Pharmaceutical Water Pharmaceutical Water SystemsSystems

Mason P. WaterburyMason P. Waterbury

Nektar TherapeuticsNektar Therapeutics

28 June 0528 June 05

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Let’s talk about:Let’s talk about:

– What is High Purity Water?What is High Purity Water?

– How do we make High Purity Water?How do we make High Purity Water?

– How do we store and distribute High Purity How do we store and distribute High Purity Water?Water?

– Specific challenges / solutionsSpecific challenges / solutions

Pharmaceutical Water SystemsPharmaceutical Water Systems

• What is High Purity Water?What is High Purity Water?

– Purified Water (PW)Purified Water (PW)

– Sterile Purified Water (SPW)Sterile Purified Water (SPW)

– Water for Injection (WFI)Water for Injection (WFI)

– Sterile Water for Injection (SWFI)Sterile Water for Injection (SWFI)

– Water for IrrigationWater for Irrigation

– Future Monographs (e.g., Water for Hemodialysis)Future Monographs (e.g., Water for Hemodialysis)

Pharmaceutical Water SystemsPharmaceutical Water Systems

• What is High Purity Water?What is High Purity Water?

– Purified Water (PW)Purified Water (PW)

– Sterile Purified Water (SPW)Sterile Purified Water (SPW)

– Water for Injection (WFI)Water for Injection (WFI)

– Sterile Water for Injection (SWFI)Sterile Water for Injection (SWFI)

– Water for IrrigationWater for Irrigation

– Future MonographsFuture Monographs

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Purified WaterPurified Water

– USP: “. . .obtained by a suitable process”USP: “. . .obtained by a suitable process”• Conductivity Conductivity ≤ 1.3 µS/cm @ 25º C≤ 1.3 µS/cm @ 25º C• Total Organic Carbon (TOC) ≤ 500 ppbTotal Organic Carbon (TOC) ≤ 500 ppb• Microbial ≤ 100 cfu/mlMicrobial ≤ 100 cfu/ml• No endotoxin requirementNo endotoxin requirement

– EP: “. . .prepared by distillation, by ion exchange, by EP: “. . .prepared by distillation, by ion exchange, by reverse osmosis or by any other suitable method”reverse osmosis or by any other suitable method”

– JP: “. . .purified by distillation, ion-exchange JP: “. . .purified by distillation, ion-exchange treatment, ultrafiltration or combination of these treatment, ultrafiltration or combination of these methods”methods”

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Purified Water – Example SystemPurified Water – Example System

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Water for Injection (WFI)Water for Injection (WFI)

– USP: “. . .distillation or a purification process that is USP: “. . .distillation or a purification process that is equivalent of superior to distillation”equivalent of superior to distillation”• Conductivity Conductivity ≤ 1.3 µS/cm @ 25º C≤ 1.3 µS/cm @ 25º C• Total Organic Carbon (TOC) ≤ 500 ppbTotal Organic Carbon (TOC) ≤ 500 ppb• Microbial ≤ 10 cfu / 100 mlMicrobial ≤ 10 cfu / 100 ml• Endotoxin requirement < 0.25 EU/mlEndotoxin requirement < 0.25 EU/ml

– EP: “. . .distillation”EP: “. . .distillation”

– JP: “. . .distillation. . .or by the Reverse Osmosis JP: “. . .distillation. . .or by the Reverse Osmosis Ultrafiltration of Purified Water”Ultrafiltration of Purified Water”

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Water for Injection (WFI) Distillation Water for Injection (WFI) Distillation TechniquesTechniques

– Multi-Effect Still (MES)Multi-Effect Still (MES)• Uses Plant Steam to convert feedwater to pure steamUses Plant Steam to convert feedwater to pure steam• Separators allow impurities to drop out of the pure Separators allow impurities to drop out of the pure

steamsteam• Pure steam from first effect used to convert Pure steam from first effect used to convert

feedwater to pure steam in subsequent effectsfeedwater to pure steam in subsequent effects

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Water for Injection (WFI) Distillation Water for Injection (WFI) Distillation TechniquesTechniques

– Vapor Compression (VC)Vapor Compression (VC)• Uses plant steam to convert initial feedwater to vapor (pure Uses plant steam to convert initial feedwater to vapor (pure

steam)steam)• Pure steam is compressed, elevating temperaturePure steam is compressed, elevating temperature• Compressed vapor is used to evaporate new feedwater, Compressed vapor is used to evaporate new feedwater,

giving up latent heat and condensing as WFIgiving up latent heat and condensing as WFI• Higher electrical demand, but lower steam demandHigher electrical demand, but lower steam demand

Pharmaceutical Water SystemsPharmaceutical Water Systems

• High Purity Water Storage and DistributionHigh Purity Water Storage and Distribution– Materials of Construction (Chemical and Heat Materials of Construction (Chemical and Heat

Compatibility)Compatibility)• Stainless Steel (316 or 316L)Stainless Steel (316 or 316L)• Teflon, EPDM, Silicone, Viton (gaskets, diaphragms)Teflon, EPDM, Silicone, Viton (gaskets, diaphragms)

– Fully Drainable (minimum slope 1/8” per foot, Fully Drainable (minimum slope 1/8” per foot, hygienic design of components)hygienic design of components)

– Minimize Dead Legs (<= 2 pipe diameters)Minimize Dead Legs (<= 2 pipe diameters)– Smooth Surfaces (Mechanical Polish vs. Smooth Surfaces (Mechanical Polish vs.

Electropolish)Electropolish)– Clean joints (sanitary TriClean joints (sanitary Tri®®Clamp, automatic Clamp, automatic

orbital welding)orbital welding)– Passivate interior surfaces to form barrier Passivate interior surfaces to form barrier

between water and free ironbetween water and free iron

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Storage and Distribution – SanitizationStorage and Distribution – Sanitization

– Heat (Continuous or Periodic, >81 deg. C for >1 Heat (Continuous or Periodic, >81 deg. C for >1 hour)hour)• Most popular – nothing added to systemMost popular – nothing added to system• If system continuously hot, all but eliminates concerns about If system continuously hot, all but eliminates concerns about

sanitizationsanitization• Can be a utility hogCan be a utility hog

– OzoneOzone• Gaining popularityGaining popularity• Ozone destruction and monitoring very importantOzone destruction and monitoring very important• Environmental concernsEnvironmental concerns

– ChemicalChemical• Must ensure that cleaning chemicals are completely removed Must ensure that cleaning chemicals are completely removed

from systemfrom system• Rinsing post-sanitization time and cost intensiveRinsing post-sanitization time and cost intensive

Pharmaceutical Water SystemsPharmaceutical Water Systems

• Storage and Distribution – Hot vs. Cold ?Storage and Distribution – Hot vs. Cold ?– Hot storage:Hot storage:

• WFI produced through distillation is often generated WFI produced through distillation is often generated hot, so why not store it hot?hot, so why not store it hot?

• Advantageous if there will be hot WFI distributionAdvantageous if there will be hot WFI distribution

– Cold storage:Cold storage:• Periodic heat-up & cool-down of storage tank time- Periodic heat-up & cool-down of storage tank time-

and energy-intensiveand energy-intensive

• Could expedite heat-up by dumping tank contents, Could expedite heat-up by dumping tank contents, but this is wastefulbut this is wasteful

• Best solution will vary depending on Best solution will vary depending on specific user requirementsspecific user requirements

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot and Ambient Hot Storage, Hot and Ambient DistributionDistribution

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot and Ambient DistributionHot Storage, Hot and Ambient Distribution– Cost-effective when there are many ambient Cost-effective when there are many ambient

use pointsuse points– Heat Sanitization of ambient loop by Heat Sanitization of ambient loop by

displacement of AWFI or by heating ambient displacement of AWFI or by heating ambient looploop

– Two loops mean increased installation laborTwo loops mean increased installation labor– Only one heat exchanger means all ambient Only one heat exchanger means all ambient

users get water at same temperature, no users get water at same temperature, no local temperature selectionlocal temperature selection

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot Distribution with Use Point Hot Storage, Hot Distribution with Use Point CoolersCoolers

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot Distribution with Use Point Hot Storage, Hot Distribution with Use Point CoolersCoolers– Cost-effective when there are few ambient use Cost-effective when there are few ambient use

pointspoints– Main distribution loop is continuously hot, Main distribution loop is continuously hot,

therefore self-sanitizingtherefore self-sanitizing– Can have locally adjustable use point Can have locally adjustable use point

temperaturestemperatures– Ambient point-of-use piping must be sanitized Ambient point-of-use piping must be sanitized

by flushing or pulsing HWFI through heat by flushing or pulsing HWFI through heat exchanger to drainexchanger to drain

– Additional heat exchangers means increased Additional heat exchangers means increased capital (and maintenance) costcapital (and maintenance) cost

– Some feel POU cooler piping is a dead leg, Some feel POU cooler piping is a dead leg, prone to microbial growthprone to microbial growth

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot Hot Storage, Hot DistributionDistribution with Use with Use Point Cooler Sub-loopsPoint Cooler Sub-loops

Pharmaceutical Water SystemsPharmaceutical Water Systems

Hot Storage, Hot Distribution with Use Point Hot Storage, Hot Distribution with Use Point Cooler Sub-loopsCooler Sub-loops– Cost-effective when there are few ambient use Cost-effective when there are few ambient use

pointspoints– Main distribution loop is continuously hot, therefore Main distribution loop is continuously hot, therefore

self-sanitizingself-sanitizing– Heat exchanger piping kept hot when not in useHeat exchanger piping kept hot when not in use– Can have locally adjustable use point temperaturesCan have locally adjustable use point temperatures– Dead leg question replaced by “turbulent flow” Dead leg question replaced by “turbulent flow”

question – this becomes a balancing problemquestion – this becomes a balancing problem– Additional heat exchangers means increased Additional heat exchangers means increased

capital (and maintenance) costcapital (and maintenance) cost