treatment 2. Purification 3. Storage and Distribution C C C C C C C C TOC TOC Measurement Points Conductivity C TOC TOC TOC Calibration and Test Requirements for TOC TOC REQUIREMENTS • Instrument must have a Limit of Detection of 0.050 mg C/L (50 ppb TOC). • Calibrate according to manufacturer’s recommendations. • Must distinguish inorganic carbon, i.e., CO 2 , HCO 3 , from organic carbon. • Must meet system suitability Test (ssT) periodically SYSTEM SUITABILITY TESTING (ssT) • Measure TOC of water used to prepare these solutions, R w . not to exceed 100 ppb. • Measure TOC of solution prepared to concentration of 0.50 mg carbon/L (as sucrose), R s . • Measure TOC of solution prepared to concentration 0.50 mg carbon/L (as p-benzoquinone), R ss . • The accepted frequency for testing is upon uV lamp change. • Response shall be between 85 and 115%. Response = 100 x R ss - R w R s - R w ( ) 1 3 The multi-parameter M800 METTLER TOLEDO Thornton, Inc. 36 Middlesex Turnpike Bedford MA 01730 Tel: +1-781-301-8600 Fax: +1-781-301-8701 [email protected] subject to technical changes © MeTTLeR TOLeDO Thornton, Inc. Printed in usA 58 087 003 05/13 * shaded boxes – no test required
