💎 Ultra Pure Water (UPW) — UF + RO + EDI + MB

Модуль #296. UPW (Ultra Pure Water) — для semiconductor production (resistivity 18.2 МΩ·см, total organic carbon TOC <1 ppb, particles <0.1 мкм). Применение в РК: фарм. заводы Химфарм Шымкент (USP Purified Water + WFI Water for Injection), Алматинский микроэлектроник (план Astana microchip), биотех CDMO. Технологии — UF Ultrafiltration (0.01-0.1 мкм removal bacteria + colloids) + RO Reverse Osmosis (0.0001 мкм removal salts + organics 99.5%) + EDI Electrodeionization (continuous deionization без regeneration ion-exchange resins) + final polishing MB Mixed Bed + UF terminal + UV-254 для residual organics. ASTM D5127 + USP <1231> + ISPE Baseline Pharma Water + ITRS Semiconductor + СН РК 4.04-09.

1. Состав UPW plant 50 м³/час (для фарм. завода)

Pre-treatment (городская вода): multimedia filter (sand + anthracite) для удаления particles >50 мкм + activated carbon GAC (Granular Activated Carbon) для chlorine removal (хлор kills RO membranes);
Softener (опц., при hard water): Na-ion exchange resin Lewatit для Ca/Mg → Na replacement, при hard water >10 dH ⇒ scaling RO membrane prevention;
UF Ultrafiltration: capillary hollow fiber membrane Suez Inge Aquasource 0.02 мкм pore size, polyethersulfone PES, removal bacteria 6-log + viruses 4-log + colloids; outside-in flow + backwash + CIP;
1st pass RO (Reverse Osmosis): Dow Filmtec BW30-440FR thin-film polyamide membranes, 16 pressure vessels × 6 elements per stage, recovery 70-75%, salt rejection 99.5%, output 30-50 мкСм/см conductivity;
2nd pass RO: повторный RO для final salt removal до conductivity 0.5-2 мкСм/см (resistivity 0.5-2 МΩ·см); recovery 85% (от 1st pass permeate, не raw);
EDI (Electrodeionization): Suez E-Cell MK-3 или Evoqua Ionpure IP-LX, parallel plate cells с anion + cation exchange resin + DC electric field, output resistivity 17-18 МΩ·см без resin regeneration (electricity-driven);
UV-185 nm + UV-254 nm: для TOC destruction Trojan UVOXIDATION, output TOC <1 ppb; double UV doses 100-300 mJ/cm² (vs disinfection 30 mJ/cm²);
MB Mixed Bed polish (опц. для semiconductor): mixed cation + anion ion-exchange resins в одной vessel, final polish до 18.2 МΩ·см resistivity (theoretical max);
UF terminal (final filtration): 0.04 мкм PVDF membrane Pall Microza для removing any leached particles от resin/EDI, point-of-use filter перед distribution loop;
UPW storage tank: N2-blanket SS 316L electropolished 1-5 м³ (no plastic, no rubber gaskets!), conical bottom для drainage, vent через 0.2 мкм HEPA filter;
Distribution loop: sanitary stainless 316L electropolished pipe Ø50-100 мм с 1.5 м/с min velocity (для prevent biofilm), все weld orbital автомат-сварка, slope 1% для full drainage;
Sanitization: hot water 80 °C × 1 час weekly (для kill bacteria в loop), или ozone Wedeco при 0.05-0.5 mg/L continuous (для semiconductor), CIP NaOH 1% monthly;
Online monitoring: resistivity Mettler Toledo M300 ±0.1%, TOC analyser Sievers M9 ±2 ppb, particle counter Pall HRM с laser 0.1-25 мкм, real-time SCADA Wonderware/AVEVA;
QC laboratory: ICP-MS Agilent 7900 для metals (Al/Fe/Cu/Na 0.1-1 ppb each), IC Dionex для anions (SO4/Cl/NO3 ng/L), TOC offline Shimadzu TOC-L;
Documentation + validation: IQ Installation Qualification + OQ Operational Q + PQ Performance Q + annual revalidation per ISPE Baseline Guide; full data integrity 21 CFR Part 11.

Упражнение 1 — Sequence фарм UPW

Химфарм Шымкент строит UPW plant для USP Purified Water + WFI distillation. Какая sequence по USP <1231> + ISPE?

Только обычный водопровод, после ozone-обработкиТолько distillation МПВ без ROТолько electrolysisПолная sequence Pre-treatment → 2-pass RO → EDI → UV-TOC → MB → UF terminal → distribution loop sanitized + WFI distillation column по USP <1231> + ISPE Baseline Pharma Water + EP 0008: 1) Source — городская drinking water (conductivity 200-500 мкСм/см, TOC 1-5 ppm); 2) Pre-treatment — softener Na-IX (if hardness >5 dH) + carbon filter Calgon GAC (для chlorine free <0.1 ppm — RO membrane killed by chlorine); 3) UF Ultrafiltration — Suez Aquasource 0.02 мкм PES capillary, bacteria 6-log removal, output turbidity <0.05 NTU; 4) 1st pass RO Dow Filmtec BW30-440FR, 75% recovery, 99.5% salt rejection ⇒ conductivity 5-15 мкСм/см; 5) 2nd pass RO ⇒ conductivity 0.5-2 мкСм/см (соответствует USP Purified Water specs); 6) EDI Suez E-Cell continuous electrodeionization ⇒ resistivity 16-18 МΩ·см без regeneration (vs traditional mixed-bed exhausted каждые 6 мес); 7) UV-254 nm 30-40 mJ/cm² для disinfection; UV-185 nm Trojan UVOXIDATION для TOC destruction до <50 ppb; 8) MB Mixed Bed polish — для USP Purified Water не обязательно (EDI достаточно), но для semiconductor UPW нужно для 18.2 МΩ·см final; 9) UF terminal Pall Microza 0.04 мкм PVDF point-of-use filtration перед distribution; 10) WFI Water for Injection — additional distillation column Stilmas multi-effect (4-6 columns) или vapor compression для endotoxin <0.25 EU/mL, sterile pyrogen-free; loop hot-sanitized 80 °C weekly + ozone continuous 0.05 mg/L; USP <1231> Water for Pharmaceutical Purposes + EP 0008 + JP 16 + ISPE Baseline Pharmaceutical Water + ASTM D5127 + 21 CFR Part 11 + EU GMP Annex 1

Упражнение 2 — Объём 24/7 distribution

Фарм. завод нуждается 50 м³/час UPW. UPW тенк storage 4-часовой buffer + 50% safety reserve. Какой объём storage tank (литров)?

Упражнение 3 — Капекс UPW plant 50 м³/час

Здание UPW 500 м² + cleanroom ISO 14644 кл.8 = 0.5 млрд тг
Pre-treatment multimedia + GAC carbon filter 50 м³/ч = 0.18 млрд тг
Softener Na-IX 2-train для 50 м³/ч + brine system = 0.12 млрд тг
UF Suez Aquasource 0.02 мкм 4 modules + CIP system = 0.45 млрд тг
1st pass RO Dow BW30-440FR × 16 PV × 6 elements + booster pump 75 кВт = 0.85 млрд тг
2nd pass RO smaller × 8 PV + booster pump 35 кВт = 0.45 млрд тг
EDI Suez E-Cell MK-3 × 3 modules + power supply + automation = 0.32 млрд тг
UV-185 + UV-254 Trojan UVOXIDATION 250 кВт total + UV sensors = 0.28 млрд тг
MB Mixed Bed × 2 polish vessel + regeneration skid = 0.18 млрд тг
UF terminal Pall Microza 0.04 мкм PVDF + replacement filters = 0.12 млрд тг
UPW storage tank SS 316L electropolished 350 м³ × 2 + N2 blanket = 0.95 млрд тг
Distribution loop 316L electropolished pipe Ø50-100 мм × 1000 м orbital welded = 1.2 млрд тг
Heat exchanger plate Tranter GX-91 для hot sanitization 80 °C = 0.18 млрд тг
Online monitoring resistivity Mettler M300 + TOC Sievers M9 + particle Pall HRM = 0.85 млрд тг
QC lab ICP-MS Agilent 7900 + IC Dionex + offline TOC Shimadzu + microbiology = 1.4 млрд тг
SCADA Wonderware AVEVA + validation IQ/OQ/PQ + 21 CFR Part 11 + data integrity = 0.4 млрд тг
Проектирование 5% + ПИР + НР + СП + USP/EP audit + PNR + insurance = 0.18 млрд тг

Итого capex (тг, округл. до млрд):

Упражнение 4 — Biofilm prevention в loop

UPW distribution loop SS 316L electropolished. Risk — biofilm (microbiological contamination). Что обязательно по USP + ISPE?

Никаких мер — high-purity sufficientТолько annual cleaningMulti-barrier biofilm prevention strategy по USP <1231> + ISPE Baseline + ASME BPE: 1) Material — SS 316L electropolished surface roughness Ra <0.4 мкм (vs general 1-2 мкм) — uniform smooth surface prevents bacterial attachment + permits effective sanitization; 2) Velocity — minimum 1.5 м/с continuous flow в всём loop (Reynolds Number >10 000 turbulent) для prevent stagnation zones где biofilm establishes — dead-leg <6× pipe diameter rule (max stagnant pipe 30 cm для 50 мм pipe); 3) Slope 1% — entire loop slopes для full drainage (gravity-drained when offline), no horizontal pipe без slope; 4) Sanitization — weekly hot water 80 °C × 60 minutes (thermal disinfection kills planktonic bacteria + retards biofilm), monthly chemical CIP с NaOH 1% + acid 1% phosphoric для scale removal; 5) Ozone continuous — для semiconductor UPW 0.05-0.5 mg/L ozone в loop постоянно (kills bacteria + organics), removed at POU точках через UV-185 нм; 6) UV-185 nm — постоянная continuous TOC oxidation, 0.25-1.0 кВт/м³ flow; 7) Welding — orbital automatic Schweissmaschinen Magnatech para-fluid pipe joints (no manual welds), 100% borescope inspection + dye penetrant test ASTM E165; 8) Validation — quarterly TOC + endotoxin + bacterial count + identity (Gram-positive/negative Bacillus / Pseudomonas / Mycobacterium), action limit 10 CFU/mL, alert limit 1 CFU/mL; 9) Sampling — sterile sample ports every 50 м loop + critical user points + before/after sanitization; 10) Data integrity 21 CFR Part 11 — все sanitization records + microbiological results electronic signature + audit trail; USP <1231> + ISPE Baseline Pharmaceutical Water + ASME BPE Bioprocessing Equipment + EU GMP Annex 1 + 21 CFR Part 11 + ASTM D5127 + JP 16 + EP 0008Только periodic flushing

Нормативная база

USP <1231> — Water for Pharmaceutical Purposes (United States Pharmacopeia)
EP 0008 + JP 16 — European + Japanese Pharmacopoeia water specs
ISPE Baseline Pharmaceutical Water — International Society for Pharmaceutical Engineering
ASTM D5127 — Standard Guide for Ultra-Pure Water in Electronic Industry
ASME BPE 2022 — Bioprocessing Equipment
21 CFR Part 11 — Electronic Records / Signatures
EU GMP Annex 1 (2022) — Manufacture of Sterile Medicinal Products
FDA Guidance Process Validation 2011
ITRS — International Technology Roadmap for Semiconductors (UPW for semi)
SEMI F63 — Semiconductor UPW grade
ISO 14644 — Cleanroom classification
СН РК 4.04-09 — Электрические станции (applicable for UPW)
WHO TRS 957 — Water for Pharmaceutical Use
ICH Q7 — Good Manufacturing Practice for Active Pharmaceutical Ingredients